Granted Patent B2

US 7,168,937 · App. 10/203,031 · Granted Jan 30, 2007

Abstract

Claims (69)

1. A process for the separating enantiomers of aminomethyl-aryl-cyclohexanol compounds corresponding to formula I

wherein X is chosen from

H, F, Cl, Br, I, CF 3 , O—S(O 2 )—C 6 H 4 -pCH 3 , OR 14 or OC(O)R 14 , wherein R 14 is chosen from

H; C 1 –C 10 -alkyl, C 2 –C 10 -alkenyl or C 2 –C 10 -alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C 3 –C 7 -cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical in which a C atom in the ring is replaced by N, S or O; alkylaryl or alkylheteroaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

R 3 , R 4 independently of one another are chosen from

H, C 1 –C 10 -alkyl, C 2 –C 10 -alkenyl or C 2 –C 10 -alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C 3 –C 7 -cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical in which a C atom in the ring is replaced by N, S or O; alkylaryl or alkylheteroaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

or

R 3 and R 4 together form a C 3 –C 7 -cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical in which a C atom in the ring is replaced by S, O or NR 15 , where R 15 is chosen from

H, C 1 –C 10 -alkyl, C 2 –C 10 -alkenyl or C 2 –C 10 -alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;

R 1 and R 2 independently of one another are either H or any desired substituent

and

in each case one of the substituents R 5 and R 6 corresponds to H and the other corresponds to OH, characterized in that, depending on the desired enantiomer of the aminomethyl-aryl-cyclohexanol compounds corresponding to formula I

comprising, according to reaction I, esterifying compounds corresponding to formula I and enzymatically transforming the compounds and separating enantiomerically pure compounds

or comprising, according to reaction II, enzymatically transforming

compounds corresponding to formula I in the presence of an ester and separating enantiomerically pure compounds.

2. A process according to claim 1 , comprising in reaction I, enzymatically transforming a compound corresponding to formula II

in which the substituent OC(O)R 7 corresponds to the position of R 5 or R 6 in formula I and R 7 is chosen from C 1 –C 6 -alkyl, unsubstituted or mono- or polysubstituted; as the free base or in the form of its salt, in a solvent with a lipase or esterase and separating enantiomerically pure compounds corresponding to formulae III and Ia

where compounds according to formula Ia correspond to compounds according to formula I and the substituent OH corresponds to the position of R 5 or R 6 in formula I.

3. The process according to claim 2 , characterized in that R 7 is chloroacetyl, butyl or pentyl.

4. The process according to claim 2 , characterized in that the enzyme used is an esterase.

5. The process according to claim 2 , characterized in that an aqueous buffer system is used as the solvent.

6. The process according to claim 2 , characterized in that an aqueous buffer system, preferably with a physiological pH for the enzyme used, is used as the solvent.

7. The process according to claim 5 , characterized in that at least one organic solvent is added to the aqueous buffer system up to a percentage content by volume of between 1 and 50%.

8. The process according to claim 2 , characterized in that the compound according to formula II is employed as the hydrochloride salt.

9. The process according to claim 2 , characterized in that the compounds according to formula II employed are prepared by a process in which racemic compounds according to formula I

are converted with bases in a solvent into the alcoholates and subsequently, with the addition of corresponding acid halides, into the racemic esters according to formula II

in which the substituent OC(O)R 7 corresponds to the position of R 5 or R 6 in formula I.

10. The process according to claim 1 , comprising, in reaction alternative II, enzymatically transforming a racemic compound corresponding to formula I

employed as the free base or in the form of its salt in a solvent with an ester according to formula IV

wherein, independently of one another, R 8 denotes C 1 –C 6 alkyl, substituted or unsubstituted; and R 9 denotes H or C 1 –C 6 -alkyl, substituted or unsubstituted, with a lipase or esterase and separating the enantiomerically pure compounds formed, corresponding to formulae V and Ib

wherein compounds according to formula Ib correspond to compounds according to formula I and the substituent OH corresponds to the position of R 5 or R 6 in formula I.

11. The process according to claim 10 , characterized in that in the esters according to formulae IV and V, R 8 denotes methyl or ethyl or R 9 according to formula IV denotes H or methyl.

12. The process according to claim 10 , characterized in that the ester according to formula IV is vinyl propionate, vinyl acetate or isopropenyl acetate.

13. The process according to claim 10 , characterized in that the enzyme used is a lipase.

14. The process according to claim 10 , characterized in that an organic solvent is used as the solvent.

15. The process according to claim 1 , characterized in that ester/alcohol mixtures are separated by pH-selective extraction after conclusion of the enzymatic transformation.

