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Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride

A technology of alanine methyl ester and a synthetic method, applied in the field of synthesis of 3-chloro-L-alanine methyl ester hydrochloride, can solve the problems of many by-products, low yield, long reaction time and the like, and achieves the Effects of few by-products, high reaction yield and short reaction time

Inactive Publication Date: 2019-12-20
湖北宇阳药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to overcome above-mentioned technical deficiency, propose a kind of synthetic method of 3-chloro-L-alanine methyl ester hydrochloride, solve the technical problem of long reaction time, low yield, many by-products in the prior art

Method used

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preparation example Construction

[0012] This embodiment provides a kind of synthetic method of 3-chloro-L-alanine methyl ester hydrochloride, comprising the following steps:

[0013] (a) Add L-serine to the first solvent, lower the temperature to 5-10°C, add thionyl chloride A dropwise, raise the temperature to 38°C after the dropwise addition, and react for 48 hours; after the reaction is completed, cool the above reaction mixture to crystallize , centrifugal solvent removal and drying to obtain L-serine methyl ester hydrochloride;

[0014] (b) Add the above-mentioned L-serine methyl ester hydrochloride into the second solvent, then add thionyl chloride B dropwise, and carry out a staged temperature control reaction. After the reaction is completed, the temperature is lowered to 15-25°C, and water is added to separate the layers. Subsequently, the obtained aqueous phase was subjected to cooling crystallization, pressure filtration and vacuum drying to obtain 3-chloro-L-alanine methyl ester hydrochloride.

...

Embodiment 1

[0034] Embodiment 1 of the present invention provides a kind of synthetic method of 3-chloro-L-alanine methyl ester hydrochloride, comprising the following steps:

[0035] Add 200kg of L-serine and 700L of methanol into the reactor, cool down to 10°C, and slowly add 330kg of thionyl chloride dropwise; among them, the temperature of the dropwise addition process is controlled at 12°C; after 10 hours of dropping, the temperature is raised to 38°C, After reacting for 48 hours, crystallization by cooling, centrifugation and drying gave L-serine methyl ester hydrochloride (white solid, yield 93.8%, purity 99.5%). Wherein, the solvent removed in the centrifugation process is used as the next batch of masterbatch for this reaction.

[0036] Add the above 90kg of L-serine methyl ester hydrochloride into 700L of dichloromethane, and then add 100kg of thionyl chloride B dropwise; wherein, the temperature of the dropwise addition process is controlled at 35°C; after 2 hours of dropwise a...

Embodiment 2

[0039] Embodiment 2 of the present invention provides a kind of synthetic method of 3-chloro-L-alanine methyl ester hydrochloride, comprising the following steps:

[0040] Add 200kg of L-serine, 300L of methanol and 450L of recovered methanol into the reactor, cool down to 10°C, and slowly add 270kg of thionyl chloride dropwise; among them, the temperature of the dropwise addition process is controlled at 14°C; after 8 hours of dropping, the temperature rises to 38°C, reacted for 48 hours, and finally crystallized by cooling, centrifuged and dried to obtain L-serine methyl ester hydrochloride (white solid, yield 98.1%, purity 99.1%). Wherein, the solvent removed in the centrifugation process is used as the next batch of masterbatch for this reaction.

[0041] Add the above-mentioned 90kg L-serine methyl ester hydrochloride into 900L dichloroethane, and then dropwise add 270kg of thionyl chloride B; wherein, the temperature of the dropwise addition process is controlled at 39°C; ...

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Abstract

The invention discloses a synthetic method of 3-chloro-L-alanine methyl ester hydrochloride. The method comprises the following steps: adding L-serine into a first solvent, performing cooling to 5-10DEG C, adding thionyl chloride A dropwise, performing heating to 38 DEG C after adding is completed, performing a reaction for 48 h, performing cooling crystallization on the mixture, performing centrifugation and performing drying to obtain L-serine methyl ester hydrochloride; and adding the L-serine methyl ester hydrochloride into a second solvent, adding thionyl chloride B dropwise, performinga sectional temperature control reaction, performing cooling to 15-25 DEG C after the reaction is finished, adding water for layering, and treating the obtained water phase to obtain the 3-chloro-L-alanine methyl ester hydrochloride. By adopting the sectional temperature control mode, the method has the advantages of short reaction time, mild reaction conditions, a high yield and fewer byproducts,and is convenient for enhancing the yield and product purity; the L-serine methyl ester hydrochloride does not need to be purified, so that the process is optimized; and water is added for layering,an organic phase is extracted for multiple times, adsorption is performed by activated carbon in a water phase, so that the product yield and the product purity are further improved.

Description

technical field [0001] The invention relates to the technical field of preparation of ramipril intermediates, in particular to a method for synthesizing 3-chloro-L-alanine methyl ester hydrochloride. Background technique [0002] Ramipril, chemical name is (S)-2-[N-(1-ethoxycarbonyl-3-phenyl-propyl)alanyl]-2-azabicyclo[3.3.0]octane -3-Carboxylic acid. Ramipril is an antihypertensive drug that has a good effect on patients with severe hypertension. It has the characteristics of quick onset, long duration, high tissue specificity, good tolerance, and low toxicity and side effects. [0003] 3-Chloro-L-alanine methyl ester hydrochloride is a very important intermediate for the synthesis of ramipril. In the prior art, the product is generally obtained by adding L-serine methyl ester hydrochloride and thionyl chloride into dichloromethane, raising the temperature and refluxing for about 60 hours, and evaporating to dryness. However, the disadvantages of the above method are th...

Claims

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Application Information

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IPC IPC(8): C07C227/18C07C227/16C07C229/22
CPCC07C227/18C07C227/16
Inventor 屈永民陈挺
Owner 湖北宇阳药业有限公司
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