ZA200505760B

ZA200505760B - Method for producing the enantiomeric forms of cis1,3,-cyclohexanediol derivatives

Info

Publication number: ZA200505760B
Application number: ZA200505760A
Authority: ZA
Inventors: Wolfgang Holla; Stefanie Keil
Original assignee: Sanofi Aventis Deutschland
Priority date: 2003-02-27
Filing date: 2005-07-19
Publication date: 2006-05-31
Also published as: CA2516623A1; EP1599433A1; AU2004215674B2; CO5690547A2; PT1599433E; CN100572348C; BRPI0407844A; KR20050107469A; ATE347543T1; ES2278305T3; WO2004076390A1; JP2006519001A; MXPA05009053A; DE10308350A1; NO20054456L; TW200508392A; DE502004002234D1; CY1106454T1; DK1599433T3; IL170310A

Description

Method for producing the enantiomeric forms of cis 1,3-cyclohexanediol derivatives

The invention relates to a process for preparing chiral, nonracemic, cis- configured 1,3-disubstituted cyclohexanols of the formula (I) rR1~ Ogg

GH

Variously substituted, cis-configured 1,3-disubstituted cyclohexane derivatives (compounds of the formula (I) where R' +R3 are central building blocks or precursors of the active pharmaceutical ingredients which are described in WO 03/020269 and are generally suitable for treating lipid metabolism disorders, type Il diabetes and syndrome X, inter alia.

The syntheses which are described in the patent application 03/020269 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, September 13, 1982, 5). Moreover, the alkylation by the Bu2SnO 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.

® 2 : 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. Roselii, 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)-dioctancate and (R,S)- dioctanoate. The optically active, monoacyiated, cis-configured (R,S)- monooctanoate takes up only a proportion of about 12% in the fraction of the monoacylated cyclchexanediols. 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 oO, Ne)

R17 YO R2 (1 where:

R'is

R4 o R3

X

N (CH,)n-

R5 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-Cg)-cycloalkyl; rR® is H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1-Cg)-alkyl, (C3-Csg)- cycloalkyl, phenyl; 5

R* R™ are H, F, Cl, Br, OH, NO2, CF3, OCF3, OCF3H, OCF2-CF3,

OCF2-CHF3, SCF3, O-phenyl, (C1-Cg)-alkyl, O-(C1-Cg)-alkyl, O- (C1-Ceg)-alkyl-O-(C4-Ca)-alkyl; n is from 1 to 3;

® and

R? is (C1-Cg)-alkyl where one or more CH2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO», 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-Cg)-alkyl, COOH, CO-benzoxy,

CO-0O(C1-Ce)-alkyl, tetrazole, thiazolidine-2,4-dione, indole and (Ce-C10)-aryl, where thiazolidine-2,4-dione and aryl may in turn be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc,

NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-Cg)-alkyl, COOH,

CO-benzoxy, CO-O(C1-Cg)-alkyl, (C1-Cg)-alkyl, O-(C1-Cg)-alkyl or tetrazole, or;

R? is an OH protecting group (PG), for example benzyloxymethyl, benzyl, para-methoxybenzyl or tert-butyldimethylsilyl; which comprises

A) a) alkylation (alk-R%/alk-PG) reacting cis-1,3-cyclohexanediol of the formula (Il)

HO, OH with a compound of the formula (lil) x'-R? (1) where RZ is as defined above and x! 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)

® 5 “OY O<rz (tv) where RZ 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®.0-CH=CH, or an acid anhydride r®.0- R®, where R® is as defined above, and the enzyme in an organic solvents, for example dichloromethane, 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) rRe— Ox., @) Oro v) where

R® is C(=0)-(C1-C1p)-alkyl, C(=0)-(C2-C1p)-alkenyl, C(=0)-(C3-C16)- alkynyl, C(=0)-(C3-C1g)-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, hydroxy, 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, CI, Br, CF3, and

RZ 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 Rf 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™-ClI or acid anhydrides rR®.0- rR® in the presence of bases, for example triethylamine, to the racemic ester of the formula (V)

Re— Ox, Op, v) 6 2 where R™ and R™ are each as defined above, which, to carry out the stereoselective enzymatic ester hydrolysis (EH), is then taken up in homogeneous or heterogeneous, aqueous, agueous- 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°C, and after the reaction has ended, one stereocisomer 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

Cc) 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 (alkk- R') reacting further with a compound of the formula (VI)

R4 0 R3 vi ( 1 vi

N (CH,)n - X*

RS where . 3 4 5 ring A, R”, R’, R™ and n are each as defined above and x? isCl, Br, I, OTs, OMs, OTF: in the presence of bases in a suitable solvent to give the compound of the formula (1), and e) detachment of the protecting group PG (detPG) if R? is an OH protecting group (PG) as defined above and R2, converting the compound of the formula (1a) o, .

