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WO2016202252A1 - 一种合成d-对羟基苯甘氨酸甲酯的方法 - Google Patents

一种合成d-对羟基苯甘氨酸甲酯的方法 Download PDF

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Publication number
WO2016202252A1
WO2016202252A1 PCT/CN2016/085804 CN2016085804W WO2016202252A1 WO 2016202252 A1 WO2016202252 A1 WO 2016202252A1 CN 2016085804 W CN2016085804 W CN 2016085804W WO 2016202252 A1 WO2016202252 A1 WO 2016202252A1
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hydroxyphenylglycine
methyl ester
resolving agent
weight
agent salt
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PCT/CN2016/085804
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English (en)
French (fr)
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王启斌
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山西新宝源制药有限公司
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Publication of WO2016202252A1 publication Critical patent/WO2016202252A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

Definitions

  • the present invention relates to a process for the synthesis of D-p-hydroxyphenylglycine methyl ester.
  • D-p-hydroxyphenylglycine methyl ester is used in the enzymatic synthesis of broad-spectrum antibiotic amoxicillin (amoxicillin). Since enzymatic production of amoxicillin has great advantages in environmental protection, energy consumption and production efficiency compared with other methods, the large-scale use of enzymatically produced amoxicillin in the world further drives the intermediate D-p-hydroxyl group. Development of phenylglycine methyl ester.
  • the synthesis method of D-p-hydroxyphenylglycine methyl ester is usually a chiral resolving agent (usually phenylethanesulfonic acid) to resolve DL-p-hydroxyphenylglycine to obtain L-p-hydroxyphenylglycine resolving agent salt and a mixture of D-p-hydroxyphenylglycine resolving agent salt, and the mixture is catalytically racemized with salicylaldehyde to obtain a D-p-hydroxyphenylglycine resolving agent salt, and then the D-p-hydroxyphenylglycine is decomposed with a base.
  • a chiral resolving agent usually phenylethanesulfonic acid
  • the component salt obtains D-p-hydroxyphenylglycine, and then D-p-hydroxyphenylglycine and methanol are subjected to concentrated sulfuric acid catalytic dehydration and obtained by neutralization reaction.
  • this method has the defects of long production cycle, low yield, low equipment utilization rate, complicated operation and a large amount of solid materials to be dried, which is not conducive to large-scale industrial production.
  • the object of the present invention is to overcome the defects of low yield in the production of D-p-hydroxyphenylglycine methyl ester by the existing method, and to provide a new high yield method for producing D-p-hydroxyphenylglycine methyl ester. .
  • the present invention provides a method for synthesizing D-p-hydroxyphenylglycine methyl ester, the method includes the following steps:
  • the method for synthesizing D-p-hydroxyphenylglycine methyl ester provided by the invention, on the one hand, directly replacing the existing D-p-hydroxyphenylglycine with methanol by using a D-p-hydroxyphenylglycine resolving agent salt, thereby eliminating the esterification reaction.
  • the D-p-hydroxyphenylglycine methyl ester resolving agent salt can be smoothly converted into D-p-hydroxyphenylglycine methyl ester crystal, thereby realizing D-p-hydroxyl group. Purification of phenylglycine methyl ester.
  • the method for synthesizing the D-p-hydroxyphenylglycine methyl ester further comprises the step (3)
  • the D-p-hydroxyphenylglycine methyl ester crystal obtained in the step (2) is washed with water. Then, the obtained washing liquid is combined with the mother liquid, and then methanol recovery and concentration are sequentially performed, and then DL-p-hydroxyphenylglycine, hydrochloric acid and salicylaldehyde are added to the obtained concentrate, and then the temperature is raised to 100-110 ° C.
  • hydrochloric acid as used herein may mean HCl or an aqueous solution of HCl, and the concentration of the aqueous solution of HCl may be selected within a wide range, in the preferred embodiment of the present invention.
  • the amount of hydrochloric acid was determined by a solution having a concentration of 36% by weight.
  • the method for synthesizing D-p-hydroxyphenylglycine methyl ester comprises the following steps:
  • the amount of the D-p-hydroxyphenylglycine resolving agent salt, methanol and thionyl chloride used in the present invention is not particularly limited, for example, relative to 1 mol of D-p-hydroxyphenylglycine resolving agent salt, the methanol
  • the amount may be 15 to 25 mol, preferably 17 to 20 mol; the thionyl chloride may be used in an amount of 1 to 1.5 mol, preferably 1.1 to 1.2 mol.
  • the D-p-hydroxyphenylglycine resolving agent salt means D-p-hydroxyphenylglycine a salt formed with a chiral resolving agent.
  • the chiral resolving agent may be any existing one capable of separating L-p-hydroxyphenylglycine and D-p-hydroxyphenylglycine, and the kind thereof may be a conventional choice in the art, for example, it may be benzene. At least one of ethaneethanesulfonic acid, bromo camphorsulfonic acid, tartaric acid, and the like.
  • the chiral resolving agent is particularly preferably phenylethanesulfonic acid from the viewpoint of availability of raw materials.
  • the D-p-hydroxyphenylglycine resolving agent salt can generally be D-p-hydroxyphenylglycine phenylethanesulfonate, D-p-hydroxyphenylglycine bromocamphorsulfonate, D-p-hydroxyphenylglycine tartrate At least one of the compounds is preferably D-p-hydroxyphenylglycine phenylethanesulfonate.
