阅读说明：本技术 一种乙酰氨基-3-氯丙氨酸甲酯的合成方法 (Synthesis method of acetamido-3-methyl chloropropionate ) 是由 屈永民 陈挺 于 2019-09-23 设计创作，主要内容包括：本发明公开一种乙酰氨基-3-氯丙氨酸甲酯的合成方法,包括以下步骤：将L-丝氨酸甲酯盐酸盐加入二氯甲烷中,再滴加氯化亚砜A,进行分段控温反应,随后降温至20℃,加水分层,经活性炭除杂后得到3-氯-L-丙氨酸甲酯盐酸盐水溶液；将3-氯-L-丙氨酸甲酯盐酸盐水溶液的温度控制为15～25℃,同时滴加碳酸氢钠水溶液和醋酸酐,滴加完毕后保温1～4h；经萃取、浓缩、重结晶、离心、干燥后得到乙酰氨基-3-氯丙氨酸甲酯。本发明通过采用分段控温的方式对体系进行升温,反应条件缓和,反应产率高、副产物少；通过将3-氯-L-丙氨酸甲酯盐酸盐水溶液直接作为反应的原料,提高了最终产物的收率和纯度。(The invention discloses a synthesis method of acetamido-3-methyl chloropropionate, which comprises the following steps: adding L-serine methyl ester hydrochloride into dichloromethane, then dropwise adding thionyl chloride A, carrying out segmented temperature control reaction, then cooling to 20 ℃, adding water for layering, and removing impurities by active carbon to obtain a 3-chloro-L-alanine methyl ester hydrochloride aqueous solution; controlling the temperature of the 3-chloro-L-alanine methyl ester hydrochloride aqueous solution to be 15-25 ℃, simultaneously dropwise adding a sodium bicarbonate aqueous solution and acetic anhydride, and preserving heat for 1-4 hours after dropwise adding; and performing extraction, concentration, recrystallization, centrifugation and drying to obtain the acetamido-3-methyl chloropropionate. The invention heats the system by adopting a sectional temperature control mode, the reaction condition is mild, the reaction yield is high, and the byproducts are few; the yield and purity of the final product are improved by directly using the 3-chloro-L-alanine methyl ester hydrochloride aqueous solution as a raw material for reaction.)

1. A synthetic method of acetamido-3-methyl chloropropionate is characterized by comprising the following steps:

(1) adding L-serine methyl ester hydrochloride into dichloromethane, then dropwise adding thionyl chloride A, carrying out segmented temperature control reaction at 30-60 ℃, cooling to 20 ℃ after the reaction is finished, adding water for layering, and removing impurities by activated carbon to obtain a 3-chloro-L-alanine methyl ester hydrochloride aqueous solution;

(2) controlling the temperature of the 3-chloro-L-alanine methyl ester hydrochloride aqueous solution to be 15-25 ℃; simultaneously dropwise adding a sodium bicarbonate aqueous solution and acetic anhydride, and preserving heat for 1-4 h after dropwise adding; and performing extraction, concentration, recrystallization, centrifugation and drying to obtain the acetamido-3-methyl chloropropionate.

2. The synthesis method of methyl acetamido-3-chloropropionate according to claim 1, wherein the step-by-step temperature control reaction is to control the temperature of the reaction system to be 30 ℃ for 2h, then raise the temperature to 40 ℃ for 3h, then raise the temperature to 50 ℃ for 8h, and finally raise the temperature to 60 ℃ for 8 h.

3. The method for synthesizing acetamido-3-chloropropanoic acid methyl ester according to claim 1, characterized in that the volume of water added in the water adding and demixing process is 300L, and the volume of water added in each ice water extraction process is 100L.

4. The synthesis method of acetamido-3-chloropropionine methyl ester according to claim 3, characterized in that after the water is added for layering, the concentration of the obtained 3-chloro-L-alanine methyl ester hydrochloride aqueous solution is 1-1.2 mol/L; the weight-volume ratio of the acetic anhydride to the 3-chloro-L-alanine methyl ester hydrochloride aqueous solution is (0.14-0.2): 1, wherein the unit of the weight-volume ratio is kg: L.

5. The method for synthesizing acetamido-3-chloropropionine methyl ester according to claim 4, characterized in that the mass fraction of the sodium bicarbonate aqueous solution is 10%; the weight ratio of the acetic anhydride to the sodium bicarbonate water solution is (0.7-1) to 1.

6. The synthesis method of acetamido-3-chloropropanoic acid methyl ester according to claim 1, characterized in that in the dropping process, the temperature of a reaction system is controlled to be 20-30 ℃, and the dropping time is 1-2 h; and after the dropwise addition, simultaneously adding the sodium bicarbonate aqueous solution and the acetic anhydride.

7. The method for synthesizing acetamido-3-methyl chloropropionate according to claim 1, wherein the recrystallization comprises the steps of dissolving the evaporated product in a first solvent, and cooling for recrystallization, wherein the dissolving temperature of the product in the first solvent is 30-70 ℃ and the recrystallization temperature is-10-0 ℃ in the recrystallization.

8. The method of synthesizing methyl acetamido-3-chloropropionate according to claim 7, wherein the first solvent is one or more of ethanol, isopropanol, methanol or methyl tert-butyl ether.

9. The method for synthesizing acetamido-3-chloropropionine methyl ester according to claim 1, characterized in that the L-serine methyl ester hydrochloride is prepared by the following steps: adding L-serine into a second solvent, cooling to 5-10 ℃, dropwise adding thionyl chloride B, heating to 38 ℃ after dropwise adding, and reacting for 48 hours; after the reaction is finished, cooling and crystallizing the reaction mixture, centrifugally desolventizing and drying to obtain the L-serine methyl ester hydrochloride.

10. The method for synthesizing acetylamino-3-chloropropionine methyl ester according to claim 9, characterized in that the second solvent is any one of methanol or recovered methanol obtained after centrifugal desolvation or a mixture of the two.

Technical Field

The invention relates to the technical field of preparation of ramipril intermediates, in particular to a synthesis method of acetamido-3-methyl chloropropionate.

Background

Ramipril, chemical name (S) -2- [ N- (1-ethoxycarbonyl-3-phenyl-propyl) alanyl ] -2-azabicyclo [3.3.0] octane-3-carboxylic acid. Ramipril is a hypotensive drug and has good curative effect on severe hypertension patients.

Acetylamino-3-chloropropanamine methyl ester is a very important intermediate for synthesizing ramipril. The synthesis method has various methods, but all have the problems of low yield and more byproducts. This will adversely affect the subsequent process for producing ramipril.

Chinese patent document CN104003894A discloses a method for preparing N-acetyl- β -chloro-L-alanine methyl ester, comprising: (a) taking serine as a starting material, and esterifying by methanol or ethanol; (b) chlorinating the esterified substance with thionyl chloride; (c) carrying out acylation reaction on the chlorinated substance; (d) recrystallizing the acylated substance to obtain the N-acetyl-beta-chloro-L-alanine methyl ester. The method can recycle the mother liquor and has low cost. However, it has the disadvantage that the yield of the product obtained is still low.

Disclosure of Invention

The invention aims to overcome the technical defects, provides a synthetic method of acetamido-3-methyl chloropropionate, and solves the technical problems of low yield and purity of acetamido-3-methyl chloropropionate in the prior art.

In order to achieve the technical purpose, the invention adopts the technical scheme that:

(1) adding L-serine methyl ester hydrochloride into dichloromethane, then dropwise adding thionyl chloride, carrying out segmented temperature control reaction at 25-60 ℃, cooling to 20 ℃ after the reaction is finished, adding water for layering, and removing impurities by activated carbon to obtain a 3-chloro-L-alanine methyl ester hydrochloride aqueous solution;

(2) controlling the temperature of the 3-chloro-L-alanine methyl ester hydrochloride aqueous solution to be 15-25 ℃; simultaneously dropwise adding a sodium bicarbonate aqueous solution and acetic anhydride, and preserving heat for 1-4 h after dropwise adding; and performing extraction, concentration, recrystallization, centrifugation and drying to obtain the acetamido-3-methyl chloropropionate.

In the method, the reaction rate of the reaction system can be controlled by the segmented temperature control reaction, so that the side reaction caused by overlong time of higher reaction temperature is avoided, and the yield and the purity of the product are improved.

In the method, compared with acetyl chloride, the chemical property of acetic anhydride is stable, the acetic anhydride is selected as a reaction raw material, the reaction is thorough, and byproducts are easy to treat; the sodium bicarbonate aqueous solution is alkalescent, provides an alkaline environment, is convenient for maintaining a reaction system in a stable pH range, and avoids the influence on the normal operation of the reaction due to too large pH fluctuation in the dropping process; meanwhile, the sodium bicarbonate is also beneficial to the stability of the 3-chloro-L-alanine methyl ester hydrochloride, and the decomposition of the 3-chloro-L-alanine methyl ester hydrochloride in a strong alkaline environment is avoided.

Compared with the prior art, the invention has the beneficial effects that:

in the method, the temperature of the system is raised by adopting a sectional temperature control mode, the reaction condition is mild, the reaction yield is high, and the byproducts are few.

In the method, the 3-chloro-L-alanine methyl ester hydrochloride aqueous solution is directly used as a reaction raw material, and is dissolved without being evaporated to dryness, so that the yield and the purity of a final product are improved.

The method is simple, the synthesis period is short, and the quality product is excellent.

Detailed Description

The embodiment provides a synthesis method of acetamido-3-methyl chloropropionate, which comprises the following steps:

(1) adding L-serine methyl ester hydrochloride into dichloromethane, then dropwise adding thionyl chloride A, carrying out segmented temperature control reaction at 30-60 ℃, cooling to 20 ℃ after the reaction is finished, adding water for layering, and removing impurities by activated carbon to obtain a 3-chloro-L-alanine methyl ester hydrochloride aqueous solution;

(2) controlling the temperature of the 3-chloro-L-alanine methyl ester hydrochloride aqueous solution to be 15-25 ℃; simultaneously dropwise adding a sodium bicarbonate aqueous solution and acetic anhydride, and preserving heat for 1-4 h after dropwise adding; and performing extraction, concentration, recrystallization, centrifugation and drying to obtain the acetamido-3-methyl chloropropionate.

In the method, the reaction rate of the reaction system can be controlled by the segmented temperature control reaction, so that the side reaction caused by overlong time of higher reaction temperature is avoided, and the yield and the purity of the product are improved.

In the method, the chemical property of the acetic anhydride is stable, the acetic anhydride is selected as a reaction raw material, the reaction is thorough, and byproducts are easy to treat; the sodium bicarbonate aqueous solution is alkalescent, provides an alkaline environment, is convenient for maintaining a reaction system in a stable pH range, and avoids the influence on the normal operation of the reaction due to too large pH fluctuation in the dropping process; meanwhile, the sodium bicarbonate is also beneficial to the stability of the 3-chloro-L-alanine methyl ester hydrochloride, and the decomposition of the 3-chloro-L-alanine methyl ester hydrochloride in a strong alkaline environment is avoided.

In some embodiments, the temperature of the reaction system is controlled to be 30 ℃, the reaction is carried out for 2 hours, then the temperature is raised to 40 ℃, the reaction is carried out for 3 hours, then the reaction is carried out for 8 hours after the temperature is raised to 50 ℃, and finally the reaction is carried out for 8 hours after the temperature is raised to 60 ℃. The 3-chloro-L-alanine methyl ester hydrochloride aqueous solution obtained under the parameters has higher purity and more stable system, and is more beneficial to the subsequent synthesis of acetamido-3-chloropropionine methyl ester.

In some embodiments, after the water adding and layering process is finished, the obtained organic phase is extracted with ice water for 2 times, the obtained water phase and the obtained organic phase are respectively combined, the combined organic phase can be reused after being recovered, and activated carbon is added into the combined water phase to remove impurities.

Further, the liquid-solid ratio of the water added in the water adding and layering process to the L-serine methyl ester hydrochloride is 3.3:1, and the liquid-solid ratio of the water added in each ice water extraction process to the L-serine methyl ester hydrochloride is 1.1: 1. The amount of water added in the process needs to be strictly controlled, so that the concentration of each batch of 3-chloro-L-alanine methyl ester hydrochloride aqueous solution is convenient to control, and the reaction conditions are convenient to control in the subsequent synthesis process of acetamido-3-chloropropionic acid methyl ester.

