N-aryl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide herbicides

BACKGROUND OF THE INVENTION
The present invention relates to substituted sulfonamide compounds, to herbicidal compositions containing the compounds, and to the utility of the compounds for the control of unwanted vegetation.
The control of unwanted vegetation by means of chemical agents, i.e., herbicides, is an important aspect of modern agriculture and land management. While many chemicals that are useful for the control of unwanted vegetation are known, new compounds that are more effective generally, are more effective for specific plant species, are less damaging to desirable vegetation, are safer to man or the environment, are less expensive to use, or have other advantageous attributes are desirable.
A number of sulfonamide compounds, including certain substituted �1,2,4!triazolo�1,5-a!pyrimidine-2-sulfonamide compounds (U.S. Pat. No. 4,954,163), and �1,2,4!triazolo�1,5-c!pyrimidine-2-sulfonamide compounds (U.S. Pat. No. 5,010,195 and European Application 244,948) are known and are known to possess herbicidal activity, especially on broadleaf weeds.
SUMMARY OF THE INVENTION
It has now been found that certain N-aryl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide compounds are potent herbicides for the control of unwanted vegetation, have desirable crop selectivity, and have favorable toxicological and environmental attributes.
The invention includes N-aryl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide compounds of Formula I: ##STR1## wherein W, X, Y, and Z each independently represents H, CH.sub.3, CH.sub.2 CH.sub.3, CH.sub.2 OCH.sub.3, CF.sub.3, F, Cl, Br, I, OCH.sub.2 CF.sub.3, S(C.sub.1 -C.sub.3)alkyl, or O(C.sub.1 -C.sub.3)alkyl optionally monosubstituted with F, Cl, or OCH.sub.3, with the proviso that at least one of W, X, Y, and Z represents H;
V represents H, COR', CO.sub.2 R", or CONR"'.sub.2 ;
Ar represents an aromatic moiety one of the formulas: ##STR2## A represents F, Cl, Br, CO.sub.2 R", CONR'".sub.2, (C.sub.1 -C.sub.2)haloalkyl, NO.sub.2, CN, SOR', or SO.sub.2 R';
B represents H, CH.sub.3, C.sub.2 H.sub.5, F, Cl, Br, CN, OR', SR', NR"'.sub.2, phenyl, or phenoxy, each phenyl and phenoxy optionally possessing 1 to 3 substituents selected from the group consisting of F, Cl, Br, CN, CF.sub.3, NO.sub.2, and CH.sub.3 ;
D and J each independently represents H or CH.sub.3 with the proviso that at least one of D and J represents H;
A' and B' each independently represents H, R', OR', OCH.sub.2 CH.sub.2 Cl, OCH.sub.2 CH.sub.2 OCH.sub.3, S(O).sub.n R', F, Cl, Br, I, CN, NO.sub.2, C.sub.6 H.sub.5, CO.sub.2 R", or CONR'".sub.2 with the proviso that not more than one of A' and B' represents H;
D' represents H, F, Cl, Br, I, CF.sub.3, or CH.sub.3 ;
A" represents F, Cl, Br, I, CF.sub.3, SCF.sub.3, CN, CO.sub.2 R", or CONR'".sub.2 and is located in the 4-position when the point of attachment is the 3- or 5-position and represents F, Cl, Br, I, CF.sub.3, or CH.sub.3 and is located in the 3- or 5-position when the point of attachment is the 4-position;
B" represents H when the point of attachment is the 3- or 5-position and represents H, Cl, Br, F, CH.sub.3, or OCH.sub.3 and is located the 3- or 5-position not occupied by A" when the point of attachment is the 4-position;
T represents H or F;
n represents 0, 1, or 2;
R' represents (C.sub.1 -C.sub.4)alkyl optionally singly to completely substituted with fluorine;
R" represents (C.sub.1 -C.sub.4)alkyl, (C.sub.3 -C.sub.4)alkenyl, or (C.sub.3 -C.sub.4)alkynyl;
R"' represents H or (C.sub.1 -C.sub.4)alkyl; and when V represents H, the agriculturally acceptable salts thereof.
The compounds of the invention, usually in the form of an herbicidal composition containing one or more of them in admixture with an agriculturally acceptable adjuvant or carrier, exhibit strong herbicidal properties when applied either directly to the unwanted vegetation or to the locus thereof and when applied either preemergence or postemergence.
The invention includes certain intermediates that are useful in the preparation of the herbicidal compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The herbicidal compounds of the invention are N-aryl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide compounds of Formula I: ##STR3## These compounds can be described as amides derived from substituted �1,2,4!triazolo�1,5-a!pyridine-2-sulfonic acid compounds and substituted aromatic amine compounds, such as anilines, aminopyridines, aminopyrazoles, and aminoindazoles.
The Chemical Abstracts nomenclature numbering system for �1,2,4!triazolo�1,5-a!pyridine ring compounds is as follows: ##STR4## Thus, the compounds of the invention are 2-sulfonamide compounds and the W substituents are in the 5-position, the X substituents are in the 6-position, the Y substituents are in the 7-position, and the Z substituents are in the 8-position.
The compounds of the invention include those of Formula I wherein up to three of W, X, Y, and Z independently represent CH.sub.3, CH.sub.2 CH.sub.3, CH.sub.2 OCH.sub.3, CF.sub.3, F, Cl, Br, I, OCH.sub.2 CF.sub.3, S(C.sub.1 -C.sub.3)alkyl, or O(C.sub.1 -C.sub.3)alkyl optionally monosubstituted with F, Cl, or OCH.sub.3 and the remaining one to four of W, X, Y, and z represent hydrogen. Compounds wherein two of W, X, Y, and Z represent hydrogen are usually preferred. Compounds wherein one or both of W and Z represents methoxy or wherein one of W and Z represents ethoxy or isopropoxy are, further, typically preferred. Those wherein W represents methoxy or ethoxy are typically more preferred. Compounds of Formula I wherein W represents methoxy, ethoxy, or isopropoxy, X and Z each represent hydrogen, and Y represents methyl or a halogen; or wherein W represents methoxy or ethoxy, X and Y each represent hydrogen, and Z represents methyl, methoxy, or a halogen; or wherein Z represents methoxy or ethoxy, W and Y each represent hydrogen, and X represents methyl, trifluoromethyl, or a halogen are often of special interest.
V represents hydrogen or an acyl derivative, such as CO(C.sub.1 -C.sub.4)alkyl optionally singly to completely substituted with fluorine, CO.sub.2 (C.sub.1 -C.sub.4)alkyl, CO.sub.2 (C.sub.3 -C.sub.4)alkenyl, CO.sub.2 (C.sub.3 -C.sub.4)alkynyl, CON((C.sub.1 -C.sub.4)alkyl).sub.2, CONH(C.sub.1 -C.sub.4)alkyl, or CONH.sub.2. Hydrogen is generally preferred. When V represents hydrogen, the invention includes the agriculturally acceptable salts obtained by neutralizing the resulting acid with a base.
The term Ar in Formula I represents an aromatic moiety, especially an aromatic moiety of one the following formulas: ##STR5## which includes phenyl moieties, 3-pyridinyl moieties, 1-methyl-(3-, 4-, or 5-)pyrazolyl moieties, and 1-methyl-3-indazolyl moieties.
When Ar represents a phenyl moiety, the moiety is substituted in at Least one ortho position with an electron withdrawing group. Compounds of Formula I wherein Ar represents a substituted phenyl moiety include those wherein A represents F, Cl, Br, CO.sub.2 R", CONR'".sub.2, (C.sub.1 -C.sub.2)haloalkyl, NO.sub.2, CN, SOR', or SO.sub.2 R'; B represents H, CH.sub.3, C.sub.2 H.sub.5, F, Cl, Br, CN, OR', SR', NR"'.sub.2, phenyl, or phenoxy, each phenyl and phenoxy optionally possessing 1 to 3 substituents selected from the group consisting of F, Cl, Br, CN, CF.sub.3, NO.sub.2, and CH.sub.3 ; and D and J each independently represents H or CH.sub.3 with the proviso that at least one of D and J represents H. Compounds wherein A represents F, Cl, Br, CF.sub.3, NO.sub.2, or CO.sub.2 CH.sub.3 ; B represents F, Cl, Br, CCH.sub.3, or CH.sub.3 ; J represents H; and D represents H or CH.sub.3 are often preferred. Compounds wherein A and B both represent F or Cl and D and J both represent H, wherein A and B both represent F or Cl, D represents CH.sub.3, and D represents H, wherein A represents CO.sub.2 CH.sub.3, B represents Cl or F, and D and J both represent H, and wherein A represents CF.sub.3, B represents OCH.sub.3, and D and J both represent H are often more preferred.
When Ar represents a 3-pyridinyl moiety, the moiety is substituted in at least one of the 2- and 4-positions. Compounds that are substituted in both of these positions are often preferred. Compounds of Formula I wherein Ar represents a substituted 3-pyridinyl moiety include those wherein A' and B' are selected from H, F, C, Br, I, CN, NO.sub.2, C.sub.6 H.sub.5, CO.sub.2 R", CONR'".sub.2, 2-chloroethoxy or 2-methoxyethoxy, or (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkylthio, (C.sub.1 -C.sub.4)alkylsulfinyl, or (C.sub.1 -C.sub.4)alkylsulfonyl each optionally singly to completely substituted with fluorine, and D' represents H, F, Cl, Br, I, CF.sub.3, or CH.sub.3. Compounds wherein A' represents CH.sub.3, O(C.sub.1 -C.sub.3)alkyl, F, Cl, Br, or I; B' represents F, Cl, Br, I, CH.sub.3, C.sub.2 H.sub.5, CF.sub.3, O(C.sub.1 -C.sub.3)alkyl, OCH(CH.sub.3)CF.sub.3, OCH.sub.2 CH.sub.2 F, OCH.sub.2 CHF.sub.2 or CO.sub.2 (C.sub.1 -C.sub.3)alkyl; and D' represents H are often preferred. Such compounds wherein A' represents Br, Cl, F, or OCH.sub.3, B' represents CH.sub.3, OCH.sub.3, OC.sub.2 H.sub.5, OC.sub.3 H.sub.7 (n), OC.sub.3 H.sub.7 (i), OCH(CH.sub.3)CF.sub.3, or OCH.sub.2 CH.sub.2 F, and D' represents H; or wherein A' represents OCH.sub.3 or OC.sub.2 H.sub.5, B' represents CO.sub.2 (C.sub.1 -C.sub.2)alkyl, Br, Cl, or F, and D' represents H are typically more preferred. 3-Pyridinyl moieties wherein A' represents F, Cl, Br, or OCH.sub.3, B' represents CH.sub.3, OCH.sub.3, OC.sub.2 H.sub.5, OC.sub.3 H.sub.7 (n), OC.sub.3 H.sub.7 (i), OCH(CH.sub.3)CF.sub.3, or OCH.sub.2 CH.sub.2 F, and D' represents H are sometimes especially preferred. 3-Pyridinyl moieties are often preferred Ar moieties.
When Ar represents a pyrazolyl moiety, the moiety is attached to the sulfonamide nitrogen atom at a 3-, 4-, or 5-position and has a methyl group in the 1-position. When the point of attachment is the 3- or 5-position, the moiety is substituted in the 4-position with an electron withdrawing group. The 3- or 5-position attachment compounds wherein the 4-position substituent A" represents F, Cl, Br, I, CF.sub.3, SCF.sub.3, CN, CO.sub.2 R", and CONR'".sub.2 (B" represents H) are specifically identified. Those wherein A" represents Cl, Br, I, or CF.sub.3 are usually more preferred. When the point of attachment is the 4-position, the moiety is substituted in one or both of the 3- and 5-positions. Such compounds wherein the 3- or 5-position substituent A" represents F, Cl, Br, I, CF.sub.3, and CH.sub.3 and the other 3- or 5-position substituent B" represents H, Cl, Br, F, CH.sub.3, or OCH.sub.3 are specifically identified. Pyrazolyl moieties wherein A" represents Cl, Br, I, or CF.sub.3 and B" represents H are often preferred.
When Ar represents an indazolyl moiety, the moiety is attached to the sulfonamide nitrogen atom at the 3-position, has a methyl group in the 1-position, and is optionally mono-substituted with fluorine. Such compounds having a fluoro substituent in the 4-position are often preferred.
The term alkyl as used herein includes straight chain, branched chain, and cyclic moieties. Thus, typical alkyl groups are methyl, ethyl, 1-methylethyl, propyl, cyclopropyl and the like. Methyl and ethyl are often preferred. Typical alkyl groups singly to completely substituted with fluorine include trifluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 2,3-difluoropropyl, and the like; trifluoromethyl is often preferred. The term haloalkyl is used herein to denote alkyl singly to completely substituted with fluorine or chlorine and includes trifluoromethyl, dichloromethyl, 2,2-difluoro-2-chloroethyl, and the like; trifluoromethyl is often preferred. The term halogen includes fluorine, chlorine, bromine, and iodine.
The term "agriculturally acceptable salts" is employed herein to denote compounds wherein the acidic sulfonamide proton of the compound of Formula I is replaced by a cation which itself is neither herbicidal to crop plants being treated nor significantly deleterious to the applicator, the environment, or the ultimate user of any crop being treated. Suitable cations include, for example, those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Preferred cations include sodium, potassium, magnesium, and aminium cations of the formula:
R.sup.6 R.sup.7 R.sup.8 NH.sup..sym.
wherein R.sup.6, R.sup.7, and R.sup.8 each, independently represents hydrogen or (C.sub.1 -C.sub.12)alkyl, (C.sub.3 -C.sub.12)cycloalkyl, or (C.sub.3 -C.sub.12)alkenyl, each of which is optionally substituted by one or more hydroxy, (C.sub.1 -C.sub.8)alkoxy, (C.sub.1 -C.sub.8)alkylthio or phenyl groups; provided that R.sup.6, R.sup.7, and R.sup.8 are sterically compatible. Additionally, any two of R.sup.6, R.sup.7, and R.sup.8 together may represent an aliphatic difunctional moiety containing 1 to 12 carbon atoms and up to two oxygen or sulfur atoms. Salts of the compounds of Formula I can be prepared by treatment of compounds of Formula I wherein V represents hydrogen with a metal hydroxide, such as sodium hydroxide, potassium hydroxide, or magnesium hydroxide, or an amine, such as ammonia, trimethylamine, hydroxyethylamine, bisallylamine, 2-butoxyethylamine, morpholine, cyclododecylamine, or benzylamine.
While each of the N-aryl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide compounds encompassed by Formula I is within the scope of the invention, the degree of herbicidal activity and the spectrum of weed control obtained varies depending upon the substituents present and, consequently, certain of the compounds are preferred. The compounds that are preferred in any specific situation further depends on the identity of the undesirable vegetation to be controlled, climatic factors, whether total or selective vegetation control is desired, and other factors.
A listing of some typical compounds of the invention is given in Table 1. Some of the specifically preferred compounds of the invention include: N-(2,6-dichloro-3-methylphenyl)-5-methoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2,3-dimethyl-6-nitrophenyl)-5-methoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2-fluoro-4-methyl-3-pyridinyl)-5-methoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2-chloro-4-ethoxy-3-pyridinyl)-5-methoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2-chloro-4-methyl-3-pyridinyl)-5-methoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(4-bromo-1-methyl-3-pyrazolyl)-5-methoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2-methyl-6-nitrophenyl)-5-ethoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2-methoxy-6-(trifluoromethyl)phenyl)-5-ethoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2,6-difluorophenyl)-8-chloro-5-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2-fluoro-4-methyl-3-pyridinyl)-8-chloro-5-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2-fluoro-4-methyl-3-pyridinyl)-7-chloro-5-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(4-bromo-1-methyl-3-pyrazolyl)-7-chloro-5-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2-fluoro-4-methyl-3-pyridinyl)-7-chloro-5-ethoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(4-bromo-1-methyl-3-pyrazolyl)-8-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(4-bromo-1-methyl-3-pyrazolyl)-6-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2,6-dichlorophenyl)-6-bromo-8-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2-fluoro-4-methyl-3-pyridinyl)-6-bromo-8-methoxy�1,2,4!triazolol�5-a!pyridine-2-sulfonamide, N-(2-methyl-6-nitrophenyl)-7-methyl-5-(2,2,2-trifluoroethoxy)�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, N-(2-methyl-6-nitrophenyl)-5-chloro-7-methyl-�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, and N-(2-chloro-4-methoxy-3-pyridinyl)-5,7-dimethoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide.
TABLE 1__________________________________________________________________________N-ARYL�1,2,4!TRIAZOLO�1,5-A!PYRIDINE-2-SULFONAMIDE COMPOUNDS ##STR6## % C % H % NCpd. Melting calc. calc. calc.No. W X Y Z Ar Form point, .degree.C. found found found__________________________________________________________________________1 H H H H 2,6-dichlorophenyl white 269-270 42.0 2.35 16.3 powder 41.9 2.22 16.32 H H H H 2,6-difluorophenyl white 222-223 45.6 2.60 18.1 powder 45.6 2.56 18.23 H H H H 1-methyl-4-bromo- tan 229-231 33.6 2.54 23.5 3-pyrazolyl solid 34.0 2.55 23.24 H H CH.sub.3 H 2,6-dichlorophenyl tan 232-234 43.7 2.82 15.7 powder 44.0 2.87 15.55 H H CH.sub.3 H 2,6-difluorophenyl white 231-232 48.1 3.11 17.3 powder 48.1 2.97 17.46 H H CH.sub.3 H 1-methyl-4-bromo- white 238-240 35.7 2.72 22.7 3-pyrazolyl solid 35.8 3.00 22.67 Cl H CH.sub.3 H 2-fluoro-4-methyl- yellow 253-255 44.0 2.84 19.7 3-pyridinyl powder (d) 44.2 3.09 19.78 OCH.sub.3 H CH.sub.3 H 2-fluoro-4-methyl- white 202-204 47.9 4.02 19.9 3-pyridinyl powder (d) 48.0 4.06 19.69 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2-fluoro-4-methyl- white 249-250 43.0 3.12 16.7 3-pyridinyl powder (d) 43.2 3.21 16.610 Cl H CH.sub.3 H 1-methyl-4-bromo- tan 262-264 32.6 2.48 20.7 3-pyrazolyl solid 30.7 2.59 20.711 Cl H CH.sub.3 H 2,6-dibromophenyl white 256-259 32.5 1.89 11.7 powder 32.8 2.06 11.712 Cl H CH.sub.3 H 2-methyl-6-methoxy- white 198-202 48.7 3.83 14.2 carbonylphenyl solid 48.6 4.20 14.013 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-fluoro-4-methyl- white 206-208.5 49.3 4.41 19.2 3-pyridinyl powder 49.7 4.44 19.114 Cl H CH.sub.3 H 2-fluoro-6-methoxy- mauve 216-219 45.2 3.03 14.1 carbonylphenyl powder 45.0 3.40 14.015 Cl H CH.sub.3 H 1-methyl-3-indazolyl tan 267-269 46.7 3.66 21.8 solid 46.5 3.52 21.816 CH.sub.3 H CH.sub.3 H 1-methyl-4-bromo- tan 229-232 37.4 3.40 21.8 3-pyrazolyl powder (d) 38.1 3.62 21.617 CH.sub.3 H CH.sub.3 H 2,6-dichlorophenyl white 250-252 45.3 3.26 15.1 powder 44.9 3.49 14.818 CH.sub.3 H CH.sub.3 H 2,6-difluorophenyl lt. tan 207-209 49.7 3.58 16.6 powder 49.4 3.80 16.419 OCH.sub.3 H CH.sub.3 H 1-methyl-4-bromo- white 251 (d) 35.9 3.27 20.9 3-pyrazolyl solid 36.0 3.05 20.920 OCH.sub.3 H CH.sub.3 H 2-bromo-6-chloro- white >265 39.0 2.80 13.0 phenyl solid 37.9 2.75 12.521 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-bromo-6-chloro- white 279 40.4 3.17 12.6 phenyl solid 40.4 3.08 12.622 Cl H CH.sub.3 H 2-bromo-6-fluoro- tan 226 37.2 2.16 13.4 phenyl solid 37.1 1.86 13.323 OCH.sub.3 H CH.sub.3 H 2-bromo-6-flouro- white 253 (d) 40.5 2.91 13.5 phenyl solid 40.3 3.13 13.724 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-bromo-6-fluoro- white 259 (d) 42.0 3.29 13.1 phenyl solid 41.9 3.44 13.025 Cl H CH.sub.3 H 2-methoxy-6-(tri- white 231-232.5 42.8 2.87 13.3 fluoromethyl)phenyl solid 42.9 3.00 13.526 Cl H CH.sub.3 H 2,6-dichloro-3- white 269-271 41.5 2.73 13.8 methylphenyl solid 41.5 2.92 14.027 Cl H CH.sub.3 H 2,6-difluoro-3- white 224-226 45.1 2.97 15.0 methylphenyl solid 45.1 2.62 15.228 OCH.sub.3 H CH.sub.3 H 2-methoxy-6-(tri- white 243-245 46.2 3.63 13.5 fluoromethyl)phenyl solid 46.1 3.58 13.429 OCH.sub.3 H CH.sub.3 H 1-methyl-3-indazolyl tan solid 247-248 51.7 4.07 22.6 51.9 3.87 22.430 OCH.sub.3 H CH.sub.3 H 2-chloro-6-methoxy- white 145-146 47.1 3.95 14.6 phenyl solid 47.0 3.97 14.631 OCH.sub.3 H CH.sub.3 H 2,6-dichloro-3- grey 150-151 44.9 3.52 14.0 methylphenyl powder 45.2 3.58 14.032 OCH.sub.3 H CH.sub.3 H 2,6-difluoro-3- white 144-145 48.9 3.83 15.2 methylphenyl powder 48.9 3.78 15.333 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-chloro-6-methoxy- grey 232-235 48.3 4.32 14.1 phenyl powder 48.3 4.71 14.034 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-methoxy-6-(tri- white 246-247 47.4 3.98 13.0 fluoromethyl)phenyl powder 47.4 4.03 13.035 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2,6-dichloro-3- white 260-262 46.3 3.88 13.5 methylphenyl powder 46.2 3.69 13.436 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2,6-difluoro-3- white 240-243 50.3 4.22 14.7 methylphenyl powder 50.2 4.38 14.637 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-methyl-6-nitro- white 256 (d) 49.1 4.38 17.9 phenyl solid 49.1 4.42 18.138 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2,3-dimethyl-6-nitro- yellow 255-256 50.4 4.72 17.3 phenyl solid (d) 50.4 4.88 17.239 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-fluoro-5-methyl- white 238-239 52.7 4.70 15.4 phenyl crystals (d) 52.5 4.62 15.540 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-chloro-6-methyl- white 253-255 50.5 4.50 14.7 phenyl solid (d) 50.5 4.58 14.941 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-(trifluoromethyl)- white 203-204.5 48.0 3.78 13.8 phenyl solid 47.9 3.96 13.942 OCH.sub.3 H CH.sub.3 H 2-methyl-6-nitro- yellow 231-233 47.7 4.01 18.6 phenyl powder 48.1 4.29 18.643 OCH.sub.3 H CH.sub.3 H 2,3-dimethyl-6-nitro- yellow 258-260 49.1 4.38 17.9 phenyl powder 49.2 4.60 18.044 OCH.sub.3 H CH.sub.3 H 2-flouro-5-methyl- white 229-230 51.4 4.32 16.0 phenyl solid 51.7 4.56 16.245 OCH.sub.3 H CH.sub.3 H 2-(trifluoromethyl)- white 230-231 46.6 3.39 14.5 phenyl powder 46.4 3.52 14.646 Cl H CH.sub.3 H 2-fluoro-5-methyl- white 213-214 47.4 3.41 15.8 phenyl solid 47.5 3.44 15.847 OCH.sub.3 H CH.sub.3 H 2-chloro-6-methyl- white 253-255 49.1 4.12 15.3 phenyl solid 49.3 4.24 15.348 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2-methyl-6-nitro- white 245-247 43.2 3.17 15.7 phenyl solid (d) 43.3 3.44 15.749 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2,3-dimethyl-6-nitro- yellow 242-243 44.5 3.51 15.2 phenyl (d) 44.4 3.72 15.150 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2-chloro-6-methyl- white 215-217 44.2 3.25 12.9 phenyl solid 44.0 3.49 12.851 OCH.sub.3 H CH.sub.3 H 2-chloro-4-methyl-3- tan 209-210 45.7 3.84 19.0 pyridinyl powder (d) 46.0 4.07 18.752 Cl H CH.sub.3 H 2-chloro-4-methoxy-3- yellow 219-221 40.2 2.86 18.0 pyridinyl powder (d) 40.6 3.08 18.053 OCH.sub.3 H CH.sub.3 H 2-chloro-4-methoxy-3- white 216-217 43.8 3.68 18.3 pyridinyl powder (d) 43.8 3.55 17.954 Cl H CH.sub.3 H 2-chloro-4-methyl-3- white 255-257 42.0 2.98 18.8 pyridinyl powder (d) 42.3 2.92 19.055 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2-chloro-6-iodophenyl white 248 33.0 2.03 10.3 powder 32.9 1.94 10.156 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2-fluoro-6-methoxy- tan solid 182 44.2 3.06 12.1 carbonylphenyl 44.1 2.88 12.057 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-fluoro-6-ethoxy- tan solid 212 50.0 4.20 13.7 carbonylphenyl 