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US 7,094,795 B2Granted
Process for preparing the enantiomeric forms of cis-configured 1,3-cyclohexanediol derivatives
AssigneeSanofi-Aventis Deutschland GmbH
InventorsWolfgang Holla, Stephanie Keil
Life of this patent
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Abstract
A process is described for preparing chiral, nonracemic, cis-configured 1,3-disubstituted cyclohexanols of the formula (I) where the radicals are as defined, by means of enzymatic optical resolution.
Claims28
A process for preparing a chiral, nonracemic compound of the formula I
- where:
- R1 is
- 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, (C3–C8)-cycloalkyl;
- R3 is H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1–C6)-alkyl, (C3–C8)-cycloalkyl, phenyl;
- R4, R5 are H, F, Cl, Br, OH, NO2, CF3, OCF3, OCF2H, OCF2—CF3, OCF2—CHF2, SCF3, O-phenyl, (C1–C6)-alkyl, O—(C1–C6)-alkyl, O—(C1–C6)-alkyl-O—(C1–C3)-alkyl;
- n is from 1 to 3;
- and
- R2 is (C1–C8)-alkyl where one or more CH2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO2, and alkyl may be one to trisubstituted by F, Cl, Br, CF3, ON, NO2, NHAc, NHBoc, NH—CO—C(CH3)3, hydroxyl, OCF3, O—(C1–C6)-alkyl, COOH, CO-benzoxy, CO—O(C1–C6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C6–C10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH—CO—C(CH3)3, hydroxyl, OCF3, O—(C1–C6)-alkyl, COOH, CO-benzoxy, CO—O(C1–C6)-alkyl, (C1–C6)-alkyl, O—(C1–C6)-alkyl or tetrazole;
- which comprises
- a) alkylation (alk-R2)
- reacting cis-1,3-cyclohexanediol of the formula (II)
- with a compound of the formula (III)
- X1—R2 (III)
- where R2 is as defined above and
- X1 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)
- where R2 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° C. and, after the reaction has ended, one stereoisomer is present as an ester of the formula (V)
- where
- R6 is C(═O)—(C1–C16)-alkyl, C(═O)—(C2–C16)-alkenyl, C(═O)—(C3–C16)-alkynyl, C(═O)—(C3–C16)-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, CF3, CN, NO2, hydroxyl, methoxy, ethoxy, phenyl and CO—O(C1–C4)-alkyl, CO—O(C2–C4)-alkenyl, which may in turn be substituted by 1–3 substituents from the group of F, Cl, Br, CF3, and
- R2 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 R6—Cl or acid anhydride R6—O—R6, in the presence of bases, to the racemic ester of the formula (V)
- where R6 and R2 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° 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-R1)
- reacting further with a compound of the formula (VI)
- where
- ring A, R3, R4, R5 and n are each as defined above and
- X2 is Cl, Br, I, OTs, OMs, OTf;
- in the presence of bases in a suitable solvent to give the compound of the formula (I).
34 more elements
A process for preparing a chiral, nonracemic compound of the formula I
- where:
- R1 is
- 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, (C3–C8)-cycloalkyl;
- R3 is H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1–C6)-alkyl, (C3–C8)-cycloalkyl, phenyl;
- R4, R5 are H, F, Cl, Br, OH, NO2, CF3, OCF3, OCF2H, OCF2—CF3, OCF2—CHF2, SCF3, O—phenyl, (C1–C6)-alkyl, O—(C1–C6)-alkyl, O—(C1–C6)-alkyl-O—(C1–C3)-alkyl;
- n is from 1 to 3;
- and
- R2 is (C1–C8)-alkyl where one or more CH2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO2, and alkyl may be one to trisubstituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH—CO—C(CH3)3, hydroxyl, OCF3, O—(C1–C6)-alkyl, COOH, CO-benzoxy, CO—O(C1–C6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C6–C10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH—CO—C(CH3)3, hydroxyl, OCF3, O—(C1–C6)-alkyl, COOH, CO-benzoxy, CO—O(C1–C6)-alkyl, (C1–C6)-alkyl, O—(C1–C6)-alkyl or tetrazole;
- which comprises
- a) alkylation (alk-R1)
- reacting cis-1,3-cyclohexanediol of the formula (II)
- with a compound of the formula (III)
- X1—R1 (III)
- where R1 is as defined above and
- X1 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)
- where R1 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° C. and, after the reaction has ended, one stereoisomer is present as an ester of the formula (V)
- where
- R6 is C(═O)—(C1–C16)-alkyl, C(═O)—(C2–C16)-alkenyl, C(═O)—(C3–C16)-alkynyl, C(═O)—(C3–C16)-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, CF3, CN, NO2, hydroxyl, methoxy, ethoxy, phenyl and CO—O(C1–C4)-alkyl, CO—O(C2–C4)-alkenyl, which may in turn be substituted by 1–3 substituents from the group of F, Cl, Br, CF3, and
- R1 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 R6—Cl or acid anhydride R6—O—R6, in the presence of bases, to the racemic ester of the formula (V)
- where R6 and R1 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° 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-R2)
- reacting further with a compound of the formula (VI)
- R2—X2 (VI)
- where
- R2 is as defined above and
- X2 is Cl, Br, I, OTs, OMs, OTf;
- in the presence of bases in a suitable solvent to give the compound of the formula (I).
