Process for preparing optically active glycidate esters

Details Process for preparing optically active glycidate esters Process for preparing optically active glycidate esters

1989-04-10

2003-02-18

Kumar, Shailendra (Department: 1621)

Chemistry: molecular biology and microbiology

Process of utilizing an enzyme or micro-organism to destroy...

Resolution of optical isomers or purification of organic...

C435S135000, C435S136000, C435S155000, C435S132000

Reexamination Certificate

active

06521445

ABSTRACT:

TABLE OF CONTENTS
1. Introduction
2. Background of the Invention
2.1. Diltiazem and its Analogues
2.2. The Stereochemistry of Diltiazem and Its Precursors
2.3. Techniques for Resolution of Glycidate Esters
2.4. Enzymatic Resolution of Racemic Mixtures
3. Summary of the Invention
4. Brief Description of the Figures
5. Detailed Description of the Invention
5.1. Multiphase Enzymatic Reaction Processes
5.2. Examples of Multiphase Enzymatic Resolutions
5.2.1. Procedures for Examples 1-6
5.2.2. Example 1—Stereoselective Hydrolysis of trans-3-(4-methoxy-phenyl)glycidic Acid Methyl Ester in tert-butyl Methyl Ether
5.2.3. Example 2—Stereoselective Hydrolysis of trans-3-(4-methoxy-phenyl)glycidic Acid Methyl Ester in Toluene
5.2.4. Example 3—Stereoselective Hydrolysis of trans-3-(4-methoxy-phenyl)glycidic Acid Ethyl Ester in tert-butyl Methyl Ether
5.2.5. Example 4—Stereoselective Hydrolysis of trans-3-(4-methoxy-phenyl)glycidic Acid n-Butyl Ester in tert-Butyl Methyl Ether
5.2.6. Example 5—Stereoselective Hydrolysis of trans-3-(4-methoxy-phenyl)glycidic Acid Isopropyl Ester in tert-Butyl Methyl Ether
5.2.7. Example 6—Stereoseletive Hydrolysis of trans-3-(4-methoxy-phenyl)glycidic Acid Isobutyl Ester in tert-Butyl Methyl Ether
5.2.8. Effect of Cosolvent on Apparent Enantioselectivity E: Example 7
5.2.9. Effect of Water-Immiscible Organic Solvent on Apparent Enatio-selectivity E: Example 8
5.2.10. Effect of pH on Enzyme Enatio-selectivity E: Example 9
5.2.11. Methyl Ester Hydrolysis Catalyzed by Lipase MAP—Examples 10 and 11
5.2.12. Methyl Ester Hydrolysis Catalyzed by Lipase-OF—Example 12
5.2.13. Resolution of Racemic Methyl 3-(4-Methoxyphenyl)-glycidate in a Membrane Reactor at pH 7—Example 13
5.2.14. Resolution of Racemic Methyl 3-(4-Methoxyphenyl)-glycidate in a Membrane Reactor at pH 8—Examples 14-17
5.3. Management of the Aldehyde Byproduct by Adduct Formation with Bisulfite
5.4. Examples Pertinent of Bisulfite Utilization
5.4.1. Resolution of trans-3-(4-Methoxy-phenyl)glycidic Acid Methyl Ester in a Multiphase Enzyme Membrane Reactor
5.4.2. Example 18—resolution of trans-3-(4-Methoxyphenyl)glycidic Acid Methyl Ester in a Multiphase Enzyme Membrane Reactor in the Absence of Bisulfite
5.4.3. Example 19—Resolution of trans-3-(4-Methoxyphenyl)glycidic Acid Methyl Ester in a Multiphase Enzyme Membrane Reactor Using Sodium Bisulfite
5.4.4. Example 20—Enrichment of Reaction Product from Enzymatic Resolution of trans-3-(4-Methoxyphenyl)glycidic Acid Methyl Ester Using Sodium Bisulfite
5.4.5. Example 21—Recovery of trans-3-(4-Methoxyphenyl)glycidic Acid Methyl Ester from Tolune Using Concentrated Sodium Bisulfite
5.4.6. Example 22—Degree of Inhibition on Representative Enzymes of Reaction Products
5.4.7. Example 23—Resolution of trans-3-(4-Methoxyphenyl)glycidic Acid Methyl Ester Using Sodium Bisulfite
5.4.8. Example 24—Resolution of trans-3-(4-Methoxyphenyl)glycidic Acid Methyl Ester in the Absence of Sodium Bisulfite
5.4.9. Example 25—Resolution of trans-3-(4-Methoxyphenyl)glycidic Acid Methyl Ester Using Sodium Bisulfite and Extended Reaction Time
5.4.10. Example 26—Resolution of trans-3-(4-Methoxyphenyl)glycidic Acid Methyl Ester Using Sodium Bisulfite in a Larger Scale
5.4.11. Example 27—Resolution of trans-3-(4-Methoxyphenyl)glycidic Acid Methyl Ester in a Multiphase Enzyme Membrane Reactor Using Palatase M
5.4.12. Example 28—Batch Reactions in Toluene Followed by Direct Crystallization of trans-3-(4-methoxyphenyl glycidic Acid Ester (GLOP) Therefrom
5.4.13. Example 29—Bench-Scale Dispersed Phase Enzymatic Resolution Providing High Optical Purity Solutions
5.4.14. Example 30—Large-Scale Membrane Reactor Process Providing Organic Solutions of Highly Resolved GLOP
5.4.15. Stability of GLOP in Some Representative Types of Solvents
5.5. Further Considerations with Regard to Choice of Solvent