51.0 4.46 13.358 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2,6-dichlorophenyl off-white >275 44.9 3.52 14.0 solid 42.6 3.55 13.359 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2,6-dibromophenyl white 262 33.1 2.04 10.3 powder 33.0 1.89 10.260 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2,6-dichlorophenyl white 39.6 2.44 12.3 powder 39.8 2.34 12.361 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2,6-difluorophenyl tan 254-256 48.9 3.83 15.2 powder 48.7 4.03 15.262 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2,6-fluorophenyl white 267-269 42.7 2.63 13.3 powder 39.5 2.57 12.363 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2-methoxy-6-(tri- off-white 235-237 42.2 2.91 11.5 fluoromethyl)phenyl powder (d) 42.2 2.80 11.664 OCH.sub.2 CF.sub.3 H CH.sub.3 H 4-bromo-1-methyl-5- tan solid 193-197 33.3 2.58 17.9 pyrazolyl 33.7 2.54 18.165 Cl H Cl H 2,6-dichlorophenyl lt. tan 246-248 35.0 1.47 13.6 powder 34.8 1.25 13.566 OCH.sub.3 H Cl H 2,6,-dichlorophenyl lt. tan 232-243 38.3 2.22 13.7 powder (d) 38.3 2.12 13.767 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-chloro-6-fluoro- white >265 46.8 3.67 14.6 phenyl solid 47.0 3.79 14.568 Cl H CH.sub.3 H 2-bromo-6-chloro- white 185-186 35.8 2.08 12.9 phenyl solid 35.7 2.05 12.769 OCH.sub.3 H CH.sub.3 H 2-chloro-6-fluoro- off-white 245 45.4 3.26 15.1 phenyl solid 45.5 3.42 14.970 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2-bromo-6-fluoro- white >300 37.3 2.29 6.64 phenyl powder 37.4 2.15 6.7571 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2-chloro-6-fluoro- white 248 41.1 2.53 12.8 phenyl solid 41.0 2.46 12.872 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-chloro-6-iodophenyl white >263 36.6 2.86 11.4 powder 36.7 2.58 11.473 OCH.sub.3 H CH.sub.3 H 2-chloro-6-iodophenyl white >247 35.1 2.53 11.7 powder 35.4 2.23 11.574 Cl H CH.sub.3 H 2-methyl-6-nitro- yellow 256-258 44.0 3.17 18.3 phenyl powder 44.1 3.23 18.675 Cl H CH.sub.3 H 2,3-dimethyl-6-nitro- yellow 281-283 45.5 3.57 17.7 phenyl solid 45.7 3.73 17.776 Cl H CH.sub.3 H 2-chloro-6-methyl- white 258-260 45.3 3.26 15.1 phenyl solid 45.2 3.21 15.177 Cl H CH.sub.3 H 2-(trifluoromethyl)- white 196-198 43.0 2.58 14.3 phenyl solid 42.9 2.72 14.578 Cl H CH.sub.3 H 2,6-dichlorophenyl white 257-258 39.9 2.32 14.3 powder (d) 39.8 2.35 14.379 Cl H CH.sub.3 H 2,6-difluorophenyl yellow 213-214 43.5 2.53 15.6 powder 43.5 2.51 15.780 OCH.sub.3 H CH.sub.3 H 2,6-dichlorophenyl white 269-270 43.4 3.13 14.5 powder (d) 43.3 3.13 14.481 OCH.sub.3 H CH.sub.3 H 2,6-difluorophenyl tan 248-249 47.5 3.41 15.8 powder (d) 47.4 3.48 15.882 OCH.sub.3 H CH.sub.3 H 2-fluoro-6-methoxy- mauve 220-221 48.7 3.83 14.2 carbonylphenyl solid (d) 48.9 3.82 14.283 OCH.sub.3 H CH.sub.3 H 2,6-dibromophenyl white 270 (d) 35.3 2.54 11.8 solid 35.5 2.72 11.884 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2,6-dibromophenyl white 271 (d) 36.8 2.88 11.4 powder 37.8 3.17 11.585 OCH.sub.3 H CH.sub.3 H 2-methyl-6-methoxy- off-white 212-214 52.3 4.65 14.4 carbonylphenyl solid 52.4 4.82 14.286 OCH.sub.3 H CH.sub.3 H 4-bromo-1-methyl-3- tan solid 263-264 35.9 3.27 21.0 pyrazolyl 36.0 3.59 20.887 Cl H CH.sub.3 H 2-chloro-6-methoxy- cream 240-243 43.4 3.12 14.5 phenyl solid 43.6 3.38 14.788 OCH.sub.3 H OCH.sub.3 H 2,6-dichlorophenyl yellow 252-253 41.7 3.00 13.9 powder (d) 41.8 2.67 13.689 H CH.sub.3 H Br 2,6-dichlorophenyl off-white 240-242 35.8 2.08 12.9 solid (d) 35.5 1.88 13.290 H CH.sub.3 H OCH.sub.3 2,6-dichlorophenyl tan solid 232 43.4 3.12 14.5 42.3 3.51 14.091 OCH.sub.3 H CH.sub.3 H 2-bromo-6-methoxy- off-white 225 42.2 3.32 12.3 carbonylphenyl solid 42.0 3.05 12.592 H CH.sub.3 H Br 2-fluoro-6-methoxy- pink 198 (d) 40.6 2.73 12.6 carbonylphenyl solid 40.4 2.53 12.693 Cl H CH.sub.3 H 2-fluoro-5-methyl-3- white 208-209 43.9 3.12 19.7 pyridinyl powder 43.9 3.41 19.794 OCH.sub.3 H CH.sub.3 H 2-fluoro-5-methyl-3- white 237-238 47.9 4.02 19.9 pyridinyl powder (d) 47.6 3.84 19.995 H Br H Br 2,6-dichlorophenyl brown powder96 H Br H OCH.sub.3 2,6-dichlorophenyl tan >300 34.5 2.01 12.4 powder 35.5 2.14 12.097 H H H OCH.sub.3 2,6-dichlorophenyl white 119-121 41.8 2.70 15.0 powder 41.5 2.42 13.998 OCH.sub.3 H Cl H 2-fluoro-6-methoxy- white 221-222 43.5 2.92 13.5 carbonylphenyl powder 43.1 2.90 13.599 Cl H CH.sub.3 H 4-iodo-1-methyl-3- tan solid 249-251 29.2 2.23 18.6 pyrazolyl 29.0 2.16 18.4100 Cl H Cl H 2-fluoro-6-methoxy- lt. tan 182-183 40.1 2.16 13.4 carbonylphenyl powder 39.9 2.05 13.1101 OCH.sub.3 H CH.sub.3 H 4-iodo-1-methyl-3- white 199 (d) 30.5 2.72 17.7 pyrazolyl solid 30.9 3.24 18.0102 Cl H Cl H 2-fluoro-4-methyl-3- lt. tan 221-223 38.3 2.14 18.6 pyridinyl powder 38.4 2.29 18.6103 OCH.sub.3 H Cl H 2-fluoro-4-methyl-3- lt. tan 213-214 42.0 2.98 18.8 pyridinyl powder (d) 42.3 2.70 18.7104 OCH.sub.2 CH.sub.3 H Cl H 2-fluoro-4-methyl-3- lt. tan 184-185 43.6 3.40 18.2 pyridinyl powder (d) 44.0 3.57 17.8105 Cl H Cl H 4-bromo-1-methyl-3- lt. tan 266-267 28.2 1.66 19.7 pyrazolyl powder (d) 28.0 1.35 19.5106 OCH.sub.3 H Cl H 4-bromo-1-methyl-3- white 257-258 31.3 2.39 19.9 pyrazolyl powder (d) 31.3 2.06 19.9107 Cl H Cl H 2,6-difluorophenyl white 214-215 38.1 1.59 14.8 powder 38.2 1.56 14.9108 OCH.sub.3 H Cl H 2,6-difluorophenyl white 240-241 41.7 2.42 15.0 powder (d) 41.4 2.35 14.8109 Cl Br H OCH.sub.3 2,6-difluorophenyl pale pink 262 34.4 1.78 12.4 powder 34.7 1.64 12.1110 H Br H OCH.sub.3 4-bromo-1-methyl-3- brown >300 28.3 2.16 18.0 pyrazolyl powder 32.9 2.15 15.5111 H Br H OCH.sub.3 2-fluoro-4-methyl-3- pink 198-200 37.5 2.66 16.8 pyridinyl powder 37.4 2.36 15.3112 H H Cl H 2,6-difluorophenyl white 276-278 41.8 2.05 16.3 powder (d) 41.7 2.30 16.3113 H H Cl H 2-fluoro-6-methoxy- white 205-207 43.8 2.62 14.6 carbonylphenyl powder 43.7 2.74 14.7114 H H OCH.sub.3 H 2,6-difluorophenyl white 231-232 45.9 2.96 16.4 powder 45.6 2.97 16.4115 H Cl H OCH.sub.3 2,6-difluorophenyl tan solid 223-225 41.7 2.42 15.0 (d) 41.9 2.36 14.7116 H Cl H OCH.sub.3 2-fluoro-4-methyl-3- cream 212 42.0 2.98 18.8 pyridinyl solid 41.4 2.74 27.8117 H Cl H OCH.sub.3 4-bromo-1-methyl-3- rust 225 31.3 2.39 19.9 pyrazolyl solid 31.4 2.07 17.5118 OCH.sub.3 Br H OCH.sub.3 2,6-difluorophenyl purple 222-223 37.4 2.37 12.5 solid 38.9 1.83 12.8119 Cl H CH.sub.3 H 5-chloro-2-fluoro-3- grey 225-226 38.3 2.14 18.6 pyridinyl powder (d) 38.8 1.94 18.3120 OCH.sub.3 H CH.sub.3 H 5-chloro-2-fluoro-3- white 262-264 42.0 2.98 18.8 pyridinyl powder 41.9 2.93 18.8121 OCH.sub.3 H CH.sub.3 H 1-methyl-4-(tri- white 191-193 37.0 3.10 19.9 fluoromethylthio)-3- solid 37.3 2.91 19.8 pyrazolyl122 Cl H CH.sub.3 H 2-methoxy-6-methoxy- purple 213-216 46.8 3.68 13.6 carbonylphenyl powder 47.0 3.92 13.7123 OCH.sub.3 H CH.sub.3 H 2-methoxy-6-methoxy- tan 219-221 50.2 4.46 13.8 carbonylphenyl powder 50.0 4.67 13.7124 Cl H CH.sub.3 H 4-methyl-3-pyridinyl white 223-224 46.2 3.58 20.7 powder (d) 46.1 3.89 20.6125 OCH.sub.3 H CH.sub.3 H 4-methyl-3-pyridinyl lt. grey 209-210 50.4 4.54 21.0 powder (d) 49.3 4.95 19.8126 H CF.sub.3 H OCH.sub.3 2,6-difluorophenyl off-white 172-173 41.2 2.22 13.7 solid (d) 41.6 2.26 13.6127 H CF.sub.3 H OCH.sub.3 2-fluoro-4-methyl-3- off-white 238 (d) 41.5 2.74 17.3 pyridinyl solid 41.6 2.67 17.1128 H CF.sub.3 H OCH.sub.3 4-bromo-1-methyl-3- orange 198 31.7 2.22 18.5 pyrazolyl solid 32.4 2.16 18.1129 OCH.sub.3 H CH.sub.3 H 4-iodo-1-methyl-3- tan solid 201-203 36.2 2.92 18.8 pyrazolyl 36.0 2.74 19.0130 OCH.sub.2 CH.sub.3 H CH.sub.3 H 4-bromo-i-methyl-3- tan 245-247 37.6 3.64 20.2 pyrazolyl powder 37.8 3.75 19.9131 Cl H H H 2,6-difluorophenyl tan 255-256 41.8 2.05 16.3 powder (d) 41.8 2.00 16.4132 OCH.sub.3 H H H 2,6-difluorophenyl tan 255-256 45.9 2.96 16.5 powder (d) 46.1 2.92 16.6133 OCH.sub.2 CH.sub.3 H H H 2,6-difluorophenyl tan 263-264 47.5 3.42 15.8 powder (d) 47.6 3.04 16.0134 OCH.sub.2 H CH.sub.3 H 2,6-difluorophenyl tan 217-220 48.0 3.89 14.0 CH.sub.2 OCH.sub.3 powder 48.2 4.05 14.1135 OCH.sub.2 H CH.sub.3 H 2,6-difluorophenyl tan 245-247 46.6 3.39 14.5 CH.sub.2 F powder 46.9 3.43 14.5136 OCH.sub.2 CH.sub.3 H H H 2-fluoro-4-methyl-3- lt. tan 196-197 47.9 4.02 15.8 pyridinyl powder (d) 48.0 4.27 16.0137 Br H H H 4-bromo-1-methyl-3- tan 246-247 27.5. 1.85 19.3 pyrazolyl powder (d) 27.8 1.69 19.0138 OCH.sub.3 H H H 4-bromo-1-methyl-3- tan 233-234 34.1 2.86 21.7 pyrazolyl powder (d) 34.2 3.03 21.6139 OCH.sub.2 CH.sub.3 H H H 4-bromo-1-methyl-3- tan 230-231 35.9 3.27 21.0 pyrazolyl powder (d) 36.1 3.58 21.0140 OCH.sub.3 H H H 2-fluoro-4-methyl-3- lt. tan 226-227 46.3 3.59 20.8 pyridinyl powder (d) 46.2 3.90 20.7141 Br H H H 2-fluoro-4-methyl-3- brown 233-234 37.3 2.35 18.1 pyridinyl powder (d) 37.3 2.66 18.4142 H CF.sub.3 H F 4-bromo-1-methyl-3- orange 224-227 29.8 1.59 7.23 pyrazolyl solid (d) 30.8 1.11 6.62143 H CF.sub.3 H F 2,6-difluorophenyl yellow 136-137 39.4 1.53 14.1 solid 39.5 1.20 13.9144 H CF.sub.3 H F 4-methyl-3-pyridinyl tan 172-173 39.7 2.05 17.8 powder 40.1 1.94 17.8145 H Cl H OCH.sub.3 2-bromo-6-methoxy- brown 173-175 37.9 2.54 11.8 carbonylphenyl powder (d) 38.0 2.35 11.8146 H Cl H OCH.sub.3 2-chloro-4-methyl-3- brown 175-176 40.2 2.86 18.0 pyridinyl powder (d) 40.0 2.73 16.2147 H Cl H OCH.sub.3 2-chloro-4-methoxy-3- brown 175-178 38.6 2.74 17.3pyridinyl powder (d) 38.7 2.44 16.4148 OCH.sub.3 H CH.sub.3 H 4-methoxycarbonyl-3- tan solid 181-183 47.7 4.0i 18.6 pyridinyl (d) 47.8 4.20 18.6149 Cl H CH.sub.3 H 4-methoxycarbonyl-3- tan solid 168-170 44.0 3.17 18.3 pyridinyl 43.8 3.28 18.3150 OCH.sub.3 H CH.sub.3 H 4-carboxy-3-pyridinyl white 254-256 46.3 3.61 19.3 solid (d) 46.0 3.31 19.0151 OCH.sub.3 H CH.sub.3 H 4-fluoro-1-methyl-3- tan solid 147-149 49.2 3.87 21.5 indazolyl (d) 49.1 4.12 21.4152 OCH.sub.2 H CH.sub.3 H 2,6-difluorophenyl tan 135-145 46.9 3.67 14.6 CH.sub.2 Cl powder 44.4 3.00 13.7153 OC.sub.3 H.sub.7 (n) H CH.sub.3 H 2,6-difluorophenyl tan 242-245 50.3 4.22 14.7 powder 50.3 4.35 14.5154 H Cl H OCH.sub.3 4-iodo-1-methyl-3- brown 195-200 28.2 2.15 17.9 pyrazolyl powder (d) 30.7 2.32 17.2155 H Cl H OCH.sub.2 CH.sub.3 4-bromo-1-methyl-3- orange 192-195 33.1 2.78 19.3 pyrazolyl powder (d) 33.4 2.73 18.1156 OCH.sub.3 H CH.sub.3 H 1-methyl-3-(tri- tan solid 140-142 fluoromethyl)-4- (d) pyrazolyl157 H Cl H OCH.sub.2 CH.sub.3 2-fluoro-4-methyl-3- brown 153-155 43.6 3.40 18.2 pyridinyl powder (d) 43.5 3.28 17.0158 H Cl H OCH.sub.2 CH.sub.3 2,6-difluorophenyl brown 168-170 41.8 2.25 13.9 powder (d) 41.9 2.51 14.1159 OCH.sub.3 H Cl H 4-methoxycarbonyl-3- brown 167-172 42.3 3.04 17.6 pyridinyl powder 42.3 3.14 16.5160 OCH.sub.3 H CH.sub.3 H 2-chloro-4-ethoxy-3- white 215-216 45.3 4.05 17.6 pyridinyl solid 45.3 3.76 17.6161 OC.sub.3 H.sub.7 (i) H Cl H 2-chloro-4-ethoxy-3- tan solid 203-204 47.9 4.73 16.4 pyridinyl 48.0 5.06 16.2162 H H H Cl 2,6-difluorophenyl white 263-265 41.8 2.05 16.3 powder 41.6 2.14 16.2163 H H H Cl 4-bromo-1-methyl-3- white 272-273 30.7 2.06 21.5 pyrazolyl powder (d) 30.4 2.06 21.1164 H H H Cl 2-fluoro-4-methyl-3- yellow 213-216 42.2 2.65 20.5 pyridinyl powder 41.9 2.99 20.4165 H H H OCH.sub.3 2,6-difluorophenyl white 254-255 45.9 2.96 16.5 powder 45.9 2.55 16.4166 H H H OCH.sub.3 4-bromo-1-methyl-3- off-white 214-216 34.1 2.86 21.7 pyrazolyl powder (d) 34.0 3.04 21.5167 H H H OCH.sub.3 2-fluoro-4-methyl-3- white 204-206 46.3 3.59 20.8 pyridinyl powder 43.8 3.17 19.1168 OCH.sub.3 H Cl H 4-iodo-1-methyl-3- white 222-226 28.2 2.15 17.9 pyrazolyl powder (d) 28.6 2.14 18.1169 OCH.sub.3 H Cl H 2-chloro-4-methyl-3- tan 197-199 40.2 2.86 18.0 pyridinyl powder 40.9 2.65 16.2170 OCH.sub.3 H Cl H 2-chloro-4-methoxy-3- white 212-214 38.6 2.74 17.3 pyridinyl powder (d) 39.6 3.35 15.1171 OCH.sub.3 H Cl H 2-methyl-6-methoxy- white 190-192 46.8 3.68 13.6 carbonylphenyl powder 46.7 3.98 13.5172 H Cl H OC.sub.3 H.sub.7 (n) 4-bromo-1-methyl-3- yellow 185-187 34.7 3.14 18.7 pyrazolyl solid 34.9 3.31 18.1173 H Cl H OC.sub.3 H.sub.7 (n) 2-fluoro-4-methyl-3- off-white 203-204 45.1 3.78 17.5 pyridinyl solid 45.3 3.60 17.1174 Cl H CH.sub.3 H 2-fluoro-4-methyl-3- white 223-225 45.5 3.54 18.9 pyridinyl solid 45.5 3.37 18.6175 Cl H CH.sub.3 H 4-bromo-1-methyl-3- tan 240-242 33.1 2.78 19.3 pyrazolyl powder (d) 33.8 3.04 18.9176 Cl H CH.sub.3 H 2,6-difluorophenyl tan 234-236 42.2 3.07 13.8 powder (d) 42.3 2.85 14.4177 OC.sub.3 H.sub.7 (n) H Cl H 2,6-difluorophenyl white 199-200 44.7 3.25 13.9 powder (d) 44.7 3.24 13.6178 OCH.sub.3 H CH.sub.3 H 2-fluoro-4-ethyl-3- white 221-222 49.3 4.41 19.2 pyridinyl powder (d) 49.5 4.23 19.1179 H Cl H OC.sub.3 H.sub.7 (i) 2,6-difluorophenyl yellow 168-170 44.7 3.25 13.9 solid 44.8 3.25 13.5180 H Cl H OC.sub.3 H.sub.7 (i) 2-fluoro-4-methyl-3- yellow 228-230 45.1 3.78 17.2 pyridinyl solid (d) 45.1 3.76 16.6181 H Cl H OC.sub.3 H.sub.7 (i) 4-bromo-1-methyl-3- white 209-210 34.7 3.14 18.7 pyrazolyl solid 34.5 3.02 18.6182 H CH.sub.3 H H 2,6-difluorophenyl yellow 229-233 48.2 3.11 17.8 powder (d) 49.3 3.23 17.1183 H H H CH.sub.3 2,6-difluorophenyl yellow 221-223 48.2 3.11 17.3 powder (d) 48.5 3.13 16.8184 Cl H CH.sub.3 H 2-chloro-4-propoxy-3- colorless 205-216 43.3 3.63 16.8 pyridinyl solid (d) 43.2 3.75 16.6185 OCH.sub.3 H CH.sub.3 H 2-chloro-4-(1-methyl- tan solid 243-245 43.3 3.63 16.8 ethoxy-3-pyridinyl (d) 43.1 3.50 16.5186 OCH.sub.3 H CH.sub.3 H 2-chloro-4-propoxy-3- colorless 206-207 46.7 4.41 17.0 pyridinyl solid (d) 47.0 4.46 17.2187 OCH.sub.3 H CH.sub.3 H 2-chloro-4-(1-methyl- white 236-237 46.7 4.41 17.0 ethoxy-3-pyridinyl solid (d) 46.0 4.33 16.7188 OCH.sub.3 H Cl H 4-bromo-1-methyl-5- tan 119 (d) 31.3 2.39 19.9 pyrazolyl powder 33.1 3.14 17.4189 OC.sub.3 H.sub.7 (i) H CH.sub.3 H 2,6-difluorophenyl white 235-237 50.3 4.22 14.7 powder 50.4 4.03 14.8190 OCH.sub.3 H Cl H 2-chloro-6-methoxy- white 211-214 41.8 2.80 12.0 carbonylphenyl powder 39.6 2.44 11.8191 OCH.sub.3 H H Cl 2,6-difluorophenyl lt. grey >300 41.7 2.42 15.0 powder 41.7 2.58 15.1192 OCH.sub.3 H H Br 4-bromo-1-methyl-3- lt. tan >300 31.3 2.39 19.9 pyrazolyl powder 31.8 2.44 19.8193 OCH.sub.3 H H Br 2-fluoro-4-methyl-3- lt. tan >300 42.0 2.98 18.8 pyridinyl powder 42.1 3.19 18.9194 OCH.sub.3 H CH.sub.3 H 4-chloro-1-methyl-3- tan solid 235-237 40.4 3.67 23.6 pyrazolyl 40.2 3.75 23.7195 OCH.sub.3 H CH.sub.3 H 5-chloro-1-methyl-4- tan solid 207-209 40.4 3.67 23.6 pyrazolyl 40.2 4.08 23.5196 OCH.sub.2 H CH.sub.3 H 4-bromo-1-methyl-3- tan 244-246 36.0 3.26 19.4 CH.sub.2 F pyrazolyl powder (d) 36.7 3.15 18.9197 OCH.sub.2 H Cl H 2,6-difluorophenyl tan 210-212 43.0 3.13 13.4 CH.sub.2 OCH.sub.3 powder (d) 43.1 3.27 13.1198 OCH.sub.3 H Br H 2,6-difluorophenyl lt. tan 235-236 37.2 2.16 13.4 powder (d) 37.2 2.18 13.4199 OCH.sub.3 H Br H 2-fluoro-4-methyl-3- lt. tan 210-211 37.5 2.66 16.8 pyridinyl powder (d) 37.7 2.54 16.6200 OCH.sub.3 H Br H 4-bromo-1-methyl-3- lt. tan 241-242 28.3 2.16 18.0 pyrazolyl powder (d) 28.7 2.25 18.3201 OCH.sub.3 H H Br 2,6-difluorophenyl off-white >300 37.2 2.16 13.4 powder 36.8 2.12 13.3202 OCH.sub.3 H H Br 2-fluoro-4-methyl-3- tan >300 37.5 2.66 16.8 pyridinyl powder 36.9 2.50 16.5203 OCH.sub.3 H H Br 4-bromo-1-methyl-3- off-white >300 28.3 2.16 18.0 pyrazolyl powder 28.5 2.13 17.9204 OCH.sub.3 H CH.sub.3 H 2,4,5-trichloro-3- colorless 235-236 36.9 2.38 16.6 pyridinyl solid (d) 37.0 2.49 16.5205 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-chloro-4-ethoxy-3- colorless 200-201 46.7 4.41 17.0 pyridinyl solid 46.7 4.18 16.9206 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-chloro-4-methoxy-3- white 239-240 45.3 4.05 17.6 pyridinyl solid (d) 45.1 4.13 17.4207 Cl H CH.sub.3 H 2-chloro-4-methoxy- white 250-251 38.6 2.74 17.3 carbonyl-3-pyridinyl powder (d) 40.0 2.66 16.3208 OC.sub.3 H.sub.7 (i) H CH.sub.3 H 2-chloro-4-methoxy-3- white 244-245 46.7 4.41 17.0 pyridinyl powder (d) 46.2 4.11 16.9209 OCH.sub.2 CF.sub.3 H CH.sub.3 H 2-chloro-4-methoxy-3- white 222-224 39.9 2.90 15.5 pyridinyl solid (d) 39.6 2.53 15.1210 OCH.sub.2 CH.sub.3 H CH.sub.3 H 2-chloro-4-(1-methyl- white 217-218 47.9 4.73 16.4 ethoxy)-3-pyridinyl solid (d) 47.6 4.69 16.3211 OCH.sub.2 CH.sub.3 H CH.sub.3 H 4-ethoxycarbonyl-3- white 191-192 50.4 4.46 17.4 pyridinyl powder (d) 50.8 4.72 17.3212 OCH.sub.3 H CH.sub.3 H 2-chloro-4-methoxy- white 230-231 43.8 3.43 17.0 carbonyl-3-pyridinyl powder (d) 44.0 3.46 16.8213 OCH.sub.2 CH.sub.3 H Cl H 2-chloro-4-methyl-3- lt. brown 229-230 pyridinyl powder (d)214 OCH.sub.3 H Cl H 2-chloro-4-ethoxy-3- lt. brown 161-162 pyridinyl powder (d)215 OCH.sub.2 CH.sub.3 H Cl H 2-chloro-4-ethoxy-3- lt. brown 203-204 pyridinyl powder (d)216 OCH.sub.2 CH.sub.3 H Cl H 2-chloro-4-methoxy-3- lt. brown 224-225 40.2 3.13 16.4 pyridinyl powder (d) 40.6 3.26 6.6217 OCH.sub.3 H CH.sub.3 H 2-methoxy-4-methyl-3- white 235-237 49.6 4.72 19.3 pyridinyl powder (d) 49.5 4.57 19.0218 OC.sub.3 H.sub.7 (i) H Cl H 2-chloro-4-methyl-3- tan solid 226-227 43.3 3.63 16.8 pyridinyl (d) 43.1 3.70 16.2219 OC.sub.3 H.sub.7 (i) H Cl H 2-chloro-4-methoxy-3- off-white 154-1255 41.7 3.50 16.2 pyridinyl solid 41.4 3.26 15.7220 H CF.sub.3 H OCH.sub.3 2-chloro-4-methyl-3- off-white 225-227 38.4 2.53 16.0 pyridinyl solid 38.6 2.20 16.1221 H CF.sub.3 H OCH.sub.2 CH.sub.3 2-chloro-4-methoxy-3- off-white 162-163 39.9 2.90 15.5 pyridinyl solid 37.5 3.22 14.7222 Cl H CH.sub.3 H 2-methoxy-4-methyl-3- off-white 221-222 45.7 3.84 19.0 pyridinyl solid 45.3 3.95 19.2223 OCH.sub.3 H H Cl 2-chloro-4-methoxy-3- off-white >300 (d) 38.6 2.74 17.3 pyridinyl solid 38.4 2.75 17.1224 OC.sub.3 H.sub.7 (n) H H Cl 2-chloro-4-methoxy-3- off-white 168-170 41.7 3.50 16.2 pyridinyl powder (d) 41.8 3.55 16.0225 OC.sub.2 H.sub.5 H H Cl 2-chloro-4-methoxy-3- off-white 231-233 41.7 3.50 16.2 pyridinyl powder (d) 40.3 3.31 16.3226 OCH.sub.3 H CH.sub.3 H 2-fluoro-4-methoxy-3- white 257-258 45.8 3.84 19.1 pyridinyl solid (d) 45.8 3.87 19.0227 OC.sub.2 H.sub.5 H CH.sub.3 H 2-fluoro-4-methoxy-3- white 240-241 47.2 4.23 18.4 pyridinyl solid (d) 46.7 4.55 18.1228 OCH.sub.3 H H Br 2-chloro-4-methoxy-3- tan solid 220-222 34.8 2.47 15.6 pyridinyl (d) 34.9 2.47 15.5229 OCH.sub.3 H H Br 4-methoxycarbonyl-3- tan 154-156 38.0 2.73 15.8 pyridinyl powder (d) 38.2 2.79 15.6230 OCH.sub.3 H CH.sub.3 H 2-chloro-4-(2,2,2- white 213-214 39.9 2.90 15.5 trifluoroethoxy)-3- solid 38.9 3.12 15.2 pyridinyl213 OC.sub.2 H.sub.5 H CH.sub.3 H 2-chloro-4-(2,2,2- white 211-212 41.3 3.25 15.0 trifluoroethoxy)-3- solid 41.1 3.30 15.0 pyridinyl232 OCH.sub.3 H CH.sub.3 H 2-bromo-4-methoxy-3- white 214-215 39.3 3.30 16.4 pyridinyl solid (d) 39.0 3.46 16.0233 OC.sub.2 H.sub.5 H CH.sub.3 H 2-bromo-4-methoxy-3- off-white 245-246 40.7 3.65 15.8 pyridinyl solid (d) 40.9 3.85 15.9234 H CH.sub.3 H OCH.sub.3 2-chloro-4-methoxy-3- tan 198-200 43.8 3.68 18.3 pyridinyl powder 43.0 3.76 17.9235 OCH.sub.3 H CH.sub.3 H 2-fluoro-4-ethoxy-3- white 253-255 47.2 4.23 18.4 pyridinyl solid 47.3 4.00 18.5236 OC.sub.2 H.sub.5 H CH.sub.3 H 2-fluoro-4-ethoxy-3- tan solid 206-208 48.6 4.59 17.7 pyridinyl 48.7 4.72 17.9237 Cl H CH.sub.3 H 2-fluoro-4-ethoxy-3- white 218-219 43.6 3.40 18.2 pyridinyl solid 43.6 3.38 18.4238 OC.sub.2 H.sub.5 H CH.sub.3 H 2-chloro-4-(n)propoxy white 130-132 47.9 4.73 16.4 3-pyridinyl solid 47.6 4.67 16.4239 OCH.sub.3 H CH.sub.3 H 2-chloro-4-(2-fluoro- off-white 218-220 43.3 3.64 16.8 ethoxy)-3-pyridinyl solid (d) 43.1 3.60 16.7240 OC.sub.2 H.sub.5 H CH.sub.3 H 2-chloro-4-(2-fluoro- white 210-212 44.7 3.99 16.3 ethoxy)-3-pyridinyl solid (d) 44.5 4.19 16.6241 OC.sub.2 H.sub.5 H H Cl 2,6-difluorophenyl white >300 (d) 41.3 3.22 13.8 powder 41.3 2.65 13.6 hydrate242 OCH.sub.3 H H Br 2-chloro-6-methoxy- tan 202-204 37.9 2.54 11.8 carbonylphenyl powder (d) 37.8 2.56 11.6243 OCH.sub.3 H CH.sub.3 H 4-bromo-1-methyl-3- white 234-236 35.9 3.27 21.0 pyrazolyl powder 35.1 3.24 21.4244 OCH.sub.3 H CH.sub.3 H 1-methyl-4-(tri- tan solid 240-236 35.9 3.27 21.0 fluoromethyl)-3- 40.2 3.14 21.4 pyrazolyl245 Cl H CH.sub.3 H 1-methyl-3-(tri- tan solid 211-212 36.8 2.85 19.8 fluoromethyl)-5- 36.8 2.74 19.8 methoxy-4-pyrazolyl246 OCH.sub.3 H CH.sub.3 H 1-methyl-3-(tri- off-white 186-188 40.0 3.60 20.0 fluoromethyl)-5- solid 38.8 3.52 19.4 methoxy-4-pyrazolyl247 OC.sub.2 H.sub.5 H CH.sub.3 H 1-methyl-3-(tri- brown 205-207 41.5 3.94 19.4 fluoromethyl)-5- solid 40.5 3.52 19.1 methoxy-4-pyrazolyl248 OCH.sub.3 H CH.sub.3 H 1,3-dimethyl-5-(tri- off-white 247-249 41.6 3.74 20.8 fluoromethyl)-4- solid 41.1 4.07 20.6 pyrazolyl249 OCH.sub.2 H.sub.5 H CH.sub.3 H 1,3-dimethyl-5-(tri- tan solid 251-252 43.1 4.10 20.1 fluoromethyl)-4- 43.4 4.16 20.3 pyrazolyl250 OCH.sub.3 H CH.sub.3 H 1-methyl-3-(tri- off-white 226-228 36.8 2.85 19.8 fluoromethyl)-5- solid 36.9 3.04 19.5 chloro-4-pyrazolyl251 OC.sub.2 H.sub.5 H CH.sub.3 H 1-methyl-3-(tri- white 239-240 38.3 3.22 19.2 fluoromethyl)-5- solid 38.6 3.46 19.2 chloro-4-pyrazolyl252 Cl H H OCH.sub.3 2,6-difluorophenyl off-white 190-191 41.7 2.42 15.0 powder (d) 41.3 2.37 15.0253 Cl H H OCH.sub.3 2-chloro-4-methoxy-3- white 253-253 38.6 2.74 17.3 pyridinyl powder (d) 38.8 2.90 17.4254 Cl H H OCH.sub.3 1-methyl-4-bromo-3- lt. tan 269-270 31.3 2.39 19.9 pyrazoyl powder (d) 31.9 2.39 19.6255 OCH.sub.3 H H OCH.sub.3 2,6-difluorophenyl off-white 319-320 45.1 3.27 15.1 powder (d) 43.4 3.13 14.8256 OCH.sub.3 H H OCH.sub.3 2-chloro-4-methoxy-3- lt. tan 256-258 42.1 3.53 17.7 pyridinyl powder (d) 41.7 2.85 17.3257 OCH.sub.3 H H OCH.sub.3 1-methyl-4-bromo-3- tan 257-258 34.5 3.14 20.1 pyrazoyl powder (d) 34.1 2.98 19.8258 OCH.sub.2 H.sub.5 H CH.sub.3 H 1,5-dimethyl-3- (ethoxycarbonyl)-4- pyrazolyl259 OCH.sub.3 H F H 4-bromo-1-methyl-3- pyrazolyl260 OCH.sub.3 H CF.sub.3 H 2,6-difluorophenyl261 H F H OCH.sub.3 2,6-difluorophenyl262 OCH.sub.3 H H F 2,6-difluorophenyl263 OCH.sub.3 H H I 4-bromo-1-methyl-3- pyrazolyl__________________________________________________________________________
The compounds of Formula I wherein V represents hydrogen can generally be prepared by combining a 2-chlorosulfonyl�1,2,4!triazolo�1,5-a!pyridine compound of Formula II: ##STR7## with an appropriately substituted aromatic primary amine compound of Formula III: ##STR8## in the presence of pyridine or a methylpyridine compound, and, optionally but preferably, a catalytic amount of dimethyl sulfoxide. The substituents W, X, Y, and Z of Formula II and the substituents A, B, J, D, A', B', D', A", B", and T are as defined hereinbefore for the compounds of Formula I. Compounds of Formula II wherein one or both of W and Z represents Cl or OCH.sub.3 or wherein W represents OCH.sub.2 CH.sub.3 or OC.sub.3 H.sub.7 (i) are often preferred as are compounds of Formula II wherein two of W, X, Y, and Z represent hydrogen.