  • the structure of D-p-hydroxyphenylglycine phenylethanesulfonate is as shown in the following formula (1):
  • the D-p-hydroxyphenylglycine resolving agent salt is commercially available or can be prepared by various methods known to those skilled in the art. According to a preferred embodiment of the present invention, the D-p-hydroxyphenylglycine resolving agent salt is obtained by using DL-p-hydroxyphenylglycine and sodium phenylethanesulfonate in hydrochloric acid and salicylaldehyde at 100-110 ° C. The reaction is obtained in the presence of 8-12 hours.
  • the DL-p-hydroxyphenylglycine may be used in an amount of 75 to 90 parts by weight, and the hydrochloric acid may be used in an amount of 50 to 60 parts by weight, based on 100 parts by weight of sodium phenylethanesulfonate.
  • the salicylic acid may be used in an amount of 2 to 3 parts by weight; preferably, the DL-p-hydroxyphenylglycine is used in an amount of 80 to 85 parts by weight relative to 100 parts by weight of sodium phenylethanesulfonate.
  • the amount of hydrochloric acid used is 53-56 parts by weight, and the salicylaldehyde is used in an amount of 2.2-2.8 parts by weight.
  • the conditions of the esterification reaction in the step (1) of the present invention are not particularly limited as long as the D-p-hydroxyphenylglycine resolving agent salt is reacted with methanol to obtain a D-p-hydroxyphenylglycine methyl ester resolving agent salt.
  • the esterification reaction is carried out under reflux conditions, and the esterification reaction is carried out for a period of from 1 to 5 hours, more preferably from 3 to 5 hours.
  • the type of the basic metal hydroxide is not particularly limited in the present invention, for example, It is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • the basic metal hydroxide may be used in a pure form or in the form of an aqueous solution thereof, preferably the latter. When the basic metal hydroxide is used in the form of its aqueous solution, the concentration is preferably from 5 to 10% by weight.
  • the concentration of the aqueous solution of D-p-hydroxyphenylglycine methyl ester used in the step (2) may be from 1 to 5% by weight, preferably from 2 to 3% by weight.
  • the D-p-hydroxyphenylglycine methyl ester aqueous solution mainly functions as a seed crystal, and the D-p-hydroxyphenylglycine methyl ester resolving agent salt and the basic metal hydroxide react at the above temperature and pH to obtain D.
  • the D- crude p-hydroxyphenylglycine methyl ester, and the presence of the above seed crystals can induce crystallization purification of the newly formed crude D-p-hydroxyphenylglycine methyl ester.
  • the method for synthesizing D-p-hydroxyphenylglycine methyl ester according to the present invention in the step (2), the D-p-hydroxyphenylglycine methyl ester relative to 100 parts by weight of the D-p-hydroxyphenylglycine resolving agent salt
  • the amount of D-p-hydroxyphenylglycine methyl ester in the aqueous solution may be from 0.5 to 2 parts by weight, preferably from 0.5 to 1 part by weight.
  • the D-p-hydroxyphenylglycine methyl ester resolving agent salt may be added at a rate of 1-2 g/min, preferably 1.2-1.7 g/min; the dropping rate of the basic metal hydroxide may be It is 1-2 g/min, preferably 1.5-2 g/min.
  • the conditions for crystallizing in the step (2) of the present invention are not particularly limited.
  • the conditions for the crystal growth include a crystal growth temperature of 10-15 ° C and a pH of 7.5-8.0.
  • the conditions for the crystal growth include a crystal growth temperature of 10-14 ° C, a pH of 7.6-7.8, a crystal growth time of 1-5 hours, and D-p-hydroxybenzene obtained by crystal growth under the preferred conditions.
  • the yield and purity of glycine methyl ester are both higher.
  • the method further comprises the step (3), the D-p-hydroxyphenylglycine methyl ester crystal obtained in the step (2) is washed with water, and then The obtained washing liquid is combined with the mother liquid, followed by methanol recovery and concentration, and then DL-p-hydroxyphenylglycine, hydrochloric acid and salicylaldehyde are added to the obtained concentrate, and then the temperature is raised to 100-110 ° C to react 8- After 12 hours, the salicylaldehyde was removed and the product was filtered after the reaction was completed.
  • the D-p-hydroxyphenylglycine resolving agent salt is returned as raw material to the step (1), which can realize the reaction cycle and the full utilization of the raw materials, and has more industrial application prospects. .
  • step (3) the amount of the DL-p-hydroxyphenylglycine is used relative to 100 parts by weight of the resolving agent salt in the concentrated liquid.
  • the hydrochloric acid may be used in an amount of 50-60 parts by weight, and the salicylaldehyde may be used in an amount of 2-3 parts by weight; preferably, relative to 100 parts by weight of the concentrate
  • the resolving agent salt, the DL-p-hydroxyphenylglycine is used in an amount of 80-85 parts by weight, the hydrochloric acid is used in an amount of 53-56 parts by weight, and the salicylaldehyde is used in an amount of 2.2-2.8 parts by weight.
  • the method for removing salicylaldehyde in the step (3) of the present invention is not particularly limited, and it can be carried out by various conventional methods.
  • salicylaldehyde is removed by the following method: water added to the reaction product obtained after the end of the reaction, followed by evaporation of water to entrain the salicylaldehyde therein, and the specific operation is in the art. It is well known to the person and will not be described here.
  • the yield of D-p-hydroxyphenylglycine methyl ester in the step (2) the actual yield of D-p-hydroxyphenylglycine methyl ester ⁇ D-p-hydroxyphenylglycine methyl ester theoretical yield ⁇ 100%.
  • This example is intended to illustrate the method of synthesizing D-p-hydroxyphenylglycine methyl ester provided by the present invention.