5.5.1. The Effect of Solvent on Enzyme Activity
5.5.2. Determination of the Non-Enzymatic Degradation of Substrate Ester
5.6. Post-Enzyme Resolution Clean-Up of Crude Reaction Products by Extraction with a Carbonyl Adduct-Forming Agent
5.6.1. Example 34—Purification of Crude Organic Solution by Extraction with Aqueous Bisulfite Anion
5.7. Reactivity of the Oxirane Ring
1. INTRODUCTION
The esters of trans-3-(4-methoxyphenyl)glycidic acid have utility as precursors in the chemical synthesis of diltiazem. Moreover, these compounds present a very attractive point in the overall synthetic route to diltiazem at which to introduce the desired stereochemistry into the diltiazem precursors through resolution of the racemic glycidic esters and use of the correct, optically purified precursor ester. The present invention pertains to a novel enzymatic method for resolving a racemic mixture of esters of the (2R,3S)- and (2S,3R)-enantiomers of trans-3-(4-methoxyphenyl)glycidic acid. It also pertains to a process for diltiazem production incorporating this resolution step and to membrane reactor means for improving the efficiency of enzymatic resolution of this diltiazem intermediate. The amelioration of the effects of an inhibitory aldehyde by-product of the reaction process by means of its formation of an adduct with an agent provided in the aqueous reaction phase is also an aspect of the present invention. Moreover, selected organic solutions of the optically active glycidic ester intermediates have been developed which are particularly useful in subsequent processes involving the isolation of the intermediate directly from the solution or use of the solution to introduce a new reagent for a further chemical transformation.
2. BACKGROUND OF THE INVENTION
2.1. Diltiazem and its Analogues
Diltiazem, the chemical structure of which is shown in
FIG. 1
, is an optically active pharmaceutical compound. More specifically, diltiazem, the chemical name of which is (+)-5-[2-(dimethylamino)ethyl]-cis-2,3-dihydro-3-hydroxy-2-(p-methoxyphenyl)-1,5-benzothiazapin-4(5)-one acetate (ester), consists of a substituted benzothiazapene wherein both chiral carbon atoms have the S absolute stereo-configuration (H. Inoue et al., U.S. Pat. No. 3,562,257). Diltiazem has proven useful for the treatment of angina due to coronary artery spasm, and for exertional angina. The beneficial therapeutic effects achieved with diltiazem are believed to be derived from the inhibition of calcium ion influx during depolarization of the cell membrane in both cardiac and smooth muscle. Diltiazem is known to prevent coronary artery spasm, both spontaneous and ergonovine provoked, and to decrease peripheral vascular resistance. Diltiazem is marketed by Tanabe and by Marion Laboratories in the United States, where it is sold under the tradename Cardizem®. Analogues to diltiazem are also known to exist, e.g., wherein the benzothiazapene moiety has a single chlorine substituent on the aromatic ring.
Diltiazem is currently being manufactured via a process similar to that shown in FIG.
2
. The first step in the synthetic sequence involves the Lewis acid-catalyzed nucleophilic attack of o-nitrothiophenol on methyl trans-3-(4-methoxyphenyl)glycidate, as a mixture of enantiomers, to give the threo compound shown (H. Inoue et al.,
J. Chem. Soc. Perkin Trans. I,
1984, 1725; H. Inoue et al.,
J. Chem. Soc. Perkin Trans. I,
1985, 421; H. Inoue et al., U.S. Pat. No. 4,420,628). This threo compound then needs to be resolved at a subsequent step in the synthetic pathway in order to arrive at the optically active final product (diltiazem).
Alternative production routes to diltiazem utilize o-aminothiophenol in place of o-nitrothiophenol in the step involving opening of and addition to the oxirane ring (S. Nagao et al., U.S. Pat. No. 4,416,819). Such alternative processes also utilize methyl trans-3-(4-methoxyphenyl)-glycidate as an intermediate, and thus are subject to improvement by the process of the present invention.
2.2. The Stereochemistry of Diltiazem and its Precursors
It is known that the above pharmacological effects reside in only one of the two enantiomers of the diltiazem, namely, the d-enantiomer (Merck Index, 10th Edition, 1986, p. 466

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