Patent EA-003609-B1 (EA)
Title: Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids
Inventor: WEBB KEVIN
IPC: C07C255/46
Filed: 1998-10-07
Abstract: 1. A method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids of formula I in which R1 is (CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C1-2alkyl; R6 is a C3-6cycloalkyl or C4-6cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; X is YR2, halogen, nitro, NH2, or formylamine; X2 is O or NR8; Y is O or S (O) m'; m' is 0, 1, or 2; R2 is independently selected from-CH3 or-CH2CH3 optionally substituted by 1 or more halogens; R3 is hydrogen, halogen, C1-4alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4alkyl, -CH=CR8'R8',cyclopropyl optionally substituted by R8',CN2OR8, NR8R10, CH2NR8R10, C(Z')H, C(O)OR8, C(O) NR8R10, or C [triple bond] CR8'; R8 is hydrogen or C1-4alkyl optionally substituted by one to three fluorines; R8'is R8 or fluorine; R10 is OR8 or R11; R11 is hydrogen, or C1-4alkyl optionally substituted by one to three fluorines; Z' is O, NR9, NOR8, NCN, C(-CN)2, CR8CN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8R8; R' and R" are independently hydrogen or -C(O)OX where X is hydrogen or Li; which method comprises: a) combining a Group I(a) or Group II(a) metal halide, with an aprotic dipolar amide-based solvent and water and a compound of formula II(a) or II(b), where R1, R3, X2 and X are the same as for formula (I); b) heating the combination to a temperature of at least about 60 degree for several hours, optionally under an inert atmosphere; wherein further carrying out: c) precipitating out a compound of formula (I) by adding a sufficient LiOH amount to said combination to form a compound of formula (I), in which X is Li in a -C(O)OX group; d) removing the amide-based solvent and water from said precipitate, and optionally i) purifying further the precipitate, or ii) acidifying the precipitate to obtain the free acid. 2. The process of claim 1 wherein the product is a compound wherein R1 is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; and R2 is CF2H or methyl; and R3 is CN. 3. The process of claim 1 or 2 wherein the Group I(a) or II(a) metal halide is lithium or magnesium halide. 4. The process of any one of claims 1-3 wherein the Group I(a) or II(a) metal halide is lithium bromide or magnesium bromide. 5. The process of any one of claims 1-4 in which the aprotic dipolar amidebased solvent is dimethylformamide, dimethylacetamide, or N-methyl pyrrolidinone. 6. The process of any one of claims 1-5 wherein the Group I(a) or II(a) metal halide is lithium bromide and the amide-based solvent is dimethylformamide. 7. The process of any one of claim 1-6 wherein water is present in an amount greater than 0.1 % by weight/weight of the contents of the reaction vessel. 8. The process of any one of claim 1-7 wherein the compound of formula II(a) or II(b) is cis-6-[3-(cyclopentyloxy)-4-methoxyphenyl)]-1-oxaspiro [2.5] octane-2,6-dicarbonitrile. 9. A product of the process of any one of claims 1-8 which is cis-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarboxylate. 10. A compound which is cis-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarboxylate. 11. A composition of matter comprising essentially pure cis-lithium-4-cyano4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarboxylate.