Synthesis method of methyl 2-acetylamino-3-chloropropionate

A technology of chloroalanine methyl ester and alanine methyl ester, which is applied in the field of preparation of ramipril intermediates, can solve the problems of low yield and purity, and achieves high reaction yield, few by-products, and high-quality products. excellent effect

Inactive Publication Date: 2020-01-03
湖北宇阳药业有限公司
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0005] The object of the present invention is to overcome above-mentioned technical deficiency, propose a kind of synthetic method of acetylam

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  • Synthesis method of methyl 2-acetylamino-3-chloropropionate

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[0015] This embodiment provides a kind of synthetic method of acetylamino-3-chloroalanine methyl ester, comprising the following steps:

[0016] (1) Add L-serine methyl ester hydrochloride into dichloromethane, then dropwise add thionyl chloride A, carry out segmental temperature control reaction at 30-60°C, cool down to 20°C after the reaction, add water Layering, obtaining 3-chloro-L-alanine methyl ester hydrochloride aqueous solution after activated carbon removal of impurities;

[0017] (2) Control the temperature of the above-mentioned 3-chloro-L-alanine methyl ester hydrochloride solution to 15-25°C; add aqueous sodium bicarbonate solution and acetic anhydride dropwise at the same time, and keep warm for 1-4 hours after the addition; Acetylamino-3-chloroalanine methyl ester was obtained after extraction, concentration, recrystallization, centrifugation and drying.

[0018] In the method, the staged temperature control reaction can control the reaction rate of the reacti...

Embodiment 1

[0043] Embodiment 1 of the present invention provides a kind of synthetic method of acetylamino-3-chloroalanine methyl ester, comprising the following steps:

[0044](1) Add 200kg L-serine and 700L methanol into the reaction kettle, cool down to 10°C, and slowly add 330kg of thionyl chloride dropwise; wherein, the temperature of the dropwise addition process is controlled at 12°C; after 10 hours of dropping, the temperature is raised to 38°C, reacted for 48 hours, finally crystallized by cooling, centrifuged and dried to obtain L-serine methyl ester hydrochloride. Wherein, the solvent removed in the centrifugation process is used as the next batch of masterbatch for this reaction.

[0045] (2) Add 90kg of L-serine methyl ester hydrochloride into 700L of dichloromethane, and then dropwise add 100kg of thionyl chloride; after 2 hours of dropping, control the temperature of the reaction system to 30°C, and react for 2 hours. Then raise the temperature to 40°C, react for 3h, then...

Embodiment 2

[0050] Embodiment 2 of the present invention provides a kind of synthetic method of acetylamino-3-chloroalanine methyl ester, comprising the following steps:

[0051] (1) Add 200kg of L-serine, 300L of methanol and 450L of recovered methanol into the reaction kettle, cool down to 10°C, and slowly add 270kg of thionyl chloride dropwise; wherein, the temperature of the dropping process is controlled at 14°C; After completion, the temperature was raised to 38°C, reacted for 48 hours, and finally crystallized by cooling, centrifuged and dried to obtain L-serine methyl ester hydrochloride. Wherein, the solvent removed in the centrifugation process is used as the next batch of masterbatch for this reaction.

[0052] (2) Add 90kg of L-serine methyl ester hydrochloride into 700L of dichloromethane, and then dropwise add 100kg of thionyl chloride; after 2 hours of dropping, control the temperature of the reaction system to 30°C, and react for 2 hours. Then raise the temperature to 40°...

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Abstract

The invention discloses a synthesis method of methyl 2-acetylamino-3-chloropropionate. The method comprises the following steps: adding L-serine methyl ester hydrochloride into dichloromethane, dropwise adding thionyl chloride A, carrying out a sectional controlled-temperature reaction, then performing cooling to 20 DEG C, adding water for layering, and removing impurities by activated carbon so as to obtain an aqueous 3-chloro-L-alanine methyl ester hydrochloride solution; controlling the temperature of the aqueous 3-chloro-L-alanine methyl ester hydrochloride solution to be 15-25 DEG C, dropwise adding an aqueous sodium bicarbonate solution and acetic anhydride at the same time, and keeping the temperature for 1-4 h after drop-by-drop addition is completed; and carrying out extracting, concentrating, recrystallizing, centrifuging and drying to obtain the methyl 2-acetylamino-3-chloropropionate. The system is heated in a sectional controlled-temperature mode, so the method has the advantages of mild reaction conditions, high reaction yield, and few byproducts; and the aqueous 3-chloro-L-alanine methyl ester hydrochloride solution is directly used as a reaction raw material, so that the yield and the purity of the final product are improved.

Description

technical field [0001] The invention relates to the technical field of preparation of ramipril intermediates, in particular to a method for synthesizing acetylamino-3-chloroalanine methyl ester. 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. [0003] Acetylamino-3-chloroalanine methyl ester is a very important intermediate for the synthesis of ramipril. There are multiple methods for synthesis, but all of them have the problems of low yield and many by-products. This will adversely affect the subsequent production process of ramipril. [0004] Chinese patent document CN104003894A discloses a preparation method of N-acetyl-β-chloro-L-alanine methyl ester, comprising: (a) using serine as a starting material, esterified with methanol or ethanol; (b) Chlorination of the es...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C233/47C07C227/18C07C227/16C07C229/20
CPCC07C231/02C07C227/18C07C227/16C07C229/20C07C233/47
Inventor 屈永民陈挺
Owner 湖北宇阳药业有限公司
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