A kind of synthetic method of azetidine-3-carboxylic acid

A technique for the synthesis of azetidine, applied in the direction of organic chemistry, etc., can solve the problem of high market price of benzhydryl-3-hydroxyazetidine, poisoning of operators, and high price of downstream products and other issues, to achieve the effect of avoiding human injury and environmental pollution, cost reduction, and the prospect of large-scale industrial production

Active Publication Date: 2021-10-01
甘肃博克斯生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The synthesis process requires the use of a large amount of highly toxic sodium cyanide, causing poisoning and other adverse effects on the operators, and the waste water produced has the potential risk of polluting the environment
In addition, the market price of the initial raw material benzhydryl-3-hydroxyazetidine used in this route is relatively expensive, causing the price of downstream products to remain high

Method used

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  • A kind of synthetic method of azetidine-3-carboxylic acid
  • A kind of synthetic method of azetidine-3-carboxylic acid
  • A kind of synthetic method of azetidine-3-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1: the synthesis of intermediate product (B)

[0024] Add 110g of 2,2-dimethylolmalonate-1,3-diethyl ester, 1.5L of dichloromethane, and 150g of triethylamine into a clean 3L three-necked flask, stir mechanically for 10min, cool down to 0°C, and slowly Add 115g of methanesulfonyl chloride dropwise, control the temperature at 0-5°C, a large amount of solid salts are formed, react overnight at room temperature after dropping, add 1L of water to wash the next day, separate the layers, dry the organic layer, concentrate and dry to obtain the intermediate product (B) 180g, yield 95.7%, without purification.

Embodiment 2

[0025] Embodiment 2: the synthesis of intermediate product (C)

[0026] Add 1.5L of toluene to a clean 3L three-necked flask, then add 180g of the intermediate product (B) obtained in Example 1, continue to add 87g of diphenylmethylamine and 150g of triethylamine, heat to 110°C for reflux reaction, and a solid is formed , refluxed overnight, stopped the reaction, filtered to remove salt, washed the organic layer with water, dried and concentrated to obtain 120 g of intermediate product (C), which did not need to be purified.

Embodiment 3

[0027] Embodiment 3: the synthesis of intermediate product (D)

[0028] Add 120g of the intermediate product (C) obtained in Example 2 into 1L of 6N hydrochloric acid, heat to 80°C, keep it warm overnight, and gas is generated, pay attention to prevent flushing, and evaporate the water to dryness the next day to obtain a brown oily object , adding 300mL of acetone and heating for recrystallization to obtain 78g of intermediate product (D), the appearance of which is light yellow solid. 1H-NMR Spectrum (CDCl3), δ (ppm): 3.00-3.90 (5H, m), 4.95 (1H, s), 7.25-7.28 (2H, m), 7.33 (4H, m), 7.53 (4H, m ).

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Abstract

The present invention relates to the field of organic synthesis, and in particular to a synthetic method of azetidine-3-carboxylic acid, which comprises 2,2-dimethylolmalonate-1,3-diethyl ester, through methanesulfonyl chloride After protection, it reacts with benzhydrylamine, then undergoes decarboxylation and de-benzhydryl protection to obtain the final product azetidine-3-carboxylic acid. The synthetic method uses 2,2-dimethylolmalonic acid-1,3-diethyl ester as a raw material, which is cheap and easy to obtain, and the cost of the whole synthetic route is reduced by more than 30% compared with the original synthetic route, and it does not require The highly toxic substance sodium cyanide is used, which has great prospects for industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a synthesis method of azetidine-3-carboxylic acid. Background technique [0002] Azetidine-3-carboxylic acid is an important intermediate, and its downstream products can be used to synthesize a variety of immunosuppressants, especially for the treatment or prevention of diseases or diseases mediated by the interaction of lymphocytes, as shown in the Chinese patent No. CN101679235A discloses azetidine derivatives and their use as prostaglandin E2 antagonists. [0003] At present, the synthetic route of azetidine-3-carboxylic acid is as follows US20100249399: [0004] [0005] The synthesis process requires the use of a large amount of highly toxic sodium cyanide, which has adverse effects such as poisoning on the operators, and the waste water produced has the potential risk of polluting the environment. In addition, the market price of the initial raw material benzhydryl-3-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/04
CPCC07D205/04
Inventor 秦勇陈悦
Owner 甘肃博克斯生物技术有限公司
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