The preparation is usually accomplished by placing a 2-chlorosulfonyl�1,2,4!triazolo�1,5-a!pyridine compound of Formula II, an aromatic amine compound of Formula III, and an inert solvent, such as acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, tetrahydrofuran, and the like, in a vessel and then adding the pyridine or methylpyridine, preferably pyridine, and a catalytic amount of dimethyl sulfoxide. The mixture is allowed to react, typically at ambient temperature, but heating if necessary. After a substantial quantity of the compound of Formula I has formed or a substantial quantity of the chlorosulfonyl compound of Formula II has been consumed, the desired product is recovered, typically by removing the solvent by evaporation, adding water, and removing the liquids from the solid that forms by centrifugation or filtration. The recovered product can be purified, if desired, by extracting with an immiscible organic solvent, such as methylene chloride, and with water. Alternatively, the desired compounds of Formula I can be purified by recrystallization and by other commonly used methods.
Approximately equimolar quantities of the compounds of Formulas II and III are generally used in the preparation of compounds of Formula I although a substantial excess of one or the other may be employed. The pyridine compound is generally employed in an amount of from at least 1 to about 5 moles per mole of compound of Formula II. Dimethyl sulfoxide is typically used in less than an equimolar amount; amounts over about 0.3 mole per mole of compound of Formula II are usually deleterious. Acetonitrile is often the preferred solvent.
It is sometimes advantageous to prepare the compounds of Formula I by condensing a compound of Formula II with an N-trialkylsilyl derivative of a substituted aromatic amine compound of Formula III. The method employed is analogous to that described in U.S. Pat. No. 4,910,706 for N-trialkylsilylanilines. The reaction conditions required are essentially the same as those described hereinabove for the condensation of a chlorosulfonyl compound of Formula II with a substituted aromatic amine of Formula III with the exception that the pyridine compound base may be omitted. The substituted N-trialkylsilyl derivatives of aromatic amines employed can be prepared from the corresponding substituted aromatic amine compounds by treatment with a trialkylsilyl halide and a trialkylamine essentially as described in U.S. Pat. No. 4,910,206 for aniline compounds. Sodium iodide is typically employed as a catalyst when the halide is chloride. The N-trialkylsilyl compounds are typically prepared and used immediately and without purification.
Compounds of Formula I wherein V represents hydrogen and W, Y, or Z represents OCH.sub.2 CF.sub.3, S(C.sub.1 -C.sub.3)alkyl, or O(C.sub.1 -C.sub.3)alkyl optionally monosubstituted with F, Cl, or OCH.sub.3 can be made from the corresponding compounds of Formula I wherein W, Y, or Z represents F, Cl, or Br by treatment with an appropriate nucleophilic reagent, such as sodium methoxide or sodium methanethiolate in methanol, acetonitrile, or dimethyl sulfoxide. Similarly, such compounds wherein W, Y, or Z represents F or Br can sometimes be made from corresponding compounds wherein W, Y, or Z represents C1 by treatment with an alkali metal halide, such as potassium fluoride. Typically, chloro compounds are the most readily available and are employed. The reaction conditions employed are similar to those used for the related exchange reactions of 2- and 4-halopyrimidines and pyridines. Non-aqueous media are preferred. The amount of heat and the time required are dependent on the position of the halogen, the identity of the halogen, the other substituents present, and the medium employed. The selective replacement of a halogen in the W position can readily be achieved as this halogen is much more reactive than are halogens in the X, Y, and Z positions. Halogens in the Z position are more reactive than those in the X position.
Many compounds of Formula I wherein one or more of X and Z represents F, Cl, Br, or H can be also be prepared by first preparing a compound of Formula I wherein one or both of X and Z represents nitro, reducing the nitro group to an amino group using standard reaction procedures for the reduction of a nitro group to an amino group well-known to those in the art, and then converting the amino group to a F, Cl, Br, I, OH, or H group by diazotization under appropriate reaction conditions generally known in the art.
Compounds of Formula I wherein V represents COR', CO.sub.2 R", or CONR"'.sub.2 wherein R', R", and R"' are as defined hereinabove can be prepared from compounds of Formula I wherein V represents hydrogen by acylation with a compound of the formula ClCOR', ClCO.sub.2 R", or ClCONR"'.sub.2 using conventional procedures known in the art for the acylation of sulfonamides.
The 2-chlorosulfonyl�1,2,4!triazolo�1,5-a!pyridine compounds of Formula II can be prepared by chloroxidation of 2-benzylthio�1,2,4!triazolo�1,5-a!pyridine compounds of Formula IV: ##STR9## wherein W, X, Y, and Z are as defined hereinabove. Such compounds wherein one or both of W and Z represents Cl or OCH.sub.3 or wherein W represents OCH.sub.2 CH.sub.3 or OC.sub.3 H.sub.7 (i) are often preferred as are compounds wherein two of W, X, Y, and Z represent hydrogen. The chloroxidation reaction can be carried out under the reaction conditions usually employed for such reactions. In a typical operation, the compound of Formula IV is dissolved or suspended in a water-immiscible organic solvent, such as chloroform or dichloromethane, water is added, and chlorine is added with good agitation to the mixture at temperatures below about 20.degree. C. when the reaction is complete, the organic solvent phase is separated and wasted with water and the solvent is typically removed by evaporation to obtain the desired chlorosulfonyl compound as a crude product. This crude product can be purified by standard methods, such as by recrystallization, extraction, or chromatography.
Compounds of Formula IV wherein W, Y, or Z represents I, F, OCH.sub.2 CF.sub.3, S(C.sub.1 -C.sub.3)alkyl, or O(C.sub.1 -C.sub.3)alkyl optionally monosubstituted with F, Cl, or OCH.sub.3 can be made from the corresponding compounds of Formula IV wherein W, Y, or Z represents F, Cl, or Br by treatment with an appropriate nucleophilic reagent, such as sodium methoxide or sodium methanethiolate in methanol or potassium ethoxide in ethanol, acetonitrile, or dimethyl sulfoxide. The reaction conditions are similar to those employed to make the corresponding conversion of compounds of Formula I wherein W, Y, or Z represents F, Cl, or Br to analogs wherein W, Y, or Z represents OCH.sub.2 CF.sub.3, S(C.sub.1 -C.sub.3)alkyl or O(C.sub.1 -C.sub.3)alkyl optionally monosubstituted with F, Cl, or OCH.sub.3. Heat is applied, if necessary, to accelerate the reaction. Compounds of Formula IV wherein W represents F, OCH.sub.2 CF.sub.3, S(C.sub.1 -C.sub.3)alkyl or O(C.sub.1 -C.sub.3)alkyl optionally mono-substituted with F, Cl, or OCH.sub.3 and one or more of X, Y, and Z represents Cl or Br can be made in this way from compounds wherein W and one or more of X, Y, and Z represents chloro or bromo by the selective reaction of the chloro or bromo substituent in the 5-position (W) because it is considerably more easily displaced. Similarly, compounds of Formula IV wherein Z represents F, OCH.sub.2 CF.sub.3, S(C.sub.1 -C.sub.3)alkyl or O(C.sub.1 -C.sub.3)alkyl optionally mono-substituted with F, Cl, or OCH.sub.3 and X represents chloro or bromo can be made from compounds wherein both X and Z represent chloro or bromo by selective reaction.
Compounds of Formula IV wherein W represents Cl can be prepared in three steps from a substituted glutaconic anhydride. The anhydride is first treated with the reaction product of thiosemicarbazide and benzyl chloride in the presence of a tertiary amine, such as triethylamine, and in a solvent, such as 2-propanol. The reaction can be carried out by heating the reaction mixture described for a period, adding an alkali metal alkoxide, such as sodium methoxide and heating for another period, and then acidifying the reaction mixture and recovering the insoluble solid product that forms. This solid product can then converted to a compound of Formula IV wherein W represents OH by carefully heating until the evolution of carbon dioxide ceases. This compound of Formula I wherein W represents OH can then be converted to the corresponding compound wherein W represents Cl by combining it with an excess of phosphorus oxychloride and a tertiary amine, such as N,N-dimethylaniline, and heating. The product can then be recovered by removing the excess phosphorus oxychloride by evaporation under reduced pressure.
Compounds of Formula IV wherein one or both of X and Z represents F, Cl, Br, I, OH, or H can also be prepared by first preparing a compound of Formula IV wherein one or both of X and Z represents nitro, reducing the nitro group to an amino group using standard reaction procedures for the reduction of a nitro group to an amino group well-known to those in the art, and then converting the amino group to a F, Cl, Br, I, OH, or H group by diazotization under appropriate reaction conditions. Compounds wherein one of X and Z represents OR can be prepared from the corresponding compound wherein one of X and Z represents CH by consecutive treatment with phosphorus oxychloride and an alkali metal salt of the alcohol ROH. Compounds wherein W and/or Y represents chloro or bromo can be obtained by halogenation of the amino compounds before diazotization. Appropriate reaction conditions for such reactions are generally known in the art.
It has been found, however, that the reduction of a compound of Formula IV wherein W and X represent hydrogen, Y represents hydrogen, methyl, or a halogen, and Z represents nitro (2-benzylthio-8-nitro�1,2,4!triazolo�1,5-a!pyridine and certain 7-substituted analogs) with stannous chloride in the presence of stannic chloride and a reactive medium comprising hydrogen chloride or a C.sub.1 -C.sub.3 alcohol produces not only the corresponding compound of Formula IV wherein Z represents amino, but also the corresponding compound of Formula IV wherein W represents chloro or alkoxy and Z represents amino. The latter can be made to be the dominate product. The amino compounds obtained can be converted into compounds of Formula IV wherein W represents chloro or alkoxy and Z represents hydrogen or a halogen by standard means.
When the reactive medium contains hydrogen chloride as an essential ingredient, an 8-amino-2-benzylthio-5-chloro�1,2,4!triazolo�1,5-a!pyridine compound is obtained along with a small amount of an 8-amino-2-benzylthio�1,2,4!triazolo�1,5-a!pyridine compound. The reactive medium generally includes a solvent, which can be water, N-methyl-2-pyrrolidinone, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, or other suitable solvent. Concentrated aqueous hydrochloric acid is the generally preferred reactive medium in this embodiment. When the reactive medium contains an alcohol as an essential ingredient, a 5-alkoxy-8-amino-2-benzylthio�1,2,4!triazolo�1,5-a!pyridine compound is obtained. Methanol, ethanol, and propanol are examples of suitable alcohols. The reaction is generally carried cut by combining one molar equivalent of a 2-benzylthio-8-nitro�1,2,4!triazolo�1,5-a!pyridine compound with at least about 3 molar equivalents of stannous chloride, one molar equivalent of stannic chloride, and an excess of hydrogen chloride or at least one molar equivalent of the alcohol. The alcohols are typically employed in a large excess. The reaction mixture is heated at about 50.degree. to about 120.degree. C. with good agitation to effect the simultaneous reduction and substitution. The products can be recovered by standard means, including by dissolving the hydrochloride that is formed initially in water, basifying with an alkali metal hydroxide, and recovering the product by filtration or by solvent extraction.
Compounds of Formula IV wherein one or both of X and Z represents nitro can be prepared from (3 or 5)-nitro-2-hydrazinopyridine compounds by consecutive reactions with carbon disulfide, hydrogen peroxide, and benzyl chloride and triethylamine. The reactions take place at ambient temperatures and are exothermic. A reaction period of up to several days is sometimes required to assure that all of the product is in the desired, rearranged state, but rearrangement takes place spontaneously under the reaction conditions. The method is similar to that disclosed in the art for the preparation of 2-benzylthio�1,2,4!triazolo�1,5-c!pyrimidine compounds.
Many compounds of Formula IV can be prepared by the reaction 1-((1-imidazolylthionyl)amino)-2-iminopyridine compounds of Formula V: ##STR10## with benzyl chloride in a solvent, such as butanol, by heating. The desired compounds of Formula V can be recovered by conventional means.
Compounds of Formula V can be prepared by combining O-mesitylenesulfonylacetohydroxamate and perchloric acid in dioxane at temperatures below ambient, adding the solution obtained to 2-aminopyridine compounds of Formula VI: ##STR11## at temperatures below ambient, and then adding 1,1'-thiocarbonyldiimidazole to the mixture. The desired compounds of Formula VI can be recovered by conventional means.
It has additionally been found that compounds of Formula IV can be prepared from the corresponding 2-amino�1,2,4!triazolo�1,5-a!pyridine of Formula VII: ##STR12## wherein W, X, Y, and Z are as defined for compounds of Formula I. Compounds of Formula VII wherein one or both of W and Z represents Cl or OCH.sub.3 or wherein W represents OCH.sub.2 CH.sub.3 or OC.sub.3 H.sub.7 (i) are often preferred as are compounds of Formula II wherein two of W, X, Y, and Z represent hydrogen. The method is closely related to the chemistry disclosed in J. Chemical Society Chemical Communications, 1980 756-757. It is especially useful for the preparation of compounds of Formula I wherein W represents chloro, methoxy, ethoxy, or isopropoxy, X and Z each represent hydrogen, and Y represents methyl or a halogen; or wherein W represents chloro, methoxy or ethoxy, X and Y each represent hydrogen, and Z represents methyl, methoxy, or a halogen; or wherein Z represents chloro, methoxy or ethoxy, W and Y each represent hydrogen, and X represents methyl, trifluoromethyl, or a halogen. The preparation is preferably carried out by adding an excess of t-butyl nitrite to a solution consisting of a compound of Formula VII and dibenzyl disulfide in a compatible organic solvent, such as acetonitrile, and heating the combination to reflux until the evolution of gas subsides. The reaction is exothermic. The desired compounds of Formula IV can be recovered by conventional means, such as by removing the volatile components of the product mixture by evaporation, and can be purified by conventional means, such as by column chromatography or recrystallization.
Compounds of Formula VII can be prepared by treatment of appropriately substituted N-(2-pyridinyl)-N-carboethoxythiourea compounds with hydroxylamine in a solvent such as ethanol and heating for a few hours. The hydroxylamine is typically generated by neutralization of the hydrochloride with a hindered tertiary amine, such as diisopropylethylamine, or an alkoxide, such as sodium ethoxide. The desired compounds of Formula VII can be recovered by conventional means, such as by removal of the volatile components of the reaction mixture by evaporation, and can be purified by conventional means, such as by extraction with water and/or other solvents in which they are sparingly soluble. N-(2-Pyridinyl)-N-carboethoxythiourea compounds can be obtained by treatment of appropriately substituted 2-aminopyridine compounds with ethoxycarbonyl isothiocyanate. Compounds of Formula VII tan also be prepared from 2-cyanoaminopyridine compounds by the methods disclosed in Monatshefte fur Chemie, 114, 789-798 (1983).
The substituted anilines and 3-, 4-, and 5-aminopyrazoles that are required as intermediates for the compounds of Formula I are known in the art or can be prepared by general methods known in the art. The substituted 3-aminopyridines and 3-aminoindazoles that are required as intermediates can be prepared by the methods presented herein, are known in the art, or can be prepared by general methods known in the art.
4-Alkoxy-3-amino-2-chloropyridine compounds can be prepared by chlorination of known 4-alkoxy-3-aminopyridine compounds. 4-Alkoxy-3-amino-2-fluoropyridine compounds can be prepared from 4-alkoxy-2-fluoropyridine compounds by lithiation with butyl lithium and treatment of the intermediate with diphenyl phosphoryl azide. 4-Alkoxy-2-fluoropyridine compounds can be prepared by reduction of 4-Alkoxy-3,5-dichloro-2-fluoropyridine compounds with hydrogen. Many 4-substituted 2-alkoxy-3-aminopyridine compounds can be prepared from 2-alkoxy-3-aminopyridine compounds by lithiation of the corresponding t-butoxycarbonyl derivative and reaction of this with an electrophilic reagent in processes closely related to those disclosed in J. Organic Chemistry, 60, 1875-1877 (1995). Thus, 2-alkoxy-3-amino-4-fluoropyridine compounds can be prepared from t-butyl N-(2-alkoxy-3-pyridinyl)carbamates by fluorination with N-fluorodibenzenesulfonimide of the intermediate obtained on lithiation with t-butyl lithium followed by treatment with anhydrous p-toluenesulfonic acid to remove the protecting t-butoxycarbonyl group. Similarly, 2-alkoxy-3-amino-4-chloropyridine compounds can be obtained by chlorination of t-butyl N-(2-alkoxy-3-pyridinyl)carbamates with hexachloroethane in an analogous process. Alkyl 3-amino-2-alkoxyisonicotinate compounds can be prepared analogously from t-butyl N-(2-alkoxy-3-pyridinyl)carbamate compounds by lithiating with butyl lithium, treating the intermediate formed with carbon dioxide and then an alkyl iodide, and finally removing the protecting t-butoxycarbonyl group by treatment with anhydrous t2-toluenesulfonic acid. The amine-protected t-butyl N-(2-alkoxy-3-pyridinyl)carbamate compounds can be prepared from 2-alkoxy-3-aminopyridine compounds by treatment with di-t-butyl dicarbonate. 3-Amino-2-chloroisonicotinic acid esters can be prepared by chlorination of 3-aminoisonicotinic acid esters using 1,3-dichloro-5,5-dimethylhydantion as the chlorinating agent. 3-Amino-2-fluoro-4-methylpyridine can be prepared by palladium on carbon catalyzed reduction of 2-fluoro-4-methyl-3-nitropyridine with hydrogen. This compound can be converted to other 4-alkyl-3-amino-2-fluoropyridine compounds by alkylation of the methyl group. These and other 3-aminopyridine compounds of Formula III can be made using a variety of preparative methods well-established in the art.
While in is possible to utilize the 1,2,4-triazolo�1,5-a!pyridine-2-sulfonamide compounds of Formula I directly as herbicides, it is preferable to use them in mixtures containing an herbicidally effective amount of the compound along with at least one agriculturally acceptable adjuvant or carrier. Suitable adjuvants or carriers should not be phytotoxic to valuable crops, particularly at the concentrations employed in applying the compositions for selective weed control in the presence of crops, and should not react chemically with the compounds of Formula I or other composition ingredients. Such mixtures can be designed for application directly to weeds or their locus or can be concentrates or formulations which are normally diluted with additional carriers and adjuvants before application. They can be solids, such as, for example, dusts, granules, water dispersible granules, or wettable powders, or liquids, such as, for example, emulsifiable concentrates, solutions, emulsions or suspensions.
Suitable agricultural adjuvants and carriers that are useful in preparing the herbicidal mixtures of the invention are well known to those skilled in the art.
Liquid carriers that can be employed include water, toluene, xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone, cyclohexanone, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol monomethyl ether and diethylene glycol monomethyl ether, methanol, ethanol. isopropanol, amyl alcohol, ethylene glycol, propylene glycol, glycerine, and the like. Water is generally the carrier of choice for the dilution of concentrates.
Suitable solid carriers include talc, pyrophyllite clay, silica, attapulgus clay, kieseiguhr, chalk, diatomaceous earth, lime, calcium carbonate, bentonite clay, Fuller's earth, cotton seed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour, lignin, and the like.
It is frequently desirable to incorporate one or more surface-active agents into the compositions of the present invention. Such surface-active agents are advantageously employed in both solid and liquid compositions, especially those designed to be diluted with carrier before application. The surface-active agents can be anionic, cationic or nonionic in character and can be employed as emulsifying agents, wetting agents, suspending agents, or for other purposes. Typical surface active agents include salts of alkyl sulfates, such as diethanol-ammonium lauryl sulfate; alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate; alkylphenol-alkydene oxide addition products, such as nonylphenol-C.sub.18 ethoxylate; alcohol-alkylene oxide addition products, such as tridecyl alcohol-C.sub.16 ethoxylate; soaps, such as sodium stearate; alkylnaphthalenesulfonate salts, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryl trimethylammonium chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono and dialkyl phosphate esters.
Other adjuvants commonly utilized in agricultural compositions include antifoam agents, compatibilizing agents, sequestering agents, neutralizing agents and buffers, corrosion inhibitors, dyes, odorants, penetration aids, spreading agents, sticking agents, dispersing agents, thickening agents, freeze point depressants, antimicrobial agents, and the like. The compositions can also contain other compatible components, for example, other herbicides, plant growth regulants, fungicides, insecticides, and the like and can be formulated with liquid fertilizers or solid, particulate fertilizer carriers such as ammonium nitrate, urea and the like.
The concentration of the active ingredients in the herbicidal compositions of this invention is generally from about 0.001 to about 98 percent by weight. Concentrations from about 0.01 to about 90 percent by weight are often employed. In compositions designed to be employed as concentrates, the active ingredient is generally present in a concentration from about 5 to about 98 weight percent, preferably about 10 to about 90 weight percent. Such compositions are typically diluted with an inert carrier, such as water, before application. The diluted compositions usually applied to weeds or the locus of weeds generally contain about 0.001 to about 5 weight percent active ingredient and preferably contain about 0.01 to about 0.5 percent.
The present compositions can be applied to weeds or their locus by the use of conventional ground or aerial dusters, sprayers, and granule applicators, by addition to irrigation water, and by other conventional means known to those skilled in the art.
The compounds of Formula I have been found to be useful preemergence and postemergence herbicides. They can be employed at non-selective (higher) rates of application to control essentially all of the vegetation in an area and, often, at selective (lower) rates of application for the selective control of undesirable vegetation in grass crops, such as corn, wheat, barley, and rice as well as in broadleaf crops, such as soybeans and cotton. While each of the compounds encompassed by Formula I is within the scope of the invention, the degree of herbicidal activity, the selectivity, and the spectrum of weed control obtained varies depending upon the substituents present. The selection of a specific compound of the invention for a specific application can be done readily without invention from the data and information presented herein along with standard testing.
The term herbicide is used herein to mean an active ingredient which controls or adversely modifies the growth of plants. An herbicidally effective or vegetation controlling amount is an amount of active ingredient which causes an adversely modifying effect and includes deviations from natural development, killing, regulation, dessication, retardation, and the like. The terms plants and vegetation are meant to include germinant seeds, emerging seedlings and established vegetation.
Herbicidal activity is exhibited by the compounds of the present invention when they are applied directly to the plant or to the locus of the plant at any stage of growth or before emergence. The effect observed depends upon the plant species to be controlled, the stage of growth of the plant, the application parameters of dilution and spray drop size, the particle size of solid components, the environmental conditions at the time of use, the specific compound employed, the specific adjuvants and carriers employed, the soil type, and the like, as well as the amount of chemical applied. These and other factors can be adjusted as is known in the art to promote selective herbicidal action. Generally, it is preferred to apply the compounds of Formula I postemergence to relatively immature plants to achieve the maximum control of broadleaf weeds.
Application rates of about 0.001 to about 1 Hg/Ha are generally employed in postemergence operations; for preemergence applications, rates of about 0.01 to about 10 Kg/Ha are generally employed.

EXAMPLES
The following Examples are presented to illustrate the various aspects of this invention and should not be construed as limitations to the claims.
1. Preparation of 1-((1-Imidazolylthionyl)amino)-2-aminopyridine
A solution of ethyl O-mesitylenesulfonylacetohydroxamate (39.5 g (grams), 0.138 mol (mole)) in dioxane (225 mL (milliliters)), which was prepared according to Tetrahedron Letters 40, 4133-4135 (1972), was cooled to about 8.degree. C. Perchloric acid (17.4 mL of 70 percent, 0.203 mol) was added dropwise with stirring over 5 min (minutes). The reaction was then allowed to warm to room temperature over 1.5 hours. It was then diluted with ice water and the solids that formed were recovered by filtration and washed with water. The damp solids obtained were mixed with chloroform (300 mL) and the organic layer that formed was added dropwise with stirring and cooling to a solution of 2-aminopyridine (12.4 g, 0.131 mol) in chloroform (300 mL) at 5.degree. C. The temperature rose to 10.degree. C. during the addition. The reaction was allowed to warm to room temperature and then 1,1'-thiocarbonyldiimidazole (30.0 g, 0.168 mol) was added and the mixture was warmed to 40.degree. C. for several hours. The mixture was then cooled in an ice bath and the solid that slowly separated was recovered by filtration to obtain the 10.4 g (36 percent of theory) of title compound as a white powder melting at 174.degree.-175.degree. C. (d).
.sup.1 H NMR Nuclear Magnetic Resonance Spectroscopy (200 megahertz)) (DMSO-d.sub.6 (dimethyl sulfoxide)): 8.48 (s, 1H), 7.90 (s, 1H), 7.87 (d, 1H, J=4.0), 7.73 (t, 1H, J=4.0), 7.6-8.0 (broad s, 2H), 7.04 (d, 1H, J=4.0) 6.93 (s, 1H), 6.83 (t, 1H, J=4.0).
Elemental Analysis C.sub.9 H.sub.9 N.sub.5 S Calc.: % C, 49.3; % H, 4.14; % N, 31.9; % S, 14.6 Found: % C, 49.5; % H, 4.06; % N, 32.2; % S, 14.3
2. Preparation of 2-Benzylthio�1,2,4!triazolo�1,5-a!pyridine
1-((1-Imidazolylthionyl)amino)-2-iminopyridine (9.9 g, 0.045 mol), benzyl chloride (8.6 g, 0.068 mol) and 1-propanol (100 mL) were mixed and heated to reflux for 2 hours. The solvent was removed by evaporation under reduced pressure and the residue obtained was mixed with dichloromethane. The resulting solution was washed with water and concentrated by evaporation under reduced pressure. The residue obtained was triturated with hexane to obtain 9.4 g (86 percent of theory) of the title compound as a white powder melting at 79.degree.-81.degree. C.
.sup.1 H NMR (DMSO-d.sub.6): 8.85 (d, 1H, J=4.0), 7.72 (d, 1H, J=4.0), 7.63 (t, 1H, J=4.0), 7.2-7.5 (m, 5H), 7.12 (t, 1H, J=4.0), 4.50 (s, 2H); .sup.13 C NMR (DMSO-d.sub.6): 163.7, 150.9, 137.6, 130.6, 129.5, 128.8, 128.7, 128.5, 128.4, 127.2, 114.6, 113.7, 34.6.
