Process for preparing the enantiomeric forms of cis-configured 1,3-cyclohexanediol derivatives Number:7,094,795 from the United States Patent and Trademark Office (PTO) owispatent A process is described for preparing chiral, nonracemic, cis-configured 1,3-disubstituted cyclohexanols of the formula (I) ##STR00001## where the radicals are as defined, by means of enzymatic optical resolution.<H cyclohexanediol, enantiomeric, Process, for, pre, 7094795.html, Patent, pto, 7094795

Title: Process for preparing the enantiomeric forms of cis-configured 1,3-cyclohexanediol derivatives

Abstract: A process is described for preparing chiral, nonracemic, cis-configured 1,3-disubstituted cyclohexanols of the formula (I) ##STR00001## where the radicals are as defined, by means of enzymatic optical resolution.

Patent Number: 7,094,795 Issued on 08/22/2006 to Holla, et al.

Inventors: Holla; Wolfgang (Kelkheim, DE), Keil; Stephanie (Hofheim, DE)
Assignee: Sanofi-Aventis Deutschland GmbH (Frankfurt, DE)

Appl. No.: 10/789,053

Filed: February 27, 2004

Foreign Application Priority Data


Feb 27, 2003 [DE]			103 08 350

Current U.S. Class: 514/374 ; 548/236

Current International Class: A61K 31/42 (20060101); C07D 263/34 (20060101)

Field of Search: 514/374 548/236

References Cited [Referenced By]

U.S. Patent Documents


6624185	September 2003	Glombik et al.
6884812	April 2005	Glombik et al.

Foreign Patent Documents


WO 01/57232	Aug., 2001	WO
WO 03/020269	Mar., 2003	WO

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Primary Examiner: Saeed; Kamal A.
Assistant Examiner: Chung; Susannah L.
Attorney, Agent or Firm: Kurys; Barbara E.

Claims

What is claimed is:

1. A process for preparing a chiral, nonracemic compound of the formula I ##STR00103## where: R.sup.1 is ##STR00104## where: ring A is phenyl, 5 12 membered heteroaromatic ring which may contain from one to four heteroatoms from the group of N, O and S, 8 to 14 membered aromatic ring, (C.sub.3 C.sub.8)-cycloalkyl; R.sup.3 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.8)-cycloalkyl, phenyl; R.sup.4, R.sup.5 are H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2H, OCF.sub.2--CF.sub.3, OCF.sub.2--CHF.sub.2, SCF.sub.3, O-phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; n is from 1 to 3; and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, ON, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole; which comprises a) alkylation (alk-R2) reacting cis-1,3-cyclohexanediol of the formula (II) ##STR00105## with a compound of the formula (III) X.sup.1--R.sup.2 (III) where R.sup.2 is as defined above and X.sup.1 is Cl, Br, I, OMs, OTs, OTf; in the presence of bases in a suitable solvent to give a racemic compound of the formula (IV) ##STR00106## where R.sup.2 is as defined above; b1) enzymatic ester formation (EF)+separation (S) subjecting the resulting compounds of the formula (IV) to stereoselective enzymatic ester formation (EF), in which the alcohols are admixed with an acyl donor and the enzyme in an organic solvent and the resulting mixture is stirred at -20 to 80.degree. C. and, after the reaction has ended, one stereoisomer is present as an ester of the formula (V) ##STR00107## where R.sup.6 is C(.dbd.O)--(C.sub.1 C.sub.16)-alkyl, C(.dbd.O)--(C.sub.2 C.sub.16)-alkenyl, C(.dbd.O)--(C.sub.3 C.sub.16)-alkynyl, C(.dbd.O)--(C.sub.3 C.sub.16)-cycloalkyl, where one or more carbon atoms may be replaced by oxygen atoms and be substituted by 1 3 substituents from the group of F, Cl, Br, CF.sub.3, CN, NO.sub.2, hydroxyl, methoxy, ethoxy, phenyl and CO--O(C.sub.1 C.sub.4)-alkyl, CO--O(C.sub.2 C.sub.4)-alkenyl, which may in turn be substituted by 1 3 substituents from the group of F, Cl, Br, CF.sub.3, and R.sup.2 is as defined above, and the other stereoisomer is present unchanged as the alcohol of the formula (IV), and are therefore separated from each other by utilizing their different chemical or physicochemical properties (separation S) or b2) enzymatic ester hydrolysis [=chemical esterification (CE)+enzymatic hydrolysis (EH)]+separation (S) subjecting the resulting compound of the formula (IV) to a stereoselective enzymatic ester hydrolysis, in which the racemic alcohol is initially converted by chemical esterification (CE), for example by means of acid chloride R.sup.6--Cl or acid anhydride R.sup.6--O--R.sup.6, in the presence of bases, to the racemic ester of the formula (V) ##STR00108## where R.sup.6 and R.sup.2 are each as defined above, which, to carry out the stereoselective enzymatic ester hydrolysis (EH), is then taken up in homogeneous or heterogenous, aqueous, aqueous-organic or organic medium, and reacted, in the presence of an enzyme in the case of hydrolysis with water and in the case of alcoholysis with an alcohol, at a temperature of 10 80.degree. C., and after the reaction has ended, one stereoisomer is present as the alcohol of the formula (IV) and the other is present unchanged as the ester of the formula (V) and can thus be separated from each other as described under b1), and the enantiomer of the formula (IV) occurring as an alcohol is further processed as described under d), or c) chemical hydrolysis (CH) hydrolyzing the enantiomer of the formula (V) occurring as an ester to the chemically enantiomeric alcohol by known methods and d) alkylation (alk-R.sup.1) reacting further with a compound of the formula (VI) ##STR00109## where ring A, R.sup.3, R.sup.4, R.sup.5 and n are each as defined above and X.sup.2 is Cl, Br, I, OTs, OMs, OTf; in the presence of bases in a suitable solvent to give the compound of the formula (I).

2. The process of claim 1, wherein compounds of the formula (III) X.sup.1--R.sup.2 (III) are used where X.sup.1 is Cl, Br, I, OMs or OTs.

