Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Patent
1995-12-11
1998-12-29
Saucier, Sandra E.
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
C12P 4100
Patent
active
058540628
DESCRIPTION:
BRIEF SUMMARY
This application claims benefit of international application PCT/GB94/00793, filed Apr. 15, 1994.
This invention relates to a method of chiral resolution of tertiary alcohols and to novel compounds useful in the method.
Certain tertiary alcohols are useful compounds in pharmaceutical and agrochemical outlets, for example, the compounds disclosed in GB 1529818, EP-B-15756, EP-B-44605, EP-B-61835, EP-B-131684, EP-A-47594, GB 2064520 and EPA-472392. These compounds usually have an optically active chiral centre and resolution of the compounds can lead to benefits for example, greater activity or lower toxicity with one of the optically active isomers.
European patent application EPA-472392 discloses the compound -1H-1,2,4-triazol-1-yl!-3-(1H-1,2,4-triazol-1-yl)propan-2-ol, which has antifungal activity, and is valuable in treatment of fungal infections in man and in other animals. Intermediates for the preparation of the compound are also disclosed.
EPA-472392 discloses two methods for the preparation of an optically active epoxide of formula (A) ##STR1##
The first method is a chemical synthesis as demonstrated by processes 1 to 4 of EPA-472392. Process 4 is an asymmetric oxidation process of 2-(2,4-difluorophenyl)allyl alcohol with t-butyl hydroperoxide in organic solvents such as methylene chloride in the presence of a titanium tetraalkoxide such as titanium tetraisopropoxide or titanium tetrabutoxide and of a dialkyl-tartrate.
The second method is demonstrated by processes (i) to (iv) of EPA-472392. Process (iii) involves an enzymatic asymmetric ester hydrolysis of 1-acetoxy-2-(2,4-difluorophenyl-2,3-epoxypropane performed using a hydrolytic enzyme such as an esterase or a lipase in a buffer solution or in a mixture of buffer solution and an organic solvent such as diisopropyl ether, ethanol, acetone or dimethylformamide. In this process the (+)-form undergoes ester hydrolysis selectively and (+)-2-(2,4-difluorophenyl)-2,3-epoxypropanol is obtained. The (-)-1-acetoxy-2-(2,4-difluorophenyl)-2,3-epoxypropane does not undergo ester hydrolysis and is recovered from the reaction liquid in high optical purity. In process (iv) the (-)-1-acetoxy-2-(2,4-difluorophenyl)-2,3-epoxypropane recovered from process (iii) undergoes a normal ester hydrolysis using bases such as potassium hydroxide or sodium hydroxide and (-)-2-(2,4-difluorophenyl)-2,3-epoxypropanol is obtained.
Both the (+) and (-) forms of 2-(2,4-difluorophenyl)-2,3-epoxypropanol can be converted to -1H-1,2,4-triazol-1-yl!-3-(1H-1,2,4-triazol-1-yl)propan-2-ol involving different methods. The disadvantage of this method is that the epoxide is a reactive group which is susceptible to hydrolysis and nucleophilic attack, for example by an amino group on the enzyme. This would result in the enzyme being completely or partially deactivated.
The present inventors have found that the process can be improved by enzyme catalysed resolution of an ester or diol followed by chemical steps to the corresponding resolved epoxide.
Thus, according to a first aspect of the present invention there is provided a method of preparing an optically active compound of formula ##STR2## wherein R and R.sup.1 are independently alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, aryl, aralkyl, a heterocyclic group or a C.sub.1 -C.sub.4 alkyl-heterocycle, each being optionally substituted, provided that R and R.sup.1 are not identical and * is an optically active chiral centre; the method comprising (a) treating a racemic compound of formula (II): ##STR3## wherein R and R.sup.1 are as previously defined and R.sup.2 is alkyl, aryl or aralkyl each optionally substituted, with a hydrolase; or (b) treating a racemic compound of formula (III) ##STR4## wherein R and R.sup.1 are as previously defined, with a hydrolase in the presence of an acyl donor; and converting the optically active products of (a) and/or (b) to the optically active compound of formula (I).
When either of R and R.sup.1 is aryl it is preferably phenyl or substituted phenyl.
When either of R and R.sup.1 is aralkyl it i
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Blacker Andrew John
Brewster Andrew George
Copeland Robert Jeffrey
Holt Robert Antony
Mochida Pharmaceuticals Co., Ltd.
Saucier Sandra E.
Zeneca Limited
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