Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1998-12-17
2001-03-13
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C435S280000, C560S060000
Reexamination Certificate
active
06201151
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the invention
The invention relates a process for preparing an optically active (S)-&agr;-aryl propionic acid, by hydrolyzing a racemic &agr;-aryl propionic acid thioester at various temperature in different aqueous organic solvents in the presence of an (S)-stereoselective lipase to form an (S)-&agr;-aryl propionic acid product, while the unreacted (R)-&agr;-aryl propionic acid thioester can be converted to the corresponding (S)-&agr;-aryl propionic acid thioester via a racemization reaction by adding a base as the catalyst in the solution and then hydrolyzing by the lipase described as above so that the (S)-&agr;-aryl propionic acid can be obtained theoretically at a conversion of 100% and with high optical purity. The invention also relates to a process for preparing an optically active (S)-&agr;-aryl propionic acid ester, by adding separately additional alcohol in said various organic solvents and carrying out the transesterification of a racemic thioester of &agr;-aryl propionic acid to form an (S)-&agr;-aryl propionic acid ester product, while the unreacted (R)-&agr;-aryl propionic acid thioester can be converted to the corresponding (S)-&agr;-aryl propionic acid thioester via a racemization reaction by means of the base added in the solution as the catalyst and then transesterifying again by the lipase as described above so that an (S)-&agr;-aryl propionic acid ester product can be obtained at, theoretically, a conversion of 100% and with high optical purity.
2. Description of the prior art
&agr;-Aryl propionic acids, known as profens, as shown in following formula (I), are non-steroid inflammatory drugs (NSAIDs) having effects of analgesic, antipyretic and anti-flammation. A variety of such type of drugs is commercially available such as ibuprofen (1), naproxen (2), ketoprofen (3), flurbiprofen (4) and the like. According to an estimate [Ahuja, 1997], the yearly total sale of the first three drugs was in an amount of three billion US dollars which indicates commercial values thereof and hence has been developed in effort by a number of drug manufactures and research institutes.
wherein, R is an aryl group: R1 and R2 are substitutes.
&agr;-Aryl propionic acid has enantiomers of R and S configurations with not entirely the same pharmalogical effects each other in an organism. For example, the pharmacological effect of the (S)-isomer of naproxen is 28-fold that of the (R)-isomer thereof, whereas the pharmacological effect of the (S) ibuprofen is 100-fold or more higher than that of its R isomer. Under the increasingly severe requirement of regulation for drug control, drugs marketed in the form of racemates at present will be required invariably to be soled in an optically pure form and under such circumstance, the preparation of optically active drugs by an efficient process to meet the commercial demand will be more emphasized. Further, the past study has shown that oral administration of (S)-&agr;-aryl propionic acid products might cause side effects of gastrointestinal bleeding or ulcer [Shanbhag et al., 1992], so that it becomes a common object in effort to develop prodrugs of the (S)-form ester (II) or amide derivative of the &agr;-aryl propionic acid in order to lower the toxicity induced by the acid functionality of the &agr;-aryl propionic acid. Methods for obtaining optically active substances include those described as follows [Sheldon, 1993]: (1) synthesis from naturally occurring optically active precursors; (2) asymmetrical or asymmetrically induced syntheses from prochiral compounds by using biocatalysts such as microorganisms, enzymes, and the like or asymmetrical metallic catalyst; and (3) resolution of racemates, comprising chromatography, diastereomeric salt crystallization, preferential crystallization and kinetic resolutions by using biocatalysts or diastereomeric metallic catalysts. For example, commercial processes for preparing (S)-naproxen are based mainly on diastereomeric salt crystallization of salt formed with bases such as methylphenylamine and the like, and on the asymmetrical synthesis by using asymmetrical metallic catalysts.
Recently, due to the advancing by leaps and bounds of enzymatic engineering techniques, processes involve carrying out hydrolysis or transesterification resolution on racemic ester of &agr;-aryl propionic acid [Chest, 1986; Palmer et al., 1993; Sigh et al., 1988; Sigh, 1986], as well as the esterification resolution on racemic &agr;-aryl propionic acid [Mertoli et al., 1996; Mustranta, 1992; Tsai et al., 1994 ] in the presence of organic solvents by using esterases or lipases having high stereoselectivity.
However, no matter which resolution method was used to resolve racemates, theoretically, only at most 50% of the desired optically active product can be obtained thereby. In contrary, the inventor of this application has developed a process for preparing (S)-&agr;-aryl propionic acid or (S) esters thereof by carrying out hydrolysis or transesterification dynamic resolution on racemic thioester of &agr;-aryl propionic acid compounds (III) in the presence of organic solvents by using both of lipase and base as catalysts, characterized in that it can break through the 50% yield limit of the desired optically active products and obtain the 100% of theoretical conversion. Since, no one has reported in the literature regarding the application of such a process for preparing (S)-&agr;-aryl propionic acid or (S) ester thereof, the process according to the invention is a novel process and is also a practical process in view of the high optical purity and conversion higher than 50% of the product obtained thereby.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the invention to provide a process for preparing an optically active (S)-&agr;-aryl propionic acid, by hydrolyzing a racemic thioester of &agr;-aryl propionic acid at various temperature in different aqueous organic solvents in the presence of an (S)-stereoselective lipase to form an (S)-&agr;-aryl propionic acid product, while the unreacted (R)-&agr;-aryl propionic acid thioester can be converted to the corresponding (S)-&agr;-aryl propionic acid thioester via a racemization reaction by adding a base as the catalyst in the solution and then hydrolyzing by the lipase described as above so that the (S)-&agr;-aryl propionic acid can be obtained theoretically at a conversion of 100% and with high optical purity.
The another object of the invention is to provide a process for preparing an optically active (S)-&agr;-aryl propionic acid ester, by adding separately additional alcohol in various microaqueous organic solvents and carrying out the transesterification of a racemic thioester of &agr;-aryl propionic acid to form an (S)-&agr;-aryl propionic acid ester product, while the unreacted (R)-&agr;-aryl propionic acid thioester can be converted to the corresponding (S)-&agr;-aryl propionic acid thioester via a racemization reaction by means of the base added in the solution as the catalyst and then transesterifying again by the lipase as described above so that an (S)-&agr;-aryl propionic acid ester product can be obtained at, theoretically, a conversion of 100% and with high optical purity.
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Chang Chun-Sheng
Tsai Shau-Wei
Drum & Roth
Geist Gary
National Science Council of Republic of China
Oh Taylor V
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