Patent Grant
7488824
This application is a 371 of International Application No. PCT/EP2004/002291 filed Mar. 5, 2004, which claims priority to CH 373/03 filed Mar. 7, 2003, the contents of which are incorporated herein by reference.
The present invention relates to a novel process for the preparation of 6-haloalkyl-3-nicotinic acid esters and also to novel enamine intermediates for use in that process.
6-Haloalkyl-3-nicotinic acid esters are valuable intermediates for the preparation of herbicides such as those described, for example, in WO 01/94339.
From Heterocycles, Vol. 48, No. 4, 1998, pages 779-785 it is known to prepare 6-trifluoro-3-nicotinic acid ethyl esters substituted by aryl in the 4-position, corresponding to formula A, by means of dehydrogenation and subsequent oxidation of the compound of formula B in accordance with the following scheme
As a result of the uneconomic multi-step procedure, that process is not well suited to the large-scale preparation of 6-haloalkyl-3-nicotinic acid ethyl esters.
According to Heterocycles, Vol. 46, 1997, pages 129-132, 6-trifluoro-3-nicotinic acid methyl esters substituted by phenyl or alkyl in the 2-position, corresponding to formula C,
can be prepared by reacting a compound of formula E with a compound of formula D in benzene and in the presence of trifluoroacetic acid. In addition to unsatisfactory yields, that process has the serious disadvantage for large-scale preparation that the quality of the enamine (E) used as starting material continuously deteriorates during storage as a result of polymerisation reactions, making it considerably more difficult to ensure a consistent product quality.
The problem of the present invention is consequently to make available a novel process for the preparation of 6-haloalkyl-3-nicotinic acid esters which makes it possible to prepare those compounds at reasonable cost, in high yields and with good quality.
The present invention accordingly relates to a process for the preparation of compounds of formula I
wherein
wherein R3 is C1-C8alkyl or C3-C6cycloalkyl and R4 and R05 are as defined for formula I, with a compound of formula III
wherein R, R1, R2 and X1 are as defined for formula I, in an inert solvent in the presence of a proton source.
The alkyl groups appearing in the substituent definitions may be straight-chained or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl and also the branched isomers thereof. Alkoxy, alkenyl and alkynyl groups are derived from the mentioned alkyl groups. The alkenyl and alkynyl groups may be mono- or poly-unsaturated.
Halogen is generally fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. The same is also correspondingly true for halogen in conjunction with other meanings such as haloalkyl or halophenyl.
Haloalkyl groups preferably have a chain length of from 1 to 6 carbon atoms. Haloalkyl is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl or 2,2,2-trichloroethyl; preferably trichloromethyl, difluorochloromethyl, difluoromethyl, trifluoromethyl or dichlorofluoromethyl.
As haloalkenvl there come into consideration alkenyl groups substituted one or more times by halogen, halogen being fluorine, chlorine, bromine or iodine, especially fluorine or chlorine, for example 2,2-difluoro-1-methylvinyl, 3-fluoropropenyl, 3-chloropropenyl, 3-bromopropenyl, 2,3,3-trifluoropropenyl, 2,3,3-trichloropropenyl and 4,4,4-trifluoro-but-2-en-1-yl. Among the C3-C6alkenyl groups substituted once, twice or three times by halogen, preference is given to those that have a chain length of from 3 to 5 carbon atoms.
As haloalkynyl there come into consideration alkynyl groups substituted one or more times by halogen, halogen being bromine, iodine or, especially, fluorine or chlorine, for example 3-fluoropropynyl, 3-chloropropynyl, 3-bromopropynyl, 3,3,3-trifluoropropynyl and 4,4,4-trifluoro-but-2-yn-1-yl. Among the alkynyl groups substituted one or more times by halogen, preference is given to those that have a chain length of from 3 to 5 carbon atoms.
Alkoxy groups preferably have a chain length of from 1 to 6 carbon atoms. Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy or the pentyloxy or hexyloxy isomers; preferably methoxy or ethoxy. Alkylcarbonyl preferably is acetyl or propionyl. Alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl; preferably methoxycarbonyl or ethoxycarbonyl. Haloalkoxy groups preferably have a chain length of from 1 to 8 carbon atoms. Haloalkoxy is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy or 2,2,2-trichloroethoxy; preferably difluoromethoxy, 2-chlorethoxy or trifluoromethoxy. Alkylthio groups preferably have a chain length of from 1 to 8 carbon atoms. Alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio, preferably methylthio or ethylthio. Alkylsulfinyl is, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl or tert-butylsulfinyl; preferably methylsulfinyl or ethylsulfinyl.
