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Synthetic method of azetidine-3-formic acid

A technology of azetidine and synthesis method, applied in the direction of organic chemistry and the like, can solve the problem that the price of downstream products remains high, the poisoning of operators, and the high market price of diphenylmethyl-3-hydroxy azetidine. and other problems, to achieve the effect of large-scale industrial production prospects, cost reduction, avoidance of human injury and environmental pollution

Active Publication Date: 2018-05-25
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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  • Synthetic method of azetidine-3-formic acid
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  • Synthetic method of azetidine-3-formic 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 invention relates to the field of organic synthesis and particularly relates to a synthetic method of azetidine-3-formic acid. The synthetic method comprises the following steps of adopting 2,2-bis(hydroxymethyl)malonic acid-1,3-diethyl ester to react with benzhydrylamine after protection of methylsulfonyl chloride, and then by decarboxylation and diphenylmethyl-removing protection, obtaininga final product, namely the azetidine-3-formic acid. The synthetic method has the advantages that the 2,2-bis(hydroxymethyl)malonic acid-1,3-diethyl ester is adopted as a raw material, and is cheap and easy to obtain; compared with the original synthesis route, the cost of the whole synthesis route is reduced by 30% or more, and a highly-toxic substance (sodium cyanide) is not adopted, so that theindustrial production prospect is great.

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 Applications(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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