3. The process of claim 2, wherein compounds of the formula (III) X.sup.1--R.sup.2 (III) are used where X.sup.1 is Cl, Br or l.

4. The process of claim 1, wherein a compound of the formula (I) ##STR00110## is prepared where: R.sup.1 is ##STR00111## where ring A is phenyl, 5 12 membered heteroaromatic ring which may contain from one or more heteroatoms from the group of N, O and S, fused/bicyclic 8 to 14 membered aromatic ring, (C.sub.3 C.sub.8)-cycloalkyl; R.sup.3 is H, CF.sub.3, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.8)-cycloalkyl, phenyl; R.sup.4, R.sup.5 are H, F, Br, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl; n is from 1 to 2 and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, were thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole.

5. The process of claim 4, wherein a compound of the formula (I) ##STR00112## is prepared where: R.sup.1 is ##STR00113## where ring A is phenyl; R.sup.3 is (C.sub.1 C.sub.4)-alkyl; R.sup.4, R.sup.5 are H, (C.sub.1 C.sub.4)-alkyl, O--(C.sub.1 C.sub.4)-alkyl; n is 1 and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole.

6. The process as claimed in any of claims 1, 2, 3, 4 or 5, wherein the compound of the formula (I) is (1R,3S)-2-{3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-1- -oxymethyl}-6-methylbenzoic acid.

7. The process as claimed in any of claims 1, 2, 3, 4 or 5, wherein the compound of the formula (I) is (1R,3S)-2-{3-[2-(4-methylphenyl)-5-methyloxazol-4-yl-methoxy]cyclohexyl-1- -oxymethyl}-6-methylbenzoic acid.

8. A process for preparing a chiral, nonracemic compound of the formula I ##STR00114## where: R.sup.1 is ##STR00115## where: ring A is phenyl, 5 12 membered heteroaromatic ring which may contain from one to four heteroatoms from the group of N, O and S, 8 to 14 membered aromatic ring, (C.sub.3 C.sub.8)-cycloalkyl; R.sup.3 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.8)-cycloalkyl, phenyl; R.sup.4, R.sup.5 are H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2H, OCF.sub.2--CF.sub.3, OCF.sub.2--CHF.sub.2, SCF.sub.3, O--phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; n is from 1 to 3; and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole; which comprises a) alkylation (alk-R1) reacting cis-1,3-cyclohexanediol of the formula (II) ##STR00116## with a compound of the formula (III) X.sup.1--R.sup.1 (III) where R.sup.1 is as defined above and X.sup.1 is Cl, Br, I, OMs, OTs, OTf; in the presence of bases in a suitable solvent to give a racemic compound of the formula (IV) ##STR00117## where R.sup.1 is as defined above; b1) enzymatic ester formation (EF)+separation (S) subjecting the resulting compounds of the formula (IV) to stereoselective enzymatic ester formation (EF), in which the alcohols are admixed with an acyl donor and the enzyme in an organic solvent and the resulting mixture is stirred at -20 to 80.degree. C. and, after the reaction has ended, one stereoisomer is present as an ester of the formula (V) ##STR00118## where R.sup.6 is C(.dbd.O)--(C.sub.1 C.sub.16)-alkyl, C(.dbd.O)--(C.sub.2 C.sub.16)-alkenyl, C(.dbd.O)--(C.sub.3 C.sub.16)-alkynyl, C(.dbd.O)--(C.sub.3 C.sub.16)-cycloalkyl, where one or more carbon atoms may be replaced by oxygen atoms and be substituted by 1 3 substituents from the group of F, Cl, Br, CF.sub.3, CN, NO.sub.2, hydroxyl, methoxy, ethoxy, phenyl and CO--O(C.sub.1 C.sub.4)-alkyl, CO--O(C.sub.2 C.sub.4)-alkenyl, which may in turn be substituted by 1 3 substituents from the group of F, Cl, Br, CF.sub.3, and R.sup.1 is as defined above, and the other stereoisomer is present unchanged as the alcohol of the formula (IV), and are therefore separated from each other by utilizing their different chemical or physicochemical properties (separation S) or b2) enzymatic ester hydrolysis [=chemical esterification (CE)+enzymatic hydrolysis (EH)]+separation (S) subjecting the resulting compound of the formula (IV) to a stereoselective enzymatic ester hydrolysis, in which the racemic alcohol is initially converted by chemical esterification (CE), for example by means of acid chloride R.sup.6--Cl or acid anhydride R.sup.6--O--R.sup.6, in the presence of bases, to the racemic ester of the formula (V) ##STR00119## where R.sup.6 and R.sup.1 are each as defined above, which, to carry out the stereoselective enzymatic ester hydrolysis (EH), is then taken up in homogeneous or heterogeneous, aqueous, aqueous-organic or organic medium, and reacted, in the presence of an enzyme in the case of hydrolysis with water and in the case of alcoholysis with an alcohol, at a temperature of 10 80.degree. C., and after the reaction has ended, one stereoisomer is present as the alcohol of the formula (IV) and the other is present unchanged as the ester of the formula (V) and can thus be separated from each other as described under b1), and the enantiomer of the formula (IV) occurring as an alcohol is further processed as described under d), or c) chemical hydrolysis (CH) hydrolyzing the enantiomer of the formula (V) occurring as an ester to the chemically enantiomeric alcohol by known methods and d) alkylation (alk-R.sup.2) reacting further with a compound of the formula (VI) R.sup.2--X.sup.2 (VI) where R.sup.2 is as defined above and X.sup.2 is Cl, Br, I, OTs, OMs, OTf; in the presence of bases in a suitable solvent to give the compound of the formula (I).

9. The process of claim 8, wherein compounds of the formula (VI) X.sup.2--R.sup.2 (VI) are used where X.sup.2 is Cl, Br, I, OMs or OTs.

10. The process of claim 9, wherein compounds of the formula (VI) X.sup.2--R.sup.2 (VI) are used where X.sup.2 is Cl, Br or I.