Elemental Analysis C.sub.13 H.sub.11 N.sub.3 S Calc.: % C, 64.7; % H, 4.59; % N, 17.4; % S, 13.3 Found: % C, 64.5; % H, 4.86; % N, 17.3; % S, 11.8
3. Preparation of 2-Chlorosulfonyl�1,2,4!triazolo�1,5-a!pyridine
2-Benzylthio�1,2,4!triazolo�1,5-a!pyridine (8.6 g, 0.036 mol) was dissolved in dichloromethane (75 mL) and water (75 mL) and cooled in an ice bath with very good stirring. Chlorine (11.9 g, 0.168 mol) was added slowly at 3.degree.-7.degree. C. and was given another half hour to react. The layers were separated and the organic layer was dried over magnesium sulfate and sodium sulfate and then concentrated by evaporation under reduced pressure to obtain an oily residue. The residue was triturated with hexane to obtain 6.0 g (78 percent of theory) of the title compound as a white powder melting at 116.degree.-118.degree. C.
.sup.1 H NMR (CDCl.sub.3): 8.74 (dr, 1H, J=3.4, 0.5), 7.94 (dt, 1H, J=3.4, 0.5), 7.79 (td, 1H, J=3.4, 0.5), 7.38 (td, 1H, J=3.4, 0.5); .sup.13 C NMR (CDCl.sub.3): 164.2, 151.0, 132.7, 129.6, 118.5, 117.5.
4. Preparation of N-(2,6-Dichlorophenyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide
Chlorotrimethylsilane (7.0 mL, 6.0 g, 0.055 mol), triethylamine (7.7 mL, 5.6 g, 0.055 mol) and 2,6-dichloroaniline (4.5 g, 0.027 mol) were added with stirring to a solution of anhydrous sodium iodide (8.3 g, 0.055 mol) in acetonitrile (75 mL) and the resulting mixture was stirred for another half hour. The volatile materials were removed by evaporation under reduced pressure and the residue obtained was extracted into ether. The extract was concentrated by evaporation under reduced pressure and the residue obtained was added to a solution of 2-chlorosulfonyl�1,2,4!triazolo�1,5-a!pyridine (2.0 g, 0.0092 mol) in acetonitrile (50 mL) with stirring. Dimethyl sulfoxide (130 .mu.L, 0.144 g, 0.0018 mol) was then added and the mixture was allowed to react for 3.5 hours. The solvent was then removed by evaporation under reduced pressure and the residue obtained was diluted with dichloromethane. The resulting solution was washed well with water, dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The residue obtained was triturated with hexane and the solids that formed were recovered by filtration. The solids were washed with ether and a small amount of dichloromethane to obtain 2.1 g (68 percent of theory) of the title compound as a white powder melting at 269.degree.-270.degree. C.
.sup.1 H NMR (DMSO-d.sub.6): 10.86 (s, 1H), 9.08 (d, 1H, J=3.4), 7.98 (d, 1H, J=4.4), 7.82 (t, 1H, J=4.4), 7.28-7.52 (m, 4H).
Elemental Analysis C.sub.12 H.sub.8 Cl.sub.2 N.sub.4 O.sub.2 S Calc.: % C, 42.0; % H, 2.35; % N, 16.3; % S, 9.34 Found: % C, 41.9; % H, 2.22; % N, 16.3; % S, 9.08
N-(2,6-Difluorophenyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide, a white powder melting at 222.degree.-223.degree. C., was prepared by the same procedure in 56 percent yield.
.sup.1 H NMR (DMSO-d.sub.6): 10.75 (s, 1H), 9.07 (d, 1H, J=3.5), 7.98 (d, 1H, J=4.5), 7.83 (t, 1H, J=3.5), 7.02-7.48 (m, 5H).
Elemental Analysis C.sub.12 H.sub.8 F.sub.2 N.sub.4 O.sub.2 S Calc.: % C, 46.5; % H, 2.60; % N, 18.1; % S, 10.3 Found: % C, 46.5; % H, 2.56; % N, 18.2; % S, 10.2
5. Preparation of 1,2-Diamino-4,6-dimethylpyridinum mesitylate
A solution of ethyl O-mesitylenesulfonylacetohydroxamate (51.0 g, 0.179 mol) in dioxane (300 mL) was cooled until the dioxane started to freeze. Seventy percent perchloric acid (22.5 mL, 0.263 mol) was then added dropwise and the reaction was allowed to warm to room temperature. After 1.5 hours the mixture was diluted with water and filtered and the collected solids were washed well with water. The damp solids were mixed with chloroform and the resulting organic solution portion of the mixture obtained was added slowly to an ice-cooled (5.degree. C.) solution of 2-amino-4,6-dimethylpyridine (21.0 g, 0.172 mol) in chloroform (300 mL). The reaction was warmed to room temperature overnight and was then heated at reflux for several hours. The solvent was evaporated and the residue was triturated with ether and a small amount of chloroform. The resulting solid was recovered by filtration and rinsed with chloroform to obtain 22.9 g (39 percent of theory) of the title compound as a white powder melting at 193.degree.-195.degree. C.
Elemental Analysis C.sub.16 H.sub.23 N.sub.3 O.sub.2 S Calc.: % C, 57.0; % H, 6.87; % N, 12.5; % S, 9.50 Found: % C, 57.1; % H, 7.01; % N, 12.6; % S, 9.51
.sup.1 H NMR (DMSO-d.sub.6): 8.16 (s, 2H), 6.73 (s, 2H), 6.70 (s, 1H), 6.57 (s, 1H), 6.18 (s, 2H), 2.48 (s, 6H), 2.45 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H).
6. Preparation of 2-Benzylthio-5,7-dimethyl�1,2,4!triazolo�1.5-a!pyridine
1,2-Diamino-4,6-dimethylpyridinium mesitylate (14.0 g, 0.041 mol) and 1,1'-thiocarbonyldiimidazole (7.4 g, 0.041 mol) were mixed in chloroform (100 mL) and heated at reflux for an hour. The solvent was removed by evaporation under reduced pressure and the residue was triturated with ether and ethyl acetate and filtered to obtain 6.8 g of 1,2-diamino-4,6-dimethylpyridinium mesitylate as an insoluble solid and a filtrate. The insoluble solid was combined with another 8.3 g (15.1 g total) of the same material and with 1,1'-thiocarbonyldiimidazole (10.0 g, 0.056 mol) and the resulting mixture was stirred at room temperature for 3 days. The solvent was removed by evaporation under reduced pressure and the residue was diluted with ether and tetrahydrofuran and the mixture was filtered to obtain a filtrate. The earlier ether and ethyl acetate filtrate plus this ether and tetrahydrofuran filtrate were combined and concentrated by evaporation under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography on silica gel eluting with 15 percent ethyl acetate in hexane to obtain 3.5 g (20 percent of theory) of the title compound as a white powder melting at 69.degree.-70.degree. C.
.sup.1 H NMR (CDCl.sub.3): 7.1-7.5 (m, 6H), 6.5 (s, 1H), 4.5 (s, 2H), 2.6 (s, 3H), 2.4 (s, 3H); .sup.13 C NMR (CDCl.sub.3): 164.1, 151.8, 140.9, 137.6, 137.1, 129.1, 128.4, 127.2, 114.7, 111.2, 35.9, 21.5, 17.4.
Elemental Analysis C.sub.15 H.sub.15 N.sub.3 S Calc.: % C, 66.9; % H, 5.61; % N, 15.6; % S, 11.9 Found: % C, 67.0; % H, 5.90; % N, 15.9; % S, 11.7
2-Benzylthio-7-methyl�1,2,4!triazolo�1,5-a!pyridine was prepared similarly from 1-((1-imidazolylthionyl)amino)-2-imino-4-methylpyridine. The product was a while powder melting at 81.degree.-83.degree. C.
.sup.1 H NMR (CDCl.sub.3): 8.28 (d, 1H, J=3.5), 7.23-7.46 (m, 6.67 (d, 1H, J=3.5), 4.48 (s, 2H), 2.40 (s, 3H); .sup.13 C NMR (CDCl.sub.3): 208.9, 164.9, 141.2, 137.2, 129.0, 128.5, 127.4, 126.7, 115.4, 113.9, 35.9, 21.5.
Elemental Analysis C.sub.14 H.sub.13 N.sub.3 S Calc.: % C, 65.9; % H, 5.13; % N, 16.5; % S, 12.6 Found: % C, 65.8; % H, 5.43; % N, 16.5; % S, 12.3
7. Preparation of 2-Chlorosulfonyl-5,7-dimethyl�1,2,4!triazolo�1,5-a!pyridine
2-Benzylthio-5,7-dimethyl�1,2,4!triazolo�1,5-a!pyridine (3.3 g, 0.012 mol) was mixed with dichloromethane 50 mL) and water (50 mL) with good stirring. Chlorine (4.7 g, 0.066 mol) was added slowly at 3.degree.-6.degree. C. and the mixture allowed to react for another half hour. The organic layer was separated, dried over a mixture of magnesium and sodium sulfates, and concentrated by evaporation under reduced pressure. The residue was triturated with hexane and the resulting solids were recovered by filtration to obtain 2.7 g of the title compound as a white powder melting at 125.degree.-126.degree. C.
.sup.1 H NMR (CDCl.sub.3): 7.52 (s, 1H), 6.96 (s, 1H), 2.81 (s, 1H), 2.52 (s, 1H).
2-Chlorosulfonyl-7-methyl�1,2,4!triazolo�1,5-a!pyridine was prepared by the same procedure. An 86 percent of theory yield of this material was obtained as a pale yellow powder melting at 142.degree.-144.degree. C.
.sup.1 H NMR (CDCl.sub.3): 8.57 (d, 1H, J=3.7), 7.66 (s, 1H), 7.14 (d, 1H, J=3.7), 2.57 (s, 3H).
2-Chlorosulfonyl-5-chloro-7-methyl�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. A 91 percent of theory yield of this material was obtained as a pale yellow powder melting at 130.degree.-132.degree. C.
.sup.1 H NMR (CDCl.sub.3): 7.62 (s, 1H), 7.25 (s, 1H), 2.57 (s, 3H). 2-Chlorosulfonyl-5,7-dichloro�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. A 100 percent yield this compound was obtained as a pale yellow solid melting at 164.degree.-166.degree. C.
Elemental Analysis C.sub.6 H.sub.2 Cl.sub.2 N.sub.3 O.sub.2 S Calc.: % C, 25.2; % H, 0.70; % N, 14.7; % S, 11.2 Found: % C, 25.2; % H, 0.65; % N, 14.4; % S, 10.9
2-Chlorosulfonyl-5-chloro�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. An 80 percent yield of this compound was obtained as a brownish powder melting at 102.degree.-103.degree. C.
2-Chlorosulfonyl-5-bromo-1,2,4-triazolo�1,5-a!pyridine was prepared similarly. An 89 percent yield of this compound was obtained as a brown powder melting at 96.degree.-97.degree. C.
6-Bromo-2-chlorosulfonyl-8-methoxy�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. An 85 percent yield of this compound was obtained as a yellow solid.
.sup.1 H NMR (CDCl.sub.3): 8.47 (s, 1H), 7.11 (s, 1H), 4.13 (s, 3H).
6-Chloro-2-chlorosulfonyl-8-methoxy�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. An 84 percent yield of this compound was obtained as an orange gum.
.sup.1 H NMR (CDCl.sub.3): 8.38 (d, 1H, J=1.8), 7.00 (d, 1H, J=1.8), 4.13 (s, 3H).
8-Chloro-2-chlorosulfonyl-5-methoxy�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. A 96 percent yield of this compound was obtained as a tan powder melting at 147.degree.-149.degree. C.
8-Bromo-2-chlorosulfonyl-5-methoxy�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. A 90 percent yield of this compound was obtained as a tan powder melting at 120.degree.-122.degree. C. with decomposition.
7-Bromo-2-chlorosulfonyl-5-methoxy�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. A 95 percent yield of this compound was obtained as a tan powder melting at 113.degree.-115.degree. C.
8-Chloro-2-chlorosulfonyl�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. An 84 percent yield of this compound was obtained as a pale yellow powder melting at 129.degree.-131.degree. C.
8. Preparation of 1,2-Diamino-4-methylpyridinium mesitylate
Ethyl O-mesitylenesulfonylacetohydroxamate (53.4 g, 0.191 mol) was dissolved in dioxane (300 mL) and cooled below 10.degree. C. Perchloric acid (24.5 mL of 70 percent, 0.286 mol) was added dropwise with stirring. After 2 hours the solution was diluted with ice water and filtered to recover the solids. The damp solids were mixed with chloroform (300 mL) and the organic solution obtained was recovered and added to 2-amino-4-methylpyridine (19.6 g, 0.181 mol) in chloroform (300 mL) at 5.degree.-10.degree. C. The solution was warmed to room temperature for an hour. The solvent was then removed by evaporation under reduced pressure and the residue obtained was triturated with ether and then dichloromethane. The solids obtained were recovered by filtration to obtain 42.7 g (73 percent of theory) of the title compound as a white powder melting at 133.degree.-136.degree. C.
.sup.1 H NMR (DMSO-d.sub.6): 8.15 (s, 2H), 7.88 (d, 1H, J=3.4), 6.61-6.83 (m, 6H), 2.49 (s, 6H), 2.26 (s, 3H), 2.16 (s, 3H).
9. Preparation of 1-((1-Imidazolylthionyl)amino)-2-imino-4-methylpyridine
1,2-Diamino-4-methylpyridinium mesitylate (1.0 g, 0.0031 mol) and 1,1'-thiocarbonyldiimidazole (0.6 g, 0.0031 mol) were mixed in chloroform (25 mL) at room temperature. After a few hours the yellow color was gone and more 1,1'-thiocarbonyldiimidazole (0.6 g, 0.0031 mol) was added and the mixture was shirred overnight. The volatiles were removed by evaporation under reduced pressure and the residue obtained was triturated with ether. The resulting solids were purified by medium pressure liquid chromatography on silica gel eluting initially with 2 percent methanol in dichloromethane and gradually changing to 5 percent methanol in dichloromethane. The solvent was removed by evaporation under reduced pressure and the residue obtained was mixed with ether. The resulting solids were recovered by filtration to obtain 0.25 g (35 percent of theory) of the title compound as an off-white powder melting at 176.degree.-177.degree. C.
.sup.1 H NMR (DMSO-d.sub.6): 8.46 (s, 1H), 7.87 (s, 1H), 7.74 (d, 1H, J=3.4), 7.58 (broad s, 2H), 6.92 (s, 1H), 6.80 (s, 1H), 6.68 (dd, 1H, J=1.0, 3.4), 2.34 (s, 3H).
Elemental Analysis C.sub.10 H.sub.11 N.sub.5 S Calc.: % C, 51.5; % H, 4.75; % N, 30.0; % S, 13.7 Found: % C, 51.4; % H, 4.85; % N, 30.2; % S, 13.7
1-((1-Imidazolylthionyl)amino)-2-imino-3,5-dibromopyridine was prepared in the same manner. The product was obtained in 96 percent yield as a pale yellow solid melting at 185.degree.-186.degree. C.
.sup.1 H NMR (DMSO-d.sub.6): 8.51 (d, 1H, J=1.8), 8.46 (s, 1H), 8.41 (d, 1H, J=2.1), 8.13 (brs, 2H), 7.86 (s, 1H), 6.93 (s, 1H).
1-((1-Imidazolylthionyl)amino)-2-imino-3,5-dichloropyridine was prepared in the same manner. The produce was obtained in 86 percent yield as a pale yellow solid melting at 176.degree.-178.degree. C.
Elemental Analysis C.sub.9 H.sub.7 N.sub.5 Cl.sub.2 S Calc.: % C, 37.5; % H, 2.45; % N, 24.3; % S, 11.1 Found: % C, 37.7; % H, 2.50; % N, 24.0; % S, 11.2
.sup.1 H NMR (DMSO-d.sub.6): 8.48 (s, 1H), 8.39 (s, 1H), 8.38 (s, 1H), 8.29 (brs, 2H), 7.89 (s, 1H), 6.95 (s, 1H); .sup.13 C NMR (DMSO-d.sub.6): 181.1, 147.7, 138.7, 138.0, 136.4, 128.0, 120.5, 118.4, 117.8, 115.7.
10. Preparation of N-(2,6-Dichlorophenyl)-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamid
2-Chlorosulfonyl-7-methyl�1,2,4!triazolo�1,5-a!pyridine (1.2 g, 0.0052 mol), 2,6-dichloroaniline (1.7 g, 0.010 mol) and pyridine (0.40 g, 0.0052 mol) were dissolved in anhydrous acetonitrile (20 mL). Dimethyl sulfoxide (60 .mu.L, 0.0008 mol) was added with stirring. The reaction was allowed to stir overnight. The volatiles were removed by evaporation under reduced pressure and the residue obtained was taken up in dichloromethane. The resulting mixture was washed well with dilute aqueous hydrochloric acid and the organic solution phase was recovered and concentrated by evaporation under reduced pressure. The resulting residue was triturated with hexane and the solids that formed were recovered by filtration and dried to obtain 0.7 g (38 percent of theory) of the title compound as a tan powder melting at 232.degree.-234.degree. C.
Elemental Analysis C.sub.13 H.sub.10 Cl.sub.2 N.sub.4 O.sub.2 S Calc.: % C, 43.7; % H, 2.82; % N, 15.7; % S, 8.98 Found: % C, 44.0; % H, 2.87; % N, 15.5; % S, 9.15.
.sup.1 H NMR (DMSO-d.sub.6): 10.80 (s, 1H), 8.91 (d, 1H, J=3.5), 7.42 (s, 1H), 7.19-7.50 (m, 4H), 2.47 (s, 3H).
11. Preparation of 4-Methylglutaconic Anhydride
The procedure found in J. Am. Chem. Soc., 75, 2377-9 (1953) was generally followed. Ethyl isodehydroacetate acetate (100 g, 0.51 mol) was added to a warm solution of sodium hydroxide (68.5 g., 0.71 mol) in water (500 mL) and stirred for an hour until the mixture became clear. The solution was acidified with concentrated hydrochloric acid (200 mL) and was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was mixed with acetic anhydride (250 mL) and the resulting mixture was heated at reflux for 20-30 min. The solvent was removed by evaporation under reduced pressure and the residue obtained was crystallized from ether to obtain 60.8 g (94 percent of theory) of the title compound as a tan powder melting at 70.degree.-72.degree. C.
.sup.1 H NMR (CDCl.sub.3): 6.01 (s, 1H), 3.41 (s, 2H), 2.04 (s, 3H).
The reaction works equally with methyl rather than ethyl isodehydroacetate. Acetyl chloride can be used instead of acetic anhydride, but acetic anhydride typically gave better results.
12. Preparation of 2-Benzylthio-5-hydroxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine
A mixture of thiosemicarbazide (50.0 g, 0.554 mol) and benzyl chloride (67.1 g, 0.53 mol) in 2-propanol (1 L) was heated to reflux with stirring for 2 hours. The reaction mixture was then cooled and 4-methylglutaconic anhydride (60.8 g, 0.482 mol) and triethylamine (75 mL, 53.6 g, 0.53 mol) were added. The reaction mixture was again heated at reflux with stirring for an hour. Sodium methoxide in methanol solution (250 mL of 25 percent, 1.09 mol) was then added and the yellow-brown mixture obtained was heated at reflux with stirring for 2.5 hours. The volatiles were removed by evaporation under reduced pressure and the residue obtained was combined with dilute aqueous acetic acid (150 mL) and ethyl acetate. The organic phase was recovered, washed well with water and concentrated by evaporation under reduced pressure. The residue obtained was heated with a heat gun under reduced pressure for 30 minutes until the bubbling had stopped and the reaction mixture had solidified. The mixture was cooled and diluted with methanol and the resulting solids were recovered by filtration to obtain 54.5 g (41 percent of theory) of the title compound as a yellow-brown powder melting at 214.degree.-216.degree. C.
Elemental Analysis C.sub.13 H.sub.11 ClN.sub.4 S Calc.: % C, 62.0; % H, 4.83; % N, 15.5; % S, 11.9 Found: % C, 61.9; % H, 4.88; % N, 15.5; % S, 11.5
13. Preparation of 2-Benzylthio-5-chloro-7-methyl�1,2,4!triazolo�1,5-a!pyridine
N,N-Dimethylaniline (21,9 g, 0.18 mol) was added slowly to a mixture of 2-benzylthio-5-hydroxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine (44.5 g, 0.164 mol) in 150 mL of phosphorus oxychloride with stirring. The mixture was heated at reflux with stirring for 20 hours. The excess phosphorus oxychloride was then removed by evaporation under reduced pressure. The residue obtained was dissolved in ethyl acetate, washed well with water and quickly concentrated by evaporation under reduced pressure to drive off the excess water. The residue was again dissolved in ethyl acetate and the resulting mixture was filtered with suction through a bed of silica gel. The filtrate was concentrated by evaporation under reduced pressure and the residue obtained was mixed with hexane. The resulting mixture was filtered to recover the solids and dried to obtain the 37.5 g. (79 percent of theory) of the title compound as a tan powder melting at 108.degree.-110.degree. C.
Elemental Analysis C.sub.14 H.sub.12 ClN.sub.3 S Calc.: % C, 58.0; % H, 4.17; % N, 14.5; % S, 11.1 Found: % C, 58.4; % H, 3.93; % N, 14.6; % S, 11.0
.sup.1 H NMR (CDCl.sub.3): 7.20-7.52 (m, 6H), 6.86 (s, 1H), 4.51 (s, 2H), 2.44 (s, 3H); .sup.13 C NMR (CDCl.sub.3): 165.4, 152.5, 141.7, 131.2, 129.1, 128.4, 128.1, 127.3, 115.2, 112.2, 35.8, 21.4.
14. Preparation of 2-Benzylthio-5-methoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine
A mixture of 2-benzylthio-5-chloro-7-methyl�1,2,4!triazolo�1,5-a!pyridine (5.0 g, 0.017 mol), sodium methoxide in methanol (16 mL of 25 percent, 3.7 g, 0.070 mol) and methanol (100 mL) were heated at reflux with stirring for 4 hours. The reaction mixture was then cooled, acidified with acetic acid (10 mL), and concentrated by evaporation under reduced pressure. The residue obtained was dissolved in dichloromethane and the resulting solution was washed well with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue obtained was mixed with hexane and filtered to recover the solids. The solids were dried to obtain 4.7 g (97 percent of theory) of the title compound as a tan powder melting an 85.degree.-87.degree. C.
.sup.1 H NMR (CDCl.sub.3): 7.24-7.46 (m, 5H), 7.02 (s, 1H), 6.06 (s, 1H), 4.51 (s, 2H), 4.10 (s, 3H), 2.43 (s, 3H).
Elemental Analysis C.sub.15 H.sub.15 N.sub.3 OS Calc.: % C, 63.1; % H, 5.30; % N, 14.7; % S, 11.2 Found: % C, 62.9; % H, 5.12; % N, 14.7; % S, 11.3
15. Preparation of N-(2,6-Dichlorophenyl)-5-chloro-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide
The title compound was prepared from 2-chlorosulfonyl-5-chloro-7-methyl�1,2,4!triazolo�1,5-a!pyridine using the procedure of Example 10. The white solid compound, which was obtained in 62 percent yield, had a melting point of 257.degree.-258.degree. C.
Elemental Analysis C.sub.13 H.sub.9 C.sub.13 N.sub.4 O.sub.2 S Calc.: % C, 39.9; % H, 2.32; % N, 14.3; % S, 8.19 Found: % C, 39.8; % H, 2.35; % N, 14.3; % S, 8.03
.sup.1 H NMR (DMSO-d.sub.6): 10.80 (s, 1H), 7.81 (s, 1H), 7.60 (s, 1H), 7.03-7.48 (m, 3H), 2.48 (s, 3H).
16. Preparation of N-(2,6-Dichlorophenyl)-5-methoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide
N-(2,6-Dichlorophenyl)-5-chloro-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide (3.0 g, 0.0077 mol) and 25 percent sodium methoxide in methanol (12 mL, 2.8 g, 0.050 mol) were combined in methanol (100 mL) and heated to reflux with stirring for 2 hours. The reaction mixture was cooled and acidified with acetic acid and the volatiles were removed by evaporation under reduced pressure. The residue obtained was diluted with dichloromethane and the mixture was washed with water. The organic solution phase was filtered and the filtrate was concentrated by evaporation under reduced pressure. The residue obtained was mixed with ether and filtered to recover the solids. The solids were dried to obtain 2.6 g (87 percent of theory) of the title compound as a white powder melting at 269.degree.-270.degree. C.(d).
Elemental Analysis C.sub.14 H.sub.12 Cl.sub.2 N.sub.4 O.sub.3 S Calc.: % C, 43.4; % H, 3.13; % N, 14.5; % S, 8.27 Found: % C, 43.3; % H, 3.13; % N, 14.4; % S, 8.18
.sup.1 H NMR (DMSO-d.sub.6): 10.79 (s, 1H), 7.28-7.50 (m, 4H), 6.72 (s, 1H), 4.12 (s, 3H), 2.47 (s, 3H).
N-(2,6-Difluorophenyl)-5-methoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide was prepared by the same procedure from N-(2,6-difluorophenyl)-5-chloro-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide. The product was obtained as a light tan powder melting at 248.degree.-249.degree. C.
Elemental Analysis C.sub.14 H.sub.12 F.sub.2 N.sub.4 O.sub.3 S Calc.: % C, 47.6; % H, 3.41; % N, 15.8; % S, 9.05 Found: % C, 47.4; % H, 3.48; % N, 15.8; % S, 9.05
.sup.1 H NMR (DMSO-d.sub.6): 10.66 (s, 1H), 7.02-7.46 (m, 4H), 6.73 (s, 1H), 4.12 (s, 3H), 2.47 (s, 3H).
17. Preparation of 2-Hydrazino-3-nitropyridine
2-Chloro-3-nitropyridine (100 g, 0.63 mol), hydrazine monohydrate (70.4 mL, 72.6 g, 1.45 mol) and methanol (1.3 L) were mixed and heated to reflux with stirring. After 30 min the reaction mixture was cooled and filtered collecting the insoluble materials. The filtrate was concentrated by evaporation under reduced pressure and the residue obtained as well as the insoluble materials from the filtration were diluted with water. The insoluble solids present were collected by filtration, washed with water, and dried to obtain 95.2 g (98 percent of theory) of the title compound as a bright yellow powder melting at 168.degree.-169.degree. C.
Elemental Analysis C.sub.5 H.sub.6 N.sub.4 O.sub.2 Calc.: % C, 39.0; % H, 3.90; % N, 36.4; % S, 8.27 Found: % C, 39.1; % H, 4.17; % N, 36.1; % S, 8.18
18. Preparation of 2-Benzylthio-8-nitro�1,2,4!triazolo�1,5-a!pyridine
2-Hydrazino-3-nitropyridine (95.2 g, 0.618 mol) was combined with acetonitrile (1 L) and carbon disulfide (114 mL, 143.9 g, 1.89 mol) was added. The resulting mixture was stirred for 1.5 hours. Hydrogen peroxide (78.6 mL of 30 percent aqueous solution, 23.6 g, 0.693 mol) was added dropwise over a 20-min period with cooling at 15.degree.-20.degree. C. The mixture was stirred for another 2 hours and was then cooled in an ice bath. Benzyl chloride (91.7 g, 0.72 mol) was added and then triethylamine (110 mL, 79.6 g, 0.79 mol) was added slowly with stirring over a 2-hour period. The reaction was exothermic. The mixture was stirred at room temperature over the weekend. The volatiles were removed by evaporation under reduced pressure and the residue obtained was diluted with dichloromethane and water. The resulting mixture was filtered through Celite.RTM. to remove the precipitated sulfur. The organic phase of the filtrate was recovered, washed with water, and concentrated by evaporation under reduced pressure. The solid residue obtained was diluted with hexane, recovered by filtration, and dried to obtain 174.0 g (98 percent of theory) of the title compound as a brown powder melting at 125.degree.-126.degree. C.(d).
Elemental Analysis C.sub.13 H.sub.10 N.sub.4 O.sub.2 S Calc.: % C, 54.5; % H, 3.52; % N, 19.6; % S, 11.2 Found: % C, 54.8; % H, 3.64; % N, 19.7; % S, 11.3
19. Preparation of 8-Amino-2-benzylthio�1,2,4!triazolo�1,5-a!pyridine
2-Benzylthio-8-nitro�1,2,4!triazolo�1,5-a!pyridine (174.0 g, 0.61 mol), iron filings (204.2 g., 3.65 mol) and acetic acid (2 L) were combined and heated with stirring at 70.degree.-80.degree. C. for 6 hours. The reaction mixture was cooled and diluted with water and dichloromethane. The resulting mixture was filtered through Celite.RTM., the liquid phases in the filtrate were separated, and the aqueous layer was extracted with a little more dichloromethane. The organic phase and extract were combined and washed several times with water and then with dilute aqueous sodium hydroxide. The resulting organic solution was concentrated by evaporation under reduced pressure and the residue obtained was mixed with ether. The insoluble solids were collected by filtration and dried to obtain 106.3 g of the title compound as a brown powder melting at 116.degree.-117.degree. C. An additional 14.2 g of lower purity product was isolated from the ether filtrate (77 percent of theory total yield). This reduction was also carried out with iron powder and calcium chloride in aqueous ethanol and with stannous chloride in hydrochloric acid.