Alkylsulfonyl is, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl or tert-butylsulfonyl; preferably methylsulfonyl or ethylsulfonyl. Alkoxyalkoxy groups preferably have a chain length of from 1 to 8 carbon atoms. Examples of alkoxyalkoxy are: methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy, propoxymethoxy and butoxybutoxy. Alkylamino is, for example, methylamino, ethylamino, n-propylamino, isopropylamino or the butylamine isomers. Dialkylamino is, for example, dimethylamino, methylethylamino, diethylamino, n-propylmethylamino, dibutylamino or diisopropylamino. Preference is given to alkylamino groups having a chain length of from 1 to 4 carbon atoms. Alkoxyalkyl groups preferably have a chain length of from 2 to 6 carbon atoms. Alkoxyalkyl is, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, n-propoxymethyl, n-propoxyethyl, isopropoxymethyl or isopropoxyethyl. Alkylthioalkyl groups preferably have from 2 to 8 carbon atoms. Alkylthioalkyl is, for example, methylthiomethyl, methylthioethyl, ethylthiomethyl, ethylthioethyl, n-propylthiomethyl, n-propylthioethyl, isopropylthiomethyl, isopropylthioethyl, butylthiomethyl, butylthioethyl or butylthiobutyl. The cycloalkyl groups preferably-have from 3 to 8 ring carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Phenyl, including phenyl as part of a substituent such as phenoxy, benzyl, benzyloxy, benzoyl, phenylthio, phenylalkyl and phenoxyalkyl, may be present in substituted form, in which case the substituents may be in the ortho-, meta- and/or para-position(s). Preferred substituent positions are the positions ortho and para to the ring attachment position.
In accordance with the process according to the invention there are preferably prepared those compounds of formula I wherein
or the group —R1—X1—R2 together is C1-C6alkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6-alkynyl, C2-C6haloalkynyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6haloalkyl, C1-C6haloalkylthio, C1-C6haloalkylsulfinyl, C1-C6haloalkylsulfonyl, C1-C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylamino, di(C1-C6alkyl)amino, C1-C6alkylaminosulfonyl, di(C1-C6alkyl)aminosulfonyl, —NH—S—R13, —N—(C1-C4alkylthio)-R13, —NH—SO—R14, —N—(C1-C4alkylsulfonyl)-R14, —NH—SO2—R15, —N—(C1-C4alkylsulfonyl)-R15, nitro, cyano, halogen, hydroxy, amino, formyl, rhodano-C1-C6alkyl; cyano-C1-C6alkyl, oxiranyl, C3-C6alkenyloxy, C3-C6alkynyloxy, C1-C6alkoxy-C1-C6alkoxy, cyano-C1-C6alkenyloxy, C1-C6alkoxycarbonyloxy-C1-C6alkoxy, C3-C6alkynyloxy, cyano-C1-C6alkoxy, C1-C6alkoxycarbonyl-C1-C6alkoxy, C1-C6alkylthio-C1-C6alkoxy, alkoxycarbonyl-C1-C6alkylthio, alkoxycarbonyl-C1-C6alkylsulfinyl, alkoxycarbonyl-C1-C6alkylsulfonyl, C1-C6alkylsulfonyloxy, C1-C6haloalkylsulfonyloxy, phenyl, benzyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzylthio, benzylsulfinyl or benzylsulfonyl, it being possible for the phenyl groups to be substituted one or more times by halogen, methyl, ethyl, trifluoromethyl, methoxy or by nitro;
The process according to the invention is especially suitable for the preparation of those compounds of formula I wherein R1 is —CH2—, —CH2CH2—, —CH2CH2CH2—, —CF2—, —CH═CHCH2—, —CH(CH3)— or —C≡CCH2—, but preferably —CH2—, the free valency on the left in each case being attached to the pyridine ring.
Preference is furthermore given to the preparation of those compounds of formula I wherein X1 is oxygen, sulfonyl or a group —NR18SO2—, especially oxygen.