11. The process of claim 8, wherein a compound of the formula (I) ##STR00120## is prepared where: R.sup.1 is ##STR00121## where ring A is phenyl, 5 12 membered heteroaromatic ring which may contain from one or more heteroatoms from the group of N, O and S, fused/bicyclic 8 to 14 membered aromatic ring, (C.sub.3 C.sub.8)-cycloalkyl; R.sup.3 is H, CF.sub.3, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.8)-cycloalkyl, phenyl; R.sup.4, R.sup.5 are H, F, Br, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl; n is from 1 to 2 and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--O(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole.

12. The process of claim 11, wherein a compound of the formula (I) ##STR00122## is prepared where: R.sup.1 is ##STR00123## where ring A is phenyl; R.sup.3 is (C.sub.1 C.sub.4)-alkyl; R.sup.4, R.sup.5 are H, (C.sub.1 C.sub.4)-alkyl, O--(C.sub.1 C.sub.4)-alkyl; n is 1 and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.13).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole.

13. The process as claimed in any of claims 8 12, wherein the compound of the formula (I) is (1R,3S)-2-{3-[2-(3-methoxyphenyl)-5methyloxazol-4-ylmethoxy]cyclohexyl-1-- oxymethyl}-6-methylbenzoic acid.

14. The process as claimed in any of claims 8 12, wherein the compound of the formula (I) is (1R,3S)-2-{3-[2-(4-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-1-- oxymethyl}-6-methylbenzoic acid.

15. A process for preparing a chiral, nonracemic compound of the formula I ##STR00124## where: R.sup.1 is ##STR00125## where: ring A is phenyl, 5 12 membered heteroaromatic ring which may contain from one to four heteroatoms from the group of N, O and S, 8 to 14 membered aromatic ring, (C.sub.3 C.sub.8)-cycloalkyl; R.sup.3 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.8)-cycloalkyl, phenyl; R.sup.4, R.sup.5 are H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2H, OCF.sub.2--CF.sub.3, OCF.sub.2--CHF.sub.2, SCF.sub.3, O--phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; n is from 1 to 3; and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole; which comprises a) alkylation (alk-PG) reacting cis-1,3-cyclohexanediol of the formula (II) ##STR00126## with a compound of the formula (III) X.sup.1--PG (III) where PG is an OH protecting group, for example benzyloxymethyl, benzyl, para-methoxybenzyl or tert-butyldimethylsilyl; and X.sup.1 is Cl, Br, I, OMs, OTs, OTf; in the presence of bases in a suitable solvent to give a racemic compound of the formula (IV) ##STR00127## where PG is as defined above; b1) enzymatic ester formation (EF)+separation (S) subjecting the resulting compounds of the formula (IV) to stereoselective enzymatic ester formation (EF), in which the alcohols are admixed with an acyl donor and the enzyme in an organic solvent and the resulting mixture is stirred at -20 to 80.degree. C. and, after the reaction has ended, one stereoisomer is present as an ester of the formula (V) ##STR00128## where R.sup.6 is C(.dbd.O)--(C.sub.1 C.sub.16)-alkyl, C(.dbd.O)--(C.sub.2 C.sub.16)-alkenyl, C(.dbd.O)--(C.sub.3 C.sub.16)-alkynyl, C(.dbd.O)--(C.sub.3 C.sub.16)-cycloalkyl, where one or more carbon atoms may be replaced by oxygen atoms and be substituted by 1 3 substituents from the group of F, Cl, Br, CF.sub.3, CN, NO.sub.2, hydroxyl, methoxy, ethoxy, phenyl and CO--O(C.sub.1 C.sub.4)-alkyl, CO--O(C.sub.2 C.sub.4)-alkenyl, which may in turn be substituted by 1 3 substituents from the group of F, Cl, Br, CF.sub.3, and PG is as defined above, and the other stereoisomer is present unchanged as the alcohol of the formula (IV), and are therefore separated from each other by utilizing their different chemical or physicochemical properties (separation S) or b2) enzymatic ester hydrolysis [=chemical esterification (CE)+enzymatic hydrolysis (EH)]+separation (S) subjecting the resulting compound of the formula (IV) to a stereoselective enzymatic ester hydrolysis, in which the racemic alcohol is initially converted by chemical esterification (CE), for example by means of acid chloride R.sup.6--Cl or acid anhydride R.sup.6--O--R.sup.6, in the presence of bases, to the racemic ester of the formula (V) ##STR00129## where R.sup.6 and PG are each as defined above, which, to carry out the stereoselective enzymatic ester hydrolysis (EH), is then taken up in homogeneous or heterogeneous, aqueous, aqueous-organic or organic medium, and reacted, in the presence of an enzyme in the case of hydrolysis with water and in the case of alcoholysis with an alcohol, at a temperature of 10 80.degree. C., and after the reaction has ended, one stereoisomer is present as the alcohol of the formula (IV) and the other is present unchanged as the ester of the formula (V) and can thus be separated from each other as described under b1), and the enantiomer of the formula (IV) occurring as an alcohol is further processed as described under d), or c) chemical hydrolysis (CH) hydrolyzing the enantiomer of the formula (V) occurring as an ester to the chemically enantiomeric alcohol by known methods and d) alkylation (alk-R.sup.1) reacting further with a compound of the formula (VI) ##STR00130## where ring A, R.sup.3, R.sup.4, R.sup.5 and n are each as defined above and X.sup.1 is Cl, Br, I, OTs, OMs, OTf; in the presence of bases in a suitable solvent to give the compound of the formula (Ia) as defined below, and e) detachment of the protecting group PG (detPG) converting the compound of the formula (Ia) ##STR00131## where R.sup.1 and PG are each as defined above, by detaching the protecting group by known methods to a compound of the formula (VII) ##STR00132## where R.sup.1 is as defined above, f) alkylation (alk-R.sup.2) then reacting it with a compound of the formula (III) X.sup.1--R.sup.2 (III) where X.sup.1 and R.sup.2 are each as defined above, in the presence of bases in a suitable solvent to give a compound of the formula (I), the product or the enantiomeric form.

16. The process of claim 15, wherein compounds of the formula (III) X.sup.1--R.sup.2 (III) are used where X.sup.1 is Cl, Br, I, OMs or OTs.

