阅读说明：本技术 一种对羟基苯甘氨酸甲酯合成方法 (Synthetic method of p-hydroxyphenylglycine methyl ester ) 是由 李利强 李飞 张志强 于 2020-12-31 设计创作，主要内容包括：本发明提出了一种对羟基苯甘氨酸甲酯合成方法,包括以下步骤：(1)将D-对羟基苯甘氨酸加入到甲醇中,搅拌均匀,然后在30-50℃的条件下,滴加氯化亚砜,得到D-对羟基苯甘氨酸甲酯的甲醇溶液；(2)对D-对羟基苯甘氨酸甲酯的甲醇溶液减压整出甲醇,减压条件为真空度≤0.090MPa,然后加水搅拌,酸性条件下活性炭脱色,得到D-对羟基苯甘氨酸甲酯的水溶液；(3)向D-对羟基苯甘氨酸甲酯的水溶液中滴加15-20wt％的氨水,调节pH为9-10,氨水滴加时间为3-6h,D-对羟基苯甘氨酸甲酯结晶析出,最后通过离心分离,得到D-对羟基苯甘氨酸甲酯产品。本发明制备的D-对羟基苯甘氨酸甲酯回收率高,纯度高。(The invention provides a synthesis method of p-hydroxyphenylglycine methyl ester, which comprises the following steps: (1) adding D-p-hydroxyphenylglycine into methanol, stirring uniformly, and then dropwise adding thionyl chloride at the temperature of 30-50 ℃ to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester; (2) decompressing the methanol solution of D-p-hydroxyphenylglycine methyl ester to obtain methanol, wherein the decompression condition is that the vacuum degree is less than or equal to 0.090MPa, then adding water and stirring, and decoloring by active carbon under the acidic condition to obtain the aqueous solution of D-p-hydroxyphenylglycine methyl ester; (3) and (2) dropwise adding 15-20 wt% of ammonia water into the aqueous solution of the D-p-hydroxyphenylglycine methyl ester, adjusting the pH to 9-10, adjusting the dropwise adding time of the ammonia water to 3-6h, crystallizing and separating out the D-p-hydroxyphenylglycine methyl ester, and finally, performing centrifugal separation to obtain the D-p-hydroxyphenylglycine methyl ester product. The D-p-hydroxyphenylglycine methyl ester prepared by the method has high recovery rate and high purity.)

1. A synthetic method of p-hydroxyphenylglycine methyl ester is characterized by comprising the following steps:

(1) adding D-p-hydroxyphenylglycine into methanol, stirring uniformly, and then dropwise adding thionyl chloride at the temperature of 30-50 ℃ to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester;

(2) decompressing the methanol solution of D-p-hydroxyphenylglycine methyl ester to obtain methanol, wherein the decompression condition is that the vacuum degree is less than or equal to 0.090MPa, then adding water and stirring, and decoloring by active carbon under the acidic condition to obtain the aqueous solution of D-p-hydroxyphenylglycine methyl ester;

(3) and (2) dropwise adding 15-20 wt% of ammonia water into the aqueous solution of the D-p-hydroxyphenylglycine methyl ester, adjusting the pH to 9-10, adjusting the dropwise adding time of the ammonia water to 3-6h, crystallizing and separating out the D-p-hydroxyphenylglycine methyl ester, and finally, performing centrifugal separation to obtain the D-p-hydroxyphenylglycine methyl ester product.

2. The method for synthesizing methylparaben according to claim 1, wherein in step (1), the molar ratio of D-p-hydroxyphenylglycine, methanol and thionyl chloride is 1:6: 1.02.

3. The method for synthesizing p-hydroxyphenylglycine methyl ester according to claim 1, wherein in the step (2), the amount of water added is 3-6 times of the weight of the D-p-hydroxyphenylglycine methyl ester.

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of p-hydroxyphenylglycine methyl ester.