  • the crystal was crystallized for 2 hours, and the pH value after the crystallization was recorded. After 2 hours, if the pH of the crystal liquid was lower than 7.6, it was necessary to continue to add 8
  • the weight % sodium hydroxide aqueous solution was adjusted to pH 7.6 to obtain a crystallization liquid.
  • the crystal solution was centrifuged to obtain a cake and a mother liquid, and then the filter cake was washed three times with 4500 mL of water, and the washing liquid was collected by high-speed centrifugal dehydration.
  • the filter cake was air-dried at 50 ° C for 5 hours to obtain 2680 g of D-p-hydroxyphenylglycine methyl ester in a yield of 87.1%.
  • the mother liquor and the washing liquid produced after the neutralization were combined to a total of 28,000 g, and 10,000 g of methanol was distilled and recovered.
  • the bottom liquid after recovering methanol was continuously concentrated under reduced pressure to evaporate 8900 g of water.
  • 2828 g of DL-p-hydroxyphenylglycine, 1875 g of hydrochloric acid (36% by weight, the same below), and 70 g of salicylaldehyde were added to the obtained concentrate (3535 g of sodium phenylethanesulfonate), and then the temperature was raised to 102 ° C.
  • the reaction was refluxed for 10 h.
  • This example is intended to illustrate the method of synthesizing D-p-hydroxyphenylglycine methyl ester provided by the present invention.
  • the mother liquor and the washing liquid produced after the neutralization were combined to a total of 28,000 g, and 10,000 g of methanol was distilled and recovered.
  • the bottom liquid after recovering methanol was continuously concentrated under reduced pressure to evaporate 8900 g of water.
  • 3000 g of DL-p-hydroxyphenylglycine, 1980 g of hydrochloric acid, and 100 g of salicylaldehyde were added to the obtained concentrate (3535 g of sodium phenylethanesulfonate), and the mixture was heated to 102 ° C and kept under reflux for 15 hours. After the reaction was completed, 2000 mL of water was added, followed by distillation to entrain salicylaldehyde.
  • This example is intended to illustrate the method of synthesizing D-p-hydroxyphenylglycine methyl ester provided by the present invention.
  • the mother liquor and the washing liquid produced after the neutralization were combined to a total of 28,000 g, and 10,000 g of methanol was distilled and recovered.
  • the bottom liquid after recovering methanol was continuously concentrated under reduced pressure to evaporate 8900 g of water.
  • 2900 g of DL-p-hydroxyphenylglycine, 1920 g of hydrochloric acid and 88 g of salicylaldehyde were added to the obtained concentrate (3535 g of sodium phenylethanesulfonate), and the mixture was heated to 102 ° C for 10 hours under reflux.
  • 2000 mL of water was added, followed by water distillation to entrain salicylaldehyde.
  • This example is intended to illustrate the method of synthesizing D-p-hydroxyphenylglycine methyl ester provided by the present invention.
  • D-p-hydroxyphenylglycine methyl ester was synthesized according to the method of Example 1, except that step (3) was not included.
  • the crystal was crystallized for 2 hours, and the pH value after the crystallization was recorded. After 2 hours, if the pH of the crystal liquid was lower than 7.6, it was necessary to continue to add 8
  • the weight % sodium hydroxide aqueous solution was adjusted to pH 7.6 to obtain a crystallization liquid.
  • the crystal solution was centrifuged to obtain a cake and a mother liquid, and then the filter cake was washed three times with 4500 mL of water, and the washing liquid was collected by high-speed centrifugal dehydration. The filter cake is air-dried at 50 ° C After drying for 5 hours, 1832 g of D-p-hydroxyphenylglycine methyl ester was obtained in a yield of 85%.
  • the preparation method of DD salt 2 is as follows:
  • the temperature was lowered to 30-35 ° C, and the filter cake was washed with 4000 mL of water, and then dried to obtain 5850 g of DD salt 2, and 150 g of DD salt 2 was added to supplement 6000 g, which was used as a raw material for the esterification reaction.
  • This comparative example is used to illustrate the method of synthesizing the synthesized D-p-hydroxyphenylglycine methyl ester.
  • This comparative example is used to illustrate the method of synthesizing the synthesized D-p-hydroxyphenylglycine methyl ester.
  • the D-p-hydroxyphenylglycine methyl ester was synthesized according to the method of Example 1, except that during the neutralization reaction in the step (2), the pH of the titration was 6.0, and the pH of the crystal was 6.5.
  • the specific steps are as follows:
  • the mother liquor and the washing liquid produced after the neutralization were combined to a total of 28,000 g, and 10,000 g of methanol was distilled and recovered.
  • the bottom liquid after recovering methanol was continuously concentrated under reduced pressure to evaporate 8900 g of water.
  • 2830 g of DL-p-hydroxyphenylglycine, 1875 g of hydrochloric acid, and 70 g of salicylaldehyde were added to the obtained concentrate (3535 g of sodium phenylethanesulfonate), and the mixture was heated to 102 ° C and kept under reflux for 10 hours.
  • 2000 mL of water was added, followed by water distillation to entrain salicylaldehyde.
  • the method provided by the present invention can produce D-p-hydroxyphenylglycine methyl ester in a higher yield.
  • the yield of the esterification step in the method of mixing D-p-hydroxyphenylglycine, methanol and concentrated sulfuric acid solution in Comparative Example 1 and then distilling off methanol is much lower than that of the examples, and it can be seen that the method of the present invention simplifies esterification.
  • the efficiency of the esterification reaction is increased based on the reaction step.