17. The process of claim 16, wherein compounds of the formula (III) X.sup.1--R.sup.2 (III) are used where X.sup.1 is Cl, Br or I.

18. The process of claim 15, wherein a compound of the formula (I) ##STR00133## is prepared where: R.sup.1 is ##STR00134## where ring A is phenyl, 5 12 membered heteroaromatic ring which may contain from one or more heteroatoms from the group of N, O and S, fused/bicyclic 8 to 14 membered aromatic ring, (C.sub.3 C.sub.8)-cycloalkyl; R.sup.3 is H, CF.sub.3, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.6)-cycloalkyl, phenyl; R.sup.4, R.sup.5 are H, F, Br, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl; n is from 1 to 2 and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole.

19. The process of claim 18, wherein a compound of the formula (I) ##STR00135## is prepared where: R.sup.1 is ##STR00136## where ring A is phenyl; R.sup.3 is (C.sub.1 C.sub.4)-alkyl; R.sup.4, R.sup.5 are H, (C.sub.1 C.sub.4)-alkyl, O--(C.sub.1 C.sub.4)-alkyl; n is 1 and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1--C.sub.6)-alkyl, (C.sub.1C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole.

20. The process as claimed in any of claims 15 19, wherein the compound of the formula (I) is (1R,3S )-2-{3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-1-oxyme- thyl}-6-methylbenzoic acid.

21. The process as claimed in any of claims 15 19, wherein the compound of the formula (I) is (1R,3S)-2-{3-[2-(4-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-1-- oxymethyl}-6-methylbenzoic acid.

22. A process for preparing a chiral, nonracemic compound of the formula I ##STR00137## where: R.sup.1 is ##STR00138## where: ring A is phenyl, 5 12 membered heteroaromatic ring which may contain from one to four heteroatoms from the group of N, O and S, 8 to 14 membered aromatic ring, (C.sub.3 C.sub.8)-cycloalkyl; R.sup.3 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.8)-cycloalkyl, phenyl; R.sup.4, R.sup.5 are H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2H, OCF.sub.2--CF.sub.3, OCF.sub.2--CHF.sub.2, SCF.sub.3, O--phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; n is from 1 to 3; and R.sup.2 is (C.sub.1 C.sub.6)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole; which comprises a) alkylation (alk-PG) reacting cis-1,3-cyclohexanediol of the formula (II) ##STR00139## with a compound of the formula (III) X.sup.1--PG (III) where PG is an OH protecting group, for example benzyloxymethyl, benzyl, para-methoxybenzyl or tert-butyldimethylsilyl; and X.sup.1 is Cl, Br, I, OMs, OTs, OTf; in the presence of bases in a suitable solvent to give a racemic compound of the formula (IV) ##STR00140## where PG is as defined above; b1) enzymatic ester formation (EF)+separation (S) subjecting the resulting compounds of the formula (IV) to stereoselective enzymatic ester formation (EF), in which the alcohols are admixed with an acyl donor and the enzyme in an organic solvent and the resulting mixture is stirred at -20 to 80.degree. C. and, after the reaction has ended, one stereoisomer is present as an ester of the formula (V) ##STR00141## where R.sup.6 is C(.dbd.O)--(C.sub.1 C.sub.16)-alkyl, C(.dbd.O)--(C.sub.2 C.sub.16)-alkenyl, C(.dbd.O)--(C.sub.3 C.sub.16)-alkynyl, C(.dbd.O)--(C.sub.3 C.sub.16)-cycloalkyl, where one or more carbon atoms may be replaced by oxygen atoms and be substituted by 1 3 substituents from the group of F, Cl, Br, CF.sub.3, CN, NO.sub.2, hydroxyl, methoxy, ethoxy, phenyl and CO--O(C.sub.1 C.sub.4)-alkyl, CO--O(C.sub.2 C.sub.4)-alkenyl, which may in turn be substituted by 1 3 substituents from the group of F, Cl, Br, CF.sub.3, and PG is as defined above, and the other stereoisomer is present unchanged as the alcohol of the formula (IV), and are therefore separated from each other by utilizing their different chemical or physicochemical properties (separation S) or b2) enzymatic ester hydrolysis [=chemical esterification (CE)+enzymatic hydrolysis (EH)]+separation (S) subjecting the resulting compound of the formula (IV) to a stereoselective enzymatic ester hydrolysis, in which the racemic alcohol is initially converted by chemical esterification (CE), for example by means of acid chloride R.sup.6--Cl or acid anhydride R.sup.6--O--R.sup.6, in the presence of bases, to the racemic ester of the formula (V) ##STR00142## where R.sup.6 and PG are each as defined above, which, to carry out the stereoselective enzymatic ester hydrolysis (EH), is then taken up in homogeneous or heterogeneous, aqueous, aqueous-organic or organic medium, and reacted, in the presence of an enzyme in the case of hydrolysis with water and in the case of alcoholysis with an alcohol, at a temperature of 10 80.degree. C., and after the reaction has ended, one stereoisomer is present as the alcohol of the formula (IV) and the other is present unchanged as the ester of the formula (V) and can thus be separated from each other as described under b1), and the enantiomer of the formula (IV) occurring as an alcohol is further processed as described under d), or c) chemical hydrolysis (CH) hydrolyzing the enantiomer of the formula (V) occurring as an ester to the chemically enantiomeric alcohol by known methods and d) alkylation (alk-R.sup.2) reacting further with a compound of the formula (VI) R.sup.2--X.sup.2 (VI) where R.sup.2 is as defined above and X.sup.2 is Cl, Br, I, OTs, OMs, OTf; in the presence of bases in a suitable solvent to give the compound of the formula (Ia) as defined below, and e) detachment of the protecting group PG (detPG) converting the compound of the formula (Ia) ##STR00143## where R.sup.2 and PG are each as defined above, by detaching the protecting group by known methods to a compound of the formula (VII) ##STR00144## where R.sup.2 is as defined above, f) alkylation (alk-R.sup.1) then reacting it with a compound of the formula (III) X.sup.1--R.sup.1 (III) where X.sup.1 and R.sup.1 are each as defined above, in the presence of bases in a suitable solvent to give a compound of the formula (I), the product or the enantiomeric form.