Background

P-hydroxyphenylglycine methyl ester is an important intermediate of antibiotics and is used for synthesizing side chains of the semi-synthetic beta-lactam antibiotics. The existing preparation method of p-hydroxyphenylglycine methyl ester has the problems of overlong reaction time, difficult crystallization and purification of products and the like. Chinese patent CN111153821A discloses a preparation method of D-p-hydroxyphenylglycine methyl ester, under the condition of concentrated sulfuric acid, in the presence of concentrated sulfuric acid, under the condition of 65-80 ℃, D-p-hydroxyphenylglycine and methanol are subjected to methyl esterification reaction to obtain D-p-hydroxyphenylglycine sulfate, then methanol and water are evaporated under reduced pressure, D-p-hydroxyphenylglycine seed crystals and water are added under the condition of 20-25 ℃, then alkali metal hydroxide is added to adjust the pH value to be 7.5-8, and then crystal growth is carried out under the condition of 10-20 ℃, wherein the alkali metal hydroxide is sodium hydroxide, potassium hydroxide or lithium hydroxide. The method has higher esterification reaction temperature, is easy to cause the oxidation of methanol and influences the proceeding of the esterification reaction; strong alkali such as sodium hydroxide, potassium hydroxide and the like is adopted to adjust the pH value, so that D-p-hydroxyphenylglycine crystals are easily hydrolyzed, and the recovery rate of the product is reduced.

Disclosure of Invention

The invention provides a method for synthesizing p-hydroxyphenylglycine methyl ester, and the prepared D-p-hydroxyphenylglycine methyl ester has high recovery rate and high purity.

The technical scheme of the invention is realized as follows: a synthetic method of p-hydroxyphenylglycine methyl ester comprises the following steps:

(1) adding D-p-hydroxyphenylglycine into methanol, stirring uniformly, and then dropwise adding thionyl chloride at the temperature of 30-50 ℃ to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester;

(2) decompressing the methanol solution of D-p-hydroxyphenylglycine methyl ester to obtain methanol, wherein the decompression condition is that the vacuum degree is less than or equal to 0.090MPa, then adding water and stirring, and decoloring by active carbon under the acidic condition to obtain the aqueous solution of D-p-hydroxyphenylglycine methyl ester;

(3) and (2) dropwise adding 15-20 wt% of ammonia water into the aqueous solution of the D-p-hydroxyphenylglycine methyl ester, adjusting the pH to 9-10, adjusting the dropwise adding time of the ammonia water to 3-6h, crystallizing and separating out the D-p-hydroxyphenylglycine methyl ester, and finally, performing centrifugal separation to obtain the D-p-hydroxyphenylglycine methyl ester product.

Further, in the step (1), the molar ratio of the D-p-hydroxyphenylglycine to the methanol to the thionyl chloride is 1:6: 1.02.

Further, in the step (2), the water amount is 3-6 times of the weight of the D-p-hydroxyphenylglycine methyl ester.

The invention has the beneficial effects that:

the invention controls the reaction temperature at 30-50 ℃, reduces the reaction temperature, ensures the efficiency of the esterification reaction and avoids the oxidation of methyl ester; excess methanol is evaporated out by decompression, the vacuum degree is less than or equal to 0.090MPa, the evaporation rate is accelerated, the methanol consumption is reduced, the obtained acid salt of D-p-hydroxyphenylglycine methyl ester is soluble in water, the pH value is adjusted to 9-10 by using ammonia water, the ammonia water dripping time is 3-6h, the D-p-hydroxyphenylglycine methyl ester is ensured to be fully precipitated, the recovery rate is increased, and if the dripping speed is too high, the D-p-hydroxyphenylglycine methyl ester cannot be fully precipitated, and the recovery rate is lower. The recovery rate of the synthetic method is more than or equal to 106 percent (the mass ratio of the synthesized D-p-hydroxyphenylglycine methyl ester to the D-p-hydroxyphenylglycine), and the purity of the D-p-hydroxyphenylglycine methyl ester is more than or equal to 98.5 percent.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.