20. Preparation of 8-Amino-2-benzylthio-5,7-dichloro�1,2,4!triazolo�1,5-a!pyridine
8-Amino-2-benzylthio�1,2,4!triazolo�1,5-a!pyridine (20.0 g, 0.078 mol), N-chlorosuccinimide (10.4 g, 0.078 mol) and carbon tetrachloride were combined and heated to reflux with stirring for 1 hour. The reaction mixture was cooled, more N-chlorosuccinimide (10.4 g) was added, and the reaction heated to reflux with stirring for another hour. The reaction mixture was then cooled and filtered. The filtrate was concentrated by evaporation under reduced pressure and the residue obtained was purified by column chromatography on silica gel eluting with dichloromethane. The product fractions were concentrated by evaporation under reduced pressure and the residues were combined and mixed with ether. The insoluble solids were collected by filtration and dried to obtain 18.0 g (71 percent of theory) of the title compound as a light tan powder melting at 118.degree.-119.degree. C.
21. Preparation of 2-Benzylthio-5,7-dichloro�1,2,4!triazolo�1,5-a!pyridine
8-Amino-2-benzylthio-5,7-dichloro�1,2,4!triazolo�1,5-a!pyridine (25.8 g, 0.079 mol), t-butyl nitrite (18.9 mL, 16.4 g, 0.158 mol) and tetrahydrofuran (1.5 L) were combined and heated at reflux with stirring. Gas evolution began immediately and stopped after a few minutes, but the reaction was heated at reflux for an hour. The volatiles were removed by evaporation under reduced pressure and the residue obtained was chromatographed on silica gel eluting with dichloromethane. The product fractions were concentrated by evaporation under reduced pressure and the residue obtained was mixed with ether. The insoluble solid material was collected by filtration. The ether filtrate was concentrated by evaporation under reduced pressure and the residue was rechromatographed on silica gel eluting with 10 percent ethyl acetate in hexane. The product fractions were concentrated by evaporation under reduced pressure and the residue obtained was combined with the insoluble solid material obtained before to obtain 12.2 g (50 percent of theory) of the title compound as a red-brown powder melting at 88.degree.-89.degree. C.
Elemental Analysis C.sub.13 H.sub.9 Cl.sub.2 N.sub.3 S Calc: % C, 50.3; % H, 2.92; % N, 13.6; % S, 10.3 Found: % C, 50.1; % H, 2.92; % N, 13.6; % S, 10.2
2-Benzylthio-5,7-dibromo�1,2,4!triazolo�1,5-a!pyridine was prepared similarly from 8-amino-2-benzylthio-5,7-dibromo�1,2,4!triazolo�1,5-a!pyridine. A 32 percent yield of this compound was obtained as a light tan powder melting at 113.degree.-114.degree. C.
22. Preparation of N-(2,6-Dichlorophenyl)-5-methoxy-7-chloro�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide
Sodium methoxide in methanol (1.1 mL of 25 percent solution, 0.26 g, 0.005 mol) was added to a solution of N-(2,6-dichlorophenyl)-5,7-dichloro�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide (0.9 g, 0.02 mol) in dimethyl sulfoxide (30 mL) at ambient temperature with stirring. The reaction was complete in a few minutes, but was stirred for 30 min. The mixture was then acidified with acetic acid and diluted with dichloromethane. The resulting organic phase was recovered and washed with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was mixed with hexane and the insoluble solids were collected by filtration and dried to obtain 0.8 g (90 percent of theory) of the title compound as a light tan powder melting at 232.degree.-234.degree. C.(d).
Elemental Analysis C.sub.13 H.sub.9 Cl.sub.3 N.sub.4 O.sub.3 S Calc.: % C, 38.3; % H, 2.22; % N, 13.7; % S, 7.87 Found: % C, 38.3; % H, 2.12; % N, 13.7; % S, 7.63
23. Preparation of N-(2,6-Dichlorophenyl)-5,7-dimethoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide
Sodium methoxide in methanol (3.0 mL of 25 percent solution, 0.71 g, 0.013 mol) was added to a solution of N-(2,6-dichlorophenyl)-5-methoxy-7-chloro�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide (0.66 g, 0.0016 mol) in dimethyl sulfoxide (30 mL) with stirring over several hours. The mixture was allowed to react and was then acidified with acetic acid and diluted with dichloromethane. The resulting organic phase was recovered and washed with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel starting with 0.5 percent acetic acid in dichloromethane and gradually increasing the strength to 0.5 percent acetic acid plus 1.0 percent ethanol in dichloromethane. The product fractions were concentrated by evaporation under reduced pressure to obtain 118 mg (13 percent of theory) of the title compound as a pale yellow powder melting at 252.degree.-253.degree. C.(d).
Elemental Analysis C.sub.14 H.sub.12 Cl.sub.2 N.sub.4 O.sub.4 S Calc.: % C, 41.7; % H, 3.00; % N, 13.9; % S, 7.95 Found: % C, 41.8; % H, 2.67; % N, 13.6; % S, 8.00
24. Preparation of N-(2-fluoro-5-methyl-3-pyridinyl)-5-methoxy-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide
To a solution of 0.70 g (1.9 mmol) of N-(2-fluoro-5-methyl-3-pyridinyl)-5-chloro-7-methyl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide in 25 mL of dry dimethyl sulfoxide was added with stirring 1.0 mL (4.6 mmol) of sodium methoxide as a 25 percent solution in methanol. After 3 min, 3 mL of acetic acid was added and the solution was diluted with 600 mL of dichloromethane. The resulting solution was washed with water (5.times.100 mL), dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 0.5 g (71 percent of theory) of the title compound as a white solid melting at 262.degree.-264.degree. C. with decomposition.
Elemental Analysis C.sub.13 H.sub.11 ClFN.sub.5 O.sub.3 S Calc.: % C, 42.0; % H, 2.98; % N, 18.8; % S, 8.62 Found: % C, 41.9; % H, 2.93; % N, 18.8; % S, 8.47
.sup.1 H NMR (DMSO-d.sub.6): 10.7 (br, 1H), 8.1 dd, 1H), 8.05 (dd, 1H), 7.4 (s, 1H), 6.8 (s, 1H), 4.1 (s, 1H), 2.5 (s, 3H).
25. Preparation of 8-Amino-2-benzylthio-5-chloro�1,2,4!triazolo�1,5-a!pyridine
A solution of 8-amino-2-benzylthio�1,2,4!triazolo�1,5-a!pyridine (14.0 g, 0.0546 mol) and 1,3-dichloro-5,5-dimethylhydantoin (5.4 g, 0.0273 mol) were combined in 500 mL of dichloromethane and the mixture was heated at reflux with stirring for two hours. Additional 1,3-dichloro-5,5-dimethylhydantoin (5.0 g, 0.025 mol) was added and the reaction was heated with stirring for an additional hour. The reaction mixture was cooled and dilute aqueous sodium bisulfite was added with stirring and allowed to react for an hour. The mixture was then washed with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel eluting with dichloromethane to obtain 6.0 g (38 percent of theory) of the title compound as a light tan powder melting at 113.degree.-114.degree. C.
Elemental Analysis C.sub.13 H.sub.11 ClN.sub.4 S Calc.: % C, 53.7; % H, 3.81; % N, 19.3; % S, 11.0 Found: % C, 53.9; % H, 3.84; % N, 19.5; % S, 11.0
26. Preparation of 2-Benzylthio-5-chloro�1,2,4!triazolo�1,5-a!pyridine
A solution of 8-amino-2-benzylthio-5-chloro�1,2,4!triazolo�1,5-a!pyridine (9.0 g, 0.031 mol) and acetic acid (2.0 g, 0.033 mol) in tetrahydrofuran (100 mL) was added dropwise with stirring over 30 min to a solution of t-butyl nitrite (6.4 g, 0.062 mol) in tetrahydrofuran (500 mL) at 50.degree.-55.degree. C. and allowed to react another 15 minutes after the addition was complete. The volatiles were removed by evaporation under reduced pressure and the residue obtained was chromatographed on silica gel eluting with a gradient of 5-15 percent ethyl acetate in hexane. The product fractions were concentrated by evaporation under reduced pressure to obtain 3.4 g (37 percent of theory) the title compound as a dark low-melting solid.
27. Preparation of 8-Amino-2-benzylthio-5-bromo�1,2,4!triazolo�1,5-a!pyridine
8-Amino-2-benzylthio�1,2,4!triazolo�1,5-a!pyridine (25.6 g, 0.1 mol), N-bromosuccinimide (17.8 g, 0.1 mol) and 2 L of dichloromethane were combined with stirring for an hour. The solution was washed with dilute aqueous sodium bisulfite and then with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 25 percent ethyl acetate in hexane. The product fractions were concentrated by evaporation under reduced pressure and the solid residue obtained was extracted with ether and dried to obtain 17.5 g (52 percent of theory) of the title compound as a light tan powder melting at 125.degree.-126.degree. C.
Elemental Analysis C.sub.13 H.sub.11 BrN.sub.4 S Calc.: % C, 46.6; % H, 3.31; % N, 16.7; % S, 9.56 Found: % C, 46.7; % H, 3.34; % N, 17.0; % S, 9.56
28. Preparation of 8-Amino-2-benzylthio-5-chloro�1,2,4!triazolo�1,5-a!pyridine by Reduction
A mixture of 1.0 g (3.5 mmol) of 2-benzylthio-8-nitro�1,2,4!triazolo�1,5-a!pyridine, 1.35 g (3.85 mmol) of stannic chloride pentahydrate, and 10 mL of concentrated hydrochloric acid was prepared and heated to 90.degree. C. with stirring. A solution of 1.99 g (10.5 mmol) of stannous chloride in 10 mL of concentrated aqueous hydrochloric acid was added slowly over a 1-hour period. After a short reaction period the mixture was allowed to cool and the solids present were collected by filtration. The collected solids were placed in water and the mixture was basified with dilute aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane and the organic extract was concentrated by evaporation under reduced pressure to obtain 0.60 g (66 percent of theory) of product as a brown solid. This solid was found to be 93 percent the title compound and 7 percent 8-amino-2-benzylthio�1,2,4!triazolo�1,5-a!pyridine by high pressure liquid chromatography. The pure compound melts at 113.degree.-114.degree. C.
29. Preparation of 8-Amino-2-benzylthio-5-ethoxy�1,2,4!triazolo�1,5-a!pyridine by Reduction
2-Benzylthio-8-nitro�1,2,4!triazolo�1,5-a!pyridine (5.0 g, 0.017 mol) and stannic chloride petrahydrate (7.3 g, 0.021 mol) were mixed with 100 mL of ethanol and the mixture was heated to reflux with stirring. A solution of stannous chloride (13.2 g, 0.07 mol) in 100 mL of ethanol was added dropwise with stirring over 45 minutes and the heating was continued another 20 minutes after the addition was complete. The reaction mixture was diluted with dichloromethane. The resulting mixture was washed well with 2N aqueous hydrochloric acid and was then concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel eluting first with 5 percent ethyl acetate in dichloromethane and gradually increasing to 20 percent ethyl acetate in dichloromethane. The product fractions were concentrated by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed well with 2N aqueous sodium hydroxide, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was mixed with hexane and the insoluble solids were recovered by filtration and dried to obtain 1.7 g (33 percent of theory) of the title compound as a dark tan powder melting at 106.degree.-107.degree. C.
Elemental Analysis C.sub.15 H.sub.16 N.sub.4 OS Calc.: % C, 60.0; % H, 5.37; % N, 18.7; % S, 10.7 Found: % C, 59.8; % H, 5.49; % N, 18.8; % S, 10.5
30. Preparation of 1,2-Diamino-3,5-dichloropyridinium Mesitylate
2-Amino-3,5-dichloropyridine (9.48 g, 58.1 mmol) was dissolved in chloroform (100 mL) in a round bottom flask and the mixture was cooled to 5.degree. C. in an ice bath. To this mixture was added dropwise with stirring a freshly prepared solution of O-mesitylenesulfonylhydoxylamine (15.5 g, 69.8 mmol) in chloroform. (warning; this compound is an explosive solid). A thick white precipitate began to form after 15 min. The mixture was allowed to warm to room temperature while stirring overnight. The solids present were recovered by filtration, washed with chloroform (3.times.100 mL), and dried to obtain 17.5 g (80 percent of theory) of the title compound as a white crystalline solid melting at 231.degree.-232.degree. C.
Infrared Analysis (KBr): 3407, 3203, 3025, 2936, 1656, 1369, 1182, 1086, 1014, 679, 600, 548 cm.sup.-1 ;
.sup.1 H NMR (DMSO-d.sub.6): 8.81 (s, 2H), 8.42 (s, 2H), 7.01 (s, 2H), 6.73 (s, 2H), 2.50 (s, >6H), 2.16 (s, 3H).
1,2-Diamino-3,5-dibromopyridinium mesitylate was prepared similarly and was obtained in 92 percent yield as an off-white solid melting at 212.degree.-213.degree. C.
.sup.1 H NMR (DMSO-d.sub.6): 8.67 (brs, 2H), 8.58 (d, 1H, J=2.1), 8.47 (d, 1H, J=2.1), 6.99 (s, 2H), 6.74 (s, 2H), 2.49 (s, >6H), 2.17 (s, 3H).
Elemental Analysis C.sub.14 H.sub.17 Br.sub.2 N.sub.3 O.sub.3 S Calc.: % C, 36.1; % H, 3.68; % N, 9.01; % S, 6.88 Found: % C, 35.9; % H, 3.98; % N, 8.89; % S, 6.86
31. Preparation of 2-Benzylthio-6,8-dichloro�1,2,4!triazolo�1,5-a!pyridine
1-((1-Imidazolylthionyl)amino)-2-imino-3,5-dichloropyridine (1.0 g, 3.5 mmol) was combined with n-butanol (10 mL) in a round bottom flask and heated to 100.degree. C. with stirring. Benzyl chloride (0.48 mL, 4.2 mmol) was added and the mixture was heated at reflux with stirring for 1.5 hour. The volatiles were then removed by evaporation under reduced pressure and the solid residue obtained was triturated with hexane (20 mL), water (20 mL), and hexane (20 mL). The resulting solid was washed with hexane on a filter and dried to obtain 0.80 g (74 percent of theory) of the title compound as a pale yellow solid melting at 115.degree.-116.degree. C.
Elemental Analysis C.sub.13 H.sub.9 N.sub.3 Cl.sub.2 S Calc.: % C, 50.3; % H, 2.92; % N, 13.6; % S, 10.3 Found: % C, 49.4; % H, 2.32; % N, 13.8; % S, 10.1
.sup.1 H NMR (DMSO-d.sub.6): 9.28 (s, 1H), 8.08 (s, 1H), 7.46 (d, 2H, J=7.2), 7.27-7.31 (m, 3H), 4.50 (s, 2H); .sup.13 C NMR (DMSO-d.sub.6): 164.9, 148.2, 137.2, 130.5, 128.9, 128.5, 127.4, 126.5, 119.7, 119.4, 34.7.
2-Benzylthio-6,8-dibromo�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. The product was obtained in 84 percent yield as a pale yellow solid melting at 122.degree.-124.degree. C.
Elemental Analysis C.sub.13 H.sub.9 N.sub.3 Br.sub.2 S Calc.: % C, 39.1; % H, 2.27; % N, 10.5; % S, 8.03 Found: % C, 38.8; % H, 2.34; % N, 10.6; % S, 8.17
.sup.1 H NMR (DMSO-d.sub.6): 9.34 (d, 1H, J=1.8), 8.23 (d, 1H, J=1.5), 7.47 (d, 2H, J=6.9), 7.25-7.33 (m, 3H), 4.49 (s, 2H).
32. Preparation of 2-Benzylthio-6-bromo-8-methoxy�1,2,4!triazolo�1,5-a!pyridine
2-Benzylthio-6,8-dibromo�1,2,4!triazolo�1,5-a!pyridine (9.5 g, 23.8 mmol) was mixed with acetonitrile (50 mL) in a round bottom flask. Sodium methoxide (13.1 mL of 25 percent solution in methanol, 57.1 mmol) was added and the mixture was heated at reflux for 2 hours. Glacial acetic acid (10 mL) was added and the entire reaction mixture was poured into a mixture of ice and water (300 mL). The brown precipitate that formed was recovered by filtration and dried. This was chromatographed on silica gel eluting with a 1:1 mixture of ethyl acetate and hexane. Product-containing fractions were combined and concentrated under reduced pressure to obtain 6.58 g (80 percent of theory) of the title compound as a pale yellow solid.
Elemental Analysis C.sub.14 H.sub.12 N.sub.3 BrSO Calc.: % C, 48.0; % H, 3.45; % N, 12.0; % S, 9.75 Found: % C, 47.8; % H, 3.36; % N, 11.9; % S, 9.22
.sup.1 H NMR (DMSO-d.sub.6): 8.85 (d, 1H, J=1.5), 7.42 (d, 2H, J=7.5), 7.23-7.31 (m, 4H), 4.46 (s, 2H), 3.97 (s, 3H).
2-Benzylthio-6-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. The product was obtained in 87 percent yield as a tan solid melting at 125.degree.-126.degree. C.
.sup.1 H NMR (DMSO-d.sub.6): 8.84 (d, 1H, J=1.5), 7.46 (d, 2H, J=6.9), 7.26-7.36 (m, 2H), 7.24 (d, 1H, J=1.5), 4.50 (s, 2H) , 4.02 (s, 3H).
2-Benzylthio-6-chloro-8-ethoxy�1,2,4!triazolo�1,5-a!pyridine was prepared similarly. The product was obtained in 100 percent yield as a pale orange oil.
.sup.1 H NMR (DMSO-d.sub.6): 8.83 (d, 1H, J=1.2), 7.45 (d, 2H, J=7.2), 7.26-7.34 (m, 3H), 7.22 (d, 9H, J=1.2), 1H), 4.49 (s, 2H), 4.28 (q, 2H, J=7.2), 1.41 (t, 3H, J=6.9).
33. Preparation of 6-Bromo-5-chloro-2-chlorosulfonyl-8-methoxy�1,2,4!triazolo�1,5-a!pyridine
2-Benzylthio-6-bromo-8-methoxy�1,2,4!triazolo�1,5-a!pyridine (2.0 g, 5.7 mmol) was dissolved in dichloromethane (30 mL) in a three-necked flask equipped with high-speed stirrer and a dry ice condenser and was cooled in an ice bath to 5.degree. C. Aqueous hydrochloric acid (2N, 30 mL, 60 mmol) and then sodium hypochlorite (5 percent aqueous solution, 50 mL, 34 mmol) were added with stirring. The mixture was allowed to react for 2 hours. The layers were then separated and the aqueous layer was washed with dichloromethane (2.times.10 mL). The dichloromethane layer and wash were combined, washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), and concentrated by evaporation under reduced pressure to obtain a gum. This was triturated with hexane to obtain 1.94 g (97 percent of theory) of the title compound as a yellow gum.
.sup.1 H NMR (CDCl.sub.3): 7.14 (s, 1H); 4.13 (s, 3H).
34. Preparation of 2-Benzylthio-5,8-dichloro�1,2,4!triazolo�1,5-a!pyridine
A mixture of 9.9 g (0.10 mol) of copper(I) chloride with 300 mL of acetonitrile was prepared and 8.7 mL (6.8 g, 0.066 mol) of 90 percent t-butyl nitrite was added with stirring. After 10 minutes 9.5 g (0.033 mol) of 8-amino-2-benzylthio-5-chloro�1,2,4!triazolo�1,5-a!pyridine was added and the reaction mixture was allowed to react with stirring for 3 days. The mixture was then diluted with dichloromethane and 2N aqueous hydrochloric acid, and after mixing this well, the phases were separated. The organic layer was washed with 2N aqueous hydrochloric acid and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane to obtain 6.5 g (63 percent of theory) of the title compound as a yellow powder melting at 103.degree.-104.degree. C.
Elemental Analysis C.sub.13 H.sub.9 Cl.sub.2 N.sub.3 S Calc.: % C, 50.3; % H, 2.92; % N, 13.6; % S, 10.3 Found: % C, 50.4; % H, 2.08; % N, 13.6; % S, 10.3
2-Benzylthio-8-chloro�1,2,4!triazolo�1,5-a!pyridine was prepared similarly from 8-amino-2-benzylthio�1,2,4!triazolo�1,5-a!pyridine. A 65 percent yield of this compound was obtained as a yellow powder melting at 82.degree.-83.degree. C.
Elemental Analysis C.sub.13 H.sub.10 ClN.sub.3 S Calc.: % C, 56.6; % H, 3.66; % N, 15.2; % S, 11.6 Found: % C, 56.6; % H, 3.33; % N, 15.3; % S, 11.5
35. Preparation of 2-Benzylthio-8-chloro-5-methoxy�1,2,4!triazolo�1,5-a!pyridine
2-Benzylthio-5,8-dichloro�1,2,4!triazolo�1,5-a!pyridine (6.0 g, 0.019 mol) and 25 percent sodium methoxide in methanol (26.5 mL, 6.3 g, 0.116 mol) were combined in methanol and the mixture was heated to reflux for 2 hours. The mixture was then cooled, acidified with acetic acid, and concentrated by evaporation under reduced pressure. The residue was dissolved in dichloromethane and the solution was washed with water and concentrated by evaporation under reduced pressure. The residue was triturated with hexane and the resulting solids were collected by filtration and dried to obtain 5.76 g (99 percent of theory) of the title compound as a light tan powder melting at 90.degree.-91.degree. C.
Elemental Analysis C.sub.14 H.sub.12 ClN.sub.3 OS Calc.: % C, 55.0; % H, 3.96; % N, 13.7; % S, 10.5 Found: % C, 54.9; % H, 4.02; % N, 13.4; % S, 10.7
36. Preparation of 2-Benzylthio-8-bromo-5-chloro�1,2,4!triazolo�1,5-a!pyridine
Copper(I) bromide (4.9 g., 0.0034 mol) was combined with 200 mL of acetonitrile for 15 minutes and then 3.0 mL (2.3 g, 0.0023 mol) of 90 percent t-butyl nitrite was added and the mixture was stirred for a few minutes. 8-Amino-2-benzylthio-5-chloro�1,2,4!triazolo�1,5-a!pyridine (3.3 g, 0.0013 mol) was then added and the resulting mixture was stirred for 2 days. The resulting mixture was concentrated by evaporation under reduced pressure and the residue was chromatographed on silica gel eluting with dichloromethane. After the solvent of the product fractions was removed by evaporation under reduced pressure, the residue was mixed with hexane and the solid material was recovered by filtration and dried to obtain 2.6 g (56 percent of theory) of the title compound as a yellow powder melting at 122.degree.-124.degree. C.
Elemental Analysis C.sub.13 H.sub.9 BrClN.sub.3 S Calc.: % C, 44.0; % H, 2.56; % N, 11.9; % S, 9.04 Found: % C, 43.9; % H, 2.59; % N, 11.9; % S, 8.86
37. Preparation of 2-Benzylthio-8-bromo-5-methoxy�1,2,4!triazolo�1,5-a!pyridine
2-Benzylthio-8-bromo-5-chloro�1,2,4!triazolo�1,5-a!pyridine (7.7 g, 0.0217 mol) and 25 percent sodium methoxide in methanol (19.9 mL, 4.7 g, 0.0868 mol) were mixed with 400 mL of methanol and the mixture was heated to reflux for 1.5 hours. It was then cooled and acidified with acetic acid. The volatiles were removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with water and concentrated by evaporation under reduced pressure. The resulting residue was triturated with hexane and the solids obtained were recovered by filtration and dried to obtain 7.3 g (96 percent of theory) of the title compound as a light tan powder melting at 78.degree.-79.degree. C.
Elemental Analysis C.sub.14 H.sub.12 BrN.sub.3 OS Calc.: % C, 48.0; % H, 3.45; % N, 12.0; % S, 9.16 Found: % C, 48.0; % H, 3.52; % N, 12.2; % S, 9.01
38. Preparation of N-(2,6-Difluorophenyl)-8-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide
N-(2,6-Difluorophenyl)-8-chloro�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide (0.8 g, 0.0023 mol) and 25 percent sodium methoxide in methanol (1.6 mL, 0.37 g, 0.007 mol) were combined with 20 mL of dimethyl sulfoxide and the resulting solution was stirred at ambient temperature overnight. Another 1.6 mL of 25 percent sodium methoxide in methanol was added and the reaction mixture was stirred another 3 days. The mixture was then acidified with acetic acid and diluted with dichloromethane. The resulting solution was washed well with water and concentrated by evaporation under reduced pressure. The residue, which appeared to contain considerable starting material, was dissolved in 20 mL of dimethyl sulfoxide and potassium methoxide (0.4 g, 0.0057 mol) was added with stirring at ambient temperature. After about 3 hours the mixture was acidified with acetic acid and diluted with dichloromethane. The resulting solution was washed well with water and concentrated by evaporation under reduced pressure. The residue was mixed with hexane and the solids present were collected by filtration, washed with ether and with dichloromethane and dried to obtain 0.30 g (38 percent of theory) of the title compound as a white powder melting at 254.degree.-255.degree. C.
Elemental Analysis C.sub.13 H.sub.10 F.sub.2 N.sub.4 O.sub.3 S Calc.: % C, 45.9; % H, 2.96; % N, 16.5; % S, 9.42 Found: % C, 45.9; % H, 2.55; % N, 16.4; % S, 9.34
39. Preparation of 8-Amino-2-benzylthio-5,7-dibromo�1,2,4!triazolo�1,5-a!pyridine
8-Amino-2-benzylthio�1,2,4!triazolo�1,5-a!pyridine (14.0 g, 0.055 mol) was dissolved in dichloromethane and N-bromosuccinimide (9.7 g., 0.055 mol) was added with stirring at ambient temperature. After 1 hour, another 6.0 g of N-bromosuccinimide was added. The mixture was allowed To stir overnight and was then washed well with dilute aqueous sodium bisulfite solution and with water and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with 30 percent ethyl acetate in hexane to obtain 10.0 g (44 percent of theory) of the title compound as a dark gray powder melting at 116.degree.-118.degree. C.
40. Preparation of 2-Benzylthio-7-bromo-5-methoxy�1,2,4!triazolo�1,5-a!pyridine
2-Benzylthio-5,7-dibromo�1,2,4!triazolo�1,5-a!pyridine (11.6 g, 0.029 mol) and 25 percent sodium methoxide in methanol (13.0 mL, 3.1 g, 0.057 mol) were combined with 300 mL of acetonitrile and the mixture was heated to reflux with stirring for an hour. An additional 26 mL of 25 percent sodium methoxide in methanol was then added. After a 15-min reaction period, the mixture was acidified with acetic acid and the volatiles were removed by evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with 20 percent ethyl acetate in hexane to obtain 4.97 g (49 percent of theory) of the title compound as a tan powder melting at 80.degree.-82.degree. C.
Elemental Analysis C.sub.14 H.sub.12 BrN.sub.3 OS Calc.: % C, 48.0; % H, 3.45; % N, 12.0; % S, 9.16 Found: % C, 48.2; % H, 3.42; % N, 11.9; % S, 9.24
41. Preparation of 3-Amino-2-fluoro-4-methylpyridine
To a solution of 10.1 g (65 mmol) of 2-fluoro-4-methyl-3-nitropyridine in 200 mL of ethyl acetate was added 25 g (0.40 mol) of acetic acid and 0.8 g of 5 percent palladium on carbon catalyst. This mixture was shaken under 50 psig (pounds per square inch gauge, 2400 kiloPascals) pressure of hydrogen for 18 hours, was filtered, and was concentrated by evaporation under reduced pressure to obtain an oil. This oil was partitioned between dilute aqueous sodium bicarbonate and ether. The organic phase was separated, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography to obtain 7.2 g (88 percent of theory) of the title compound as a colorless solid melting at 63.degree.-64.degree. C.
Elemental Analysis C.sub.6 H.sub.7 FN.sub.2 Calc.: % C, 57.1; % H, 5.59; % N, 22.2 Found: % C, 57.2; % H, 5.73; % N, 22.1
.sup.1 H NMR CDCl.sub.3 : 7.4 (d, 1H, J=5.0); 6.8 (d, 1H, J=5.0); 3.7 (br, 2H); 2.1 (s, 3H); .sup.13 C NMR CDCl.sub.3 : 152.6 (d, J=229); 134.1 (d, J=8.6); 133.8 (d, J=14.5); 128.1 (d, J=27.1); 123.3, 16.4 (d, J=4.1).
3-Amino-2-fluoro-5-methylpyridine was prepared analogously from 2-fluoro-5-methyl-3-nitropyridine. This compound was obtained in 89 percent yield as white solid melting at 27.degree.-28.5.degree. C.