  • Comparative Example 1 and Comparative Example 2 it can be seen from Comparative Example 1 and Comparative Example 2 that it is difficult to obtain a higher yield in the neutralization step because the pH value in the neutralization step is not within the range of the pH value defined in the present application.

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Abstract

本发明涉及化合物合成领域，公开了一种合成D-对羟基苯甘氨酸甲酯的方法，该方法包括以下步骤：(1)在氯化亚砜的存在下，将D-对羟基苯甘氨酸拆分剂盐与甲醇进行酯化反应，得到D-对羟基苯甘氨酸甲酯拆分剂盐；(2)在10-15℃下，将该D-对羟基苯甘氨酸甲酯拆分剂盐和碱性金属氢氧化物滴加至D-对羟基苯甘氨酸甲酯水溶液中，滴加过程中将体系的pH值控制在6.5-7，待所述D-对羟基苯甘氨酸甲酯拆分剂盐滴加完毕后继续滴加碱性金属氢氧化物至体系的pH值为7.5-8，然后在温度为10-15℃、pH值为7.5-8的条件下进行养晶，之后将得到的结晶液过滤，得到D-对羟基苯甘氨酸甲酯晶体和母液。采用本发明提供的方法能够以较高的收率生产D-对羟基苯甘氨酸甲酯。

Description

一种合成D-对羟基苯甘氨酸甲酯的方法 技术领域
本发明涉及一种合成D-对羟基苯甘氨酸甲酯的方法。
背景技术
D-对羟基苯甘氨酸甲酯作为一种医药中间体，被用于广谱抗生素羟氨苄青霉素(阿莫西林)的酶法合成生产中。由于酶法生产阿莫西林相对于其它方法在环保、能耗、生产效率等方面均具有很大优势，因此酶法生产阿莫西林在世界范围内的大量使用进一步带动了中间体D-对羟基苯甘氨酸甲酯的发展。
目前D-对羟基苯甘氨酸甲酯的合成方法通常是用手性拆分剂(通常为苯基乙磺酸)拆分DL-对羟基苯甘氨酸，得到L-对羟基苯甘氨酸拆分剂盐和D-对羟基苯甘氨酸拆分剂盐的混合物，并将该混合物采用水杨醛进行催化消旋得到D-对羟基苯甘氨酸拆分剂盐，然后用碱中和该D-对羟基苯甘氨酸拆分剂盐得到D-对羟基苯甘氨酸，之后再将D-对羟基苯甘氨酸与甲醇进行浓硫酸催化脱水并经中和反应得到。然而，该方法存在生产周期长、收率低、设备利用率低、操作繁杂且有大量固体物料需要干燥的缺陷，不利于大规模工业化生产。
发明内容
本发明的目的是为了克服采用现有的方法生产D-对羟基苯甘氨酸甲酯时存在收率低的缺陷，而提供一种新的收率高的生产D-对羟基苯甘氨酸甲酯的方法。
具体地，本发明提供了一种合成D-对羟基苯甘氨酸甲酯的方法，该方 法包括以下步骤：
(1)在氯化亚砜的存在下，将D-对羟基苯甘氨酸拆分剂盐与甲醇进行酯化反应，得到D-对羟基苯甘氨酸甲酯拆分剂盐；
(2)在10-15℃下，将步骤(1)得到的D-对羟基苯甘氨酸甲酯拆分剂盐和碱性金属氢氧化物滴加至D-对羟基苯甘氨酸甲酯水溶液中，滴加过程中将体系的pH值控制在6.5-7，待所述D-对羟基苯甘氨酸甲酯拆分剂盐滴加完毕后继续滴加碱性金属氢氧化物至体系的pH值为7.5-8，然后在温度为10-15℃、pH值为7.5-8的条件下进行养晶，之后将得到的结晶液过滤，得到D-对羟基苯甘氨酸甲酯晶体和母液。
本发明提供的合成D-对羟基苯甘氨酸甲酯的方法，一方面，采用D-对羟基苯甘氨酸拆分剂盐替代现有的D-对羟基苯甘氨酸与甲醇直接进行酯化反应，省去了现有的用碱中和D-对羟基苯甘氨酸拆分剂盐得到D-对羟基苯甘氨酸的步骤，由原来的两步反应变成一步反应，有效避免了原料的损失；另一方面，在上述特殊酯化反应的基础上配合特殊的后续滴定处理，能够使得D-对羟基苯甘氨酸甲酯拆分剂盐顺利转化为D-对羟基苯甘氨酸甲酯晶体，从而实现了D-对羟基苯甘氨酸甲酯的提纯。
根据本发明的一种优选实施方式，当所述D-对羟基苯甘氨酸甲酯的合成方法还包括步骤(3)，将步骤(2)得到的D-对羟基苯甘氨酸甲酯晶体进行水洗，然后将得到的洗液与所述母液合并后依次进行甲醇回收和浓缩，之后往得到的浓缩液中加入DL-对羟基苯甘氨酸、盐酸和水杨醛，然后将温度升至100-110℃反应8-12小时，反应结束后去除水杨醛并将产物过滤，得到D-对羟基苯甘氨酸拆分剂盐，将该D-对羟基苯甘氨酸拆分剂盐作为原料返回至步骤(1)中时，能够实现反应的循环和原料的充分利用，更具工业应用前景。