In accordance with the process according to the invention, special preference is given to the preparation of those compounds of formula I wherein R2 is CH3, CH2CH3, CH2OCH3, CH2OCH2CH3, CH2CH2OCH3, CH2CH2OCH2CH3, CH2CF3, propargyl, cyclopropylmethyl, benzyl, CH2CH2SO2CH3 or CH2CH2OCH2CH2OCH3, but preferably CH2CH2OCH3, with very special preference being given to those compounds wherein X1 is oxygen and R1 is —CH2—.
In accordance with the process according to the invention, preference is given to the preparation of those compounds of formula I wherein R05 is hydrogen, CH3, CH2Cl, CH2Br or CH2OCH3, but especially hydrogen.
From that group, those compounds wherein R is ethoxy or methoxy may be prepared especially advantageously.
Furthermore, in accordance with the process according to the invention there may be advantageously prepared compounds of formula I wherein R2 is
Where no free valency is indicated in those preferred meanings of R2, as in the case of, for example,
the attachment position is at the carbon atom marked “CH”.
Furthermore, there may also be advantageously prepared those compounds wherein the group —R1—X1—R2 together is a four- to ten-membered, monocyclic or fused bicyclic, ring system, which may be aromatic, partially saturated or saturated and contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur and/or contains one or two groups selected from —C(═O)—, —C(═S)—, —C(═NR20)— and —SO2—, the ring system being attached to the pyridine ring via a carbon atom or preferably via a nitrogen atom by way of a C1-C4alkylene chain, especially a methylene chain. Among such ring systems special mention may be made of the following preferred, four- to seven-membered ring systems attached via a nitrogen atom to the methylene group, the attachment position being shown in each case at the bottom left:
wherein r is 0, 1 or 2; R51, R53, R56 and R65 are each independently of the others hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6alkenyl, C3-C6alkynyl, C1-C3alkoxy-C1-C3alkyl, C1-C6alkoxy, C3-C6alkenyloxy, C3-C6alkynyloxy, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C3-C6alkenylthio or C3-C6alkynylthio; R52 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6alkenyl, C3-C6alkynyl, C1-C6alkoxy, amino, or phenyl which may in turn be substituted by R70; R54, R55 and R60 are each independently of the others hydrogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6alkenyl, C3-C6alkynyl or C3-C6cycloalkyl; R57, R63, R66, R67, R68 and R69 are each independently of the others C1-C6alkyl, or phenyl which may in turn be substituted by R70; R64 is C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6alkenyl, C3-C6alkynyl, or phenyl which may in turn be substituted by R70; R58 and R61 are hydrogen, halogen, C1-C6alkyl or C1-C6haloalkyl; R59 is C1-C6alkyl, C1-C6haloalkyl, C1-C3alkoxy-C1-C3alkyl, C3-C6alkenyl or C3-C6alkynyl; R62 is hydrogen, C1-C6alkyl, C1-C4alkoxycarbonyl or C1-C4alkylthiocarbonyl; or R51 together with R52, or R54 together with an adjacent group R56, or R58 together with an adjacent group R59, or R60 together with an adjacent group R61, or, when r is 2, two adjacent groups R56 or two adjacent groups R61 together may form a saturated or unsaturated C1-C5alkylene or C3-C4alkenylene bridge, which may in turn be substituted by a group R70 or interrupted by oxygen, sulfur or nitrogen; each R70 is independently halogen, C1-C3alkyl, C1-C3haloalkyl, hydroxy, C1-C3alkoxy, C1-C3haloalkoxy, cyano or nitro; X is oxygen, sulfur or NR6; X3, X4 and X5 are oxygen or sulfur; X6 and X7 are oxygen, sulfur, S(O) or SO2; and X8 is CH2, oxygen, sulfur, S(O), SO2 or NR71, wherein R71 is hydrogen or C1-C6alkyl.
In the context of the present invention, preference is given to the group R1—X1—R2 together being C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, C3-C6cycloalkyl, C1-C6alkoxy or C1-C6alkylthio, e.g. methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, fluoromethyl, 2-fluoroethyl, difluoroethyl, trifluoroethyl, vinyl, 1-propenyl, methoxy, ethoxy, methylthio or ethylthio.