Elemental Analysis C.sub.6 H.sub.7 FN.sub.2 Calc.: % C, 57.1; % H, 5.59; % N, 22.2 Found: % C, 56.9; % H, 5.65; % N, 22.6
.sup.1 H NMR CDCl.sub.3 : 7.2 (d, 1H); 6.8 (d, 1H); 3.7 (br, 2H); 2.1 (s, 3H); .sup.13 C NMR CDCl.sub.3 : 151.8 (d, J=229); 134.5 (d, J=12.6); 132.2 (d, J=3.9); 129.9 (d, J=28.7); 125.8 (d, J=5.3), 17.8.
42. Preparation of 3-Amino-2-chloro-4-methoxypyridine
To a solution of 6.4 g (51 mmol) of 3-amino-4-methoxypyridine in 30 mL of 37 percent aqueous hydrochloric acid was slowly added 7.8 g of 30 percent aqueous hydrogen peroxide at room temperature with stirring. After 30 min this solution was slowly poured into 300 mL of saturated aqueous sodium bicarbonate and the resulting mixture was extracted with ether (3.times.200 mL). The ethereal extracts were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a light brown solid. This solid was purified by column chromatography eluting with 17:83 acetone:hexane to obtain 6.54 g (81 percent of theory) of the title compound as colorless needles melting at 86.degree.-87.degree. C.
Elemental Analysis C.sub.6 H.sub.7 ClN.sub.2 O Calc.: % C, 45.4; % H, 4.45; % N, 17.7 Found: % C, 45.4; % H, 4.65; % N, 17.8
.sup.1 H NMR CDCl.sub.3 : 7.7 (d, 1H, J=5.4), 6.6 (d, 1H, J=5.4), 4.0 (br, 2H), 3.8 (s, 3H); .sup.13 C NMR CDCl.sub.3 : 153.3, 138.5, 135.6, 129.9, 105.2, 55.9.
3-Amino-2-chloro-4-ethoxypyridine was prepared from 3-amino-4-ethoxypyridine in an analogous procedure and was obtained as a white solid melting at 72.degree.-73.degree. C.
Elemental Analysis C.sub.7 H.sub.9 ClN.sub.2 O Calc.: % C, 48.7; % H, 5.26; % N, 16.2 Found: % C, 48.9; % H, 4.98; % N, 16.5
.sup.1 H NMR CDCl.sub.3 : 7.7 (d, 1H, J=5.4), 6.6 (d, 1H, J=5.4), 4.1 (q, 2H, J=7.0), 4.0 (br, 2H), 1.5 (t, 3H, J=7.0).
3-Amino-2-chloro-4-propoxypyridine was prepared from 3-amino-4-propoxypyridine in an analogous procedure and was obtained as a white solid melting at 46.degree.-47.degree. C.
Elemental Analysis C.sub.8 H.sub.11 ClN.sub.2 O Calc.: % C, 51.5; % H, 5.94; % N, 15.0 Found: % C, 51.8; % H, 5.97; % N, 15.2
.sup.1 H NMR CDCl.sub.3 : 7.7 (d, 1H, J=5.4), 6.6 (d, 1H, J=5.4), 4.1 (br, 2H), 4.0 (t, 2H, J=6.5), 1.84 (m, 2H), 1.0 (t, 3H, J=7.4). 3-Amino-2-chloro-4-(1-methylethoxy)pyridine was prepared from 3-amino-4-(1-methylethoxy)pyridine in an analogous procedure and was obtained as an amber oil.
Elemental Analysis C.sub.8 H.sub.11 ClN.sub.2 O Calc.: % C, 51.5; % H, 5.94; % N, 15.0 Found: % C, 51.1; % H, 5.87; % N, 15.4
.sup.1 H NMR CDCl.sub.3 : 7.7 (d, 1H, J=5.5), 6.6 (d, 1H, J=5.4), 4.6 (m, 1H, J=6.0), 4.0 (br, 2H), 1.34 (d, 6H, J=6.0).
43. Preparation of 3-Amino-2-ethylthio-4-methylpyridine
2-Ethylthio-4-methyl-3-nitropyridine (10.0 g, 50.4 mmol) was added slowly with stirring to a solution of 57 g (0.25 mole) of stannous chloride in 250 mL of concentrated aqueous hydrochloric acid. An exothermic reaction took place. The solution was held at 70.degree. C. for 30 min, cooled, and then poured slowly into saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with ember and the extract was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 5.8 g (68 percent of theory) of a light yellow oil that solidified upon standing. This solid was recrystallized from hexane to obtain 3.2 g of the title compound as a white solid melting at 37.degree.-38.degree. C.
Elemental Analysis C.sub.8 H.sub.12 N.sub.2 S Calc.: % C, 57.1; % H, 7.19; % N, 16.7; % S, 19.1 Found: % C, 57.3; % H, 6.88; % N, 16.8; % S, 19.0
.sup.1 H NMR CDCl.sub.3 : 7.8 (d, 1H, J=4.8), 6.7 (d, 1H, J=4.8), 3.8 (br, 2H), 3.2 (q, 2H, J=7.4), 2.1 (s, 3H), 1.3 (t, 3H, J=7.4); .sup.13 C NMR CDCl.sub.3 : 142.2, 139.5, 139.3, 128.9, 122.4, 25.4, 17.0, 15.0.
44. Preparation of Methyl 3-Amino-2-chloroisonicotinate
A mixture of 18 g (118 mmol) of methyl 3-aminoisonicotinate and 12 g (60 mmol) of 1,3-dichloro-5,5-dimethylhydantoin in 1500 mL of tetrachloroethylene was warmed slowly to 80.degree. C. with stirring and held there for 3 hours. The solution was then cooled, filtered, washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a dark oil. This oil was purified by careful column chromatography to obtain 6.7 g (30 percent of theory) of the title compound as a colorless solid melting at 91.degree.-92.degree. C.
Elemental Analysis C.sub.7 H.sub.7 ClN.sub.2 O.sub.2 Calc.: % C, 45.1; % H, 3.78; % N, 15.0 Found: % C, 45.2; % H, 3.94; % N, 15.1
.sup.1 H NMR CDCl.sub.3 : 7.7 (d, 1H, J=5.1); 7.6 (d, 1H, J=5.1); 6.2 (br, 2H); 3.9 (s, 3H); .sup.13 C NMR CDCl.sub.3 : 166.7, 141.9, 139.0, 134.7, 122.8, 116.5, 52.3.
45. Preparation of 3-Amino-4-ethyl-2-fluoropyridine
Trimethylsilyl chloride (2.2 g, (0.18 mmol) and sodium iodide (2.7 g, 0.18 mmol) were added to a solution of 3.6 g (0.15 mmol) of t-butyl N-(4-ethyl-2-fluoro-3-pyridyl)carbamate in 50 mL of dry acetonitrile with stirring at ambient temperature. After 2 hours the mixture was poured into ether and the resulting solution was washed with dilute aqueous sodium bisulfite, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain an oil. This oil was purified by column chromatography to obtain 1.6 g (76 percent of theory) of the title compound as a gold oil.
Elemental Analysis C.sub.7 H.sub.9 FN.sub.2 Calc.: % C, 60.0; % H, 6.47; % N, 20.0 Found: % C, 59.8; % H, 6.66; % N, 20.2
.sup.1 H NMR CDCl.sub.3 : 7.4 (d, 1H, J=5.0); 6.8 (d, 1H, J=5.0); 3.7 (br, 2H); 2.45 (q, 2H, J=7.5); 1.2 (t, 3H, J=7.5).
3-Amino-4-(1-methylethyl)-2-fluoropyridine was prepared in an analogous way from t-butyl N-(4-(1-methylethyl)-2-fluoro-3-pyridyl)carbamate. This compound was obtained in 92 percent yield as a gold oil.
Elemental Analysis C.sub.8 H.sub.11 FN.sub.2 Calc.: % C, 62.3; % H, 7.19; % N, 12.3 Found: % C, 62.5; % H, 7.24; % N, 12.6
.sup.1 H NMR CDCl.sub.3 : 7.4 (d, 1H, J=5.2); 6.8 (d, 1H, J=5.1); 3.8 (br, 2H); 2.87 (m, 1H); 1.2 (d, 6H, J=6.8).
46. Preparation of t-butyl N-(4-Ethyl-2-fluoro-3-pyridyl)carbamate
A solution of lithium diisopropylamine (LDA) was prepared from 19.3 mL (137 mmol) of diisopropylamine and 55 mL (137 mmol) of 2.5M n-butyllithium in hexane in 250 mL of dry tetrahydrofuran at -20.degree. C. A solution of 14.4 g (62.5 mmol) of 1-butyl N-(4-methyl-2-fluoro-3-pyridyl)carbamate in 80 mL of dry tetrahydrofuran was added dropwise with stirring at a rate slow enough to maintain the temperature below -60.degree. C. After a 30-min reaction period, 27 g (190 mmol) of methyl iodide was added and the solution was allowed to warm to -10.degree. C. The resulting mixture was diluted with 100 mL of aqueous ammonium chloride and 200 mL of ether and the phases were separated. The aqueous phase was washed with ether (3.times.100 mL). The organic phase and washes were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a gold oil. This oil was purified by column chromatography to obtain 11.4 g (76 percent of theory) of the title compound as a white solid melting at 84.degree.-86.degree. C.
.sup.1 H NMR CDCl.sub.3 : 7.7 (d, 1H, J=5.08); 6.8 (d, 1H, J=5.08); 6.1 (br, 1H); 2.45 (q, 2H, J=7.6); 1.2 (s, 9H); 1.0 (t, 3H, J=7.6).
t-Butyl N-(4-(1-methylethyl)-2-fluoro-3-pyridyl)carbamate was prepared analogously from t-butyl N-(4-ethyl-2-fluoro-3-pyridyl)carbamate. This compound was obtained in 69 percent yield as a colorless solid melting at 60.degree.-62.degree. C.
Elemental Analysis C.sub.13 H.sub.19 FN.sub.2 O.sub.2 Calc.: % C, 61.4; % H, 7.53; % N, 11.0 Found: % C, 61.6; % H, 7.78; % N, 11.3
.sup.1 H NMR CDCl.sub.3 : 7.9 (d, 1H, J=5.4); 7.0 (d, 1H, J=5.4); 6.0 (br, 1H); 3.2 (m, 1H); 1.4 (s, 9H); 1.2 (d, 6H, J=5.2).
47. Preparation of 3-Amino-2,4,5-trichloropyridine
Thirty percent aqueous hydrogen peroxide (3.0 g, 26 mmol) was added dropwise with stirring at 15.degree. C. to a solution of 8.0 g (49 mmol) of 3-amino-4,5-dichloropyridine in 450 mL of 37 percent aqueous hydrochloric acid. After 30 min another 2.6 g (23 mmol) of 30 percent aqueous hydrogen peroxide was added and the solution was allowed to slowly warm to room temperature. The resulting mixture was diluted with water, neutralized with sodium carbonate, and extracted with ether. The ethereal extract was dried over magnesium sulfate and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a viscous oil. This oil was partially purified by chromatography to obtain 2.5 g (26 percent of theory) of the title compound, a white solid melting at 88.degree.-90.degree. C., and 5.3 g of a mixture of the title compound and 3-amino-2,4,5,6-tetrachloropyridine.
Elemental Analysis C.sub.5 H.sub.3 Cl.sub.3 N.sub.2 Calc.: % C, 30.4; % H, 1.53; % N, 14.2 Found: % C, 30.5; % H, 1.47; % N, 14.1
.sup.1 H NMR CDCl.sub.3 : 7.7 (s, 1H); 4.6 (br, 2H).
48. Preparation of 3-Amino-4-fluoro-2-methoxypyridine
A solution 5.0 g (26.2 mmol) of p-toluenesulfonic acid monohydrate in 150 mL of toluene was refluxed to azeotropically remove the water and was then allowed to cool. A 5.0 g (20.6 mmol) amount of t-butyl N-(4-fluoro-2-methoxy-3-pyridyl)carbamate was added and the solution was heated to reflux with stirring for 5 min. The mixture was cooled and the liquid was removed by decantation. The solid residue was partitioned between ether and saturated aqueous sodium carbonate and the organic phase was recovered, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by flash chromatography to obtain 2.7 g (91 percent of theory) of the title compound as a near-clear oil.
Elemental Analysis C.sub.6 H.sub.7 FN.sub.2 O Calc.: % C, 50.7; % H, 4.96; % N, 19.7 Found: % C, 50.9; % H, 5.26; % N, 19.1
.sup.1 HNMR (CDCl.sub.3): 7.5 (dd, 1H, j=5.7, 7.8); 6.6 (dd, 1H, j=5.7, 9.4); 3.9 (s, 3H); 3.7 (br, 2H).
49. Preparation of t-Butyl N-(4-Fluoro-2-methoxy-3-pyridinyl)carbamate
To a solution of 8 g (35.7 mmol) of t-butyl N-(2-methoxy-3-pyridyl)carbamate in 200 mL of dry tetrahydrofuran was added with stirring at -60.degree. C., 46.2 mL (78.5 mmol) of 1.7M t-butyl lithium in pentane. The resulting solution was allowed to warm slowly with stirring to -20.degree. C. over a 20 to 30 min period. It was then cooled to about -60.degree. C. and 12.2 g (38.7 mmol) of N-fluorodibenzenesulfonimide was added with stirring all at once. The mixture was allowed to warm to -20.degree. C. and was poured into 500 mL of ether. The resulting ethereal solution was washed with a mixture of 2.5 g (41.7 mmol) of acetic acid and 150 mL of water. The aqueous phase was extracted with 200 mL of ether. The ethereal extracts were combined, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by flash chromatography to obtain 6.7 g (77 percent of theory) of the title compound as a colorless solid melting at 75.degree.-77.degree. C.
Elemental Analysis C.sub.11 H.sub.15 FN.sub.2 O.sub.3 Calc.: % C, 54.5; % H, 6.24; % N, 11.6 Found: % C, 54.2; % H, 6.39; % N, 11.4
.sup.1 H NMR (CDCl.sub.3): 7.88 (dd, 1H, j=5.8, 7.6); 6.68 (dd, 1H, j=5.8, 8.9); 5.9 (br, 1H); 3.9 (s, 3H); 1.45 (s, 9H).
50. Preparation of Methyl 3-Amino-2-ethoxyisonicotinate
A solution 7.5 g (39.4 mmol) of p-toluenesulfonic acid monohydrate in 150 mL of toluene was refluxed to azeotropically remove the water. The mixture was allowed to cool and then 11.0 g (37.1 mmol) of t-butyl N-(4-carboxymethyl-2-ethoxy-3-pyridyl)carbamate was added with stirring and the solution was heated to 95.degree. C. for 15 min. The resulting mixture was cooled and the liquid was removed by decantation. The solid residue was partitioned between ether and saturated aqueous sodium carbonate. The organic phase was recovered, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by column chromatography to obtain 6.4 g (88 percent of theory) of the title compound as a light yellow solid melting at 59.degree.-60.5.degree. C.
Elemental Analysis C.sub.9 H.sub.12 N.sub.2 O.sub.3 Calc.: % C, 55.1; % H, 6.16; % N, 14.3 Found: % C, 54.6; % H, 6.00; % N, 14.5
.sup.1 H NMR (CDCl.sub.3): 7.3 (d, 1H, j=5.6); 7.1 (d, 1H, j=5.6); 5.9 (br, 2H); 4.3 (q, 2H, j=7.1); 3.8 (s, 3H); 1.37 (t, 3H, j=7.1).
Methyl 3-amino-2-methoxyisonicotinate, an amber oil, was prepared analogously.
Elemental Analysis C.sub.8 H.sub.10 N.sub.2 O.sub.3 Calc.: % C, 50.0; % H, 4.80; % N, 16.7 Found: % C, 50.2; % H, 5.26; % N, 16.6
.sup.1 H NMR (CDCl.sub.3): 7.3 (d, 1H, j=5.6); 7.1 (d, 1H, j=5.6); 5.9 (br, 2H); 3.96 (s, 3H); 3.8 (s, 3H).
Ethyl 3-amino-2-methoxyisonicotinate, a light yellow oil, was prepared analogously.
Elemental Analysis C.sub.9 H.sub.12 N.sub.2 O Calc.: % C, 55.1; % H, 6.16; % N, 14.3 Found: % C, 54.2; % H, 6,56; % N, 14.6
.sup.1 H NMR (CDCl.sub.3): 7.3 (d, 1H, j=5.6); 7.1 (d, 1H, j=5.6); 5.9 (br, 2H); 4.28 (q, 2H, j=7.2); 3.9 (s, 3H); 1.33 (t, 3H, j=7.14).
51. Preparation of t-Butyl N-(4-Carboxymethyl-2-ethoxy-3-pyridinyl)carbamate
To a solution of | 2.0 g (50.3 mmol) of t-butyl N-(2-ethoxy-3-pyridinyl)carbamate in 200 mL of dry tetrahydrofuran was added with stirring at -50.degree. C., 66 mL (111 mmol) of 1.7M t-butyl lithium in pentane. The resulting solution was allowed to warm slowly to 0.degree. C. over a 20 to 30 min. period and was then cooled to -60.degree. C. and poured into 500 mL of ether saturated with crushed dry ice (carbon dioxide). The resulting mixture was acidified at room temperature with 3.0 g (50 mmol) of acetic acid and the fine white solid precipitate that formed was collected by filtration and dried under reduced pressure at 50.degree. C. to obtain 17.0 g of a lithium salt containing some tetrahydrofuran. This salt was combined with 30.0 g (211 mmol) of iodomethane in 150 mL of dry dimethyl sulfoxide and the mixture was stirred for 1 hr. It was then poured into 400 mL of water. The aqueous mixture was extracted with 500 then 200 mL of ether. The ether extracts were combined, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by column chromatography to obtain 11.5 g (77 percent of theory) of the title compound as a colorless solid melting at 94.degree.-95.5.degree. C.
Elemental Analysis C.sub.14 H.sub.20 N.sub.2 O.sub.5 Calc.: % C, 56.8; % H, 6.80; % N, 9.45 Found: % C, 56.8; % H, 7.00; % N, 9.63
.sup.1 H NMR (CDCl.sub.3): 7.8 (d, 1H, j=5.3); 7.1 (d, 1H, j=5.3); 6.9 (br, 1H); 4.4 (q, 2H, j=7.0); 3.8 (s, 3H); 1.46 (s, 9H); 1.37 (t, 3H, j=7.0).
t-Butyl N-(4-carboxyethyl-2-methoxy-3-pyridinyl)carbamate, a colorless solid melting at 40.degree.-41.degree. C., was prepared analogously.
Elemental Analysis C.sub.14 H.sub.20 N.sub.2 O.sub.5 Calc.: % C, 56.8; % H, 6.80; % N, 9.45 Found: % C, 56.6; % H, 6.76; % N, 9.26
.sup.1 H NMR (CDCl.sub.3): 7.9 (d, 1H, j=5.3); 7.1 (d, 1H, j=5.25); 6.9 (br, 1H); 4.27 (q, 2H, j=7.15); 3.96 (s, 3H); 1.45 (s, 9H); 1.33 (t, 3H, j=7.14).
t-Butyl N-(4-Carboxymethyl-2-methoxy-3-pyridinyl)carbamate, a colorless solid melting at 107.degree.-108.degree. C., was obtained analogously.
Elemental Analysis C.sub.13 H.sub.18 N.sub.2 O.sub.5 Calc.: % C, 55.3; % H, 6.43; % N, 9.92 Found: % C, 55.5; % H, 6.22; % N, 10.1
.sup.1 H NMR (CDCl.sub.3): 7.9 (d, 1H, j=5.3); 7.1 (d, 1H, j=5.4); 6.9 (br, 1H); 3.97 (s, 3H); 1.46 (s, 9H).
52. Preparation of t-Butyl N-(4-Chloro-2-ethoxy-3-pyridinyl)carbamate
To a solution of 15 g (63 mmol) of t-butyl N-(2-ethoxy-3-pyridinyl)carbamate in 175 mL of dry tetrahydrofuran was added with stirring at -60.degree. C., 78 mL (132 mmol) of 1.7M t-butyl lithium in pentane. The resulting solution was allowed to warm to -10.degree. C. over a 30 min. period and was then cooled to -60.degree. C. A A 22.3 g (94 mmol) amount of hexachoroethane was added all at once with stirring and the mixture are allowed to warm to ambient temperature. It was then diluted with 600 mL of ether and the resulting solution was washed with 150 mL of water, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by column chromatography to obtain 11.1 g (65 percent of theory) of the title compound as a colorless solid melting at 73.degree.-74.degree. C.
Elemental Analysis C.sub.12 H.sub.17 ClN.sub.2 O.sub.3 : Calc.: % C, 52.9; % H, 6.28; % N, 10.3 Found: % C, 53.0; % H, 6.30; % N, 10.3
.sup.1 H NMR (CDCl.sub.3): 7.88 (d, 1H, j=5.5); 6.93 (d, 1H, j=5.5); 6.0 (br, 1H); 4.4 (q, 2H, j=7.0); 1.5 (s, 9H); 1.39 (t, 3H, j=7.0.).
53. Preparation of t-Butyl N-(2-Ethoxy-3-pyridinyl)carbamate
To a solution of 38.1 g (0.28 mol) of 3-amino-2-ethoxypyridine in 400 mL of dry dioxane was added with stirring 60 g (0.28 mol) of di-t-butyl dicarbonate and the solution was slowly heated to reflux over a 4 hr period. The resulting solution was cooled below reflux and another 5.0 g (23 mmol) of di-t-butyl dicarbonate was added with stirring the the mixture was reheat at reflux for 1 hr. The volatiles were removed by evaporation under reduced pressure and the residue obtained was purified by column chromatography to obtain 58.3 g (89 percent of theory) of the title compound as a colorless oil.
Elemental Analysis C.sub.12 H.sub.18 N.sub.2 O.sub.3 Calc.: % C, 60.5; % H, 7.61; % N, 11.8 Found: % C, 59.7; % H, 9.03; % N, 11.9
.sup.1 H NMR (CDCl.sub.3): 8.2 (broad d, 1H, j=7.0); 7.7 (d, 1H, j=5.0); 6.9 (br, 1H); 6.8 (dd, 1H, j=5.0, 5.0), 4.4 (q, 2H, j=7.1); 1.47 (s, 9H); 1.36 (t, 3H, j=7.1).
54. Preparation of 3-Amino-4-ethoxy-2-fluoropyridine
To a solution of 19 g (74 mmol) of t-butyl N-(4-ethoxy-2-fluoro-3-pyridinyl)carbamate and 12.2 g (81.5 mmol) of sodium iodide in 400 mL of dry acetonitrile was added with stirring 8.9 g (81.5 mmol) of trimethylsilyl chloride. The mixture was allowed to react for 4 hr and then a 100 mL solution of aqueous sodium bicarbonate was added with stirring. The resulting mixture was extracted with 1 L of ether and the ether extract was dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by column chromatography to obtain 6.3 g (55 percent of theory) of the title compound as a colorless solid melting at 76.degree.-77.degree. C.
Elemental Analysis C.sub.7 H.sub.9 FN.sub.2 O Calc.: % C, 53.5; % H, 5.81; % N, 17.9 Found: % C, 54.3; % H, 6.44; % N, 17.7
.sup.1 H NMR (CDCl.sub.3): 7.5 (d, 1H, j=5.74); 6.5 (d, 1H, j=5.64); 4.1 (q, 2H, j=7.0); 3.6 (br, 2H); 1.4 (t, 3H, j=6.9).
3-Amino-2-fluoro-4-methoxypyridine, a colorless solid melting at 48.degree.-50.degree. C., was prepared analogously.
Elemental Analysis C.sub.6 H.sub.7 FN.sub.2 O Calc.: % C, 50.7; % H, 4.96; % N, 19.7 Found: % C, 50.9; % H, 5.13; % N, 19.9
.sup.1 H NMR (CDCl.sub.3): 7.5 (d, 1H, j=5.57); 6.63 (d, 1H, j=5.47); 3.8 (s, 3H); 3.7 (br, 2H).
3-Amino-2-fluoro-4-propoxypyridine, a colorless oil, was prepared analogously.
Elemental Analysis C.sub.8 H.sub.11 FN.sub.2 O Calc.: % C, 55.5; % H, 6.51; % N, 16.5 Found: % C, 56.7; % H, 6.66; % N, 16.2
.sup.1 H NMR (CDCl.sub.3): 7.4 (d, 1H, j=5.61); 6.5 (d, 1H, j=5.71); 4.5 (t, 2H, j=6.5); 3.7 (br, 2H); 1.8 (m, 2H, j=7.3); 1.0 (t, 3H, j=7.4).
3-Amino-2-fluoro-4-(1-methylethoxy)pyridine, a gold oil, was prepared analogously.
Elemental Analysis C.sub.8 H.sub.11 FN.sub.2 O Calc.: % C, 55.5; % H, 6.51; % N, 16.5 Found: % C, 56.9; % H, 6.69; % N, 16.4
.sup.1 H NMR (CDCl.sub.3): 7.5 (d, 1H, j=5.57); 6.6 (d, 1H, j=5.71); 4.5 (m, 1H, j=6.0); 3.6 (br, 2H); 6.6 (d, 6H, j=6.1).
55. Preparation of t-Butyl N-(4-ethoxy-2-fluoro-3-pyridinyl)carbamate
To a solution of 18.5 g (131 mmol) of 4-ethoxy-2-fluoropyridine in 300 mL of dry tetrahydrofuran at -78.degree. C. was added slowly, with stirring and cooling to maintain the temperature below -65.degree. C., 58 mL of 2.5M butyl lithium in hexane. The mixture was allowed to react for 1 hr and then the resulting slurry was poured into 1300 mL of ether containing excess powdered dry ice (carbon dioxide). The fine white precipitate that formed was collected by filtration and dried under reduced pressure for 90 min. The hygroscopic solid obtained was taken into 700 mL of t-butanol and 68 g (0.24 mol) of diphenyl phosphoryl azide was added with stirring. This mixture was slowly warmed to reflux for 2 hr during which time there was a vigorous evolution of nitrogen. The resulting slurry was filtered and the filtrate was diluted with 800 mL of dichloromethane. The organic phase was separated, washed with water (2.times.100 mL), and concentrated by evaporation to obtain a semi-solid residue. This was dissolved in fresh dichloromethane and the solution was dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by column chromatography to obtain 19.5 g (63 percent of theory) of the title compound as a colorless solid melting at 130.degree.-131.degree. C.
Elemental Analysis C.sub.12 H.sub.17 FN.sub.2 O.sub.3 Calc.: % C, 56.2; % H, 6.69; % N, 10.9 Found: % C, 56.1; % H, 6.99; % N, 11.3
.sup.1 H NMR (CDCl.sub.3): 7.85 (d, 1H, j=5.7); 6.6 (d, 1H, j=5.7); 6.0 (br, 1H); 4.1 (q, 2H, j=7.0); 1.4 (t, 3H, j=6.9); 1.35 (t, 3H, j=7.0).
t-Butyl N-(2-fluoro-4-(1-methylethoxy)-3-pyridinyl)carbamate, a colorless solid melting at 80.degree.-81.5.degree. C., was obtained analogously.
Elemental Analysis C.sub.13 H.sub.19 FN.sub.2 O.sub.3 Calc.: % C, 57.8; % H, 7.09; % N, 10.4 Found: % C, 57.9; % H, 6.94; % N, 10.7
.sup.1 H NMR (CDCl.sub.3): 7.9 (d, 1H, j=5.9); 6.7 (d, 1H, j=5.96); 6.0 (br, 1H); 4.6 (m, 1H, j=6.1); 1.45 (s, 9H); 1.35 (d, 6H, j=6.1).
t-Butyl N-(2-fluoro-4-propoxy-3-pyridinyl)carbamate, a colorless solid melting at 84.degree.-86.degree. C., was obtained analogously.
Elemental Analysis C.sub.13 H.sub.19 FN.sub.2 O.sub.3 Calc.: % C, 57.8; % H, 7.09; % N, 10.4 Found: % C, 57.8; % H, 7.37; % N, 10.5
.sup.1 H NMR (CDCl.sub.3): 7.9 (d, 1H, j=5.8); 6.7 (d, 1H, j=5.8); 5.8 (br, 1H); 4.0 (t, 2H, j=6.5); 1.83 (m, 2H, j=7.36); 1.46 (s, 9H); 1.0 (t, 3H, j=7.5).
56. Preparation of 4-Ethoxy-2-fluoropyridine
To a solution of 60.5 g (0.31 mol) of 3,5-dichloro-4-ethoxy-2-fluoropyridine and 32.2 g (0.32 mol) of sodium acetate in 400 mL of ethanol in a 1 L stirred steel Parr bomb was added 3 g of 5 percent palladium on carbon catalyst. The reactor was charged with 500 pounds per square inch gauge (3550 kiloPascals) of hydrogen and heated with stirring to 100.degree. C. for 4 hr. The mixture was cooled, filtered, and concentrated by evaporation. The residue was dissolved in ether and the resulting solution was dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by bulb to bulb distillation (60.degree.-80.degree. C. at 0.5 mm Hg (67 Pascals) to obtain 18.5 g (42 percent of theory) of the title compound as a colorless oil which solidified upon standing and melted at 35.degree.-36.degree. C.
