Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1996-05-28
1997-12-30
Richter, Johann
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
548255, 5482692, C12P 1710, C07D24908
Patent
active
057029288
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/01416 of Jul. 17, 1995.
FIELD OF THE INVENTION
The present invention relates to a process for producing a compound having the formula (II-R). In addition, the present invention relates to a process for producing a compound having the formula (I-R). Furthermore, the present invention relates to a method for racemizing a compound having the formula, (I-R), (I-S), (II-R) or (II-S), and leading to a compound having the formula (II) with the optical activity reduced or eliminated. Of compounds having the formula (II-R), particularly, R(-)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl) propane-1,2-diol is important as the intermediate for synthesizing medicines such as anti-fungal agents.
In the present invention, the formulas (I), (II), (I-R), (I-S), (II-R), or (II-S) stand for the compounds of the following structures, respectively. ##STR2##
In this specification, the formulas (I) and (II) represent not only racemates, comprising both diastereoisomers in the same ratio, but also a mixture comprising both isomers in a different ratio, one of the isomers in a higher ratio than that of the other. Also the formulas (I-R), (I-S), (II-R) or (II-S) represent the compound wherein the content of either the R-isomer or the S-isomer is higher than the other, regardless of their optical purity.
BACKGROUND OF THE INVENTION
The conventional methods for preparing R-(-)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propane-1,2-diol comprise:
1) asymmetric oxidation of 2-(2,4-difluorophenyl)allylalcohol with t-butyl hydroperoxide in the presence of titanium tetraisopropoxide and diethyl L(+)-tartrate to first synthesize S-(-)-2-(2,4-difluorophenyl)-2,3-epoxypropanol, which is then reacted with 1,2,4-triazole in the presence of potassium carbonate or the like to obtain R-(-)-2,(2,4-difluorophenyl)-3-(1H-1,2,4-triazole-1-yl)propane-1,2- diol (see the specifications in TokkaiHei 5-91183 and Eur. Patent 539938), and
2) hydrolysis of 1-acetoxy-2-(2,4-difluorophenyl)-2,3-epoxypropane with a hydrolase to produce R-(-)-1-acetoxy-2-(2,4-difluorophenyl)-2,3-epoxypropane, which is converted, first by the ester hydrolytic reaction, to S-(-)-2-(2,4-difluorophenyl) -2,3-epoxypropanol, and then led to R-(-)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propane-1,2-diol in the presence of potassium carbonate as in the previous method (see TokkaiHei 5-91183).
However, method 1) comprises complicated procedures and method 2 offers a poor yield.
Another conventional method for racemizing optically active alcohol comprises the acetylation or tosylation of the optically active secondary alcohol, followed by reaction with acetic acid in the presence of a strong acid to give racemic acetic acid ester, which is deacetylated to give racemic alcohol (1)(Journal of American Chemical Society, 87, p.3682 (1965), (2) Journal of Chemical Society, p.965 (1954), (3) Journal of Chemical Society, p.840 (1939). The procedure in the above method is not simple, because it comprises the conversion of a hydroxyl group linked to the asymmetric carbon to a carboxylic acid ester, followed by the racemization and then hydrolysis of said ester. Furthermore, there is no indication of a method for directly racemizing a tertiary alcohol having a hydroxyl or acyloxy group on the adjacent carbon.
The present invention aims to provide a method for preparing a compound represented by the formula (II-R) with high optical purity using an economical and simple means. The present invention also aims to provide a method for preparing a compound represented by the formula (I-R). Furthermore, the present invention aims to provide a method for producing a compound having the formula (II) with the optical activity reduced or nullified by racemizing a compound having the formula (I-R), (I-S), (II-R) or (II-S) by convenient means.
DISCLOSURE OF THE INVENTION
During developmental studies on an economic and convenient method for preparing a compound having the formula (II-R) with high optical purity, we found that lipase, especially micro
REFERENCES:
Lovey, Raymond G. et al., Tetrahedron Letters, vol. 35, No. 33, pp. 6047-6050 (1994) (Aug. 15, 1994).
Blundell, Paul et al., Synlett, Apr./94, pp. 263-265.
Ikura Kiyoshi
Imoto Takafumi
Kawada Naoki
Yamazaki Noritsugu
Daicel Chemical Industries Ltd.
Oswecki Jane C.
Richter Johann
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