35 more elements
A process for preparing a chiral, nonracemic compound of the formula I
- where:
- R1 is
- 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, (C3–C8)-cycloalkyl;
- R3 is H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1–C6)-alkyl, (C3–C8)-cycloalkyl, phenyl;
- R4, R5 are H, F, Cl, Br, OH, NO2, CF3, OCF3, OCF2H, OCF2—CF3, OCF2—CHF2, SCF3, O—phenyl, (C1–C6)-alkyl, O—(C1–C6)-alkyl, O—(C1–C6)-alkyl-O—(C1–C3)-alkyl;
- n is from 1 to 3;
- and
- R2 is (C1–C8)-alkyl where one or more CH2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO2, and alkyl may be one to trisubstituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH—CO—C(CH3)3, hydroxyl, OCF3, O—(C1–C6)-alkyl, COOH, CO-benzoxy, CO—O(C1–C6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C6–C10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH—CO—C(CH3)3, hydroxyl, OCF3, O—(C1–C6)-alkyl, COOH, CO-benzoxy, CO—O(C1–C6)-alkyl, (C1–C6)-alkyl, O—(C1–C6)-alkyl or tetrazole;
- which comprises
- a) alkylation (alk-PG)
- reacting cis-1,3-cyclohexanediol of the formula (II)
- with a compound of the formula (III)
- X1—PG (III)
- where PG is an OH protecting group, for example benzyloxymethyl, benzyl, para-methoxybenzyl or tert-butyldimethylsilyl;
- and
- X1 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)
- 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° C. and, after the reaction has ended, one stereoisomer is present as an ester of the formula (V)
- where
- R6 is C(═O)—(C1–C16)-alkyl, C(═O)—(C2–C16)-alkenyl, C(═O)—(C3–C16)-alkynyl, C(═O)—(C3–C16)-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, CF3, CN, NO2, hydroxyl, methoxy, ethoxy, phenyl and CO—O(C1–C4)-alkyl, CO—O(C2–C4)-alkenyl, which may in turn be substituted by 1–3 substituents from the group of F, Cl, Br, CF3, 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 R6—Cl or acid anhydride R6—O—R6, in the presence of bases, to the racemic ester of the formula (V)
- where R6 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° 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-R1)
- reacting further with a compound of the formula (VI)
- where
- ring A, R3, R4, R5 and n are each as defined above and
- X1 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)
- where R1 and PG are each as defined above,
- by detaching the protecting group by known methods to a compound of the formula (VII)
- where R1 is as defined above,
- f) alkylation (alk-R2)
- then reacting it with a compound of the formula (III)
- X1—R2 (III)
- where X1 and R2 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.
45 more elements
A process for preparing a chiral, nonracemic compound of the formula I
- where:
- R1 is
- 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, (C3–C8)-cycloalkyl;
- R3 is H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1–C6)-alkyl, (C3–C8)-cycloalkyl, phenyl;
- R4, R5 are H, F, Cl, Br, OH, NO2, CF3, OCF3, OCF2H, OCF2—CF3, OCF2—CHF2, SCF3, O—phenyl, (C1–C6)-alkyl, O—(C1–C6)-alkyl, O—(C1–C6)-alkyl-O—(C1–C3)-alkyl;
- n is from 1 to 3;
- and
- R2 is (C1–C6)-alkyl where one or more CH2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO2, and alkyl may be one to trisubstituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH—CO—C(CH3)3, hydroxyl, OCF3, O—(C1–C6)-alkyl, COOH, CO-benzoxy, CO—O(C1–C6)-alkyl, tetrazole, thiazolidin-2,4-dione, indole and (C6–C10)-aryl, where thiazolidin-2,4-dione and aryl in turn maybe substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz NH—CO—C(CH3)3, hydroxyl, OCF3, O—(C1–C6)-alkyl, COOH, CO-benzoxy, CO—O(C1–C6)-alkyl, (C1–C6)-alkyl, O—(C1–C6)-alkyl or tetrazole;
- which comprises
- a) alkylation (alk-PG)
- reacting cis-1,3-cyclohexanediol of the formula (II)
- with a compound of the formula (III)
- X1—PG (III)
- where PG is an OH protecting group, for example benzyloxymethyl, benzyl, para-methoxybenzyl or tert-butyldimethylsilyl;
- and
- X1 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)
- 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° C. and, after the reaction has ended, one stereoisomer is present as an ester of the formula (V)
- where
- R6 is C(═O)—(C1–C16)-alkyl, C(═O)—(C2–C16)-alkenyl, C(═O)—(C3–C16)-alkynyl, C(═O)—(C3–C16)-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, CF3, CN, NO2, hydroxyl, methoxy, ethoxy, phenyl and CO—O(C1–C4)-alkyl, CO—O(C2–C4)-alkenyl, which may in turn be substituted by 1–3 substituents from the group of F, Cl, Br, CF3, 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 R6—Cl or acid anhydride R6—O—R6, in the presence of bases, to the racemic ester of the formula (V)
- where R6 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° 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-R2)
- reacting further with a compound of the formula (VI)
- R2—X2 (VI)
- where
- R2 is as defined above and
- X2 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)
- where R2 and PG are each as defined above,
- by detaching the protecting group by known methods to a compound of the formula (VII)
- where R2 is as defined above,
- f) alkylation (alk-R1)
- then reacting it with a compound of the formula (III)
- X1—R1 (III)
- where X1 and R1 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.
46 more elements
Dependencies are inferred from the claim text.