Claims
- 1. A process for preparing a compound of Formula I ##STR32## wherein: ##STR33## represents: a) 6-membered heterocyclyl containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 nitrogen atoms, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2,
- C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2,
- aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, or when aryl is substituted on adjacent carbons they can form a 5- or 6-membered fused ring having one, two or three heteroatoms selected from O, N, and S, this ring is unsubstituted or substituted on carbon or nitrogen with one, two or three substituents selected from the group consisting of: H, OH, CO.sub.2 R.sup.6, Br, Cl, F, I, CF.sub.3, N(R.sup.7).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2 ;
- R.sup.1 is:
- a) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl,
- b) aryl, or
- c) heteroaryl;
- heteroaryl is defined as a 5- or 6-membered aromatic ring containing one, two or three heteroatoms selected from O, N and S , which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2 ;
- R.sup.2 is: OR.sup.4 or N(R.sup.5).sub.2 ;
- R.sub.3 is:
- a) H,
- b) C.sub.1 -C.sub.8 alkyl,
- c) C.sub.2 -C.sub.8 alkenyl,
- d) C.sub.2 -C.sub.8 alkynyl,
- e) C.sub.1 -C.sub.8 alkoxyl,
- f) C.sub.3 -C.sub.7 cycloalkyl,
- g) S(O).sub.t R.sup.5,
- h) Br, Cl, F, I,
- i) aryl,
- j) heteroaryl,
- k) N(R.sup.5).sub.2,
- l) NH.sub.2,
- m) --CHO,
- n) --CO--C.sub.1 -C.sub.8 alkyl,
- o) --CO--aryl,
- p) --CO--heteroaryl, or
- q) --CO.sub.2 R.sup.4 ;
- n is: 0 to 5;
- t is: 0, 1 or 2;
- R.sup.4 is: H, or C.sub.1 -C.sub.8 alkyl;
- R.sup.5 is: H, C.sub.1 -C.sub.8 alkyl, or aryl;
- R.sup.6, is: H, C.sub.1 -C.sub.8 alkyl, or aryl; and
- R.sup.7 is: H, C.sub.1 -C.sub.8 alkyl, aryl, alkyl and aryl are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2 ; or when two R.sup.7 substutients are on the same nitrogen they can join to form a ring of 3 to 6 atom;
- comprising the following steps:
- 1) adding chlorodi(C.sub.1 -C.sub.4)-alkylphosphate to a mixture of a compound of formula II and a first solvent at a temperature of about -30.degree. C. to about 0.degree. C., ##STR34## and 2) adding a slurry of a base in a second solvent to the phosphate containing solution while maintaining the temperature of the reaction mixture between about -78.degree. C. to about 25.degree. C. to produce the compound of Formula I.
- 2. The process as recited in claim 1, wherein the first non-acidic, aprotic solvent is selected from the group consisting of: tetrahydrofuran, diethyl ether, methyl t-butyl ether, toluene, benzene, hexane, pentane, and dioxane, or a mixture of said solvents.
- 3. The process as recited in claim 2, wherein the chlorodi(C.sub.1 -C.sub.4)-alkylphosphate is utilized in about 1.0 to about 2.0 equivalents.
- 4. The process as recited in claim 3, wherein the second non-acidic, aprotic solvent is selected from the group consisting of: tetrahydrofuran, diethyl ether, methyl t-butyl ether, toluene, benzene, hexane, pentane, and dioxane, or a mixture of said solvents.
- 5. The process as recited in claim 4, wherein the base is selected from sodium hydride, lithium diisopropylamide, lithium diethylamide, lithium dimethylamide and lithium hexamethyldisilazide.
- 6. The process as recited in claim 5, which includes the following additional steps:
- 3) aging the reaction mixture for about 2 to about 12 hours at a temperature of about -78.degree. C. to about 25.degree. C. to produce the compound of Formula I;
- 4) quenching the reaction mixture by addition of water and an acid, while maintaining the temperature of the reaction mixture at less than 30.degree. C. producing a biphasic solution composed of an aqueous layer and an organic layer containing the compound of Formula I;
- 5) separating the biphasic solution to isolate the organic layer containing the compound of Formula I in organic solvent(s) from the aqueous layer; and
- 6) evaporating the organic solvent from the orgainc layer to isolate the compound of Formula I.
- 7. The process as recited in claim 6, wherein base is utilized in a ratio of about 2.0 to about 4.0 equivalents of base per equivalent of the chlorodi(C.sub.1 -C.sub.4)-alkylphosphate.
- 8. The process as recited in claim 7, wherein the first solvent is toluene.
- 9. The process as recited in claim 8, wherein the chlorodi(C.sub.1 -C.sub.4)-alkylphosphate is utilized in 1.5 equivalents.
- 10. The process as recited in claim 9, wherein the second solvent is tetrahydrofuran.
- 11. The process as recited in claim 10, wherein base is utilized in a ratio of about 3.0 equivalents of base per equivalent of the chlorodi(C.sub.1 -C.sub.4)-alkylphosphate.
- 12. The process as recited in claim 11, wherein the temperature range in Steps 2 and 3 is about -15.degree. C. to about 10.degree. C.
Parent Case Info
This non-provisional application claims priority from provisional application U.S. Ser. No. 60/081,250 filed on Apr. 9, 1998 (now abandoned).
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