In the context of the present invention, preference is given to R being methyl, ethyl, n-propyl or isopropyl, especially ethyl.
R3 is preferably methyl or ethyl, very especially ethyl.
R4 is preferably trifluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, especially trifluoromethyl, chlorodifluoromethyl or difluoromethyl.
As inert solvents for the method according to the invention there are suitable, for example, aromatic solvents such as benzene, chlorobenzene, fluorobenzene, xylenes, toluene, or alcohols such as methanol or ethanol, and also ethyl acetate, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, acetone, butanone, halogenated solvents such as, for example, methylene chloride, trichloromethane, dichloroethylene or trichlorethane, ethers such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, dioxane or methyl tert-butyl ether. Ethanol and toluene are especially preferred.
Organic or mineral acids are suitable as the proton source. Examples of suitable proton sources are HCl, HBr, H2SO4, carboxylic acids such as acetic acid and derivatives thereof such as trifluoroacetic acid and trichloroacetic acid, sulfonic acids such as methanesulfonic acid or p-toluenesulfonic acid and also carbonic acid. As the proton source for the process according to the invention special preference is given to trifluoroacetic acid.
The reactions can be carried out at ambient temperature or at elevated temperature. In general, addition of the reactants is carried out at a temperature from ambient temperature to the boiling point of the solvent, especially from 20 to 140° C., preferably from 40 to 120° C., with subsequent heating of the reaction mixture, advantageously to the boiling point of the solvent.
The compounds of formula II are known or are accessible by known methods. Processes for the preparation of compounds of formula II are described, for example, in J. Org Chem. (1995) vol 95, 3523, in H. Amil, T. Kobayashi, H. Terasawa, K. Uneyama, Org. Lett. 3(20), 3103-3105 (2001) and also A. Colla, G. Clar, S. Krimmer, P. Fischer, M. A. P. Martins, Synthesis-Stuttgart (6),483-486 (1991).
Some of the compounds of formula III are known. The preparation of such compounds is described in H. G. O. Becker, J. Prakt. Chem. (1961), Vol 12, 294., in WO 00/24714 and also in D. H. Wu, W. Wang, J. Labelled Compd. Rad 39(2),105-107(1997).
The compounds of formula III wherein —R1—X1—R2 is —CH2—O—CH2—CH2—O—CH3, that is to say compounds of formula IIIa
wherein R is as defined for formula III, are novel and were developed specifically for the preparation of compounds of formula I, and the present invention accordingly relates thereto. In a preferred compound of formula IIIa, R is methyl or ethyl.
Compounds of formula III can be prepared using processes known to the person skilled in the art, for example by reacting the unsaturated ketones on which they are based with ammonia gas as described in Preparation Example P1 hereinbelow.
In a preferred embodiment of the process according to the invention, the starting compounds of formula III are prepared from the 3-oxo-carboxylic acid esters on which they are based by introducing ammonia gas and then, without further isolation, reacting directly with the compounds of formula II. That process is especially advantageous for the large-scale preparation of compounds of formula I.
The compounds of formula I either may be used directly in the reaction mixture for further reactions or alternatively may be isolated. Isolation of the compounds of formula I can be carried out, for example, by extraction of the reaction mixture and subsequent removal of the solvent from the product-containing phase by customary methods.
The process according to the invention will be explained in greater detail in the following Preparation Examples:
A mixture of 1.37 g (6 mmol) of 3-oxo-4-methoxyethoxy-butanoic acid ethyl ester (1) in 13 ml of ethanol is introduced into a reaction vessel and cooled to a temperature of 0° C. using an ice/water bath.
Ammonia gas is then introduced for a period of 30 minutes, with stirring, and the reaction mixture is stirred for a further 20 minutes at a temperature of 0° C. After removing the cooling bath, the reaction mixture is allowed to warm up to a temperature of 20° C. and ammonia gas is then introduced for a further hour. The reaction mixture is then stirred for 20 hours.
After removal of the solvent in vacuo, there are obtained 1.3 g (95% of theory) of 3-amino-4-methoxyethoxy-but-2-enoic acid ethyl ester (2) in the form of an orange-coloured oil.