In some embodiments, the concentration of the obtained 3-chloro-L-alanine methyl ester hydrochloride aqueous solution is 1-1.2 mol/L; the weight-volume ratio of the acetic anhydride to the 3-chloro-L-alanine methyl ester hydrochloride aqueous solution is (0.14-0.2): 1, and preferably 0.16: 1. Wherein the unit of the weight volume ratio is kg to L. Under the condition of the proportion, the full proceeding of acylation reaction can be ensured, the waste of raw materials is avoided, and the product with higher yield can be obtained.

In some embodiments, the mass fraction of the sodium bicarbonate aqueous solution is 10%, and the weight ratio of the acetic anhydride to the sodium bicarbonate aqueous solution is (0.7-1): 1.

In some embodiments, the above-described dropping of the aqueous sodium bicarbonate solution and acetic anhydride is performed under vacuum.

In some embodiments, in the dropping process of the sodium bicarbonate aqueous solution and the acetic anhydride, the temperature of the reaction system is controlled to be 20-30 ℃, and the dropping time is 1-2 hours; and after the dropwise addition, simultaneously adding the sodium bicarbonate aqueous solution and the acetic anhydride.

In some embodiments, the extraction process is to extract the reaction solution after heat preservation by using an extracting agent to obtain an aqueous phase and an organic phase, extract the obtained aqueous phase by using the extracting agent again, combine the obtained organic phases after multiple extractions, and wash the combined organic phases with water.

In the process, the obtained water phase enters a sewage station, and the obtained organic phase is concentrated for later use. Specifically, the organic phase recovered in the concentration process can be used as an extractant for the next batch of materials to extract the next batch of reaction liquid.

In some embodiments, the extractant is one of chloroform or dichloromethane.

In some embodiments, the organic phase is further subjected to reduced pressure evaporation after the concentration, wherein the temperature of the reduced pressure evaporation is 30-40 ℃, and preferably 30-35 ℃.

In the process, the organic phase can be recycled.

In some embodiments, the recrystallization process is to add the product after reduced pressure evaporation to dryness into a first solvent for dissolution, and then cool and recrystallize, wherein in the recrystallization process, the dissolution temperature of the product in the first solvent is 30-70 ℃, and the recrystallization temperature is-10-0 ℃.

In some embodiments, the first solvent is one or more of ethanol, isopropanol, methanol, or methyl tert-butyl ether.

In the method, the first solvent is adopted to replace ethyl acetate in the prior art, so that the first solvent and a product are prevented from undergoing ester exchange in the recrystallization process, the product purity is further improved, and the recovery is convenient.

In some embodiments, the volume ratio of the first solvent to the product after reduced pressure evaporation to dryness is (1-2): 1, preferably 1: 1. under the proportion, the impurity can be completely removed, and the waste of the first solvent is avoided.

In some embodiments, the drying temperature is 60 ℃ and the drying time is 6-8 h.

In some embodiments, the above L-serine methyl ester hydrochloride is prepared by: adding L-serine into a second solvent, cooling to 5-10 ℃, dropwise adding thionyl chloride B, heating to 38 ℃ after dropwise adding, and reacting for 48 hours; after the reaction is finished, cooling and crystallizing the reaction mixture, centrifugally desolventizing and drying to obtain the L-serine methyl ester hydrochloride.

Wherein the second solvent is any one of methanol or recovered methanol obtained after centrifugal desolventization or a mixture of two. In the process, the methanol does not need to be purified and can be directly used as a raw material for the lower reaction, so that the process flow is saved, and the waste of the methanol is avoided. Further, when the second solvent is a mixture of methanol and recovered methanol, the volume ratio of methanol to recovered methanol is (0.6-0.7): 1. In the proportion range, the L-serine methyl ester hydrochloride with higher purity and yield can be obtained, the using amount of the methanol can be controlled, and the waste of the recovered methanol is avoided. Furthermore, when the second solvent is a mixture of methanol and recovered methanol, the addition amount of the thionyl chloride B is 80% -85% of the addition amount when the second solvent is only methanol, and the content of the thionyl chloride B in the reaction system can be controlled within the range, so that the system is kept stable.

The synthesis reaction equation of the L-serine methyl ester hydrochloride of the invention is as follows:

in order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.