Patent EA-001783-B1 (EA)
Title: Compounds and method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids
Inventor: ALLEN ANDREW
IPC: C07B61/00
Filed: 1998-02-12
Abstract: 1. A process for preparing a compound of formula (I)   R1 is -(CR4R5)rR6 wherein the alkyl moieties may be unsubstituted or substituted with one or more halogens; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C1-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alkyl, halo substituted aryloxy C1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl. tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then r is 2 to 6; or b) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; X is YR2; X2 is O or NR8; Y is O or S(O)m; m' is O, 1, or 2; R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; and R3 is CN R8 is hydrogen or C1-4 alkyl optionally substituted by one to three fluorines; R' and R" are independently hydrogen or -C(O)OH; which method comprises treating a compound of formula II (a) or II (b)   where R1, R3, X2 and X are the same as for formula (I), with at least about 1.5 equivalents of a Lewis acid at a temperature between 60 degree C and 100 degree C optionally under an inert atmosphere; wherein the compound of formula (II) is prepared by b) reacting a ketone of formula (A)   wherein R1, R3, X2 and X are the same as in formula (I) with a molar excess ofchloroacetonitrile, an inorganic base, and a catalytic amount of benzyltriethylammonium chloride in a water miscible solvent; wherein the compound of formula (A) is prepared by c) decarboxylating a beta-keto ester of formula B   wherein R1, R3, X2 and X are the same as in formula (I) by heating a solution of the the beta-keto ester with dimethylsulfoxide to about 150 degree C; wherein the beta-keto ester of formula B is prepared by d) cyclizing a pimelate of formula C   wherein R1, R3, X2 and X are the same as in formula (I) with about 2 equivalents of a strong base at about 75 degree C, wherein the compound of formula C is prepared by e) reacting a nitrile of formula D   wherein R1, R3, X2 and X are the same as in formula (I) with an alkyl acrylate in a 3-4-fold molar excess in the presence of a catalytic amount ofTriton-B, wherein formula (D) compounds are prepared by f) reacting a compound of formula (E)   wherein R1, X2 and X are the same as in formula (I) with about a 50% molar excess of an alkali metal cyanide, wherein formula (E) compounds are prepared by; g) reacting an alcohol of formula (F)   wherein R1, X2 and X are the same as in formula (I) with excess hydrochloric acid, wherein formula (F) compounds are prepared by; h) reducing an aldehyde of formula (G)   wherein R1, X2 and X are the same as in formula (I) wherein the reduction is carried out using an inorganic reducing agent. 2. The method of claim 1 wherein in step a) the Lewis acid is lithium bromide, and water is added as a cosolvent. 3. The method of claim 1 or 2 wherein in step a) about 2 equivalents of water are used as the cosolvent. 4. The method of claim 1 to 3 wherein in step a) the reaction mixture is heated to about 90-95  degree C for up to about 8 hours. 5. The method of claim 1 to 4 wherein the reaction mixture is treated by adding an inorganic base, and further a huperchlorite salt. 6. The method of claim 1 wherein, in step b) the inorganic base is aqueous potassium hydroxide and the water-miscible solvent is tetrahydrofyran and the reaction is carried out at a temperature of about 0  degree C. 7. The method of claim 1 wherein in step c) the strong base is sodium methoxide which is present in about 1.5 molar equivalents and the reaction is carried out at about 70 to 75  degree C for up to 2 hours. 8. The method of claim 1 wherein steps c) and d) are combined by cyclizing the pimelate by reacting it with sodium methoxide decarboxylating the resulting beta-keto ester without isolating it by adding dimethylsulfoxide to the ester-containing solution and heating that solution to about 145 degree C for up to 2 hours. 9. The method of claim 8 wherein after the cyclization reaction step is completed, the reaction mixture is cooled to about room temperature and the pH is adjusted to 6.8-7.2 before adding dimethylsulfoxide. 10. The method of claim 1, step e), wherein the alkyl acrylate is methyl acrylate. 