23. The process of claim 22, wherein compounds of the formula (VI) X.sup.1--R.sup.2 (VI) are used where X.sup.2 is Cl, Br, I, OMs or OTs.

24. The process of claim 23, wherein compounds of the formula (VI) X.sup.2--R.sup.2 (VI) are used where X.sup.2 is Cl, Br or I.

25. The process of claim 22, wherein a compound of the formula (I) ##STR00145## is prepared where: R.sup.1 is ##STR00146## where ring A is phenyl, 5 12 membered heteroaromatic ring which may contain from one or more heteroatoms from the group of N, O and S, fused/bicyclic 8 to 14 membered aromatic ring, (C.sub.3 C.sub.8)-cycloalkyl; R.sup.3is H, CF.sub.3, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.8)-cycloalkyl, phenyl; R.sup.4, R.sup.5 are H, F, Br, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl; n is from 1 to 2 and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole.

26. The process of claim 25, wherein a compound of the formula (I) ##STR00147## is prepared where: R.sup.1 is ##STR00148## where ring A is phenyl; R.sup.3 is (C.sub.1 C.sub.4)-alkyl; R.sup.4, R.sup.5 are H, (C.sub.1 C.sub.4)-alkyl, O--(C.sub.1 C.sub.4)-alkyl; n is 1 and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole.

27. The process as claimed in any of claims 22 26, wherein the compound of the formula (I) is (1R ,3S)-2-{3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-1-ox- ymethyl}-6-methylbenzoic acid.

28. The process as claimed in any of claims 22 26, wherein the compound of the formula (I) is (1R,3S)-2-{3-[2-(4-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-1-- oxymethyl}-methylbenzoic acid.

Description

DESCRIPTION

The invention relates to a process for preparing chiral, nonracemic, cis-configured 1,3-disubstituted cyclohexanols of the formula (I)

##STR00002##

Variously substituted, cis-configured 1,3-disubstituted cyclohexane derivatives (compounds of the formula (I) where R.sup.1.noteq.R.sup.2) are central building blocks or precursors of the active pharmaceutical ingredients which are described in WO 03/020,269 and are generally suitable for treating lipid metabolism disorders, type II diabetes and syndrome X, inter alia.

The syntheses which are described in the patent application Ser. No. 03/020,269 of the nonracemic, cis-configured 1,3-cyclohexane derivatives cannot be considered as industrial processes: for example, alkylations with NaH/DMF on the multi-kg scale cannot be carried out safely (C&EN, Sep. 13, 1982, 5). Moreover, the alkylation by the Bu.sub.2SnO method on the industrial scale entails unacceptably high cost and inconvenience; the removal of the tin compounds from the desired products is very difficult and usually incomplete even when chromatographic separating methods are used. The disposal of the tin compounds is a further problem and a cost factor. The separation of the enantiomers (optical resolution) by chromatography on a chiral phase is likewise inconvenient and too expensive. In addition, it is necessary for chromatographic enantiomer resolution that the racemic compound is present in good chemical purity, which can be achieved in many cases by additional, preceding chromatography.

Other methods which have been described in literature for synthesizing cis-1,3-cyclohexanediol building blocks or derivatives, for example the opening of epoxycyclohexanes (P. Crotti, V. Di Bussolo, L. Favero, M. Pineschi, F. Marianucci, G. Renzi, G. Amici, G. Roselli, Tetrahedron 2000, 56, 7513 7524 and cit. lit.) or the metallized-catalyzed hydroboration of cyclohexene derivatives (J. A. Brinkmann, T. T. Nguyen, J. R. Sowa, Jr., Org. Lett. 2000, 2, 981 983; C. E. Garrett, G. C. Fu, J. Org. Chem. 1998, 63, 1370 1371) are predominantly unsatisfactory with regard to the regioselectivity and the stereoselectivity. The total number of stages is additionally distinctly higher. They cannot be considered as industrial processes.

The synthesis of cis-1,3-cyclohexanediol derivatives starting from cis,cis-1,3,5-cyclohexanetriol or cis,cis-1,3,5-cyclohexanetriol derivatives (L. Dumortier, M. Carda, J. Van der Eycken, G. Snatzke, M. Vandewalle, Tetrahedron: Asymmetry 1991, 2, 789 792; H. Suemune, K. Matsuno, M. Uchida, K. Sakai, Tetrahedron: Asymmetry 1992, 3, 297 306) are likewise very complicated and uneconomic as a consequence of the high number of stages and therefore unsuitable for industrial use. The enzymatic reaction of the cis/trans mixture of 1,3-cyclohexanediol with S-ethyl thiooctanoate cannot be considered as an industrial process. Apart from the odor nuisance which can barely be avoided when working with the sulfur compounds and the fact that to achieve the required conversion, the ethanethiol which is released has to be removed continuously, the reaction described leads to a mixture of 9 isomeric forms or derivatives of cyclohexanediol, i.e. the unconverted isomers (S,S)-diol, (R,R)-diol and (R,S)-diol, also the monoacylated products (S,S)-monooctanoate, (R,R)-monooctanoate and (R,S)-monooctanoate, and thirdly the group of the diacylated products (S,S)-dioctanoate, (R,R)-dioctanoate and (R,S)-dioctanoate. The optically active, monoacylated, cis-configured (R,S)-monooctanoate takes up only a proportion of about 12% in the fraction of the monoacylated cyclohexanediols. A preparation and isolation of this product on the preparative scale has not been described, but in view of the ratios of amounts and the separating problem outlined, cannot be economic. In addition, it is known that partially acylated di- or polyhydroxy compounds tend to acyl group migrations. When this occurs, for example, in the course of the purification of the (R,S)-monooctanoate (for example in the chromatography on silica gel or in aqueous extraction) or in the course of a subsequent reaction (for example during the alkylation of the free hydroxyl group), this leads to a distinct reduction in the optical purity or to racemization.