R17” ‘, nN Ope (1a) where 3 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 BugNF, to a compound of the formula (VII)

® . 0, .

R17 OH (vi) where R' is as defined above, , 2 f) alkylation (alk- R™) then reacting it with a compound of the formula (lil) x'-R? on where x and R? are each as defined above, in the presence of bases in a suitable solvent to give a compound of the formula (1), 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% — EF + S/CE + EH + S [> CH] > alk- R' [>> DetPG — alk-

RY — product/enantiomeric form to:

B) alk-R'— EF + SICE + EH + S [> CH] — alk- R [> DetPG > alk-

RA] —> product/enantiomeric form or

C) alkk-PG —» EF + S/ICE + EH + S -» CH — alk- R® — DetPG — alk- rR] — product/enantiomeric form or

D) ak-PG — EF + S/ICE + EH + S — alk- R' > DetPG — alk- R> product/enantiomeric form.

®

Possible process variants are illustrated hereinbelow in Schemes | to 1V:

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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 (ll) with a compound of the formula (111) with a PG selected as R? 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-methoxybenzy! or tert-butyldimethyisilyl, 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 (la), 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 (lil) where R? 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 (lif) where RZ is as desired in the product to give a compound of the formula (VIII) 10) oO rz” Qf “Pe (vin) then converting it by detaching the PG group to give a compound of the formula (IV)

Claims

Claims:

1. A process for preparing a chiral, nonracemic compound of the formula5 oO, R17 Ops 0) where: R'is R4 0 R3 Ring A \ 1 N (CH,)n- R5 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-Cg)-cycloalkyl; R® is H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1-Cg)-alkyl, (C3-Cg)- cycloalkyl, phenyf; R* R® are H, F, Cl, Br, OH, NO2, CF3, OCF3, OCFzH, OCF2-CF3, OCF2-CHF2, SCF3, O-phenyl, (C4-Cg)-alkyl, O-(C1-Cg)-alkyl, O- (C1-Cg)-alkyl-O-(C1-C3)-alkyl; n is from 1 to 3; and RZ is (C1-Cg)-alkyl where one or more CH2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO, and alkyl may be one to

® trisubstituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO- C(CHg)3, hydroxyl, OCF3, O-(C1-Cg)-alkyl, COOH, CO-benzoxy, CO-0O(C1-Cg)-alkyl, tetrazole, thiazolidine-2,4-dione, indole and (Ce-C10)-aryl, where thiazolidine-2,4-dione and aryl may in turn be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-Cg)-alkyl, COOH, CO-benzoxy, CO-O(C1-Cg)-alkyl, (C1-Cg)-alkyl, O-(C1-Cg)-alkyl or tetrazole, or; RZ is an OH protecting group (PG), for example benzyloxymethyl, benzyl, para-methoxybenzyl or tert-butyldimethylsilyl; which comprises A) a) alkylation (alk-R%/alk-PG) reacting cis-1,3-cyclohexanediol of the formula (II) : HO, LOH with a compound of the formula (lll)

x'.R? (1) where R? is as defined above and x! isc, Br, 1, OMs, OTs, OTF: in the presence of bases in a suitable solvent to give a racemic compound of the formula (IV) HO, “Ops (iv)

y- .. ® where R? 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 acy! 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)

re—C., x O<r2 v) where R is C(=0)-(C1-Cqe)-alkyl, C(=0)-(C2-C1¢)-alkenyl, C(=0)-(C3-C1¢)- alkynyl, C(=0)-(C3-C1g)-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, CI, Br, CF3, CN, NOg2, hydroxyl, methoxy, ethoxy, phenyl and CO-O(C1-Cy4)-alkyl, CO-O(C2-C4)- alkenyl, which may in turn be substituted by 1-3 substituents from the group of F, Ci, Br, CF3, and R? 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 y- RIS ® chloride R®-Cl or acid anhydride R®-O- R®, in the presence of bases, to the racemic ester of the formula (V) —0,, \ 8]

