Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-04-16
2001-03-06
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S544000
Reexamination Certificate
active
06197953
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing optically active trans-3-substituted glycidic acid esters. More particularly, the present invention relates to a process for preparing optical isomers of trans-3-(substituted or unsubstituted phenyl)glycidic acid esters which are useful as intermediates for the synthesis of pharmaceutical compounds, and the use of the optical isomers.
Diltiazem hydrochloride, the chemical name of which is (2S, 3S)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one hydrochloride, is a pharmaceutical compound widely used as a calcium channel blocker for the treatment of angina pectoris, essential hypertension and the like (Merck Index, XII Ed., page 541).
For the preparation of diltiazem, conventionally known is a process wherein racemic trans-3-(4-methoxyphenyl)glycidic acid ester is used as the starting material and an optical resolution is carried out at a later stage in the synthesis, as disclosed in Japanese Patent Publication Kokoku No. 46-16749, No. 53-18038 and No. 61-52142.
Also, a process using a (2R,3S)-3-(4-methoxyphenyl)glycidic acid methyl ester obtained by optical resolution of the racemic trans-glycidic acid ester is proposed for the preparation of diltiazem in apanese Patent Publication Kokai No. 60-13776.
Thus, various processes for the preparation of optically active trans-3-(4-methoxyphenyl)glycidic acid esters have been investigated and, for instance, processes as mentioned below are proposed:
(a) a process comprising hydrolyzing racemic trans-3-(4-methoxyphenyl)glycidic acid methyl ester to form an alkali metal salt, forming its diastereomeric salt with an optically resolving reagent such as (−)-&agr;-methylbenzylamine, resolving the salt and esterifying again the obtained optically active salt (Japanese Patent Publication Kokai No. 61-145174 and No. 2-231480),
b) a process comprising conducting a Darzens reaction of a chloroacetic acid ester having an asymmetric ester residue such as (−)-menthyl group, (−)-2-phenylcyclohexyl group or (−)-8-phenylmenthyl group with p-anisaldehyde (Japanese Patent Publication Kokai No. 61-268663, No. 2-17170 and No. 2-17169),
(c) a process comprising enzymatically and asymmetrically hydrolyzing (2S, 3R)-isomer in racemic trans-3-(4-methoxyphenyl)glycidic acid methyl ester and recovering the remaining (2R,3S)-isomer (Japanese Patent Publication Kokai No. 2-109995 and No. 3-15398 and WO 90/04643),
(d) a process for the asymmetric synthesis of (2R, 3S)-3-(4-methoxyphenyl)glycidic acid methyl ester comprising subjecting trans-4-methoxycinnamic acid methyl ester to osmium oxidation in the presence of an asymmetric catalyst to give an optically active diol and subjecting the diol to intramolecular ring closure to give the desired compound (WO 89/02428 and WO 89/10350), and
(e) a process comprising subjecting (2S, 3R)-isomer in racemic trans-3-(4-methoxy-phenyl)glycidic acid methyl ester to enzymatic asymmetric transesterification with butanol to give (2R, 3S)-3-(4-methoxyphenyl)glycidic acid methyl ester (Japanese Patent Publication Kokai No. 4-228095 and No. 6-78790).
It is also known that some 1,5-benzothiazepine derivatives other than diltiazem have excellent pharmacological activities. For instance, Japanese Patent Publication Kokai No. 60-202871 discloses that benzothiazepine derivatives having a reverse absolute configuration of diltiazem at the 2- and 3-positions have platelet aggregation inhibitory activity and the like.
It is also known that (2S,3R)-3-(4-methylphenyl)glycidic acid methyl ester which is useful in the synthesis of this derivative is prepared by enzymatic asymmetric hydrolysis of racemic trans-3-(4-methylphenyl)glycidic acid methyl ester (Japanese Patent Publication Kokai No. 3-175995).
Japanese Patent Publication Kokai No. 8-259552 discloses a process for obtaining both isomers of trans-3-(4-methoxyphenyl)glycidic acid methyl ester in high optical purity from racemate by enzymatically and asymmetrically transesterifying the (2S, 3R)-isomer therein with butanol, recovering the untransesterified (2R, 3S)-3-(4-methoxyphenyl)glycidic acid methyl ester and chemically transesterifying the transesterified product, i.e., (2S,3R)-3-(4-methoxyphenyl)glycidic acid butyl ester to convert into the corresponding methyl ester.