1H NMR (CDCl3): 1.30 (t, 3H, CH3CH2O—), 3.40 (s, 3H, CH3O—), 3.55 (m, 2H, OCH2CH2O), 3.60 (m, 2H, OCH2CH2O), 4.10 (s, 2H, C═CCH2O—), 4.15 (q, 2H, CH3CH2O—), 4.50 (s, 1H, CH═CNH2).
13C NMR (CDCl3): 14.7 (CH3), 58.9 (CH2), 59.2 (CH3), 70.0 (CH2), 71.0 (CH2), 71.8 (CH2), 81.9 (CH), 159.7 (C), 170.3 (C).
MS: 203 (M+), 158, 157,144,129, 114, 100, 98, 83, 71, 59, 45.
A mixture of 52.3 g (0.24 mol) of 3-oxo-4-methoxyethoxy-butanoic acid ethyl ester (1) in 150 ml of toluene is introduced into a reaction vessel equipped with a water separator.
Ammonia gas is then introduced into the reaction mixture for 2 hours, with stirring. Refluxing is then carried out for 30 minutes and the water is collected in the separator. After cooling the reaction mixture to a temperature of 20° C., the procedure is repeated. Ammonia gas is again introduced for 1.5 hours, with stirring, and the reaction mixture is then refluxed in order to separate off the water.
After cooling the reaction mixture, which contains 3-amino-4-methoxyethoxy-but-2-enoic acid ethyl ester (2), to a temperature of 20° C., 48 g (0.248 mol) of 1-ethoxy-3-oxo-4-trifluorobutene (3) are added and stirring is carried out at a temperature of 20° C. for 18 hours. 1.5 ml of trifluoroacetic acid are then added, stirring is carried out at a temperature of 20° C. for 2 hours and refluxing is carried out for a further 2 hours.
The reaction mixture is then allowed to cool down to a temperature of 20° C. and is then washed with 100 ml of 1M NaHCO3. The aqueous phase is separated off and is then extracted with 150 ml of toluene and the combined organic phases are then dried over MgSO4.
After removal of the solvent in vacuo, there are obtained 65.4 g (62% of theory) of 2-methoxyethoxymethyl-3-ethoxycarbonyl-6-trifluoromethylpyridine in the form of a dark-brown oil.
1H NMR (CDCl3): 1.40 (t, 3H, CH3CH2O—), 3.35 (s, 3H, CH3O—), 3.55 (m, 2H, OCH2CH2O), 3.70 (m, 2H, OCH2CH2O), 4.45 (q, 2H, CH3CH2O—), 5.00 (s, 2H, ArCH2O—), 7.70 (s,1H, ArH), 8.30 (s, 1H, ArH).
MS: 307 (M+), 262, 248, 233, 204, 202, 161, 128, 109, 59, 45
The other compounds listed in Table 1 can also be prepared in that manner.
In the following Table, the valency on the left of the radical R1 is attached to the pyridine ring. When no free valency is indicated in the case of the substituent R2, as in the case of, for example,
the attachment position is at the carbon atom marked “CH”.
The process according to the invention can be used especially advantageously for the preparation of the following compounds of Table 2:
In Table 2 which follows, the attachment position of the individual structures of the heterocycles of the group R2 to the substituent R1—X1—, or to the C1-C4alkylene, C2-C4alkenyl-C1-C4alkylene, C2-C4alkynyl-C1-C4alkylene, —N(R12)—C1-C4alkylene, —SO—C1-C4alkylene or —SO2—C1-C4alkylene groups which connect the heterocycle of R2 to the basic structure of formula I, is that nitrogen atom which is located at the same geometric position as is indicated in the Example below.
For example, the attachment position of the group
in the case of compound A 1.001 is the position indicated by an arrow:
The free valencies in those structures represent terminal CH3 groups, as in the case of, for example, the structure
which may also be depicted as follows:
| Number | Date | Country | Kind |
|---|---|---|---|
| 373/03 | Mar 2003 | CH | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2004/002291 | 3/5/2004 | WO | 00 | 9/6/2005 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2004/078729 | 9/16/2004 | WO | A |
| Number | Date | Country |
|---|---|---|
| 1340747 | Sep 2003 | EP |
| 2001158774 | Jun 2001 | JP |
| WO 0039094 | Jul 2000 | WO |
| WO 0194339 | Dec 2001 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20060199964 A1 | Sep 2006 | US |
