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The preparation method of omeprazole intermediate

A volume ratio, dimethyl technology, applied in the direction of organic chemistry, can solve the problems of unfavorable industrial scale production, affecting production efficiency and product yield, low purity, etc., to reduce the impurity content, reduce the difficulty of purification, and simplify the purification process Effect

Active Publication Date: 2022-02-11
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

However, the purity of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride obtained by using this method is relatively low, and it is necessary to obtain a qualified product through repeated crystallization and purification. Affects production efficiency and product yield, which is not conducive to industrial scale production

Method used

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  • The preparation method of omeprazole intermediate
  • The preparation method of omeprazole intermediate
  • The preparation method of omeprazole intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1 (0.03% silver nitrate)

[0064]

[0065] Step 1: Take compound II-1 (4.9g, 17.56mmol), add 20mL water and 30mL methanol, stir and dissolve evenly, add silver nitrate (0.9mg, 0.0053mmol, 0.03%), and heat up to reflux. Ammonium persulfate solution (4.01g, 17.57mmol, ammonium persulfate dissolved in 16mL of water) was added dropwise to the reaction system for a total of 2 hours. After the drop was completed, the reaction was continued for 3h under reflux conditions, the reaction was stopped, and 30 ml of methanol was added , filtered, the filtrate was concentrated under reduced pressure to remove methanol, the residue was adjusted to pH 10 with 10mol / L NaOH solution in an ice-water bath, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain compound III (2 -hydroxymethyl-3,5-dimethyl-4-methoxypyridine) to obtain 2.90 g of brown solid, yield: 98.8%.

[0066] St...

Embodiment 2

[0067] Embodiment 2 (0.005% silver nitrate)

[0068]

[0069] Step 1: Take compound II-1 (4.9g, 17.56mmol), add 20mL water and 30mL methanol, stir and dissolve evenly, add silver nitrate (0.15mg, 0.005%), and heat up to reflux. Ammonium persulfate solution (4.01g, 17.57mmol, ammonium persulfate dissolved in 16mL of water) was added dropwise to the reaction system for a total of 2 hours. After the drop was completed, the reaction was continued for 3h under reflux conditions, the reaction was stopped, and 30 ml of methanol was added , filtered, the filtrate was concentrated under reduced pressure to remove methanol, the residue was adjusted to pH 10 with 10mol / L NaOH solution in an ice-water bath, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain compound III (2 -hydroxymethyl-3,5-dimethyl-4-methoxypyridine) to obtain 2.85 g of brown solid, yield: 97.2%.

[0070] Step 2: Add...

Embodiment 3

[0071] Example 3 (methanol / water volume ratio is 1:1)

[0072]

[0073] Step 1: Take compound II-1 (4.9g, 17.56mmol), add 14mL water and 30mL methanol, stir and dissolve evenly, add silver nitrate (0.9mg, 0.0053mmol, 0.03%), and heat up to reflux. Ammonium persulfate solution (4.01g, 17.57mmol, ammonium persulfate dissolved in 16mL of water) was added dropwise to the reaction system for a total of 2 hours. After the drop was completed, the reaction was continued for 3h under reflux conditions, the reaction was stopped, and 30 ml of methanol was added , filtered, the filtrate was concentrated under reduced pressure to remove methanol, the residue was adjusted to pH 10 with 10mol / L NaOH solution in an ice-water bath, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain compound III (2 -hydroxymethyl-3,5-dimethyl-4-methoxypyridine) to obtain 2.84 g of brown solid, yield: 96.8.0%....

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Abstract

The present invention relates to a kind of preparation method of omeprazole intermediate. The method uses N-methoxy-4-methoxy-3,5-lutidine salt as raw material, adding metal ions as additives, and under the action of persulfate, efficiently prepares 2-hydroxymethyl- 3,5‑Dimethyl‑4‑methoxypyridine, which is further converted to 2‑chloromethyl‑3,5‑dimethyl‑4‑methoxypyridine hydrochloride. This method makes the conversion rate, yield and quality of 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine all significantly improved, so that the 2-chloromethyl-3 obtained by further reaction, The purity of 5-dimethyl-4-methoxypyridine hydrochloride is improved, and the impurity content is reduced, which can effectively improve product yield and production efficiency, increase production capacity, and reduce production cost.

Description

technical field [0001] The invention relates to the technical fields of organic synthesis and medicine, in particular to a preparation method of an omeprazole intermediate. 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 methano...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/65
CPCC07D213/65
Inventor 王启卫韩成缪小荣黄国建
Owner 成都百泉生物医药科技有限公司
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