Japanese Patent Publication Kokai No. 4-217969 discloses a process for obtaining crystals of (2R, 3S)-isomer of trans-3-(4-methoxyphenyl)glycidic acid methyl ester by dissolving an equimolar mixture of (2R,3S)-isomer and (2S,3R)-isomer and (2R,3S)-isomer in t-butyl methyl ether solvent under heating, adding a crystalline seed of (2R,3S)-isomer, and crystallizing (2R,3S)-isomer, thereby giving crystalline (2R,3S)-isomer in an amount slightly larger than that of (2R, 3S)-isomer initially dissolved together with the equimolar mixture.
Also, Japanese Patent Publication Kokai No. 5-301864 discloses a process for obtaining crystals of (2R, 3S)-isomer of trans-3-(4-methoxyphenyl)glycidic acid 4-chloro-3-methylphenyl ester by thermally dissolving an equimolar mixture of (2R, 3S)-isomer and (2S, 3R)-isomer, and the (2R, 3S)-isomer in tetrahydrofuran, adding a crystalline seed of (2R, 3S)-isomer, and crystallizing (2R,3S)-isomer at 30° C., thereby giving crystalline (2R,3S)-isomer in an amount slightly larger than that of (2R,3S)-isomer initially dissolved together with the equimolar mixture.
Further, Japanese Patent Publication Kokai No. 8-259552 discloses a process for obtaining (2R,3S)-isomer of trans-3-(4-methoxyphenyl)glycidic acid methyl ester from an equimolar mixture of (2R, 3S)-isomer and (2S, 3R)-isomer by enzymatically and asymmetrically transesterifying the (2S, 3R)-isomer therein with butanol until the molar ratio of (2S, 3R)-butyl ester/(2S,3R)-methyl ester is 7.8/1, and crystallizing the (2R, 3S)-isomer therefrom.
However, in this process, in order to prevent the contamination in the desired (2R, 3S)-methyl ester due to the crystallization of the unesterified (2S, 3R)-methyl ester remaining in a small amount, the crystallization was stopped in a stage that the (2R,3S)-3-(4-methoxyphenyl)glycidic acid methyl ester still remains in the mother liquor in an amount larger than the untransesterified (2S,3R)-isomer.
Thus, despite the fact that (2R,3S)-3-(4-methoxyphenyl)glycidic acid methyl ester is scarcely transesterified in this transesterification reaction and the transesterification conversion rate of the (2S, 3R)-isomer is high, the yield of (2R,3S)-3-(4-methoxyphenyl)glycidic acid methyl ester obtained in the form of crystals is not satisfactory.
It is an object of the present invention to provide a process for optically resolving trans-3-(substituted or unsubstituted phenyl)glycidic acid esters in a simple manner in a high yield and in high optical purity.
A further object of the present invention is to provide a process for crystallizing a desired optical isomer of trans-3-(substituted or unsubstituted phenyl)glycidic acid ester from a solution containing a mixture of optical isomers thereof in high purity and in a high yield since the desired optical isomer can be crystallized up to the extent that the concentration of the desired optical isomer remaining in the mother liquor is extremely low as compared with known processes.
A still further object of the present invention is to provide a process for crystallizing a desired optical isomer of trans-3-(substituted or unsubstituted phenyl)glycidic acid ester in high purity from a reaction mixture of an enzymatic asymmetric transesterification of racemate up to the extent that the concentration of the desired optical isomer remaining in the mother liquor is extremely low as compared with known processes.
These and other objects of the present invention will become apparent from the description hereinafter.
SUMMARY OF THE INVENTION
It is found by the inventors of the present invention that if, in a solution containing a racemic trans-3-(substituted or unsubstituted phenyl)glycidic acid ester, and a
Furui Masakatsu
Furutani Toshiyuki
Birch & Stewart Kolasch & Birch, LLP
Tanabe Seiyaku Co. Ltd.
Trinh Ba K.
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