Elemental Analysis C.sub.7 H.sub.8 NO Calc.: % C, 59.6; % H, 5.71; % N, 9.92 Found: % C, 59.2; % H, 5.97; % N, 9.95
.sup.1 H NMR (CDCl.sub.3): 7.9 (d, 1H, j=5.8); 6.6 (m, 1H); 6.3 (d, 1H, j=2.2); 4.0 (q, 2H, j=7.0); 1.4 (t, 3H, j=7.0).
2-Fluoro-4-methoxypyridine, a colorless oil boiling at 119.degree.-122.degree. C. at 30 mm Hg (4.0 kiloPascals), was prepared analogously.
Elemental Analysis C.sub.6 H.sub.6 FNO Calc.: % C, 59.6; % H, 5.71; % N, 9.92 Found: % C, 59.2; % H, 5.97; % N, 9.95
.sup.1 H NMR (CDCl.sub.3): 8.0 (d, 1H, j=5.9); 6.7 (m, 1H); 6.4 (d, 1H, j=2.1); 3.9 (s, 3H).
2-Fluoro-4-(1-methylethoxy)pyridine, a colorless oil, was obtained analogously.
Elemental Analysis C.sub.8 H.sub.10 FNO Calc.: % C, 61.9; % H, 6.50; % N, 9.03 Found: % C, 61.5; % H, 6.59; % N, 9.32
.sup.1 H NMR (CDCl.sub.3): 8.0 (d, 1H, j=5.9); 6.6 (dd, 1H, j=4.5, 1.4); 6.33 (d, 1H, j=2.0); 4.0 (t, 2H, j=6.6); 1.8 (m, 2H, j=7.3); 1.0 (t, 3H, j=7.3).
2-Fluoro-4-propoxypyridine, a colorless oil, was obtained analogously.
Elemental Analysis C.sub.8 H.sub.10 FNO Calc.: % C, 61.9; % H, 6.50; % N, 9.03 Found: % C, 61.0; % H, 7.50; % N, 9.09
.sup.1 H NMR (CDCl.sub.3): 8.0 (d, 1H, j=5.9); 6.6 (m, 1H); 6.3 (d, 1H, j=2.2); 4.57 (m, 1H, j=6.1); 1.3 (d, 6H, j=6.1).
57. Preparation of 3,5-Dichloro-4-ethoxy-2-fluoropyridine
To a solution of 70.2 g (0.38 mol) of 3,5-dichloro-2,4-difluoropyridine in 600 mL of ethanol was slowly added with stirring a solution of sodium ethoxide in ethanol prepared from 16 g (0.40 mol) of sodium hydride (60 percent in mineral oil, hexane washed) in 200 mL of ethanol. The mixture was allowed to stir overnight and the brown solution obtained was filtered through powdered cellulose and concentrated by evaporation under reduced pressure. The residue was partitioned between 500 mL of ether and 400 mL of water. The organic phase was recovered, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was distilled to obtain 62 g (84 percent of theory) of the title compound as a colorless oil having a boiling point of 175.degree.-180.degree. C. at 0.4 mm Hg (53 Pascals).
Elemental Analysis C.sub.7 H.sub.6 Cl.sub.2 FN Calc.: % C, 43.3; % H, 3.12; % N, 7.22 Found: % C, 40.0; % H, 2.92; % N, 6.66
.sup.1 H NMR (CDCl.sub.3): 8.04 (s, 1H); 4.3 (q, 2H, j=7.0); 1.48 (t, 3H, j=7.1).
3,5-Dichloro-2-fluoro-4-methoxypyridine, a colorless oil, was obtained analogously.
.sup.1 H NMR (CDCl.sub.3): 8.1 (s, 1H); 4.88 (m, 1H, j=6.1); 1.4 (d, 6H, j=6.1).
1,5-Dichloro-2-fluoro-4-(1-methylethoxy)pyridine, a colorless oil, was obtained analogously.
.sup.1 H NMR (CDCl.sub.3): 8.0 (s, 1H); 4.88 (m, 1H, j=6.1); 1.4 (d, 6H, j=6.1).
3,5-Dichloro-2-fluoro-4-propoxypyridine, a colorless oil, was obtained analogously.
.sup.1 H NMR (CDCl.sub.3): 8.1 (s, 1H); 4.2 (t, 2H, j=6.7); 1.86 (m, 2H, j=7.1); 1.1 (t, 3H, j=7.3).
58. Preparation of 3-Amino-4-fluoro-1-methylindazole
Methylhydrazine (4.96 g, 108 mmol was added to a solution of 15.0 g (108 mmol) of 2,6-difluorobenzonitrile in 150 mL of ethanol and the mixture was heated to reflux with stirring for 72 hours. The volatiles were when removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with water, dried over magnesium sulfate, and evaporated to dryness under reduced pressure to obtain the title compound as a white solid. This was recrystallized from ethanol to obtain 10.1 g (57 percent of theory) of the title compound as white crystals melting at 125.degree.-127.degree. C.
Elemental Analysis C.sub.8 H.sub.8 FN.sub.3 Calc.: % C, 58.2; % H, 4.88; % N, 25.4 Found: % C, 58.7; % H, 4.76; % N, 25.9
.sup.1 H NMR CDC.sub.3 : 7.19 (m, 1H), 7.11 (d, 1H, J=8.4), 6.59 (d of d, 1H, J=8.4, 3.3), 5.26 (brs, 2H), 3.72 (s, 3H); .sup.13 C NMR CDCl.sub.3 : 157.35, 154.88, 146.20, 146.18, 143.85, 143.76, 127.62, 127.55, 105.31, 105.27, 103.44, 103.24, 101.96, 101.78, 34.74.
59. Preparation of 3-Amino-1-methyl-4-(trifluoromethylthio)pyrazole
Trifluoromethanesulfenyl chloride (11.6 g, 85.0 mmol) was added to a solution of 3-amino-1-methylpyrazole (8.0 g, 82.4 mmol) in 150 mL of dichloromethane with stirring at a rate such that the temperature did not rise above 5.degree. C. when the addition was complete the mixture was allowed to warm to ambient temperature and stir for 18 hours and was then purged with nitrogen gas for 1 hour to remove any unreacted trifluoromethanesulfenyl chloride. The solid that formed during the reaction was collected by filtration and the filtrate was concentrated by evaporation under reduced pressure to obtain additional solids. The combined solids were dissolved in water and the solution as basified with 1N aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2.times.100 mL) and the extracts were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a solid residue that appeared to be a mixture of two compounds. This solid was recrystalized from methylcyclohexane to obtain 16.2 g (40 percent of theory) of the title compound as a yellow solid melting at 138.degree.-140.degree. C. The impurity was identified as 1-methyl-3-((trifluoromethanesulfenyl)amino)-4-(trifluoromethylthio)pyrazole.
Elemental Analysis C.sub.5 H.sub.6 F.sub.3 N.sub.3 S Calc.: % C, 30.5; % H, 3.07; % N, 21.3; % S, 16.3 Found: % C, 30.5; % H, 2.87; % N, 21.1; % S, 16.5
.sup.1 H (CDCl.sub.3): 7.31 (s, 1H), 4.00 (brs, 2H), 3.68 (s, 3H);
.sup.13 C (CDCl.sub.3): 157.47, 137.04, 133.61, 130.52, 127.44, 124.35, 84.23, 38.97.
60. Preparation of Methyl 6-Chloro-3-methoxypicolinate and Methyl 3-Chloro-6-methoxypicolinate
Sodium methoxide in methanol (100 mL of 25 percent, 22.8 g, 0.42 mol) was added to a solution of methyl 3,6-dichloropicolinate (44.0 g, 0.21 mol) in acetonitrile (400 mL) and the resulting solution was stirred at room temperature for 3.5 hours. The reaction mixture was acidified with acetic acid and the solvent was removed by evaporation. The residue obtained was mixed with dichloromethane and washed sequentially with water, dilute aqueous sodium hydroxide, and dilute aqueous hydrochloric acid. The organic solvent was removed by evaporation and the residue obtained was purified by column chromatography on silica gel, eluting with 20 percent ethyl acetate in hexane until the methyl 3-chloro-6-methoxypicolinate desorbed and then with 25 percent ethyl acetate in hexane until the methyl 6-chloro-3-methoxypicolinate desorbed. Methyl 3-chloro-6-methoxypicolinate (23.4 g) was recovered as a white powder melting at 38.degree.-39.degree. C. and the methyl 6-chloro-3-methoxypicolinate (8.5 g) was recovered as a white powder melting at 81.degree.-82.degree. C.
61. Preparation of 6-Chloro-3-methoxypicolinamide
Methyl 6-chloro-3-methoxypicotinate (8.0 g, 40 mmol) was added to a mixture of dichloromethane (50 mL) and concentrated ammonium hydroxide (100 mL) at room temperature and the combination was allowed to stir overnight. The resulting mixture was filtered and the organic and aqueous layers were separated. The organic layer was concentrated by evaporation and the solid residue obtained was washed with water and a little ether and then dried to obtain 6.7 g of the title compound as a white powder melting at 223.degree.-224.degree. C.
62. Preparation of 2-Amino-6-chloro-3-methoxypyridine
Sodium hydroxide (6.1 g, 196 mmol) was dissolved in water (75 mL) and cooled in an ice bath. Chlorine (3.8 g, 53 mmol) was added slowly with stirring keeping the temperature below 5.degree. C. 6-Chloro-3-methoxypicolinamide (16.1 g, 23 mmol) was added to this solution and the mixture was stirred at 0.degree. C. for 4 hours (until the solids had dissolved). The reaction mixture was acidified with acetic acid and extracted with dichloromethane. The organic extract was concentrated by evaporation and the residue obtained was diluted with hexane. The resulting slurry was filtered and the solids collected were dried to obtain 4.1 g of the title compound as a tan powder melting at 134.degree.-135.degree. C.
Elemental Analysis for C.sub.6 H.sub.7 ClN.sub.2 O Calc.: % C, 45.4; % H, 4.45; % N, 17.7 Found: % C, 45.2; % H, 4.58; % N, 17.4
63. Preparation of N-(6-Chloro-3-methoxy-2-pyridinyl)-N'-carboethoxythiourea
Ethoxycarbonyl isothiocyanate (3.7 mL, 4.1 g, 31.5 mmol) was added slowly with stirring to a solution of 2-amino-6-chloro-3-methoxypyridine (5.0 g, 31.5 mmol) in chloroform (40 mL) and the mixture was stirred overnight. The solvent was removed by evaporation and the residue obtained was mixed with hexane. The resulting slurry was filtered and the solids collected were washed with a small amount of ether and dried to obtain 8.3 g of the title compound as a man powder melting at 184.degree.-185.degree. C. with decomposition.
The following compounds were prepared by analogous procedures from known 2-aminopyridine compounds:
N-2-Pyridinyl-N'-carboethoxythiourea (a yellow powder melting at 94.degree.-96.degree. C.).
N-(6-Chloro-2-pyridinyl)-N'-carboethoxythiourea (a pale yellow powder melting at 73.degree.-74.degree. C.).
N-(3-Methoxy-2-pyridinyl)-N'-carboethoxythiourea (a pale yellow powder melting at 147.degree.-148.degree. C.).
N-(3,6-Dichloro-2-pyridinyl)-N'-carboethoxy thiourea (a yellow powder melting at 159.degree.-161.degree. C.).
Elemental Analysis C.sub.9 H.sub.9 Cl.sub.2 N.sub.3 O.sub.2 S Calc.: % C, 36.8; % H, 3.08; % N, 14.3; % S, 10.9 Found: % C, 36.9; % H, 2.88; % N, 14.4; % S, 10.7
N-(3,5-Dichloro-2-pyridinyl)-N'-carboethoxythiourea (a yellow powder).
Elemental Analysis C.sub.9 H.sub.9 Cl.sub.2 N.sub.3 O.sub.2 S Calc.: % C, 36.8; % H, 3.08; % H, 14.3; % S, 10.9 Found: % C 36.5, % H, 3.36; % N, 14,4; % S, 11.1
N-(3-Fluoro-5-trifluoromethyl-2-pyridinyl)-N'-carboethoxythiourea. (a white powder melting at 86.degree.-90.degree. C.).
Elemental Analysis C.sub.10 H.sub.9 F.sub.4 N.sub.3 O.sub.2 S Calc.: % C, 38.6; % H, 2.91; % N, 13.5; % S, 10.3 Found: % C, 38.5; % H, 2.69; % N, 13.4; % S, 10.2
N-(3-Bromo-5-methyl-2-pyridinyl)-N'-carboethoxythiourea (a yellow powder melting at 148.degree.-150.degree. C.).
Elemental Analysis C.sub.10 H.sub.12 BrN.sub.3 O.sub.2 S Calc.: % C, 37.8; % H, 3.80; % N, 13.2; % S, 10.1 Found: % C, 37.8; % H, 3.72; % N, 13.1; % S, 10.1
64. Preparation of 2-Amino-5-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine
Hydroxylamine hydrochloride (9.6 g, 138 mmol) and diisopropylethylamine (14.4 mL, 10.7 g, 83 mmol) were mixed with ethanol (300 mL) for a few minutes and then N-(6-chloro-3-methoxy-2-pyridinyl)-N'-carboethoxythiourea (7.6 g, 27.5 mmol) was added with stirring. The resulting mixture was stirred at room temperature for 20 min and then heated to reflux for 3 hours. The volatile components were removed by evaporation and the residue obtained was mixed with water. The resulting slurry was filtered and the solids collected were washed with ether, a small amount of methanol, and finally hexane and were then dried. The title compound (3.2 g) was obtained as a tan powder melting at 207.degree.-208.degree. C.
Elemental Analysis C.sub.7 H.sub.7 ClN.sub.4 O Calc.: % C, 42.3; % H, 3.55; % N, 28.2 Found: % C, 41.7, % H, 2.91; % N, 27.9
The following compounds were prepared by analogous procedures from the products of Example 63:
2-Amino�1,2,4!triazolo�1,5-a!pyridine (a yellow powder melting at 100.degree.-102.degree. C.).
2-Amino-5-chloro�1,2,4!triazolo�1,5-a!pyridine (an off-white powder melting at 212.degree.-213.degree. C.).
Elemental Analysis C.sub.6 H.sub.5 ClN.sub.4 Calc.: % C, 42.7; % H, 2.99; % N, 33.2 Found: % C, 42.7; % H, 3.01; % N, 33.6
2-Amino-8-methoxy�1,2,4!triazolo�1,5-a!pyridine (a light tan powder melting at 204.degree.-206.degree. C.).
Elemental Analysis C.sub.6 H.sub.8 N.sub.4 O Calc.: % C, 51.2; % H, 4.91; % N, 34.1 Found: % C, 51.3; % H, 6.09; % N, 33.8
2-Amino-5,8-dichloro�1,2,4!triazolo�1,5-a!pyridine (a white powder melting at 236.degree.-238.degree. C.).
Elemental Analysis C.sub.6 H.sub.4 Cl.sub.2 N.sub.4 Calc.: % C, 35.5; % H, 1.99; % N, 27.6 Found: % C, 35.6; % H, 2.12; % N, 27.4
2-Amino-6,8-dichloro�1,2,4!triazolo�1,5-a!pyridine (a white powder melting above 280.degree. C.).
Elemental Analysis C.sub.6 H.sub.4 Cl.sub.2 N.sub.4 Calc.: % C, 35.5; % H, 1.99; % N, 27.6 Found: % C, 35.8; % H, 1.96; % N, 27.3
2-Amino-8-fluoro-6-trifluoromethyl�1,2,4!triazolo�1,5-a!pyridine (an off-white powder melting at 221.degree.-224.degree. C.).
Elemental Analysis C.sub.7 H.sub.4 F.sub.4 N.sub.4 Calc.: % C, 38.2; % H, 1.83; % N, 25.5 Found: % C, 38.1; % H, 2.04; % N, 24.1
2-Amino-8-bromo-6-methyl�1,2,4!triazolo�1,5-a!pyridine (a white powder melting above 280.degree. C.).
Elemental Analysis C.sub.7 H.sub.7 BrN.sub.4 Calc.: % C, 37.0; % H, 3.11; % N, 24.7 Found: % C, 37.0; % H, 3.14; % N, 24.7
65. Preparation of 2-Benzylthio-5-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine
t-Butyl nitrite (6.7 mL, 5.2 g, 50 mmol) was added all at once to a mixture of 2-amino-5-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine (5.0 g, 25 mmol) and dibenzyl disulfide (18.6 g, 75 mmol) in acetonitrile (250 mL) at 35.degree. C. with stirring. The reaction was exothermic, but a mantle was placed under the reaction flask to heat it to reflux rapidly. The evolution of gas began immediately and stopped after about 15 minutes. The volatiles were removed by evaporation and the residue was purified by column chromatography on silica gel eluting with 30 percent ethyl acetate in hexane. The dibenzyl disulfide eluted first followed by the title compound. The solvent was removed by evaporation and the residue was mixed with hexane and filtered. The collected solids were dried to obtain 6.1 g of the title compound as a light tan powder melting at 99.degree.-100.degree. C.
Elemental Analysis C.sub.14 H.sub.12 ClN.sub.3 OS Calc.: % C, 55.0; % H, 3.96; % N, 13.7; % S, 10.5 Found: % C, 54.9; % H, 4.08; % N, 13.9; % S, 10.5
2-Benzylthio-5-chloro�1,2,4!triazolo�1,5-a!pyridine (a pale yellow powder melting at 65.degree.-66.degree. C.) was prepared by an analogous procedure.
Elemental Analysis C.sub.13 H.sub.10 ClN.sub.3 S Calc.: % C, 56.6; % H, 3.66; % N, 15,2; % S, 11.6 Found: % C, 56.7; % H, 3.56; % N, 15.4; % S, 11.5
66. Preparation of 2-Chlorosulfonyl-5-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine
Chlorine (6.7 g, 96 mmol) was added slowly with stirring at 3.degree.-7.degree. C. to a mixture of 2-benzylthio-5-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine (6.5 g, 21 mmol) in dichloromethane (75 mL) and water (75 mL) and the reaction mixture was stirred for a 30 min period after the chlorine had been added. The layers were separated and the organic layer was dried over a mixture of magnesium and sodium sulfates and concentrated by evaporation under reduced pressure. The residue obtained was triturated with hexane, filtered, and dried to obtain 5.2 g of the title compound as a light tan powder melting at 149.degree.-151.degree. C.
67. Preparation of N-(2,6-Difluorophenyl)-5-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide
Dimethyl sulfoxide (90 microliters, 94 micrograms, 1.2 mmol) was added with stirring to a solution of 2-chlorosulfonyl-5-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine (1.7 g, 6 mmol), 2,6-difluoroaniline (1.6 g, 12 mmol) and pyridine (0.5 g, 6 mmol) in acetonitrile (20 mL) at ambient temperature. The reaction was complete in about 20 min. Dichloromethane and water were added and the solid that separated was collected by filtration. The organic layer was concentrated by evaporation and the residue obtained was washed with water and combined with the earlier obtained solid. The combined solids were then washed with ether and hexane and dried to obtain 1.4 g of the title compound as an off-white powder melting at 190.degree.-191.degree. C. (d).
Elemental Analysis C.sub.13 H.sub.9 ClF.sub.2 N.sub.4 O.sub.3 S Calc.: % C, 41.7; % H, 2.42; % N, 15.0; % S, 8.56 Found: % C, 41.3; % H, 2.37; % N, 15.0; % S, 8.69
The following compounds were prepared analogous procedures:
N-(2-Chloro-4-methoxy-3-pyridinyl)-5-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide (a white powder melting at 253.degree.-254.degree. C. (d)).
Elemental Analysis C.sub.13 H.sub.11 Cl.sub.2 N.sub.5 O.sub.4 S Calc.: % C, 38.6; % H, 2.74; % N, 17.3; % S, 7.90 Found: % C, 38.8; % H, 2.90; % N, 17.4; % S, 7.47
N-(1-Methyl-4-bromo-3-pyrazoyl)-5-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide (a light tan powder melting at 269.degree.-270.degree. C. (d)).
Elemental Analysis C.sub.11 H.sub.10 BrClN.sub.6 O.sub.3 S Calc.: % C, 31.3; % H, 2.39; % N, 19.9; % S, 7.60 Found: % C, 31.9; % H, 2.39; % N, 19.6; % S, 7.60
68. Preparation of N-(2,6-Difluorophenyl)-5,8-dimethoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide
N-(2,6-Difluorophenyl)-5-chloro-8-methoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide (1.0 g, 2.7 mmol), sodium methoxide (25 percent in methanol, 2.5 mL, 0.58 g, 11 mmol) and dimethyl sulfoxide (20 mL) were mixed with stirring and slowly heated to 70.degree. C. over a 40-min period. After a short reaction period, the reaction mixture was acidified with acetic acid and diluted with dichloromethane and water. The solid that separated was recovered by filtration. The organic layer was separated, was washed several times with water, and was concentrated by evaporation under reduced pressure. The residue obtained was washed with water and combined with the previously obtained solid. The combined solids were washed with ether and hexane and dried to obtain 0.7 g of the title compound as an off-white powder melting at 319.degree.-320.degree. C. (d).
Elemental Analysis C.sub.14 H.sub.12 F.sub.2 N.sub.4 O.sub.4 S Calc.: % C, 45.1; % H, 3.27; % N, 15.1; % S, 8.66 Found: % C, 43.4; % H, 3.13; % N, 14.8; % S, 8.23
The following compounds were prepared by analogous procedures from compounds of Example 68:
N-(2-Chloro-4-methoxy-3-pyridinyl)-5,8-dimethoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide (a light tan powder melting at 257.degree.-258.degree. C. (d)).
Elemental Analysis C.sub.14 H.sub.14 ClN.sub.5 O.sub.5 S Calc.: % C, 42.1; % H, 3.53; % N, 17.7; % S, 8.02 Found: % C, 41.7; % H, 2.85; % N, 17.3; % S, 7.74
N-(1-Methyl-4-bromo-3-pyrazoyl)-5,8-dimethoxy�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide (a tan powder melting at 257.degree.-258.degree. C. (d)).
Elemental Analysis C.sub.12 H.sub.13 BrN.sub.6 O.sub.4 S Calc.: % C, 34.5; % H, 3.14; % N, 20.1; % S, 7.68 Found: % C, 34.1; % H, 2.98; % N, 19.8; % S, 7.27
69. Evaluation of Postemergence Herbicidal Activity
Seeds of the desired test plant species were planted in Grace-Sierra MetroMix.RTM. 206 planting mixture, which typically has a pH of 6.0 to 6.8 and an organic matter content of about 30 percent, in plastic pots with a surface area of 64 square centimeters. When required to ensure good germination and healthy plants, a fungicide treatment and/or other chemical or physical treatment was applied. The plants were grown for 7-21 days in a greenhouse with an approximately 15 hr photoperiod maintained at about 23.degree.-19.degree. C. during the day and 22.degree.-28.degree. C. during the night. Nutrients and water were added on a regular basis and supplemental lighting was provided with overhead metal halide 1000 Watt lamps as necessary. The plants were employed for testing after they reached the first or second true leaf stage.
A weighed amount, determined by the highest rate to be tested, of each test compound was placed in a 20 mL glass vial and was dissolved in 4 mL of a 97:3 (volume/volume) mixture of acetone and dimethyl sulfoxide to obtain concentrated stock solutions. If the test compound did not dissolve readily, the mixture was warmed and/or sonicated. The concentrated stock solutions obtained were diluted with an aqueous mixture containing acetone, water, isopropyl alcohol, dimethyl sulfoxide, Atplus 411F crop oil concentrate, and Triton X-155 surfactant in a 48.5:39:10:1.5:1.0:0.02 v/v ratio to obtain spray solutions of known concentration. The solutions containing the highest concentration to be tested were prepared by diluting 2 mL aliquots of the stock solution with 13 mL of the mixture and lower concentrations were prepared by dilution of appropriate smaller portions of the stock solution. Approximately 1.5 mL aliquots of each solution of known concentration were sprayed evenly onto each of the test plant pots using a DeVilbiss atomizer driven by compressed air pressure of 2 no 4 psi (140 to 280 kiloPascals) to obtain thorough coverage of each plant. Control plants were sprayed in the same manner with the aqueous mixture. In this test an application rate of 1 ppm results in the application of approximately 1 g/Ha.
The treated plants and control plants were placed in a greenhouse as described above and watered by sub-irrigation to prevent wash-off of the test compounds. After 2 weeks the condition of the test plants as compared with that of the untreated plants was determined visually and scored on a scale of 0 to 100 percent where 0 corresponds to no injury and 100 corresponds to complete kill. Some of the compounds tested, application rates employed, plant species tested, and results are given in Tables 2 and 2A.