The cis-configured (R,S)-diols and the diacylated (R,S)-compounds are not optically active and therefore not of interest.

It is therefore an object of the present invention to develop a process which does not have the disadvantages mentioned.

The present invention provides a process for preparing a chiral, nonracemic compound of the formula I

##STR00003## where: R.sup.1 is

##STR00004## where: ring A is phenyl, 5 12 membered heteroaromatic ring which may contain from one to four heteroatoms from the group of N, O and S, 8 to 14 membered aromatic ring, (C.sub.3 C.sub.8)-cycloalkyl; R.sup.3 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.8)-cycloalkyl, phenyl; R.sup.4, R.sup.5 are H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2H, OCF.sub.2--CF.sub.3, OCF.sub.2--CHF.sub.2, SCF.sub.3, O-phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; n is from 1 to 3; and R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole, or; R.sup.2 is an OH protecting group (PG), for example benzyloxymethyl, benzyl, para-methoxybenzyl or tert-butyldimethylsilyl; which comprises A) a) alkylation (alk-R.sup.2/alk-PG) reacting cis-1,3-cyclohexanediol of the formula (II)

##STR00005## with a compound of the formula (III) X.sup.1--R.sup.2 (III) where R.sup.2 is as defined above and X.sup.1 is Cl, Br, I, OMs (O-mesyl), OTs (O-tosyl), OTf (O-triflate); in the presence of bases in a suitable solvent to give a racemic compound of the formula (IV)

##STR00006## where R.sup.2 is as defined above; b1) enzymatic ester formation (EF)+separation (S) subjecting the resulting compounds of the formula (IV) to stereoselective enzymatic ester formation (EF), in which the alcohols are admixed with an acyl donor, for example a vinyl ester R.sup.6--O--CH.dbd.CH.sub.2 or an acid anhydride R.sup.6--O--R.sup.6, where R.sup.6 is as defined above, and the enzyme in an organic solvents, for example dichloromethane, and the resulting mixture is stirred at -20 to 80.degree. C. and, after the reaction has ended, one stereoisomer is present as an ester of the formula (V)

##STR00007## where R.sup.6 is C(.dbd.O)--(C.sub.1 C.sub.16)-alkyl, C(.dbd.O)--(C.sub.2 C.sub.16)-alkenyl, C(.dbd.O)--(C.sub.3 C.sub.16)-alkynyl, C(.dbd.O)--(C.sub.3 C.sub.16)-cycloalkyl, where one or more carbon atoms may be replaced by oxygen atoms and be substituted by 1 3 substituents from the group of F, Cl, Br, CF.sub.3, CN, NO.sub.2, hydroxyl, methoxy, ethoxy, phenyl and CO--O(C.sub.1 C.sub.4)-alkyl, CO--O(C.sub.2 C.sub.4)-alkenyl, which may in turn be substituted by 1 3 substituents from the group of F, Cl, Br, CF.sub.3, and R.sup.2 is as defined above, and the other stereoisomer is present unchanged as the alcohol of the formula (IV), and are therefore separated from each other by utilizing their different chemical or physicochemical properties (for example R.sub.f values or solubility differences in water or other solvents) (separation S), for example by simple chromatography on silica gel, by extraction (for example heptane/methanol or org. solvent/water) or else by a further subsequent chemical reaction, for example of the alcohol, in which the ester does not take part, or b2) enzymatic ester hydrolysis [=chemical esterification (CE)+enzymatic hydrolysis (EH)]+separation (S) subjecting the resulting compounds of the formula (IV) to a stereoselective enzymatic ester hydrolysis, in which the racemic alcohol is initially converted by chemical esterification (CE), for example by means of acid chlorides R.sup.6 --Cl or acid anhydrides R.sup.6--O--R.sup.6, in the presence of bases, for example triethylamine, to the racemic ester of the formula (V)

##STR00008## where R.sup.6 and R.sup.2 are each as defined above, which, to carry out the stereoselective enzymatic ester hydrolysis (EH), is then taken up in homogeneous or heterogeneous, aqueous, aqueous-organic or organic media, and reacted, in the presence of an enzyme in the case of hydrolysis with water and in the case of alcoholysis with an alcohol, for example n-butanol, at a temperature of 10 80.degree. C., and after the reaction has ended, one stereoisomer is present as the alcohol of the formula (IV) and the other is present unchanged as the ester of the formula (V) and can thus be separated from each other as described under b1), and the enantiomer of the formula (IV) occurring as an alcohol is further processed as described under d), or c) Chemical Hydrolysis (CH) hydrolyzing the enantiomer of the formula (V) occurring as an ester to the chemically enantiomeric alcohol by known methods and d) Alkylation (alk-R.sup.1) reacting further with a compound of the formula (VI)

##STR00009## where ring A, R.sup.3, R.sup.4, R.sup.5 and n are each as defined above and X.sup.2 is Cl, Br, I, OTs, OMs, OTf; in the presence of bases in a suitable solvent to give the compound of the formula (I), and e) Detachment of the Protecting Group PG (detPG) if R.sup.2 is an OH protecting group (PG) as defined above and R.sup.2, converting the compound of the formula (Ia)

##STR00010## where R.sup.1 and PG are each as defined above, by detaching the protecting group by known methods, for example detachment of PG=benzyloxymethyl or PG=benzyl by hydrogenating over Pd/C, or detachment of PG=para-methoxybenzyl with, for example DDQ (2,3-dichloro-5,6-dicyanobenzoquinone), or detachment of PG=tert-butyldimethylsilyl, for example with Bu.sub.4NF, to a compound of the formula (VII)

