A kind of preparation method of Suwo Leisheng intermediate

An intermediate and time technology, applied in the field of medicine, can solve the problems that the product does not meet the quality standard of pharmaceutical intermediates, the catalyst cuprous iodide is difficult to remove, and the content of isomer compound 2 is high, so as to achieve high yield and product purity , Improve labor protection and reduce environmental pollution

Active Publication Date: 2022-05-20
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Chinese patent CN104557744A discloses the preparation method of intermediate compound 1, the operation is relatively simple, but the product character is poor (light green solid), the purity is low (94%~95%), and the content of isomer compound 2 is high (4%~5%) ), at the same time, the catalyst cuprous iodide is difficult to remove, and the product cannot reach the quality standard of pharmaceutical intermediates

Method used

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  • A kind of preparation method of Suwo Leisheng intermediate
  • A kind of preparation method of Suwo Leisheng intermediate
  • A kind of preparation method of Suwo Leisheng intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add 66g of acetone and 8.4g of 2-iodo-5-methylbenzoic acid into a 250ML reaction flask, stir to dissolve, add 8.9g of anhydrous potassium carbonate, heat up to reflux (55-60°C) for half an hour, then add 2.9g of 1, 2,3-triazole, 0.061g cuprous iodide. Insulate and reflux (55-60°C) for 8 hours, take samples, and take samples every 1h for testing. After the reaction is completed, cool to room temperature and filter. The filter cake is washed twice with 3g of acetone to obtain a white solid. At room temperature (20-30°C) The white solid was dissolved in 84 g of purified water and stirred for 30 min, and hydrochloric acid was added dropwise at room temperature to adjust the pH of the system to 1.5-2.0 to obtain a large amount of white solid. Filter and wash the filter cake twice with purified water. The obtained solid was dried to dryness at 50±5°C to obtain a crude compound 1.

[0029] Add the crude compound 1 obtained in the previous step, 10g of absolute ethanol and 10...

Embodiment 2

[0031] Add 1.1kg of acetone and 131g of 2-iodo-5-methylbenzoic acid into a 5L reaction flask, stir to dissolve, add 350g of anhydrous potassium carbonate, heat up to reflux (55-60°C) for half an hour, then add 114g of 1,2, 3-triazole, 2.4g cuprous iodide. Insulate and reflux (55-60°C) for 8 hours, take samples, and take samples every 1h for detection. After the reaction is completed, cool to room temperature and filter. The filter cake is washed twice with 120g of acetone to obtain a white solid. At room temperature (20-30°C) The white solid was dissolved in 1.3 kg of purified water and stirred for 30 min, and hydrochloric acid was added dropwise at room temperature to adjust the pH of the system to 1.5-2.0 to obtain a large amount of white solid. Stir for 1-2 hours, filter, and wash the filter cake twice with purified water. The obtained solid was dried to dryness at 50±5°C to obtain a crude compound 1.

[0032] Add crude compound 1, 0.2kg of absolute ethanol and 0kg of pur...

Embodiment 3

[0034]Add 2.5kg of acetone and 314g of 2-iodo-5-methylbenzoic acid into a 5L reaction flask, stir to dissolve, add 332g of anhydrous potassium carbonate, heat up to reflux (55-60°C) for half an hour, then add 108g of 1,2, 3-triazole, 2.28g cuprous iodide. Insulate and reflux (55-60°C) for 8 hours, take samples, and take samples every 1h for detection. After the reaction is completed, cool to room temperature and filter. The filter cake is washed twice with 250g acetone to obtain a white solid. At room temperature (20-30°C) The white solid was dissolved in 3.1 kg of purified water and stirred for 30 min, and hydrochloric acid was added dropwise at room temperature to adjust the pH of the system to 1.5-2.0 to obtain a large amount of white solid. Stir for 1-2 hours, filter, and wash the filter cake twice with purified water. The obtained solid was dried to dryness at 50±5°C to obtain a crude compound 1.

[0035] Add crude compound 1, 0.5kg of absolute ethanol and 0.5kg of puri...

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Abstract

The invention discloses a preparation method of a Suvoryxan intermediate, comprising the following steps: using a trace amount of cuprous iodide as a catalyst, using anhydrous potassium carbonate as a base and acetone as a solvent of three types of solvents, and 2-iodine-5 formazan Ullman reaction between benzoic acid and 1,2,3-triazole, and a high-purity Suvorexan intermediate can be obtained after one ethanol and water mixed solvent purification. The preparation method of the invention fully utilizes the theory of atomic economy, and is easy to operate, low in cost and pollution-free. It is suitable for large-scale industrial production; and after only one refinement, the chromatographic purity can reach more than 99.8%, the isomer is less than 0.1%, and the yield is more than 90%.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of a Suvorexan intermediate. Background technique [0002] Suwo Leisheng (trade name: Belsomra), is an orexin (orexin) receptor antagonist with a novel mechanism of action, which can significantly shorten the time required to fall asleep (sTSO) in patients with insomnia, and shorten the sleep time of the next day. Due to its strong targeting, side effects are less than traditional GABA agonists, there is no rebound insomnia after drug withdrawal, and there is no central nervous system and respiratory function inhibition. It is the first approved orexin receptor antagonist, which is clinically used to treat diseases such as insomnia; its structural formula is as follows: [0003] [0004] In the preparation process of Suvorexan, it is necessary to prepare the intermediate 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (hereinafter referred to as compound ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/06
CPCY02P20/55
Inventor 邹贻泉徐镜人蔡伟宣景安陈令武吉烨朱云龙刘金凤胡涛
Owner YANGTZE RIVER PHARM GRP CO LTD
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