Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2001-11-06
2004-08-17
Desai, Rita (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C560S055000, C562S405000
Reexamination Certificate
active
06777576
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a production method of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid useful as an intermediate for pharmaceutical products and the like, an intermediate therefor and a production method thereof.
BACKGROUND OF THE INVENTION
2-Cyclohexyl-2-hydroxy-2-phenylacetic acid and ester thereof are useful as intermediates for pharmaceutical products, such as oxybutynin, which is a therapeutic agent for pollakiuria, and the like. There have been proposed various production methods of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid and ester thereof.
In J. Org. Chem., Vol. 42, No. 17, 2948-2949 (1977), 2-cyclohexyl-2-hydroxy-2-phenylacetic acid ester is obtained by reacting alkyl mandelate and lithium diisopropylamide, and then reacting the obtained reaction product with cyclohexyl iodide. According to this method, expensive lithium diisopropylamide is used in 2 equivalents or more relative to alkyl mandelate and expensive and unstable cyclohexyl iodide is used, which makes this method industrially disadvantageous.
According to JP-A-11-193271, ethyl benzoylformate and cyclohexylmagnesium bromide are condensed to give ethyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, which is hydrolyzed to give 2-cyclohexyl-2-hydroxy-2-phenylacetic acid. In this condensation reaction, diethyl ether having a boiling point of 35° C. is used in an amount of about 12-fold volume relative to ethyl benzoylformate, manipulation of dangerous reaction using the boiling point of diethyl ether is required and the yield is as low as 53.3%. In an attempt to improve this method into an industrially safe one, the present inventors used tetrahydrofuran instead of diethyl ether as a solvent and reproduced the reaction. As a result, there occurred reduction due to Grignard reagent to produce ethyl mandelate as a by-product, as well as addition of the Grignard reagent to ester bond. The proportion of the starting material that became a by-product was 42% and the yield of the objective product was as low as 58%. After hydrolysis of the obtained crude ethyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, it was subjected to recrystallization and the like to increase the purity but the yield from ethyl benzoylformate of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid did not exceed 43%.
Therefore, it is concluded that none of the above methods produces 2-cyclohexyl-2-hydroxy-2-phenylacetic acid or ester thereof industrially, economically and safely in a good yield.
There have been also proposed various production methods of optically active 2-cyclohexyl-2-hydroxy-2-phenylacetic acid and ester thereof.
In WO00/23414, a method for optical resolution of a racemate of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid using optically active amine is described. This method, nevertheless, is not entirely efficient because it produces undesirable enantiomer in a half amount.
In WO00/27786, moreover, (i) optically active mandelic acid is converted to 2-tert-butyl-5-phenyl-4-oxo-1,3-dioxolane protected by tert-butyl at the 2-position, by the use of pivalaldehyde, (ii) the resulting compound is reacted with cyclohexanone in the presence of lithium bis(trimethylsilyl)-amide at −78° C., and (iii) the reaction product is subjected to reduction and hydrolysis to give optically active 2-cyclohexyl-2-hydroxy-2-phenylacetic acid. This method is industrially disadvantageous in that lithium bis(trimethylsilyl)amide is expensive, the reaction needs to be carried out at an extremely low temperature of −78° C., a number of steps are required and the like.
In J. Med. Chem., 40, 117-124 (1997), moreover, as in WO00/27786, 2-tert-butyl-5-phenyl-4-oxo-1,3-dioxolane protected by tert-butyl at the 2-position is reacted with 3-cylcohexenyl bromide in the presence of lithium diisopropylamide at −80° C. and subjected to reduction and hydrolysis to give optically active 2-cyclohexyl-2-hydroxy-2-phenylacetic acid. This method is industrially disadvantageous in that lithium diisopropylamide and 3-cyclohexenyl bromide are expensive, the reaction needs to be carried out at an extremely low temperature of −80° C. and the like.
From the foregoing, it follows that none of the above methods produces optically active 2-cyclohexyl-2-hydroxy-2-phenylacetic acid and ester thereof industrially, economically and safely in a good yield.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide an industrial method of producing 2-cyclohexyl-2-hydroxy-2-phenylacetic acid, optically active form thereof and intermediates therefor, economically and safely in a good yield.
To solve the above-mentioned problems, the present inventors considered that novel 2-(2′-cyclohexen-1′-yl)-2-hydroxy-2-phenylacetic acid ester (compound of the formula [II] below) obtained by reacting cyclohexene and benzoylformic acid ester may be usable as a precursor of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid and ester thereof, which are useful as intermediates for pharmaceutical products.
The reaction between cyclohexene and benzoylformic acid ester is called an ene reaction. In general, it is considered that a sterically complicated compound, such as benzoylformic acid ester, has poor reactivity and the reaction with olefin having a double bond in a ring, such as cyclohexene, is difficult to the degree that a reaction in a good yield is remotely available.
The present inventors have conducted this reaction in the presence of a Lewis acid, and surprisingly found that highly pure 2-(2′-cyclohexen-1′-yl)-2-hydroxy-2-phenylacetic acid ester could be obtained in a good yield. In addition, this reaction proceeds by an extremely simple manipulation of stirring at room temperature. It was found, therefore, that 2-cyclohexyl-2-hydroxy-2-phenylacetic acid and ester thereof could be obtained by a strategy completely different from conventional production, by the use of 2-(2′-cyclohexen-1′-yl)-2-hydroxy-2-phenylacetic acid ester as a precursor, which is subjected to reduction and hydrolysis.
It was also found that, while an environmentally necessarily preferable solvent, such as methylene chloride, is generally used for the ene reaction, incineratable monochlorobenzene can be used as an alternative solvent. Further, it was found that by converting benzoylformic acid to optically active benzoylformic acid ester having an asymmetric carbon atom in the ester moiety thereof (optically active form of compound of the formula [I] below) and then carrying out the aforementioned ene reaction, asymmetry is induced to give optically active 2-(2′-cyclohexen-1′-yl)-2-hydroxy-2-phenylacetic acid ester, and by subjecting this ester to hydrolysis and reduction, optically active 2-cyclohexyl-2-hydroxy-2-phenylacetic acid could be obtained.
Accordingly, the present invention provides
(1) a compound of the formula [II]
wherein R′ is linear or branched chain alkyl having 1 to 15 carbon atom(s), which is optionally substituted by at least one substituent selected from the group consisting of phenyl, naphthyl, cyclohexyl, cyclopentyl, norbornyl, methoxycarbonyl, ethoxycarbonyl and (&agr;-(2-cyclohexen-1-yl)-&agr;-hydroxy-benzyl)carbonyloxy, or cyclohexyl, cyclopentyl or norbornyl, which is optionally substituted by at least one substituent selected from the group consisting of linear or branched chain alkyl having 1 to 15 carbon atom(s) and phenyl, or an optically active form thereof,
(2) the compound of the above-mentioned (1) wherein R′ is linear or branched chain alkyl having 1 to 15 carbon atom(s), which is optionally substituted by at least one substituent selected from the group consisting of phenyl, naphthyl, cyclohexyl, cyclopentyl and norbornyl, or cyclohexyl, cyclopentyl or norbornyl, which is optionally substituted by at least one substituent selected from the group consisting of linear or branched chain alkyl having 1 to 15 carbon atom(s) and phenyl, or an optically active form thereof,
(3) a compound of the formula [V]
an opticall
Gao Wei-Guo
Igi Masami
Ikemoto Tetsuya
Takeda Mitsuhiro
Desai Rita
Leydig , Voit & Mayer, Ltd.
Reyes Hector M
Sumika Fine Chemicals Co., Ltd.
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