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Method for high enantiomer selection preparation of (S)-Omeprazole

An enantioselective, enantiomeric technology, applied in pharmaceutical formulations, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problem of large usage of chiral ligands, increased cost and operational complexity, Waste of omeprazole raw materials and other issues

Active Publication Date: 2010-11-17
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In the above-mentioned published patents for the preparation of single enantiomers of omeprazole, there are mainly the following three methods: one is to use a chiral resolution reagent to resolve the racemic omeprazole, but the traditional resolution Method is difficult to effectively split omeprazole free base, and this method can waste half of omeprazole raw material (as WO 9427988, WO 04 / 002982); The 2nd, adopt the method of biochemistry, use biological Enzyme to oxidize omeprazole sulfide or reduce omeprazole sulfone to obtain a single enantiomer of omeprazole, but this method requires special experimental equipment and experimental methods, which is relatively cumbersome and troublesome (such as WO 9617076, WO 9617077); the third is to adopt the method of asymmetric oxidation, using chiral prosthetic groups or catalysts to prepare the single enantiomer of omeprazole, which is convenient and easy compared to the former two ( Such as WO 9602535, WO 03 / 089408)
However, this method also has obvious defects at present: 1) the amount of chiral ligand used is too large, even reaching the chemical dosage; 2) the relatively expensive cumene hydroperoxide CHP is used; 3) a large amount of special organic base is required: Diisopropylethylamine, which adds cost and operational complexity

Method used

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  • Method for high enantiomer selection preparation of (S)-Omeprazole
  • Method for high enantiomer selection preparation of (S)-Omeprazole
  • Method for high enantiomer selection preparation of (S)-Omeprazole

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1 general operation

[0059] The chiral bidentate ligand (0.16mmol) was dissolved in 5mL of organic solvent, and titanium tetraisopropoxide (0.08mmol) was added under stirring, then water (1.6mmol) was added, stirring was continued, and omeprazole sulfide (1.6mmol) was added. mmol), be down to-20 DEG C, then slowly add oxidizing agent (3.2mmol) dropwise, continue reaction 12 hours, aftertreatment, promptly can obtain omeprazole. 1 H NMR (300MHz, CDCl 3 ): 2.20(s, 3H), 2.22(s, 3H), 3.67(s, 3H), 3.83(s, 3H), 4.77(m, 2H), 6.88-6.95(m, 2H), 7.62(m, 1H), 8.20(s, 1H), 12.18(bs, 1H). Chiral HPLC conditions are: Chiral The AD analysis column uses ethanol:n-hexane:acetic acid=50:50:5 as the mobile phase, the flow rate is 0.7mL / min, and the ultraviolet monitoring is at 302nm. retention time is t S =10.28,t R =15.39.

Embodiment 2

[0060] The optimization of embodiment 2 reaction conditions

[0061] The experimental operation is the same as in Example 1, and the feeding ratio is as follows: Omeprazole sulfide: (R, R)-1,2-bis(2-bromo-phenyl)-1,2-diol: titanium tetraisopropoxide :water:oxidant molar ratio is 1:0.1:0.05:1:2. The bidentate ligand used in this reaction is (R,R)-1,2-bis(2-bromo-phenyl)-1,2-diol, and the experimental results are shown in Table 1.

[0062] Table 1

[0063]

[0064]

[0065] Note: Ee is enantioselectivity. CCl 4 is carbon tetrachloride. CH 2 Cl 2 is dichloromethane. Toluene is toluene. TBHP is tert-butyl hydroperoxide. CHP is cumene hydroperoxide.

Embodiment 3

[0066] The influence of embodiment 3 ligand substituent effect on reaction

[0067] The experimental operation is the same as in Example 1, and the feeding ratio is as follows: Omeprazole sulfide: (R, R)-1,2-bis(2-bromo-phenyl)-1,2-diol derivative: tetraisopropyl The molar ratio of titanium alkoxide: water: oxidizing agent is 1:0.1:0.05:1:2. The solvent used in this reaction is toluene, and the oxidizing agent is tert-butyl hydroperoxide. The experimental results are shown in Table 2.

[0068] Table 2

[0069]

[0070]

[0071]

[0072] Note: Ee is enantioselectivity.

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Abstract

The present invention relates to antimer selective catalytic oxidation process for preparing optical active antimer or optically pure antimer (S)-omeprazole. In the presence of the titanium containing catalyst in-situ created with metal titanium reagent and chiral glycol ligand and the oxidant, omeprazole sulfide is catalytically oxidized with antimer. Compared with the process utilizing tetraisopropanol titanium-diethyl tartrate system, the process of the present invention has the advantages of cheap material, high antimer selectivity and high yield. The present invention also relates to thepreparation of (S)-omeprazole in neutralized state, partial crystallized state or completely crystallized state.

Description

technical field [0001] The invention relates to a method for preparing (S)-omeprazole with high enantioselectivity. Background technique [0002] Compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-sulfinyl]-1H-benzimidazole (commonly known as azulene Meprazole) and pharmaceutically acceptable salts thereof are described in EP 5129. Particular alkali metal salts of omeprazole are described in EP 124495 . Omeprazole is a proton pump inhibitor, which can effectively inhibit gastric acid secretion and is used as an antiulcer agent. From a more general point of view, omeprazole can be used to prevent and treat diseases related to stomach acid in mammals, especially humans. [0003] In asymmetrically substituted sulfoxide compounds, the sulfur atom is chiral. The chirality of omeprazole is shown on the sulfur atom of sulfoxide. In fact, omeprazole also has a pair of enantiomers, and (S)-(-)-enantiomer corresponds to (S)-omeprazole. [0004] Sodium, magnesium, l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12A61K31/4439A61P1/04
Inventor 姜标赵小龙王万军董佳佳徐向亚
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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