11. The method of claim 1, step f), wherein the alkali metal cyanide is sodium cyanide and the reaction is carried out at about 55  degree C. 12. The method of claim 1, step h), wherein the reducing agent is sodium borohydride. 13. The method of any of claims 1 to 12 wherein R1 is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, optionally substituted by OHC7-11 polycycloalkyl, (3- or 4-cyclopentyl), phenyl, tetrahydrofyran-3-yl, benzyl or C1-2, optionally substituted by 1 or more fliorines, -(CH2)1-3C(O)O(CH2)0-2CH3, -(CH2)1-3O(CH2)0-2CH3 and -(CH2)2-4OH; X is YR<2>, and Y is O; X2 is O; R2 is C1-2 alkyl optionally substituted by one or more halogens, where halogens are fluorine and chlorine. 14. The method of any of claims 1 to 12 wherein R1 is CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; where X is YR2; Y is O; X2 is O; and R2 is CF2H or methyl. 15. The process of any of claims 1 to 12 wherein in R1 is cyclopentyl, X2 is O, Y is O, and R2 is methyl. 16. A compound of formula (II)   wherein R1 is -(CR4R5)rR6, where alkyl moieties may be optionally substituted by one or more halogens; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C1-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alkyl, halo substituted aryloxy C1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl. tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyi and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then r is 2 to 6; or b) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; X is YR2; X2 is O or NR8; Y is O or S(O)m; m' is O, 1, or 2; R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; and R3 is CN R8 is hydrogen or C1-4 alkyl optionally substituted by one to three fluorines; T is CH or SO2R, where R is C1-6 alkyl or C0-3 alkylphenyl. 17. The compound of claim 16 wherein T is CN. 18. The compound of claim 16 or 14 wherein R1 is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, optionally substituted by OHC7-11 polycycloalkyl, (3- or 4-cyclopentyl), phenyl, tetrahydrofyran-3-yl, benzyl or C1-2, optionally substituted by 1 or more fliorines, -(CH2)1-3C(O)O(CH2)0-2CH3, -(CH2)1-3O(CH2)0-2CH3 and -(CH2)2-4OH; X is YR<2>, and Y is O; X2 is O; R2 is C1-2 alkyl optionally substituted by one or more halogens, where halogens are fluorine and chlorine. 19. The compound of any claim 16 to 18 wherein R1 is CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; where X is YR2; Y is O; X2 is O; and R2 is CF2H or methyl. 20. The compound of claim 16 wherein -cis-(+/-)-6-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-oxobicyclo-[2.5]octane-2,6-dicarbonitrile. 21. A compound od formula (III)   wherein R1 is -(CR4R5)rR6, where alkyl moieties may be optionally substituted by one or more halogens; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C1-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alkyl, halo substituted aryloxy C1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl. tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyi and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then r is 2 to 6; or b) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; X is YR2; X2 is O or NR8; Y is O or S(O)m; m' is O, 1, or 2; R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; and R3 is CN R8 is hydrogen or C1-4 alkyl optionally substituted by one to three fluorines. 22. The compound of claim 21 wherein R1 is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, optionally substituted by OHC7-11 polycycloalkyl, (3- or 4-cyclopentyl), phenyl, tetrahydrofyran-3-yl, benzyl or C1-2, optionally substituted by 1 or more fliorines, -(CH2)1-3C(O)O(CH2)0-2CH3, -(CH2)1-3O(CH2)0-2CH3 and -(CH2)2-4OH; X is YR<2>, and Y is O; X2 is O; R2 is C1-2 alkyl optionally substituted by one or more halogens, where halogens are fluorine and chlorine. 23. The compound of claim 22 wherein R1 is CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; where X is YR2; Y is O; X2 is O; and R2 is CF2H or methyl. 24. The compound of claim 23 wherein R1 is cyclopentyl, X2 is O, R2 is methyl, and Y is O. 25. A compound of formula (V)   wherein R1 is -(CR4R5)rR6, where alkyl moieties may be optionally substituted by one or more halogens; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C1-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alkyl, halo substituted aryloxy C1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl. tetrahydropy