本发明的其它特征和优点将在随后的具体实施方式部分予以详细说明。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。
在本发明中，在未作相反说明的情况下，使用的术语“盐酸”可以指HCl也可以指HCl的水溶液，HCl的水溶液的浓度可以在较宽范围内选择，在本发明的优选实施方式中，盐酸的用量以浓度为36重量％的溶液计。
本发明提供的合成D-对羟基苯甘氨酸甲酯的方法包括以下步骤：
(1)在氯化亚砜的存在下，将D-对羟基苯甘氨酸拆分剂盐与甲醇进行酯化反应，得到D-对羟基苯甘氨酸甲酯拆分剂盐；
(2)在10-15℃下，将步骤(1)得到的D-对羟基苯甘氨酸甲酯拆分剂盐和碱性金属氢氧化物滴加至D-对羟基苯甘氨酸甲酯水溶液中，滴加过程中将体系的pH值控制在6.5-7，待所述D-对羟基苯甘氨酸甲酯拆分剂盐滴加完毕后继续滴加碱性金属氢氧化物至体系的pH值为7.5-8、优选为7.6-7.8，然后在温度为10-15℃(优选10-14℃)、pH值为7.5-8(优选7.6-7.8)的条件下进行养晶，之后将得到的结晶液过滤，得到D-对羟基苯甘氨酸甲酯晶体和母液。
本发明对所述D-对羟基苯甘氨酸拆分剂盐、甲醇和氯化亚砜的用量没有特别地限定，例如，相对于1mol的D-对羟基苯甘氨酸拆分剂盐，所述甲醇的用量可以为15-25mol，优选为17-20mol；所述氯化亚砜的用量可以为1-1.5mol，优选为1.1-1.2mol。
在本发明中，所述D-对羟基苯甘氨酸拆分剂盐是指D-对羟基苯甘氨酸 与手性拆分剂形成的盐。其中，所述手性拆分剂可以为现有的各种能够将L-对羟基苯甘氨酸与D-对羟基苯甘氨酸分离的物质，其种类可以为本领域的常规选择，例如，可以为苯基乙磺酸、溴代樟脑磺酸、酒石酸等中的至少一种。从原料易得性的角度出发，所述手性拆分剂特别优选为苯基乙磺酸。相应地，D-对羟基苯甘氨酸拆分剂盐通常可以为D-对羟基苯甘氨酸苯基乙磺酸盐、D-对羟基苯甘氨酸溴代樟脑磺酸盐、D-对羟基苯甘氨酸酒石酸盐等中的至少一种，优选为D-对羟基苯甘氨酸苯基乙磺酸盐。其中，D-对羟基苯甘氨酸苯基乙磺酸盐的结构如下式(1)所示：
Figure PCTCN2016085804-appb-000001
所述D-对羟基苯甘氨酸拆分剂盐可以通过商购得到，也可以按照本领域技术人员公知的各种方法制备得到。根据本发明的一种优选实施方式，所述D-对羟基苯甘氨酸拆分剂盐通过在100-110℃下，将DL-对羟基苯甘氨酸与苯基乙磺酸钠在盐酸和水杨醛存在下反应8-12小时得到。在该制备过程中，相对于100重量份的苯基乙磺酸钠，所述DL-对羟基苯甘氨酸的用量可以为75-90重量份，所述盐酸的用量可以为50-60重量份，所述水杨酸的用量可以为2-3重量份；优选地，相对于100重量份的苯基乙磺酸钠，所述DL-对羟基苯甘氨酸的用量为80-85重量份，所述盐酸的用量为53-56重量份，所述水杨醛的用量为2.2-2.8重量份。
本发明对步骤(1)中所述酯化反应的条件没有特别地限定，只要使得D-对羟基苯甘氨酸拆分剂盐与甲醇进行反应得到D-对羟基苯甘氨酸甲酯拆分剂盐即可。优选地，所述酯化反应在回流条件下进行，酯化反应的时间为1-5小时，更优选为3-5小时。
本发明对所述碱性金属氢氧化物的种类没有特别地限定，例如，可以 选自氢氧化钠、氢氧化钾、氢氧化锂等中的至少一种。所述碱性金属氢氧化物可以以纯态的形式使用，也可以以其水溶液的形式使用，优选为后者。当所述碱性金属氢氧化物以其水溶液的形式使用时，浓度优选为5-10重量％。
根据本发明提供的合成D-对羟基苯甘氨酸甲酯的方法，步骤(2)中所用的D-对羟基苯甘氨酸甲酯水溶液的浓度可以为1-5重量％，优选为2-3重量％。其中，所述D-对羟基苯甘氨酸甲酯水溶液主要起晶种的作用，D-对羟基苯甘氨酸甲酯拆分剂盐和碱性金属氢氧化物在上述温度和pH值下发生反应获得D-对羟基苯甘氨酸甲酯粗品，而上述晶种的存在能够诱发新生成的D-对羟基苯甘氨酸甲酯粗品发生结晶纯化。
根据本发明提供的合成D-对羟基苯甘氨酸甲酯的方法，步骤(2)中，相对于100重量份的D-对羟基苯甘氨酸拆分剂盐，所述D-对羟基苯甘氨酸甲酯水溶液中D-对羟基苯甘氨酸甲酯的用量可以为0.5-2重量份，优选为0.5-1重量份。此外，所述D-对羟基苯甘氨酸甲酯拆分剂盐的滴加速率可以为1-2g/min，优选为1.2-1.7g/min；所述碱性金属氢氧化物的滴加速率可以为1-2g/min，优选为1.5-2g/min。
