Omeprazole process impurity and preparation method thereof

A process impurity, omeprazole technology, applied in the field of medicine, can solve the problems of difficult quality research, clinical drug safety monitoring, separation, structure confirmation and synthesis preparation, and difficult source of drug impurity reference substances, so as to achieve perfect quality Standards and controls, improving quality standards, and improving the effect of quality levels

Active Publication Date: 2021-02-26
成都百泉生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the problem of drug quality and safety has attracted great attention from the relevant state departments, since each drug may contain many impurities, and their content is often very low, there are many problems in its separation, structure confirmation and synthesis preparation. Difficulties, resulting in difficulties in the source of impurity reference substances for many drugs, and it is difficult to carry out quality research and clinical drug safety monitoring
Therefore, the research work of impurities is still a weak link of many drug research and development institutions and manufacturers

Method used

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  • Omeprazole process impurity and preparation method thereof
  • Omeprazole process impurity and preparation method thereof
  • Omeprazole process impurity and preparation method thereof

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Embodiment 1

[0039] The generation, separation and identification of embodiment 1 impurity

[0040] In this example, omeprazole intermediate 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride was prepared with reference to the method in patent US4544750A.

[0041] Step A: Synthesis of Compound A:

[0042]

[0043] Take 3,5-dimethyl-4-methoxypyridine nitrogen oxide (35.9g, 0.235mol) in a one-necked bottle, add 145mL of chloroform and stir to dissolve, raise the temperature to 60°C, add dropwise dimethyl sulfate (24.4mL , 0.258mol), after 5 hours, the heating was turned off to stop the reaction. Cool down, add water to extract, and evaporate to dryness to obtain 65.0 g (23.29 mmol) of Compound A as a solid, with a yield of 99.1%. Common NMR spectrum such as figure 1 shown.

[0044] Step B: Synthesis of Compound B

[0045]

[0046] Take compound A (4.9g, 17.56mmol) and add 20mL of methanol, stir and dissolve evenly, and heat up to reflux. Ammonium persulfate solution (4.0...

Embodiment 2

[0068] The preparation of embodiment 2 impurity I

[0069]

[0070] Take 1g of 3,5-dimethyl-4-methoxypyridine nitrogen oxide in a three-necked flask, add 0.2mL of chloroform and 0.5mL of water to dissolve, and slowly add 0.68mL of dimethyl sulfate dropwise. Under argon protection, react at 80°C for 3h.

[0071] Post-treatment: Cool the reaction solution obtained above to room temperature, add 4 mL of water and 4 mL of chloroform for extraction, combine the organic phases, spin dry, DCM:MeOH=20:1 (volume ratio) column chromatography to obtain impurity I. 1 H NMR (300MHz, CDCl 3 )δ7.46(s,2H),4.00(s,3H),2.05(s,6H).HRMS(ESI,M / Z):Calculated for[M-X] + :154.09,[M-X-H+Na] + :176.07, found: 154.0859, 176.0683.

Embodiment 3

[0072] The preparation of embodiment 3 impurity III

[0073]

[0074] ZrCl 4 (815mg, 3.5mmol) was dissolved in dry tetrahydrofuran (35mL), and NaBH 4 (500mg, 13.2mmol), after stirring for 10 minutes, the reaction solution A was obtained; 3,5-dimethyl-4-methoxypyridine nitrogen oxide (500mg, 3.3mmol) was dissolved in dry tetrahydrofuran (15mL) , to obtain a reaction solution B; add the reaction solution B to the reaction solution A at 0-5° C., rise to room temperature, and stir to react. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to 0°C, and dilute hydrochloric acid was added dropwise to quench the reaction. Tetrahydrofuran was distilled off under reduced pressure, the aqueous layer was extracted with ethyl acetate (30 mL×3 times), the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After the organic phase was spin-dried, it was chromatographed with ethyl acetate / p...

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Abstract

The present invention relates to an omeprazole process impurity and a preparation method thereof, the omeprazole process impurity has a structure represented by a formula I: wherein X<-> is CH3SO4<->or HSO4<->. Separation, confirmation and preparation of the omeprazole process impurity are beneficial to impurity analysis of an omeprazole intermediate and an omeprazole bulk drug, and improvement of a synthesis process of the omeprazole intermediate and the omeprazole bulk drug, so that further improvement of the quality standard and control of the omeprazole bulk drug is facilitated; the quality level of the raw material medicine is improved, and guarantee is provided for the medication safety of people.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a process impurity of omeprazole and a preparation method thereof. Background technique [0002] Omeprazole (Omeprazole), chemical name 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H- Benzimidazole, a benzimidazole proton pump inhibitor, is used for the treatment of peptic ulcer, esophageal reflux disease, gastrinoma syndrome and Helicobacter pylori. 2-Chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride is a key intermediate for the preparation of omeprazole. [0003] The preparation method of the key intermediate 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride of omeprazole is recorded in U.S. Patent US4544750A, and the method first obtains N-methoxy -4-methoxy-3,5-lutidine sulfonic acid monomethyl ester salt; N-methoxy-4-methoxy-3,5-lutidine sulfonic acid monomethyl ester salt contains A rearrangement reaction occurs in methanol soluti...

Claims

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Application Information

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IPC IPC(8): C07D213/89C07D213/68
CPCC07D213/89C07D213/68
Inventor 庞嘉东钟菁缪小荣王启卫
Owner 成都百泉生物医药科技有限公司
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