##STR00011## where R.sup.1 is as defined above, f) Alkylation (alk-R.sup.2) then reacting it with a compound of the formula (III) X.sup.1--R.sup.2 (III) where X.sup.1 and R.sup.2 are each as defined above, in the presence of bases in a suitable solvent to give a compound of the formula (I), the product or the enantiomeric form, it being also possible to change the sequence of individual reaction steps as described above under A): A) alk-R.sup.2.fwdarw.EF+S/CE+EH+S[.fwdarw.CH].fwdarw.alk-R.sup.1[.fwdarw.De- tPG.fwdarw.alk-R.sup.2].fwdarw.product/enantiomeric form to: B) alk-R.sup.1.fwdarw.EF+S/CE+EH+S[.fwdarw.CH].fwdarw.alk-R.sup.2[.fwdarw.De- tPG.fwdarw.alk-R.sup.2].fwdarw.product/enantiomeric form or C) alk-PG.fwdarw.EF+S/CE+EH+S.fwdarw.CH.fwdarw.alk-R.sup.2.fwdarw.DetPG.fwda- rw.alk-R.sup.1.fwdarw.product/enantiomeric form or D) alk-PG.fwdarw.EF+S/CE+EH+S.fwdarw.alk-R.sup.1.fwdarw.DetPG.fwdarw.alk-R.s- up.2.fwdarw.product/enantiomeric form. Possible process variants are illustrated hereinbelow in Schemes I to IV:

##STR00012##

##STR00013##

##STR00014##

##STR00015##

##STR00016##

##STR00017##

The process according to the invention is economic, simple and rapid. The process completely eliminates the risk of acyl group migration, does not require equimolar amounts of optically pure starting materials or auxiliaries, any expensive reagents, any optical resolution by chromatography on chiral phases, any disproportionately large amounts of solvent or any cost-intensive working steps.

The loss of 50% which is typical for optical resolutions can be avoided by using both enantiomers and changing the sequence of the alkylations. Preference is given to what is known as the enantioconvergent method (see Scheme IV or Method C and D)) in which the procedure is, for example, as follows: alkylation of cis-1,3-cyclohexanediol of the formula (II) with a compound of the formula (III) with a PG selected as R.sup.2 such that PG can be detached again simply and selectively in the course of the further synthesis, and PG is thus, for example, benzyl, or para-methoxybenzyl or tert-butyldimethylsilyl, subjecting the resulting compound of the formula (IV) to stereoselective enzymatic ester formation or ester hydrolysis (see above) and, after completion of separation of unconverted alcohol and ester, converting them separately and by different routes to the same optically pure product by reacting the alcohol (as described in the first part), for example, with a compound of the formula (VI) to give a compound of the formula (Ia), then converting it by detaching the PG group to give a compound of the formula (VII), and then reacting it with a compound of the formula (III) where R.sup.2 is as desired in the product to give a compound of the formula (I), and converting the isomeric ester by simple ester hydrolysis to a compound of the formula (IV), and then reacting with a compound of the formula (III) where R.sup.2 is as desired in the product to give a compound of the formula (VIII)

##STR00018## then converting it by detaching the PG group to give a compound of the formula (IV)

##STR00019## and then reacting it with a compound of the formula (VI) to give a compound of the formula (I).

##STR00020## Preference is given to using compounds of the formula (III) X.sup.1--R.sup.2 (III) where X.sup.1 is Cl, Br, I, OMs or OTs, particular preference to using those where X.sup.1 is Cl, Br or I.

Preference is given to a process for preparing the compounds of the formula (I)

##STR00021## where R.sup.1 is

##STR00022## where ring A is phenyl, 5 12 membered heteroaromatic ring which may contain one or more heteroatoms from the group of N, O and S, fused/bicyclic 8 to 14 membered aromatic ring, (C.sub.3 C.sub.8)-cycloalkyl; R.sup.3 is H, CF.sub.3, (C.sub.1 C.sub.6)-alkyl, (C.sub.3 C.sub.8)-cycloalkyl, phenyl; R.sup.4, R.sup.5 are H, F, Br, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl; n is from 1 to 2; R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, were thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole.

Particular preference is given to a process for preparing the compounds of the formula (I)

##STR00023## where: R.sup.1 is

##STR00024## where ring A is phenyl; R.sup.3 is (C.sub.1 C.sub.4)-alkyl; R.sup.4, R.sup.5 are H, (C.sub.1 C.sub.4)-alkyl, O--(C.sub.1 C.sub.4)-alkyl; n is 1; R.sup.2 is (C.sub.1 C.sub.8)-alkyl where one or more CH.sub.2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO.sub.2, and alkyl may be one to trisubstituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHBoc, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C.sub.6 C.sub.10)-aryl, were thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF.sub.3, CN, NO.sub.2, NHAc, NHTs, NHBoc, NHCbz, NH--CO--C(CH.sub.3).sub.3, hydroxyl, OCF.sub.3, O--(C.sub.1 C.sub.6)-alkyl, COOH, CO-benzoxy, CO--O(C.sub.1 C.sub.6)-alkyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or tetrazole.

The alkyl radicals in the substituents R.sup.2, R.sup.3, R.sup.4 and R.sup.5 may be either straight-chain or branched.

In this context, a heteroaromatic ring refers to both mono- and bicyclic rings having a maximum of 4 heteroatoms, in particular those which contain up to 4 nitrogen atoms and/or 1 oxygen or 1 sulfur atom, for example furan, thiophene, thiazole, oxazole, thiadiazole, triazole, pyridine, triazine, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzotriazole.

Aromatic rings may be mono- or bicyclic and also be fused, for example naphthyl, benzo[1,3]dioxole, dihydrobenzo[1,4]dioxin.

The racemic, cis-configured 1,3-cyclohexane derivatives of the formula (IV) and of the formula (VII) are prepared by monoalkylating cis-cyclohexanediol (compound of the formula II), but can also be prepared by reductively opening appropriate acetals (R. Hunter et al., J. Org. Chem. 1993, 85, 6756), and also by reductive ether formation starting from silyl ethers and aldehydes or ketones (J. S. Bajwa, X. Jiang, J. Slade, K. Prasad, O. Repic, T. J. Blacklock, Tetrahedron Lett. 2002, 43, 6709 6713).

The alkylating reagents of the formula III are commercially obtainable or can be prepared by literature methods, for example by free-radical side chain halogenation (see literature review by R. C. Larock, Comprehensive Organic Transformations, p. 313, 1989 VCH Publishers, Inc.) or from the alcohols or derivatives preparable therefrom (see literature review by R. C. Larock, Comprehensive Organic Transformations, p. 353 363, 1989 VCH Publishers, Inc.).