本发明对步骤(2)中养晶的条件没有特别地限定。如上所述，所述养晶的条件包括养晶温度为10-15℃，pH值为7.5-8.0。优选地，所述养晶的条件包括养晶温度为10-14℃，pH值为7.6-7.8，养晶时间为1-5小时，在该优选条件下进行养晶获得的D-对羟基苯甘氨酸甲酯的收率和纯度均更高。
根据本发明提供的合成D-对羟基苯甘氨酸甲酯的方法，优选地，该方法还包括步骤(3)，将步骤(2)得到的D-对羟基苯甘氨酸甲酯晶体进行水洗，然后将得到的洗液与所述母液合并后依次进行甲醇回收和浓缩，之后往得到的浓缩液中加入DL-对羟基苯甘氨酸、盐酸和水杨醛，然后将温度升至100-110℃反应8-12小时，反应结束后去除水杨醛并将产物过滤，得到 D-对羟基苯甘氨酸拆分剂盐，将该D-对羟基苯甘氨酸拆分剂盐作为原料返回至步骤(1)中，这样能够实现反应的循环和原料的充分利用，更具工业应用前景。
根据本发明提供的合成D-对羟基苯甘氨酸甲酯的方法，步骤(3)中，相对于100重量份的所述浓缩液中的拆分剂盐，所述DL-对羟基苯甘氨酸的用量可以为75-90重量份，所述盐酸的用量可以为50-60重量份，所述水杨醛的用量可以为2-3重量份；优选地，相对于100重量份的所述浓缩液中的拆分剂盐，所述DL-对羟基苯甘氨酸的用量为80-85重量份，所述盐酸的用量为53-56重量份，所述水杨醛的用量为2.2-2.8重量份。
本发明对步骤(3)中去除水杨醛的方法没有特别地限定，可以采用现有的各种方法进行。根据本发明的一种具体实施方式，通过以下方法去除水杨醛：往反应结束后得到的反应产物加入的水，之后再进行水蒸发以夹带去除其中的水杨醛，具体操作为本领域技术人员公知，在此不作赘述。
以下将通过实施例对本发明进行详细描述。以下实施例和对比例中：
步骤(1)中D-对羟基苯甘氨酸甲酯苯基乙磺酸盐的收率＝D-对羟基苯甘氨酸甲酯苯基乙磺酸盐的实际产量÷D-对羟基苯甘氨酸甲酯苯基乙磺酸盐的理论产量×100％。
步骤(2)中D-对羟基苯甘氨酸甲酯的收率＝D-对羟基苯甘氨酸甲酯的实际产量÷D-对羟基苯甘氨酸甲酯的理论产量×100％。
实施例1
该实施例用于说明本发明提供的合成D-对羟基苯甘氨酸甲酯的方法。
(1)酯化：
向30L玻璃反应器中加入甲醇11700mL，开启搅拌，取D-对羟基苯甘氨酸苯基乙磺酸盐(又称DD盐1，下同)6000g加入该玻璃反应器中，将 温度控制在低于25℃下滴加氯化亚砜2230g。滴加完氯化亚砜后升温至回流状态，保持回流3小时，酯化反应结束之后，得到酯化液。用HPLC检测，该酯化液中D-对羟基苯甘氨酸甲酯苯基乙磺酸盐的收率为98.5％。
(2)中和：
向3L玻璃反应瓶中加水2000mL和D-对羟基苯甘氨酸甲酯50g(作为晶种)，将温度控制在10℃、pH值控制在6.7下同时滴加步骤(1)得到的酯化液(滴加速率为1.25g/min)和8重量％的氢氧化钠水溶液(滴加速率为1.5g/min)，酯化液滴加完毕后继续缓慢滴加8重量％的氢氧化钠水溶液直到pH值为7.6。之后保持温度10℃继续缓慢搅拌(搅拌转速为120rmp/min，下同)养晶2小时，记录养晶后的pH值，2小时后如果晶液的pH值低于7.6则需继续滴加8重量％的氢氧化钠水溶液调pH值至7.6，得到结晶液。将该结晶液离心过滤，得到滤饼和母液，然后用4500mL水分三次对滤饼进行洗涤，高速离心脱水后收集洗液。该滤饼在50℃下鼓风干燥5小时即得D-对羟基苯甘氨酸甲酯2680g，收率为87.1％。
(3)拆分：
将中和后产生的母液和洗液合并共计28000g，蒸馏回收10000g甲醇。回收甲醇后的底液继续减压浓缩蒸出水8900g。浓缩结束后往得到的浓缩液(含苯基乙磺酸钠3535g)中加入DL-对羟基苯甘氨酸2828g、盐酸(36重量％，下同)1875g、水杨醛70g，之后升温至102℃保温回流反应10h。反应结束后加入2000mL水，再进行水蒸馏以夹带出水杨醛。蒸完水杨醛后降温至30-35℃甩滤，再用4000mL水洗涤滤饼，出料后干燥，得到5850g的DD盐1，加150g的DD盐1补齐6000g后可以作为下一轮酯化反应原料。
实施例2
该实施例用于说明本发明提供的合成D-对羟基苯甘氨酸甲酯的方法。
(1)酯化：
向30L玻璃反应器中加入甲醇13800mL，开启搅拌，取D-对羟基苯甘氨酸苯基乙磺酸盐6000g加入该玻璃反应器中，将温度控制在低于25℃下滴加氯化亚砜2430g。滴加完氯化亚砜后升温至回流状态，保持回流5小时，酯化反应结束之后，得到酯化液。用HPLC检测，该酯化液中D-对羟基苯甘氨酸甲酯苯基乙磺酸盐的收率为98.7％。
(2)中和：