Example one

A synthetic method of p-hydroxyphenylglycine methyl ester comprises the following steps:

(1) adding D-p-hydroxyphenylglycine into methanol, stirring uniformly, and then dropwise adding thionyl chloride at the temperature of 30 ℃ to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester, wherein the molar ratio of the D-p-hydroxyphenylglycine to the methanol to the thionyl chloride is 1:6: 1.02;

(2) decompressing the methanol solution of D-p-hydroxyphenylglycine methyl ester to obtain methanol, adding water and stirring under the decompression condition that the vacuum degree is less than or equal to 0.090MPa, and decoloring the methanol solution by using activated carbon under the acidic condition to obtain the aqueous solution of D-p-hydroxyphenylglycine methyl ester, wherein the added water amount is 6 times of the weight of the D-p-hydroxyphenylglycine methyl ester;

(3) and (2) dropwise adding 15 wt% of ammonia water into the aqueous solution of the D-p-hydroxyphenylglycine methyl ester, adjusting the pH to 9-10, adjusting the dropwise adding time of the ammonia water to 3h, crystallizing and separating out the D-p-hydroxyphenylglycine methyl ester, and finally, performing centrifugal separation to obtain the D-p-hydroxyphenylglycine methyl ester product.

Example two

A synthetic method of p-hydroxyphenylglycine methyl ester comprises the following steps:

(1) adding D-p-hydroxyphenylglycine into methanol, stirring uniformly, and then dropwise adding thionyl chloride at the temperature of 40 ℃ to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester, wherein the molar ratio of the D-p-hydroxyphenylglycine to the methanol to the thionyl chloride is 1:6: 1.02;

(2) decompressing the methanol solution of D-p-hydroxyphenylglycine methyl ester to obtain methanol, adding water and stirring under the decompression condition that the vacuum degree is less than or equal to 0.090MPa, and decoloring the methanol solution by using activated carbon under the acidic condition to obtain the aqueous solution of D-p-hydroxyphenylglycine methyl ester, wherein the water addition amount is 5 times of the weight of the D-p-hydroxyphenylglycine methyl ester;

(3) and (2) dropwise adding 15 wt% of ammonia water into the aqueous solution of the D-p-hydroxyphenylglycine methyl ester, adjusting the pH to 9-10, adjusting the dropwise adding time of the ammonia water to 5h, crystallizing and separating out the D-p-hydroxyphenylglycine methyl ester, and finally, performing centrifugal separation to obtain the D-p-hydroxyphenylglycine methyl ester product.

EXAMPLE III

A synthetic method of p-hydroxyphenylglycine methyl ester comprises the following steps:

(1) adding D-p-hydroxyphenylglycine into methanol, stirring uniformly, and then dropwise adding thionyl chloride at the temperature of 50 ℃ to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester, wherein the molar ratio of the D-p-hydroxyphenylglycine to the methanol to the thionyl chloride is 1:6: 1.02;

(2) decompressing the methanol solution of D-p-hydroxyphenylglycine methyl ester to obtain methanol, adding water and stirring under the decompression condition that the vacuum degree is less than or equal to 0.090MPa, and decoloring the methanol solution by using activated carbon under the acidic condition to obtain the aqueous solution of D-p-hydroxyphenylglycine methyl ester, wherein the water addition amount is 3 times of the weight of the D-p-hydroxyphenylglycine methyl ester;

(3) and (2) dropwise adding 15 wt% of ammonia water into the aqueous solution of the D-p-hydroxyphenylglycine methyl ester, adjusting the pH to 9-10, adjusting the dropwise adding time of the ammonia water to 6h, crystallizing and separating out the D-p-hydroxyphenylglycine methyl ester, and finally, performing centrifugal separation to obtain the D-p-hydroxyphenylglycine methyl ester product.

The recovery rate of the synthesis method of the first to third examples is more than or equal to 106 percent (the mass ratio of the synthesized D-p-hydroxyphenylglycine methyl ester to the D-p-hydroxyphenylglycine) and the purity of the D-p-hydroxyphenylglycine methyl ester is more than or equal to 98.5 percent.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.