Method for preparing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine

A technology of cyclopropyl methylamine and cyclopropyl carboxamide, which is applied in the field of key intermediates for preparing tasimelteon, can solve the problems of high risk of raw materials, harsh process conditions, difficult industrial scale-up and the like, and achieves high product purity and raw materials. Easy to obtain, less side effects

Inactive Publication Date: 2012-09-19
JINAN ZHIHE MEDICAL TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Both of the above two methods need to use (1R, 2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanol to synthesize (1R, 2R)-2-(2,3- The key intermediate of dihydrobenzofuran-4-yl)cyclopropylmethylamine, the synthesis steps of (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethanol are many, High cost, harsh process conditions, difficu

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  • Method for preparing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine
  • Method for preparing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine

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Experimental program
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Embodiment 1

[0037] Embodiment 1: the preparation of tasimelteon

[0038] Proceed as follows:

[0039] (1) Preparation of (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarbonyl chloride

[0040] (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylic acid 5.3g, dissolved in 100ml of dichloromethane, dropwise added thionyl chloride 12.4g, DMF0.02g, heated Reflux for 4 hours (the reflux temperature is the boiling point of the solvent methylene chloride, which is a conventional technique), take a sample and add methanol to oscillate, spot the plate to detect the disappearance of the raw materials and the reaction is complete. The solvent was distilled off with a rotary evaporator to obtain 5.8 g of oil, which was directly used in the next reaction.

[0041] (2) Preparation of (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropylcarboxamide

[0042] Add 5.8g of the oil obtained in the previous step to dissolve in 60ml of tetrahydrofuran, add dropwise 25g of ammonia water (mass concentrat...

Embodiment 2

[0047] Embodiment 2: the preparation of tasimelteon

[0048] (1) Preparation of (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarbonyl chloride

[0049] (1R,2R)-2-(2,3-Dihydrobenzofuran-4-yl)cyclopropanecarboxylic acid 4.3g, dissolved in 80ml of dichloromethane, dropwise added thionyl chloride 12.6g, DMF0.02g, room temperature Stir for 12 hours, take a sample and add methanol to oscillate, spot the plate to detect the disappearance of the raw materials and the reaction is complete. The solvent was distilled off with a rotary evaporator to obtain 4.6 g of oil, which was directly used in the next reaction.

[0050] (2) Preparation of (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropylcarboxamide

[0051] Add 50ml of tetrahydrofuran to 4.6g of the oil obtained in the previous step to dissolve, add dropwise 20g of ammonia water (mass concentration 19%), and stir at room temperature for 18 hours. Add 150ml of water, stir for 1 hour to precipitate a solid, filter, wash with wat...

Embodiment 3

[0056] Embodiment 3: the preparation of tasimelteon

[0057] (1) Preparation of (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarbonyl chloride

[0058] (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylic acid 4.8g, dissolved in 96ml of methyl tert-butyl ether, added 4.0g of phosphorus oxychloride, heated to reflux for 6 After 1 hour, take a sample and add methanol to oscillate, and point the plate to detect the disappearance of the raw material and the reaction ends. The solvent was distilled off with a rotary evaporator to obtain 5.2 g of oil, which was directly used in the next reaction.

[0059] (2) Preparation of (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropylcarboxamide

[0060] 5.2 g of the oil obtained in the previous step was dissolved in 52 ml of tetrahydrofuran, 22 g of aqueous ammonia (mass concentration 19%) was added dropwise, and stirred at room temperature for 18 hours. Add 150ml of water, stir for 1 hour to precipitate a solid, filter, wash w...

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Abstract

The invention discloses a novel method for synthesizing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine. The method comprises the following steps: chloridizing (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanecarboxylic acid to generate (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane carbonyl chloride; (2) performing ammonolysis on (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane carbonyl chloride to generate (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane formamide; and (3) reducing the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropane formamide to generate the (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethylamine. The method provided by the invention has the advantages of easily available raw materials, simplicity in operation, higher yield in each step, less side reaction, high product purity, simplicity and convenience in post-treatment, and suitability for industrialized production.

Description

technical field [0001] The invention relates to a new method for preparing the key intermediate of tasimelteon—(1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethylamine. Background technique [0002] Tasimetron, a new type of oral melatonin receptor agonist, developed by Wanda Pharmaceuticals, Maryland, USA, can simultaneously improve sleep latency and sleep retention in patients with sudden advance in sleep time, and has the potential to treat patients with circadian rhythm sleep disorders Transient insomnia. [0003] (1R,2R)-2-(2,3-Dihydrobenzofuran-4-yl)cyclopropylmethylamine is a key intermediate in the synthesis of tasimelteon. From the current literature, the synthesis route of (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethylamine is mainly given by the patent US5856529 via (1R,2R)- 2-(2,3-Dihydrobenzofuran-4-yl)cyclopropanemethanol is oxidized to aldehyde, then reacted with hydroxylamine hydrochloride to form oxime, and then reduced to generate (1R,2R)-2-(...

Claims

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Application Information

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IPC IPC(8): C07D307/81
Inventor 刘永志张宏川刘瑾
Owner JINAN ZHIHE MEDICAL TECH
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