向3L玻璃反应瓶中加水2000mL和D-对羟基苯甘氨酸甲酯60g(作为晶种)，将温度控制在14℃、pH值控制在6.9下同时滴加步骤(1)得到的酯化液(滴加速率为1.7g/min)和8重量％的氢氧化钠水溶液(滴加速率为2g/min)，酯化液滴加完毕后继续缓慢滴加8重量％的氢氧化钠水溶液直到pH值为7.8。之后保持温度14℃继续缓慢搅拌养晶2小时，记录养晶后的pH值，2小时后如果晶液的pH值低于7.8则需继续滴加8重量％的氢氧化钠水溶液调pH值至7.8，得到结晶液。将该结晶液离心过滤，得到滤饼和母液，然后用4500mL水分三次对滤饼进行洗涤，高速离心脱水后收集洗液。该滤饼在50℃下鼓风干燥5小时即得D-对羟基苯甘氨酸甲酯2700g，收率为87.7％。
(3)拆分：
将中和后产生的母液和洗液合并共计28000g，蒸馏回收10000g甲醇。回收甲醇后的底液继续减压浓缩蒸出水8900g。浓缩结束后往得到的浓缩液(含苯基乙磺酸钠3535g)中加入DL-对羟基苯甘氨酸3000g、盐酸1980g、水杨醛100g，之后升温至102℃保温回流反应15h。反应结束后加入2000mL水，再进行蒸馏以夹带出水杨醛。蒸完水杨醛后降温至30-35℃甩滤，再用4000mL水洗涤滤饼，出料后干燥，得到5850g的DD盐1，加150g的DD盐1补齐6000g后可以作为下一轮酯化反应原料。
实施例3
该实施例用于说明本发明提供的合成D-对羟基苯甘氨酸甲酯的方法。
(1)酯化：
向30L玻璃反应器中加入甲醇12000mL，开启搅拌，取D-对羟基苯甘氨酸苯基乙磺酸盐6000g加入该玻璃反应器中，将温度控制在低于25℃下滴加氯化亚砜2400g。滴加完氯化亚砜后升温至回流状态，保持回流4小时，酯化反应结束之后，得到酯化液。用HPLC检测，该酯化液中D-对羟基苯甘氨酸甲酯苯基乙磺酸盐的收率为98.72％。
(2)中和：
向3L玻璃反应瓶中加水2000mL和D-对羟基苯甘氨酸甲酯50g(作为晶种)，将温度控制在12℃、pH值控制在6.8下同时滴加步骤(1)得到的酯化液(滴加速率为1.5g/min)和8重量％的氢氧化钠水溶液(滴加速率为1.8g/min)，酯化液滴加完毕后继续缓慢滴加8重量％的氢氧化钠水溶液直到pH值为7.7。之后保持温度12℃继续缓慢搅拌养晶2小时，记录养晶后的pH值，2小时后如果晶液的pH值低于7.7则需继续滴加8重量％的氢氧化钠水溶液调pH值至7.7，得到结晶液。将该结晶液离心过滤，得到滤饼和母液，然后用4500mL水分三次对滤饼进行洗涤，高速离心脱水后收集洗液。该滤饼在50℃下鼓风干燥5小时即得D-对羟基苯甘氨酸甲酯2700g，收率为88.2％。
(3)拆分：
将中和后产生的母液和洗液合并共计28000g，蒸馏回收10000g甲醇。回收甲醇后的底液继续减压浓缩蒸出水8900g。浓缩结束后往得到的浓缩液(含苯基乙磺酸钠3535g)中加入DL-对羟基苯甘氨酸2900g、盐酸1920g、水杨醛88g，之后升温至102℃保温回流反应10h。反应结束后加入2000mL水，再进行水蒸馏以夹带出水杨醛。蒸完水杨醛后降温至30-35℃甩滤，再用4000mL水洗涤滤饼，出料后干燥，得到5850g的DD盐1，加150g的DD盐1补齐6000g后可以作为下一轮酯化反应原料。
实施例4
该实施例用于说明本发明提供的合成D-对羟基苯甘氨酸甲酯的方法。
按照实施例1的方法合成D-对羟基苯甘氨酸甲酯，不同的是，不包括步骤(3)。
实施例5
按照实施例4的方法合成D-对羟基苯甘氨酸甲酯，不同的是，将步骤(1)中使用的“D-对羟基苯甘氨酸苯基乙磺酸盐”替换为“D-对羟基苯甘氨酸溴代樟脑磺酸盐”，具体步骤如下：
(1)酯化：
向30L玻璃反应器中加入甲醇11700mL，开启搅拌，取D-对羟基苯甘氨酸溴代樟脑磺酸盐(又称DD盐2，下同)6000g加入该玻璃反应器中，将温度控制在低于25℃下滴加氯化亚砜1680g。滴加完氯化亚砜后升温至回流状态，保持回流3小时，酯化反应结束之后，得到酯化液。用HPLC检测，该酯化液中D-对羟基苯甘氨酸甲酯溴代樟脑磺酸盐的收率为95％。
(2)中和：
向30L玻璃反应瓶中加水2000mL和D-对羟基苯甘氨酸甲酯50g(作为晶种)，将温度控制在10℃、pH值控制在6.7下同时滴加步骤(1)得到的酯化液(滴加速率为1.25g/min)和8重量％的氢氧化钠水溶液(滴加速率为1.5g/min)，酯化液滴加完毕后继续缓慢滴加8重量％的氢氧化钠水溶液直到pH值为7.6。之后保持温度10℃继续缓慢搅拌(搅拌转速为120rmp/min，下同)养晶2小时，记录养晶后的pH值，2小时后如果晶液的pH值低于7.6则需继续滴加8重量％的氢氧化钠水溶液调pH值至7.6，得到结晶液。将该结晶液离心过滤，得到滤饼和母液，然后用4500mL水分三次对滤饼进行洗涤，高速离心脱水后收集洗液。该滤饼在50℃下鼓风干 燥5小时即得D-对羟基苯甘氨酸甲酯1832g，收率为85％。