Also known (see J. Chem. Soc. 1925, 127, 2275 2297; J. Chem. Soc. 1922, 121, 2202 2215) is the preparation of various 2-bromomethylbenzoyl bromides by free-radical bromination, which may then be converted by further reaction with alcohols to the bromomethylbenzoic esters belonging to the group of the alkylating reagents of the formula III.

The alkylating reagents of the formula (VI) or the alcohols X.sup.2=OH which can serve as precursors are commercially obtainable or can be prepared by literature methods [a). The Chemistry of Heterocyclic Compounds (Ed.: A. Weissberger, E. C. Taylor): Oxazoles (Ed.: I. J. Turchi); b) Methoden der Organischen Chemie, Houben-Weyl, 4.sup.th edition, Hetarene III, subvolume 1; c) I. Simit, E. Chindris, Arch. Pharm. 1971, 304, 425; d) Y. Goto, M. Yamazaki, M. Hamana, Chem. Pharm. Bull. 1971, 19 (10), 2050 2057].

The alkylating reagents of the formula III and VI are reacted with 1,3-cyclohexanediol or 1,3-cyclohexanediol derivatives in the presence of bases. Suitable bases are, for example, hydroxides such as KOH, carbonates such as Cs.sub.2CO.sub.3, alkoxides such as KOtBu and also compounds such as LDA, BuLi, LiHMDS, KH, NaH and NaHMDS. Suitable solvents are, for example, THF, MTBE, DME, NMP, DMF and chlorobenzene.

For optical resolution of the alcohols, they are taken up in organic solvents, for example dimethoxyethane (DME), methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), THF, n-hexane, cyclohexane, toluene, chlorobenzene, acetone, dimethylformamide (DMF), dichloromethane, 1,2-dichloroethane and tert-butanol, acyl donors such as vinyl acetate, vinyl propionate, vinyl butyrate, 2,2,2-trifluoroethyl 2H,2H-perfluorodecanoate, ethoxyvinyl acetate, p-nitro- or p-chlorophenyl acetate, oxime esters, acetic anhydride, propionic anhydride, succinic anhydride, glutaric anhydride, isovaleric anhydride, 2,2,2-trichloroethyl butyrate, 2,2,2-trifluoroethyl 2H,2H-perfluorodecanoate are added and the reaction mixture is subsequently admixed with a suitable enzyme and stirred at from -20 to 80.degree. C. The proportion of cosolvent in the solution is preferably 10 90%, but it is in some cases also advantageous to carry out the enzymatic reaction in pure acyl donor, for example vinyl acetate, without cosolvent.

For optical resolution of the ester derivatives, for example acetyl-, propionyl-, butyryl- or glutaryl-, they are subjected in homogeneous or heterogeneous, aqueous, aqueous-organic or organic media, in the presence of a suitable enzyme, to stereoselective hydrolysis or alcoholysis (for example with n-butanol) at a temperature of 10 80.degree. C., optionally in the presence of cosolvents (see above) and of a buffer, the reaction mixture preferably containing 2 50% by weight of ester.

The abovementioned ester derivatives can be prepared by literature methods, for example by reacting the alcohol with acid chlorides such as acetyl chloride or anhydrides such as acetic anhydride, in the presence of an amine, for example triethylamine or pyridine (see literature review by R. C. Larock, Comprehensive Organic Transformations, p. 978, 1989 VCH Publishers, Inc.).

When the reaction has ended, the products or the enantiomers can be separated in a simple manner, for example by extraction by literature methods [a). T. Yamano, F. Kikumoto, S. Yamamoto, K. Miwa, M. Kawada, T. Ito, T. Ikemoto, K. Tomimatsu, Y. Mizuno, Chem. Lett. 2000, 448; b). B. Hungerhoff, H. Sonnenschein, F. Theil, J. Org. Chem. 2002, 67, 1781] or by employing chromatographic methods.

A further method is, on completion of the enzymatic reaction, to distinctly increase the water solubility of the remaining alcohol by derivatization, for example by acylation with cyclic anhydrides, e.g. with glutaric anhydride, or by conversion to a cholin ester [a). H. Kunz, M. Buchholz, Chem. Ber. 1979, 112, 2145; b). M. Schelhaas, S. Glomsda, M. Hansler, H.-D. Jakubke, H. Waldmann, Angew. Chem. 1996, 108, 82] and thus to achieve separation from the water-insoluble or sparingly water-soluble esters by extraction. After the separation, the derivatization of the alcohols can be reversed by chemical or enzymatic hydrolysis.

A particularly interesting means for separating the enantiomers in the case of the enzymatic acylation is to select the acyl donor in such a way that the acylated enantiomer is distinctly more water-soluble than the unconverted alcohol. Suitable acyl donors are, for example, cyclic anhydrides such as succinic anhydride. On completion of the enzymatic acylation, the acylation product bears a free carboxyl group which enables rapid removal of the product by aqueous extraction under basic conditions, for example with sat. aqueous NaHCO.sub.3 solution.

In enzymatic optical resolution by ester hydrolysis, the procedure is preferably to admix an ester of the formula (I), for example where R.sup.1=COCH.sub.3, COCH.sub.2CH.sub.3 or COCH.sub.2CH.sub.2CH.sub.2COOH in an aqueous or alcoholic solution, with an esterase or lipase and stirred. It may be advantageous to buffer the solution mentioned, for example with phosphate or TRIS [=tris(hydroxymethyl)methylamine] buffer. The additive may, for example, be 0.01 1.0 molar. A favorable buffer range is pH 5 10.

The enzymes used are preferably hydrolases from mammalian livers, for example lipase from porcine pancreas (fluka), or from microorganisms, for example Lipase B from Candida antarctica (Roche Diagnostics), Lipase OF from Candida rugosa (Meito Sangyo), Lipase SL from Pseudomonas cepacia (Meito Sangyo), Lipase L-10 from Alcaligenes spec. (Roche Diagnostics)