Preparation method of chiral sulphoxide proton pump inhibitor or pharmaceutically-acceptable salt thereof

A proton pump inhibitor and sulfoxide technology, which is applied in the field of preparation of chiral sulfoxide proton pump inhibitors or their pharmaceutically acceptable salts, can solve the problem of low stereoselectivity, low stereoselectivity of chiral sulfoxide proton pump inhibitors, Absolute configuration changes, application limitations, etc., to achieve the effects of specific stereoselectivity, low production cost, and easy operation

Inactive Publication Date: 2012-05-02
CHENGDU XINJIE HIGH TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, it was found in the study that the method of preparing chiral sulfoxide proton pump inhibitors by direct oxidation of thioether compounds using Davis oxidant has defects such as low stereoselectivity (only 12.3%) and low yield (only 12%), and , changing the reaction solvent will change the absolute configuration of the reaction product, which greatly limits the application of this method

Method used

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  • Preparation method of chiral sulphoxide proton pump inhibitor or pharmaceutically-acceptable salt thereof
  • Preparation method of chiral sulphoxide proton pump inhibitor or pharmaceutically-acceptable salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 Preparation of Chiral Sulfoxide Proton Pump Inhibitors

[0040] 1) Preparation of omeprazole sulfide diazabicyclic (DBU) complex

[0041] Dissolve 0.5 g of omeprazole sulfide in 6 mL of isopropanol, drop 0.23 mL of diazabicyclo (DBU) into the reaction under stirring conditions, and stir for 30 minutes at room temperature. Concentration under reduced pressure gave 0.72 g of a light yellow oily substance with a yield of 98%.

[0042] 1 H-NMR (400 MHz, d 6 -DMSO): δ = 8.14 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.45 (dd, J 1 = 2.4Hz, J 2 = 8.8 Hz, 1H), 5.39 (s, 1H), 4.57 (s, 2H), 3.71 (s, 3H), 3.70 (s, 3H), 3.21-3.17 (m, 4H), 3.09 (t, J = 5.6 Hz, 2H), 2.31-2.29 (m, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.71-1.65 (m, 2H), 1.58-1.47 (m, 6H).

[0043] 2)( S )-Omeprazole preparation

[0044] The prepared 0.72 g omeprazole thioether diazabicyclic (DBU) complex was dissolved in 6 mL of isopropanol, and 0.35 g (1 R )-(-)-cam...

Embodiment 2

[0048] Example 2 Preparation of Chiral Sulfoxide Proton Pump Inhibitors

[0049] 1） ( S )-Omeprazole preparation

[0050] Dissolve 0.18 mL of DBU and 0.4 g of omeprazole sulfide in 5 mL of isopropanol, stir and react for 30 minutes at room temperature, then move to ice-bath conditions, add 0.28 g (1 R )-(-)-camphorsulfonazine, maintain ice-bath conditions, and stir the reaction. TLC detected that the reaction was complete. Suction filtration, the filter cake (the filter cake is camphorsulfonylimide compound, the recovery rate is 82%) was washed with isopropanol, after the filtrate was concentrated, about 2 mL of water was added, and the pH was adjusted to 7-10 with acetic acid solution, ethyl acetate The ester was extracted 3 times, and the ethyl acetate phase was dried and concentrated to obtain a foamy solid ( S )-omeprazole 0.35 g, yield: 83.3%.

[0051] HPLC determination ee: 99.18% (HPLC detection: chiral column AD, mobile phase: n-hexane / isopropanol = 60 mL / 4...

Embodiment 3

[0057] Example 3 The preparation of dexlansoprazole

[0058] Take 10g of 2-[3,5-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine-2-methylenethio]-1H-benzimidazole, put it in 250ml In the bottle, add 120ml of isopropanol. Under the condition of stirring, add DBU (diazabicyclo) 3.9g, after stirring and reacting for 30 minutes, under the condition of ice bath, add D-camphorsulfonoxazine 6.4g in the reaction bottle, stir the reaction, TLC detects that the reaction is complete, Filter the reaction solution, wash the obtained solid with 20ml of isopropanol to obtain a light yellow filtrate, concentrate to dryness under reduced pressure, add 50ml of water, stir well, add 50% acetic acid solution dropwise to the aqueous solution, adjust pH = 8-8.5, acetic acid Ethyl 50ml×3 was extracted, the ethyl acetate layers were combined and dried over anhydrous sodium sulfate, filtered, and the ethyl acetate layer was concentrated under reduced pressure to obtain a light yellow oil. Add 20ml o...

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Abstract

The invention relates to a preparation method of a chiral sulphoxide proton pump inhibitor or a pharmaceutically-acceptable salt thereof. The preparation method comprises the following step of: dissolving a chiral (1R)-(-)-(10-camphorsulfonyl)oxaziridine compound shown as a formula I and an imidazole thioether compound shown as a formula II into an appropriate solvent for undergoing an oxidation reaction to obtain the chiral sulphoxide proton pump inhibitor or the pharmaceutically-acceptable salt thereof.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of a chiral sulfoxide proton pump inhibitor or a pharmaceutically acceptable salt thereof. Background technique [0002] Proton pump inhibitors containing sulfoxide groups (such as omeprazole, lansoprazole, pantoprazole, rabeprazole, etc.) can effectively inhibit the secretion of gastric acid and are widely used in the treatment of hypersecretion of gastric acid Peptic ulcer disease caused by gastric ulcer, including gastric ulcer, intestinal ulcer, duodenal ulcer and so on. In recent years, chiral drugs containing proton pump inhibitors with sulfoxide groups have shown good pharmacokinetics and physiological activities, and the research on their enantiomer drugs has attracted much attention. US5877192 discloses its racemate drug omeprazole compared, ( S )-Omeprazole has the advantages of stronger activity, less first-pass metabolism, high bioavailabilit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B45/00C07B53/00C07D401/12
Inventor 关文捷张善军高建肖林郭瑞
Owner CHENGDU XINJIE HIGH TECH DEV CO LTD
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