R6 . “tN pa v) where R® and R? 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 o¢) 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 (ak- RY) reacting further with a compound of the formula (VI) R4 0 R3 vi 4 1 VI) N (CH)n - X° R5 where ring A, R*, R*, R® and n are each as defined above and

Ad v. ® x? scl, Br, 1, OTs, OMs, OTF; in the presence of bases in a suitable solvent to give the compound of the formula (1), and e) detachment of the protecting group PG (detPG)

if R? is an OH protecting group (PG) as defined above under R?, converting the compound of the formula (1a)

o, R17 Ope (1a)

where R! and PG are each as defined above,

by detaching the protecting group by known methods to a compound of the formula (VII)

o, Rt” OH (vi)

:

where R' is as defined above,

f) alkylation (alk- R?) then reacting it with a compound of the formula (lil)

x'-R? an where X' and R? are each as defined above,

in the presence of bases in a suitable solvent to give a compound of the formula (1), the product or the enantiomeric form,

b AC “. ® it being also possible to change the sequence of individual reaction steps as described above under A): A) alk-R? - EF + S/CE + EH + S [> CH] — ak- R' [»> DetPG — alk- R?] — product/enantiomeric form to: B) alk-R'—> EF + S/CE + EH + S [»> CH] — alk- R? [> DetPG — alk- R?] — product/enantiomeric form or C) ak-PG — EF + S/CE + EH + S — CH — alk- R? - DetPG — alk- R’ — product/enantiomeric form or D) alk-PG — EF + S/CE + EH + S — alk- R' —» DetPG — alk- R? » product/enantiomeric form.

2. The process as claimed in claim 1, wherein the processes C) and D) are employed.

3. The process as claimed in claim 1 or 2, wherein compounds of the formula (lil) X'=R? (In are used where xX! is Cl, Br, I, OMs or OTs.

4. The process as claimed in any of claims 1 to 3, wherein compounds of the formula (ill) X'-R? (In) are used where

»- Y. ® X' isCl Brorl.

5. The process as claimed in claims 1 to 4, wherein a compound of the formula (I) 0, R1” ‘, 5 O<r2 ( is prepared where: R" is R4 0 R3 Ring A \ 1 N™ Senn RS 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, (C3-Cg)-cycloalkyl; R® is H, CF3, (C1-Cg)-alkyl, (C3-Cg)-cycloalkyl, phenyl; R* RS are H, F, Br, CF3, OCF3, (C1-Cg)-alkyl, O-(C1-Cg)-alkyl; n is from 1 to 2 and . 25 rR? is (C1-Cg)-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(CHa3)3, hydroxyl, OCF3, O-(C1-Cg)-alkyl, COOH, CO-benzoxy, CO-0O(C1-Cg)-alkyl, tetrazole, thiazolidine-2,4-dione, indole and (Ce-C10)-aryl, where thiazolidine-2,4-dione and aryl may in turn be substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CH3)a, hydroxyl, OCF3, O-(C1-Cg)-alkyl, COOH,

tT. 1. ® CO-benzoxy, CO-O(C1-Cg)-alkyl, (C1-Cg)-alkyl, O-(C4-Cg)-alkyl or tetrazole.

6. The process as claimed in any of claims 1 to 5, wherein a compound ofthe formula (I) o, R1 ~ ‘, ON O<gr2 ) is prepared where: R'" is R4 0 R3 Ring A \ 1 N (CH)n- RS where ring A is phenyl, R® is (C1-Cg)-alkyl; R* R°® are H, (C1-Cg)-alkyl, O-(C1-C4)-alkyl; n is 1 and R? is (C1-Cg)-alkyl where one or more CH2 groups in the alkyl groups may be replaced by O, CO, S, SO or SO, and alkyl may be one to trisubstituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO- C(CH3)3, hydroxyl, OCF3, O-(C4-Cg)-alkyl, COOH, CO-benzoxy, CO-O(C1-Ce)-alkyl, tetrazole, thiazolidine-2,4-dione, indole and (Ce-C10)-aryl, where thiazolidine-2-4-dione and aryl may in turn be substituted by F, CI, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc, NHCbz, NH-CO-C(CHa3)3, hydroxyl, OCF3, O-(C1-Cg)-alkyl, COOH, CO-benzoxy, CO-O(C1-Cg)-alky!, (C1-Cg)-alkyl, O-(C1-Cg)-alkyl or tetrazole.