TABLE 2__________________________________________________________________________POSTEMERGENCE HERBICIDAL ACTIVITY Wild Barn- GiantCpd. Rate, Cockle- Jimson- Lambs- Morning- Velvet- Field Buck- Black- yard fox- Johnson-No. ppm bur weed quarters glory leaf Pansy wheat grass grass tail grass__________________________________________________________________________1 62.5 20 70 70 95 95 30 90 0 0 0 02 62.5 95 80 70 95 100 40 90 0 0 0 03 125 85 70 85 80 95 30 80 20 20 0 204 125 100 80 20 70 100 75 75 0 0 0 05 62.5 85 50 90 50 95 85 0 0 0 0 06 125 0 0 25 50 85 100 0 25 0 0 07 125 98 70 70 70 80 100 75 70 50 50 708 3.9 100 50 85 70 65 60 70 100 80 25 939 31.3 90 95 70 90 98 100 85 85 80 70 7510 500 80 80 20 40 80 100 40 80 70 0 011 125 80 40 20 80 85 95 50 20 50 35 012 250 90 90 60 80 95 100 70 80 98 60 8013 15.6 75 70 90 100 98 100 85 80 90 50 9014 250 100 100 60 100 80 100 90 80 98 85 7015 1000 80 30 0 40 65 25 0 60 0 0 016 125 35 80 90 100 95 100 -- 95 -- 20 5017 31.3 40 65 65 85 85 100 90 0 35 25 3518 62.5 95 95 90 75 95 95 -- 0 -- 40 1019 15.6 95 75 80 80 85 80 80 85 90 90 8020 3.9 100 90 80 80 85 85 80 35 80 50 8821 7.8 100 90 90 86 85 75 85 85 88 35 8522 83.3 85 75 50 90 90 50 30 20 35 0 023 15.6 -- -- 75 100 85 85 90 80 85 75 9024 15.6 88 -- 75 90 -- 90 90 70 89 70 8525 31.3 100 100 70 98 98 100 100 90 85 40 7026 31.3 98 70 40 80 85 100 100 20 30 20 6027 31.3 90 80 50 60 98 80 100 50 40 20 4028 1.95 90 85 60 95 75 98 100 55 70 20 7529 31.3 100 70 80 50 99 100 99 80 80 55 7530 15.6 98 98 30 100 85 90 85 98 80 30 7531 3.9 100 88 40 80 90 100 90 0 25 60 5032 7.8 90 70 78 90 88 100 100 20 80 75 8033 31.3 98 50 80 100 80 100 80 80 75 50 7534 31.3 98 70 80 98 100 100 85 70 98 40 9835 31.3 90 50 70 90 80 100 100 20 40 0 7036 31.3 90 55 80 100 80 98 99 35 70 40 9037 3.9 55 60 20 99 97 100 100 35 0 0 038 7.8 100 95 15 70 97 100 95 0 0 30 6539 15.6 97 80 60 70 93 99 70 50 35 50 8040 31.3 93 80 35 70 93 100 80 80 70 60 7541 15.6 100 85 0 93 99 90 99 50 30 45 6542 15.6 100 85 100 90 90 100 85 50 75 75 7543 62.5 -- 90 90 100 90 90 88 50 65 70 5544 7.8 -- 90 90 85 85 85 75 85 85 70 8545 15.6 -- 90 90 90 85 75 75 50 65 35 6046 250 80 100 50 80 80 80 40 70 70 50 7547 15.6 70 70 55 90 70 100 0 90 70 70 8048 7.8 100 83 10 100 80 100 80 0 0 20 1549 31.3 100 99 50 80 99 99 75 0 10 45 6550 31.3 85 99 30 70 95 80 65 70 75 50 8351 15.6 90 60 75 98 100 90 85 90 75 30 9552 500 50 80 70 90 88 100 75 20 20 25 6053 15.6 40 97 85 80 85 100 65 70 90 35 9554 62.5 40 95 85 80 100 70 65 90 80 80 9355 62.5 90 85 90 90 70 88 80 88 85 70 8556 31.3 90 85 75 87 90 100 85 90 75 70 7057 15.6 90 70 85 90 88 85 80 75 85 65 8858 3.9 70 60 90 85 85 100 90 80 50 30 6059 31.3 90 85 60 85 85 100 80 80 60 50 8560 31.3 95 85 75 85 85 95 85 90 80 60 9061 15.6 90 -- 85 85 85 98 95 85 75 60 8062 31.3 85 -- 90 80 85 100 90 75 40 60 5063 15.6 85 -- 85 80 90 90 95 90 40 55 8064 500 90 90 50 70 25 60 50 60 30 50 8065 500 75 75 60 30 60 70 60 0 0 10 4066 7.8 90 90 100 75 85 95 98 70 80 95 10067 15.6 88 -- 55 85 85 85 88 60 70 70 8569 15.6 90 -- 85 90 88 90 88 85 90 80 9070 15.6 90 88 30 88 75 80 100 70 30 30 4071 15.6 90 85 60 90 88 10 90 70 50 35 4072 7.8 90 85 88 90 80 75 85 80 75 60 7573 3.9 50 70 60 87 90 75 80 50 85 40 8574 62.5 100 90 50 80 80 80 60 60 75 50 3075 62.5 100 70 40 75 90 85 40 40 10 20 076 125 80 80 65 90 80 80 50 50 75 70 7077 125 98 60 40 90 98 80 65 50 50 45 4078 31.3 100 80 40 90 98 100 85 60 60 0 4079 62.5 90 -- 70 75 80 100 85 70 70 40 8080 0.98 85 60 20 60 80 75 100 60 60 30 60 7.8 100 100 75 90 100 90 98 98 78 40 7581 1.95 95 80 60 98 75 100 95 80 75 40 8082 31.3 100 90 70 98 85 100 100 95 98 80 9883 31.3 100 100 90 90 90 100 100 88 90 85 10084 7.8 100 30 90 90 90 100 85 90 80 50 8085 15.6 80 60 70 80 90 80 50 90 75 50 9886 3.9 90 80 70 55 50 100 80 95 75 75 4087 125 60 50 75 75 85 70 -- 75 75 20 7088 31.3 80 80 100 75 85 80 85 80 65 40 9089 125 100 85 50 85 80 95 80 30 60 40 4090 15.6 100 85 75 60 70 -- 40 50 40 30 5091 3.9 85 90 40 85 60 60 75 60 80 20 9092 125 100 80 75 85 85 85 90 80 85 50 8593 500 100 75 60 75 60 30 40 40 10 20 094 62.5 100 85 25 85 50 60 40 70 30 30 6095 125 100 -- 70 100 75 97 83 20 5 40 2096 0.49 90 80 10 70 80 80 65 10 0 0 1097 62.5 90 90 80 80 90 95 85 70 88 60 8098 1.95 85 80 60 100 97 80 75 50 60 0 8099 125 90 50 60 40 80 100 60 50 40 20 30100 250 99 -- 30 60 93 10 85 30 70 20 10101 15.6 100 80 80 98 70 80 75 80 90 75 90102 1000 80 -- 0 0 10 0 0 0 0 0 0103 7.8 93 -- 80 60 80 65 95 70 85 70 90104 31.3 95 -- 97 70 75 80 97 90 80 60 99105 500 93 -- 55 20 70 60 65 45 65 45 35106 3.9 85 -- 35 50 15 90 65 93 75 55 0107 500 97 -- 60 60 80 20 80 10 5 0 0108 1.95 97 -- 70 75 90 80 80 40 50 50 55109 31.3 98 90 55 90 65 65 75 0 10 0 40110 7.8 90 65 85 65 70 85 70 15 65 60 65111 62.5 99 60 97 93 75 97 70 75 70 65 70112 125 100 95 20 70 100 45 70 0 0 0 0113 62.5 98 90 0 100 90 20 75 0 0 0 0114 500 90 75 50 75 90 0 0 0 0 0 0115 1.95 100 85 70 100 80 65 65 45 0 60 50116 3.9 97 70 85 97 95 75 -- 25 65 0 60117 7.8 100 70 100 100 90 80 80 83 80 65 65118 62.5 100 90 60 85 80 60 80 0 75 30 80119 1000 100 15 0 -- 0 70 0 0 35 0 0120 125 100 60 60 85 75 75 0 40 35 0 0121 62.5 100 85 40 98 78 80 78 75 70 65 70122 62.5 90 90 40 80 85 70 80 0 75 70 75123 15.6 90 90 70 80 75 90 75 60 75 80 55124 1000 75 80 0 80 30 75 50 0 30 0 0125 500 85 80 80 75 40 90 30 78 80 40 80126 15.6 100 85 80 98 80 50 80 0 0 50 0127 62.5 100 75 80 80 80 70 80 80 75 75 75128 31.3 85 90 75 75 80 90 80 75 60 60 75129 15.6 100 90 75 90 70 75 80 75 75 98 90130 31.3 -- 100 60 80 75 85 60 90 80 -- 80131 250 -- 98 50 90 90 75 80 50 30 -- 75132 3.9 -- 100 30 85 90 80 80 85 55 -- 75133 125 -- 98 30 95 90 85 80 90 45 -- 75134 15.6 90 80 95 90 70 85 -- 50 70 20 50135 31.3 90 -- 85 90 85 -- 85 75 65 75 --136 125 70 90 80 90 75 80 80 75 75 0 70137 500 95 -- 70 75 70 -- 75 80 5 60 --138 31.3 90 90 90 80 80 70 80 98 85 70 95139 31.3 90 95 75 85 80 75 75 98 90 75 90140 31.3 80 90 95 85 75 75 85 75 75 60 75141 1000 70 80 60 70 40 75 75 20 20 0 40142 500 85 -- 20 100 75 -- 70 40 0 55 --143 250 95 -- 0 90 75 -- 70 -- 0 30 --144 500 89 -- 0 70 20 -- 55 -- 0 50 --145 7.8 100 -- 89 90 88 -- 65 75 65 30 --146 7.8 85 -- 80 100 80 -- 80 30 60 40 --147 31.3 80 -- 60 90 80 -- 88 80 80 75 --148 31.3 98 -- 90 75 95 -- 75 75 80 80 --151 31.3 98 -- 90 80 95 -- 80 75 80 70 --152 1000 98 -- 50 85 30 -- 75 70 60 60 --153 62.5 88 -- 75 100 85 -- 80 65 55 70 --154 15.6 100 -- 80 100 85 -- 75 70 80 75 --155 6205 100 -- 90 100 90 -- 85 88 85 75 --156 125 85 -- 85 80 70 -- 80 85 80 80 --157 15.6 100 -- 60 100 78 -- 85 60 80 70 --158 7.8 100 -- 40 86 89 -- 75 20 25 30 --159 31.3 90 -- 85 85 88 -- 88 80 85 85 --160 62.5 90 -- 85 90 80 -- 80 88 80 85 --161 125 80 -- 85 85 80 -- 85 80 80 80 --162 31.3 100 -- 80 90 -- -- -- 0 30 60 --163 125 80 -- 95 95 -- -- -- 50 75 85 --164 125 90 -- 80 100 -- -- -- 0 20 50 --165 15.6 100 -- 90 100 -- -- -- 75 80 95 --166 1.95 90 -- 85 95 -- -- -- 50 85 85 --167 31.3 90 -- 95 100 -- -- -- 30 75 90 --168 62.5 100 -- 88 90 80 -- 80 85 80 88 --169 15.6 95 -- 90 100 85 -- 85 75 85 90 --170 31.3 90 -- 85 85 70 -- 85 90 85 80 --171 31.3 100 -- 70 90 90 -- 85 90 70 25 --172 125 90 -- 80 90 90 -- 85 70 75 60 --173 125 95 -- 30 95 75 -- 85 35 30 0 --174 31.3 100 -- 85 90 80 -- 80 75 80 60 --176 31.3 100 -- 75 85 88 -- 85 70 70 60 --177 125 100 -- 60 85 85 -- 85 40 20 50 --178 31.3 100 -- 80 95 90 -- 80 70 80 60 --179 62.5 100 -- 60 80 85 -- 80 15 20 20 --180 250 95 -- 50 95 75 -- 80 30 30 25 --181 125 85 -- 88 88 85 -- 78 60 80 70 --182 500 100 -- 72 85 90 -- 75 20 0 30 --183 500 90 -- 60 100 90 -- 85 20 10 15 --186 250 100 -- 90 85 88 -- 80 80 80 85 --187 62.5 90 -- 90 85 90 -- 85 85 85 80 --188 31.3 90 -- 60 85 35 -- 80 35 75 60 --189 31.3 90 -- 85 85 75 -- 85 25 25 40 --190 7.8 100 -- 80 95 85 -- 85 40 70 30 --191 3.9 100 -- 70 90 80 -- 80 10 50 40 --192 62.5 75 -- 80 80 70 -- 80 80 75 60 --193 31.3 100 -- 70 95 55 -- 70 50 80 50 --194 15.6 100 -- 70 90 60 -- 60 80 80 85 --195 250 80 -- 70 75 50 -- 80 70 70 70 --198 31.3 100 -- 98 80 98 -- 90 30 50 70 --199 62.5 98 -- 80 100 95 -- 90 50 80 75 --200 62.5 95 -- 60 85 70 -- 80 85 90 75 --201 31.3 100 -- 85 90 95 -- 90 60 85 60 --202 125 85 -- 90 90 85 -- 90 80 85 85 --203 125 50 -- 85 85 80 -- 80 90 85 95 --204 250 90 -- 85 90 75 -- 80 40 75 30 --205 62.5 90 -- 90 90 90 -- 85 90 85 80 --208 31.3 90 -- 80 90 70 -- 90 40 70 75 --212 15.6 100 -- 40 90 40 -- 85 90 65 40 --__________________________________________________________________________
TABLE 2A__________________________________________________________________________POSTEMERGENCE HERBICIDAL ACTIVITY Wild Barn- Giant RoxCpd. Rate, Chick- Cockle- Lambs- Morning- Velvet- Field Buck- Black- yard fox- OrangeNo. ppm weed bur quarters glory leaf Pansy wheat grass grass tail Sorghum__________________________________________________________________________213 7.8 95 98 50 100 85 80 90 40 40 0 95214 7.8 90 90 60 80 70 70 90 80 65 50 95215 15.6 70 90 75 85 70 80 90 90 75 10 98216 7.8 98 90 75 90 70 90 85 90 75 20 95217 125 75 90 75 90 85 85 75 85 80 78 90218 31.3 100 70 65 85 85 78 85 35 30 30 55219 31.3 90 75 75 80 75 80 85 70 40 60 95220 125 90 80 70 80 85 88 85 75 40 60 60221 62.5 85 85 70 75 75 85 85 75 75 70 60223 31.3 90 70 90 90 60 90 60 85 65 65 90224 500 50 70 100 70 75 90 85 85 35 20 78225 250 80 85 -- 80 60 90 80 85 80 35 70226 7.8 90 100 98 70 75 80 80 80 78 70 90227 7.8 90 100 95 70 70 90 80 95 80 78 90228 62.5 95 100 90 90 85 90 75 90 80 90 95229 62.5 95 90 90 50 75 75 80 60 75 60 60230 125 70 -- 95 88 90 90 80 88 85 80 85231 125 78 -- 95 85 90 88 85 90 88 30 88232 15.6 70 -- 90 90 88 95 90 80 75 75 90233 31.3 85 -- 90 80 85 0 85 83 85 95 90234 15.6 85 99 100 80 95 83 95 98 78 85 95235 7.8 95 98 99 75 75 85 85 85 78 55 78236 15.6 98 100 100 75 70 83 80 85 80 50 78238 15.6 90 100 95 80 90 85 80 80 78 55 78239 15.6 80 70 95 90 70 78 95 98 75 78 78240 7.8 78 98 98 75 70 75 88 98 78 65 75241 31.3 80 90 40 75 95 80 80 0 0 0 0242 3.9 85 100 90 95 95 85 80 60 70 40 99243 3.9 90 100 100 95 80 80 50 70 75 35 78244 31.3 98 100 98 98 65 85 75 95 78 98 78245 125 40 -- 60 75 75 75 80 -- 75 10 20246 62.5 79 -- 90 85 90 85 85 -- 88 88 88247 62.5 70 -- 90 85 80 90 85 -- 88 80 88248 125 70 -- 70 80 80 85 88 -- 85 90 90249 125 70 -- 90 80 65 90 80 -- 85 75 90250 31.3 88 100 100 93 95 70 88 90 78 83 99251 62.5 95 100 100 95 98 60 80 98 75 78 98252 7.8 95 95 95 95 95 78 85 25 25 35 75253 62.5 80 95 95 85 78 85 80 60 80 78 80254 31.3 95 90 100 90 75 80 80 80 90 75 85255 31.3 95 95 90 85 95 78 85 50 70 78 85256 125 85 90 90 70 75 90 75 65 55 78 65257 31.3 90 95 90 80 70 85 78 80 90 95 78258 97.5 35 95 95 75 83 83 85 90 60 70 78__________________________________________________________________________
70. Evaluation of Preemergence Herbicidal Activity
Seeds of the desired test plant species were planted in a soil matrix prepared by mixing a loam soil which was composed of about 43 percent silt, 19 percent clay, and 38 percent sand and had a pH of about 8.1 and an organic matter content of about 1.5 percent and sand in a 70 to 30 ratio. The soil matrix was contained in plastic pots with a surface area of 161 square centimeters. When required to ensure good germination and healthy plants, a fungicide treatment and/or other chemical or physical treatment was applied.
A weighed amount, determined by the highest rate to be tested, of each test compound was placed in a 20 mL glass vial and was dissolved in 8 mL of a 97:3 v/v (volume/volume) mixture of acetone and dimethyl sulfoxide to obtain concentrated stock solutions. If the test compound did not dissolve readily, the mixture was warmed and/or sonicated. The stock solutions obtained were diluted with a 99.9:0.1 mixture of water and Tween.RTM. 155 surfactant to obtain application solutions of known concentration. The solutions containing the highest concentration to be tested were prepared by diluting 4 mL aliquots of the stock solution with 8.5 mL of the mixture and lower concentrations were prepared by dilution of appropriate smaller portions of the stock solution. A 2.5 mL aliquot of each solution of known concentration was sprayed evenly onto the soil of each seeded pot using a Cornwall 5.0 mL glass syringe fitted with a TeeJet TN-3 hollow cone nozzle to obtain thorough coverage of the soil in each pot. Control pots were sprayed in the same manner with the aqueous mixture. A highest application rate of 4.48 Kg/Ha is achieved when 50 mg of test compound is employed.
The treated pots and control pots were placed in a greenhouse with an approximately 15 hr photoperiod which was maintained at about 23.degree.-29.degree. C. during the day and 22.degree.-28.degree. C. during the night. Nutrients and water were added on a regular basis and supplemental lighting was provided with overhead metal halide 1000 Watt lamps as necessary. The water was added by top-irrigation. After 3 weeks the condition of the test plants that germinated and grew as compared with that of the untreated plants that germinated and grew was determined visually and scored on a scale of 0 to 100 percent where 0 corresponds to no injury and 100 corresponds no complete kill or no germination. Some of the compounds nested, application rates employed, plant species tested, and results are given in Table 3.
TABLE 3__________________________________________________________________________PREEMERGENCE HERBICIDAL ACTIVITY Wild Barn- GiantCpd. Rate, Morning- Velvet- Buck- Black- yard fox- Johnson- WildNo. Kg/Ha glory Pigweed leaf wheat grass Grass tail grass oats__________________________________________________________________________1 0.56 85 95 90 90 40 50 40 70 402 0.28 80 99 95 95 40 20 70 70 303 0.56 40 100 90 -- 0 -- 30 0 504 0.28 80 100 95 75 75 80 75 65 605 0.14 80 90 95 40 70 60 60 75 306 0.56 60 0 65 10 40 80 0 30 307 1.12 80 100 90 50 95 98 60 80 08 0.018 75 98 80 80 100 100 80 90 809 0.035 80 98 80 85 100 98 70 80 6010 0.28 90 95 60 50 98 90 75 80 5511 0.14 90 85 75 50 95 98 50 40 012 0.14 80 100 85 60 90 80 65 50 5013 0.035 60 100 85 85 100 98 95 80 7514 0.28 85 98 85 60 95 98 55 60 4516 0.28 70 80 70 -- 70 80 60 40 7017 0.28 90 100 75 -- 70 70 50 40 5018 0.28 80 95 60 -- 50 50 80 40 7519 0.14 95 98 95 98 85 95 97 98 8820 0.070 95 95 90 92 60 80 75 85 7021 0.14 90 98 85 95 85 75 75 70 7522 2.24 85 95 85 60 60 65 70 65 1023 0.070 90 98 95 92 85 90 92 99 9024 0.070 90 95 90 92 70 78 80 90 5025 0.035 90 98 80 50 70 95 40 60 5026 0.56 90 100 85 60 50 65 40 70 2027 0.28 60 100 85 50 98 70 60 30 028 0.018 50 90 75 85 90 90 50 75 2029 1.12 60 98 60 70 90 100 75 85 5030 0.035 90 100 65 95 90 98 90 85 4031 0.14 90 100 90 100 40 90 70 90 2032 0.070 85 100 85 90 98 98 90 98 4033 0.035 50 100 25 100 70 98 90 85 2034 0.070 90 100 90 90 98 95 40 85 5035 0.070 90 100 80 90 15 10 20 10 036 0.070 60 98 70 85 60 85 60 80 6037 0.035 95 100 75 100 20 65 60 0 038 0.070 85 100 60 100 0 50 20 0 1040 0.035 40 99 65 95 95 90 40 80 2041 0.070 90 100 60 100 20 99 80 85 1042 0.070 90 100 90 90 98 80 70 80 5043 0.070 50 98 60 85 30 60 60 20 044 0.070 90 100 60 90 98 95 98 90 6045 0.070 85 100 80 90 100 95 60 85 2046 0.56 50 100 50 60 80 60 50 60 047 0.070 80 0 60 90 99 85 90 85 5049 0.035 80 100 40 99 0 0 50 10 050 0.070 90 100 90 40 98 98 80 90 8051 0.035 60 98 100 90 60 95 60 80 5052 0.56 85 98 85 80 40 50 40 50 2053 0.035 10 90 90 95 98 80 90 80 8054 0.56 90 100 90 80 60 40 30 20 2055 0.56 90 90 90 88 90 87 70 90 7856 0.28 90 90 85 90 85 85 80 85 7557 0.14 90 88 90 90 80 90 80 85 6558 0.018 90 98 85 85 90 65 40 75 4059 0.035 80 95 88 90 95 70 50 80 5060 0.070 85 98 80 95 90 70 60 85 5061 0.035 90 98 80 85 90 80 80 90 6562 0.14 90 100 95 90 100 85 78 80 5063 0.070 95 90 80 80 60 70 70 -- 6064 1.12 55 45 0 0 0 0 0 90 065 2.24 75 80 55 45 20 45 45 10 2566 0.070 90 98 95 98 98 85 80 98 9067 0.035 85 90 88 90 70 60 75 75 5068 0.15 85 95 92 50 40 60 60 75 2069 0.070 95 95 90 95 80 85 90 100 8870 0.28 90 90 85 90 85 75 70 75 5071 0.070 90 60 80 92 70 65 50 95 2572 0.14 90 90 85 90 95 75 70 88 6573 0.070 90 85 80 88 90 80 75 85 4074 0.56 80 100 90 80 80 98 80 60 5075 0.56 80 98 80 80 20 50 30 40 076 0.28 75 100 70 60 50 95 60 60 5077 0.56 80 100 70 60 50 30 30 40 2078 0.28 90 100 85 40 65 90 60 -- 079 0.28 85 100 60 40 80 95 50 -- 5080 0.018 95 95 80 60 90 60 80 -- 081 0.009 30 98 30 80 85 95 85 -- 0 0.070 100 100 98 95 90 100 95 -- 9082 0.035 80 100 80 95 98 90 90 80 6083 0.035 30 98 60 85 90 90 60 80 6584 0.070 85 100 75 85 100 98 50 50 7085 0.070 75 100 50 80 80 90 75 98 7086 0.28 100 100 70 90 98 98 90 90 7587 0.56 85 100 85 40 100 98 75 85 5088 0.070 90 95 85 90 75 85 78 98 8089 0.28 90 90 80 20 60 90 85 -- 3090 0.28 80 85 90 70 98 95 90 90 8591 0.14 95 90 90 75 90 95 80 -- 8092 0.28 95 95 90 40 95 90 90 -- 7093 1.12 80 50 50 40 0 50 0 30 2094 1.12 90 80 80 90 99 90 90 95 9095 1.12 90 90 80 80 25 65 60 30 1096 0.14 90 98 95 95 88 70 60 65 6597 0.035 85 90 90 95 80 70 80 90 6598 0.009 85 95 80 85 85 45 60 90 20 0.070 90 98 85 98 95 95 98 98 8599 0.14 90 90 70 80 70 65 85 70 50100 0.56 70 75 80 100 80 60 70 70 40101 0.070 85 98 80 90 80 90 80 95 80103 0.035 90 95 80 95 80 98 85 98 70104 0.035 90 90 80 90 98 98 80 98 75105 0.070 60 70 40 30 50 50 50 75 10106 0.070 90 95 60 95 100 95 95 95 75107 0.070 40 80 20 60 0 0 0 0 0108 0.018 90 98 85 95 98 90 80 98 50109 0.28 90 98 80 90 95 75 45 90 50110 0.14 90 95 75 85 95 85 80 95 85111 0.070 85 90 90 95 90 95 90 90 85112 1.12 60 100 85 30 30 40 50 60 30113 1.12 80 100 90 60 30 80 30 70 0114 1.12 30 80 50 30 0 20 20 0 0115 0.070 90 95 95 80 95 85 70 100 70116 0.009 80 90 90 60 60 40 50 80 60117 0.035 80 100 85 100 99 90 90 90 90118 0.56 80 90 50 70 95 50 80 90 60121 0.56 85 95 80 90 95 60 90 90 80122 0.14 85 95 90 95 30 95 90 90 50123 0.070 80 99 80 90 70 90 90 90 85125 1.12 90 70 50 30 85 90 95 95 80126 0.28 95 85 98 90 95 85 70 95 90127 0.28 50 75 80 70 25 10 0 85 80128 0.14 90 85 80 60 95 75 20 85 90129 0.018 98 70 90 85 98 80 80 80 90130 0.070 90 95 88 -- 98 85 85 -- 85131 0.56 90 95 85 -- 60 65 65 -- 35132 0.035 90 95 95 -- -- 95 75 -- 60133 0.14 90 100 90 -- 95 80 75 -- 70134 0.035 90 85 80 -- 65 90 60 -- 70135 0.018 95 90 95 -- 99 98 95 -- 85136 0.14 80 95 80 -- 90 90 50 -- 40138 0.035 85 95 80 -- 98 90 90 -- 80139 0.018 90 90 80 -- 90 85 80 -- 90140 0.070 85 95 95 -- 70 90 70 -- 95145 0.14 90 70 70 -- 50 50 50 -- 30146 0.14 90 90 80 -- 60 60 50 -- 60147 0.14 70 90 85 -- 80 50 95 -- 85148 0.14 85 80 98 -- 90 95 90 -- 90151 0.14 90 90 80 -- 80 95 80 -- 50152 0.14 0 30 40 -- 80 30 0 -- 0153 0.070 90 85 90 -- 40 60 60 -- 20154 0.035 90 90 50 -- 90 70 80 -- 80155 0.035 90 90 80 -- 90 85 70 -- 90156 0.070 40 60 0 -- 40 60 80 -- 80157 0.035 90 70 80 -- 75 70 50 -- 70158 0.070 90 99 90 -- 70 75 70 -- 60159 0.56 85 95 90 -- 95 90 95 -- 90160 0.035 80 90 95 -- 99 40 85 -- 85161 0.14 85 70 90 -- 98 90 90 -- 80162 0.14 90 95 90 -- 40 60 60 -- 40163 0.28 90 85 85 -- 70 50 30 -- 60164 0.56 80 80 80 -- 50 40 30 -- 50165 0.035 95 90 95 -- 85 90 95 -- 75166 0.035 75 90 60 -- 90 85 80 -- 85167 0.14 90 80 90 -- 60 85 80 -- 50168 0.035 90 95 90 -- 99 98 95 -- 95169 0.018 90 90 90 -- 70 85 70 -- 70170 0.035 80 98 90 -- 98 70 90 -- 95171 0.018 80 90 90 -- 90 30 65 -- 75172 0.14 75 98 80 -- 75 85 75 -- 80173 0.28 75 80 80 -- 70 40 50 -- 75175 0.070 85 98 85 -- 95 95 95 -- 80176 0.070 90 98 95 -- 85 90 70 -- 70177 0.56 75 100 85 -- 80 70 50 -- 65178 0.035 85 70 85 -- 85 90 70 -- 80179 0.28 80 90 85 -- 75 70 70 -- 70180 0.28 85 80 80 -- 85 50 -- -- 75181 0.070 80 95 75 -- 75 90 70 -- 75182 0.14 80 85 95 -- 70 40 75 -- 60183 0.28 85 90 95 -- 75 30 50 -- 50186 0.070 90 90 95 -- 98 75 75 -- 90187 0.070 90 85 90 -- 95 80 85 -- 85188 0.14 70 80 30 -- 65 85 95 -- 75189 0.14 85 95 80 -- 75 85 75 -- 60190 0.070 90 85 98 -- 85 80 70 -- 50191 0.018 85 80 90 -- 75 98 70 -- 70192 0.14 80 90 80 -- 85 95 95 -- 85193 0.14 90 90 75 -- 85 95 85 -- 80194 0.035 80 95 85 -- 90 90 95 -- 80195 0.28 70 80 50 -- 80 78 60 -- 85198 0.070 85 98 95 -- 85 85 80 -- 80199 0.070 85 95 95 -- 80 90 35 -- 80200 0.070 85 95 75 -- 90 95 85 -- 85201 0.035 90 95 90 -- 80 98 78 -- 75202 0.070 80 98 70 -- 80 90 80 -- 78203 0.14 75 98 75 -- 99 98 98 -- 80204 0.56 90 90 85 -- 85 80 75 -- 60205 0.070 95 98 90 -- 95 85 95 -- 85208 0.28 88 95 90 -- 95 75 90 -- 90213 0.035 85 80 90 -- 80 60 50 -- 70214 0.14 85 95 95 -- 100 95 95 -- 100215 0.070 70 50 85 -- 100 90 45 -- 90216 0.070 75 85 95 -- 100 100 60 -- 80217 0.035 70 75 60 -- 90 95 70 -- 75218 0.28 90 100 100 -- -90 78 60 -- 90219 0.28 90 70 95 -- 100 100 60 -- 98220 0.56 30 60 75 -- 75 25 65 -- 90221 0.28 40 90 75 -- 100 75 95 -- 85223 0.28 80 95 95 -- -- 73 95 -- 80224 0.28 50 60 75 -- -- 0 40 -- 40225 0.28 80 80 90 -- -- 70 78 -- 90226 0.070 80 95 90 -- -- 98 95 -- 95227 0.035 70 80 78 -- -- 85 90 -- 90228 0.14 80 90 80 -- -- 95 90 -- 80229 0.56 80 85 80 -- -- 95 85 -- 80230 0.28 90 100 95 -- -- 70 70 -- 90231 0.14 85 90 90 -- -- 75 70 -- 90232 0.14 90 90 90 -- -- 95 80 -- 90233 0.035 70 98 80 -- 90 85 90 -- 80234 0.14 90 95 90 -- 90 95 95 -- 95235 0.14 90 98 95 -- 90 90 90 -- 85236 0.14 90 80 85 -- 100 90 90 -- 85238 0.28 85 95 85 -- 90 90 80 -- 85239 0.14 80 95 90 -- 90 90 95 -- 80240 0.070 85 95 80 -- 95 90 80 -- 80241 0.28 90 90 95 -- -- 78 70 -- 80242 0.14 95 100 90 -- -- 80 75 -- 100243 0.070 90 98 80 -- 100 100 95 -- 90244 0.14 90 95 80 -- 90 90 95 -- 90245 0.28 85 85 80 -- -- 90 70 -- 70246 0.070 90 95 78 -- -- 80 90 -- 85247 0.28 85 100 85 -- -- 95 95 -- 95248 0.28 75 98 75 -- -- 90 90 -- 90249 0.56 80 98 70 -- -- 90 95 -- 90250 0.070 80 95 90 -- 85 95 90 -- 80251 0.070 78 95 90 -- 80 95 78 -- 80__________________________________________________________________________

Number	Name	Date
4605433	Pearson et al.	Aug 1986
4818273	Kleschick et al.	Apr 1989
4822404	Kleschick et al.	Apr 1989
5013351	Jelich et al.	May 1991
5163995	Van Heertum et al.	Nov 1992

Number	Date	Country
244948	Nov 1987	EPX
2054630	Feb 1981	GBX

N-aryl�1,2,4!triazolo�1,5-a!pyridine-2-sulfonamide herbicides

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CPC

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Entry
Houston, et al., Journal of Medicinal Chemistry, 28, 467-471 (1985).
Bouteau, et al., J. Heterocyclic Chem., 27, 1649 (1990).
Vercek, et al., Monatshefte fur Chemie, 114, 789-798 (1983).
Potts, et al., Journal of Organic Chemistry, 31 265-273 (1966).
Medwid, et al., J. Med. Chem. (33) 1230-1241 (1990).