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Preparation method of zolpidem and key intermediate thereof

A technology for zolpidem and intermediates, applied in the field of pharmaceutical synthesis, can solve the problems of unstable yield, high production equipment requirements, and high production costs, achieve high reaction yield and purity, improve operational safety, and reduce production costs. Effect

Pending Publication Date: 2022-03-29
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0027] ①The reduction operation after hydroxychlorination is used, which increases the synthesis unit operation and makes the operation cumbersome;
[0029] ③Adopt noble metal catalysts (platinum, palladium, ruthenium, osmium, iridium, or rhodium catalysts), which makes the production cost higher and the corresponding platinum carbon or palladium carbon and other products are dangerous to operate;
[0030] ④Reduce and prepare related compounds with hydrogen at 1 to 4 atmospheres, which makes the operation less safe and the yield unstable;
[0031] ⑤Using difficult-to-obtain sodium methane sulfinate or highly toxic sulphate to carry out hydroxyl reduction, which makes the production cost higher and the operation safety lower
[0032] In view of the existing methods for preparing zolpidem or its key intermediates from α-hydroxyzolpidem derivatives, there are many deficiencies in the aspects of complicated operations, high requirements for production equipment, process safety, and production costs. The preparation process suitable for industrial production of zolpidem or its key intermediates with mild reaction conditions, safe and simple operation process, high product yield and high purity is still a problem to be solved at present

Method used

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  • Preparation method of zolpidem and key intermediate thereof
  • Preparation method of zolpidem and key intermediate thereof
  • Preparation method of zolpidem and key intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Under argon protection, 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide [R=N(CH 3 ) 2 , named as SM-1, 32.34g, 0.1mol], trimethylchlorosilane (TMSCl, 54.32g, 0.5mol), sodium iodide (74.95g, 0.5mol) were added in dry acetonitrile (300ml), temperature controlled 55 ℃ to after the end of the reaction, the reaction solution was down to room temperature, added in purified water (800ml), extracted with dichloromethane (300ml × 3), the organic phase was washed with saturated sodium thiosulfate solution (300ml × 3), purified water ( 300ml×2), washed with saturated brine (300ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem with a yield of 96.4% and a HPLC purity of 99.892%.

Embodiment 2

[0061] Under argon protection, 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide [R=N(CH 3 ) 2 , SM-1, 32.34g, 0.1mol], trimethylchlorosilane (TMSCl, 43.46g, 0.4mol), sodium iodide (59.96g, 0.4mol) were added to dry acetonitrile (300ml), and the temperature was controlled at 60°C After the reaction was finished, the reaction solution was cooled to room temperature, added in purified water (800ml), extracted with chloroform (300ml×3), the organic phase was washed with saturated sodium thiosulfate solution (300ml×3), purified water (300ml×2 ), washed with saturated brine (300ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem with a yield of 95.9% and an HPLC purity of 99.873%.

Embodiment 3

[0063] Under argon protection, 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide [R=N(CH 3 ) 2 , SM-1, 32.34g, 0.1mol], trimethylchlorosilane (TMSCl, 38.02g, 0.35mol), sodium iodide (52.46g, 0.35mol) were added to dry acetonitrile (300ml), and the temperature was controlled at 55°C After the reaction was finished, the reaction solution was cooled to room temperature, added in purified water (800ml), extracted with ethyl acetate (300ml×3), the organic phase was washed with saturated sodium thiosulfate solution (300ml×3), purified water (300ml×3) 2) Washing, washing with saturated brine (300ml×2), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness under reduced pressure to obtain zolpidem with a yield of 92.9% and a HPLC purity of 99.791%.

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Abstract

The invention belongs to the technical field of medicine synthesis, and provides a preparation method of zolpidem and a key intermediate thereof, under the protection of inert gas, SM is used as a raw material, and alpha-hydroxyl is reduced by trimethylchlorosilane and alkali metal iodide to obtain a compound I; the alpha-hydroxyl reduction method provided by the invention can effectively avoid the use of SOCl2, a noble metal catalyst, sodium methanesulfinate or sodium formaldehyde sulfoxylate in the prior art, reduces the production cost, improves the operation safety, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of zolpidem and a key intermediate thereof. Background technique [0002] Zolpidem tartrate (Zolpidem tartrate), the chemical name is 2-(4-methylphenyl)-N,N,6-trimethylimidazo[1,2-a]pyridine-3-acetamide tartrate, is a non-benzodiazepine Hypnotics, trade name Originally researched by Synthelabo in France, it was first listed in France in 1988. It is clinically used to treat serious sleep disorders, such as occasional insomnia and temporary insomnia; in addition, this product also has significant curative effects on insomnia caused by primary insomnia, depression, and mental illness; it has fast drug effect, Low addiction characteristics. Its chemical structural formula is as follows: [0003] [0004] At present, there are many reports on the synthesis process of zolpidem, such as CN106946876A, CN106749237A, CN103360387A, CN1013362...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 胡彦汝于成彬
Owner LUNAN PHARMA GROUP CORPORATION
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