16. The process according to claim 1 , characterized in that R 1 and R 2 in the formulae I, Ia, Ib, II, III and V independently of one another are chosen from R 10 or YR 10 , where Y=C 1 –C 10 -alkyl, C 2 –C 10 -alkenyl or C 2 –C 10 -alkinyl, branched or unbranched and mono- or polysubstituted or unsubstituted, wherein R 10 is chosen from

H, F, Cl, Br, I, CN, NO 2 , C 1 –C 8 -alkyl, C 2 –C 8 -alkenyl or C 2 –C 8 -alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C 3 –C 7 -cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical in which a C atom in the ring is replaced by S, O or N; aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

OR 11 , OC(O)R 11 , OC(O)OR 11 , OC(S)R 11 , C(O)R 11 , C(O)OR 11 , C(S)R 11 , C(S)OR 11 , SR 11 , S(O)R 11 or S(O 2 )R 11 , wherein R 11 is chosen from

H, C 1 –C 18 -alkyl, C 2 –C 18 -alkenyl or C 2 –C 18 -alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C 3 –C 7 -cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical in which a C atom in the ring is replaced by S, O or N; alkylaryl or alkylheteroaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

or

NR 12 R 13 , C(O)NR 12 R 13 or S(O 2 )NR 12 R 13 , wherein R 12 and R 13 independently of one another are chosen from

H, C 1 –C 18 -alkyl, C 2 –C 18 -alkenyl or C 2 –C 18 -alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C 3 –C 7 -cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical in which a C atom in the ring is replaced by S, O or N; alkylaryl or alkylheteroaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

or

R 12 and R 13 together form a C 3 –C 7 -cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical in which a C atom in the ring is replaced by S, O or N;

or

R 1 and R 2 together form —CH═CH—CH═CH—, wherein the naphthyl system formed can be mono- or polysubstituted.

17. The process according to claim 1 , characterized in that R 1 =R 10 , wherein R 10 is chosen from

H, F, Cl, Br, I, CF 3 , NO 2 , NH 2 ; C 1 –C 4 -alkyl or C 2 –C 4 -alkenyl, branched or unbranched and mono- or polysubstituted or unsubstituted; OR 11 , C(O)OR 11 or SR 11 , wherein R 11 is chosen from

H; C 1 –C 4 -alkyl, branched or unbranched and mono- or polysubstituted or unsubstituted; preferably H, CF 3 or CH 3 ,

or S(O 2 )NR 12 R 13 , wherein R 12 and R 13 independently of one another are chosen from

H; C 1 –C 4 -alkyl, branched or unbranched and mono- or polysubstituted or unsubstituted.

18. The process according to claims 1 , characterized in that R 2 =R 10 , wherein R 10 is chosen from

H, F, Cl, Br, I, SCH 3 ; C 1 –C 4 -alkyl, C 2 –C 4 -alkenyl, branched or unbranched and mono- or polysubstituted or unsubstituted, preferably CF 3 ; OR 11 , where R 11 is chosen from C 1 –C 4 -alkyl, branched or unbranched and mono- or polysubstituted or unsubstituted, preferably CH 3 .

19. The process according to claim 1 , characterized in that X is chosen from

H, F, Cl, OH, CF 3 , O—S(O 2 )—C 6 H 4 -pCH 3 or OC(O)R 12 where R 12 =H; C 1 –C 4 -alkyl or C 2 –C 4 -alkenyl, branched or unbranched and mono- or polysubstituted or unsubstituted,

preferably H, F, Cl, OH, O—S(O 2 )—C 6 H 4 -pCH 3 , OC(O)R 12 where R 12 =C 1 –C 4 -alkyl, preferably CH 3 .

20. The process according to claim 4 , wherein the enzyme used is a pig liver esterase.

21. The process according to claim 5 , wherein the solvent is an aqueous buffer system, with a pH of between 6.0 and 8.0.

22. The process according to claim 7 , wherein the organic solvent is acetone or butanol.

23. The process according to claim 7 , characterized in that at least one organic solvent is added to the aqueous buffer system up a percentage content by volume of between 5 and 20%.

24. The process according to claim 9 , wherein the bases include potassium tert-butylate or sodium hyride.

25. The process according to claim 9 , wherein the solvent is tetrahydrofuran or dimethylformamide.

26. The process according to claim 13 , wherein the lipase is a lipase from Candida rugosa, Candida cylindracea or Pseudomonas cepacia.

27. The process according to claim 14 , wherein the organic solvent is toluene.

28. The process according to claim 17 , wherein R 1 is chosen from H, F, Cl, OH, CH 3 , C 2 H 5 , C 2 H 3 , CF 3 , SCH 3 , OCF 3 , OCH 3 , OC 2 H 5 , C(O)OCH 3 , C(O)OC 2 H 5 .

29. The process according to claim 17 , wherein R 1 is m-OCH 3 .

30. The process according to claim 18 , wherein R 2 is H.

31. The process according to claim 19 , wherein X is OH, F or Cl.

Assignments (11)