其中，DD盐2的制备方法如下：
向30L玻璃反应器中加入水6000mL，加入D-对羟基苯甘氨酸2100g、右旋-3-溴樟脑-10-磺酸水合物4129g(购自杭州杰恒化工有限公司，CAS:24262-38-2)，之后升温至102℃保温回流反应4h。反应结束后降温至30-35℃甩滤，再用4000mL水洗涤滤饼，出料后干燥，得到5850g的DD盐2，加150g的DD盐2补齐6000g后可以作为酯化反应的原料。
对比例1
该对比例用于说明参比的合成D-对羟基苯甘氨酸甲酯的方法。
取D-对羟基苯甘氨酸拆分剂苯基乙磺酸盐6000g加入30L玻璃反应器中，然后加入2240g浓度为30重量％的氢氧化钠溶液，并将温度控制在50℃下反应8小时，得到D-对羟基苯甘氨酸。之后往该玻璃反应器中加入甲醇12000mL，开启搅拌，将温度控制在低于25℃下滴加浓硫酸(浓度为98重量％)2000g。滴加完浓硫酸后升温至回流状态，保持回流2小时，蒸出甲醇6000mL。之后补加甲醇6000mL，升温至回流状态保持回流2小时蒸出甲醇6000mL；再补加甲醇6000mL，升温至回流状态保持回流2小时蒸出甲醇6000mL；重复补加蒸出甲醇4次后酯化反应结束，得到酯化液。用HPLC检测，该酯化液中D-对羟基苯甘氨酸甲酯的收率为78.7％。
对比例2
该对比例用于说明参比的合成D-对羟基苯甘氨酸甲酯的方法。
按照实施例1的方法合成D-对羟基苯甘氨酸甲酯，不同的是，步骤(2)中和反应过程中，滴定的pH值为6.0，养晶的pH值为6.5，具体步骤如下：
(1)酯化：
向30L玻璃反应器中加入甲醇11700mL，开启搅拌，取D-对羟基苯甘 氨酸苯基乙磺酸盐6000g加入该玻璃反应器中，将温度控制在低于25℃下滴加氯化亚砜2230g。滴加完氯化亚砜后升温至回流状态，保持回流3小时，酯化反应结束之后，得到酯化液。用HPLC检测，该酯化液中D-对羟基苯甘氨酸甲酯苯基乙磺酸盐的收率为98.5％。
(2)中和：
向3L玻璃反应瓶中加水2000mL和D-对羟基苯甘氨酸甲酯50g(作为晶种)，将温度控制在10℃、pH值控制在6.0下同时滴加步骤(1)得到的酯化液(滴加速率为1.25g/min)和8重量％的氢氧化钠水溶液(滴加速率为1.5g/min)，酯化液滴加完毕后继续缓慢滴加8重量％的氢氧化钠水溶液直到pH值为6.5。之后保持温度10℃继续缓慢搅拌养晶2小时，记录养晶后的pH值，2小时后如果晶液的pH值低于6.5则需继续滴加8重量％的氢氧化钠水溶液调pH值至6.5，得到结晶液。将该结晶液离心过滤，得到滤饼和母液，然后用4500mL水分三次对滤饼进行洗涤，高速离心脱水后收集洗液。该滤饼在50℃下鼓风干燥5小时即得D-对羟基苯甘氨酸甲酯1870g，收率为60.79％。
(3)拆分：
将中和后产生的母液和洗液合并共计28000g，蒸馏回收10000g甲醇。回收甲醇后的底液继续减压浓缩蒸出水8900g。浓缩结束后往得到的浓缩液(含苯基乙磺酸钠3535g)中加入DL-对羟基苯甘氨酸2830g、盐酸1875g、水杨醛70g，之后升温至102℃保温回流反应10h。反应结束后加入2000mL水，再进行水蒸馏以夹带出水杨醛。蒸完水杨醛后降温至30-35℃甩滤，再用4000ml水洗涤滤饼，出料后干燥，得到5850g的DD盐1，加150g的DD盐1补齐6000g后可以作为下一轮酯化反应原料。
从以上结果可以看出，采用本发明提供的方法能够以较高的收率生产D-对羟基苯甘氨酸甲酯。
特别地，对比例1中将D-对羟基苯甘氨酸、甲醇和浓硫酸溶液进行混合然后蒸出甲醇的方法中酯化步骤的收率远低于实施例，可见本发明的方法在简化酯化反应步骤的基础上提高了酯化反应的效率。此外，比较实施例1与对比例2可以看出，中和步骤中pH值不在本申请限定的pH值的范围内将难以在中和步骤获得较高的收率。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合。为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。

Claims (12)

  1. 一种合成D-对羟基苯甘氨酸甲酯的方法，该方法包括以下步骤：
    (1)在氯化亚砜的存在下，将D-对羟基苯甘氨酸拆分剂盐与甲醇进行酯化反应，得到D-对羟基苯甘氨酸甲酯拆分剂盐；
    (2)在10-15℃下，将步骤(1)得到的D-对羟基苯甘氨酸甲酯拆分剂盐和碱性金属氢氧化物滴加至D-对羟基苯甘氨酸甲酯水溶液中，滴加过程中将体系的pH值控制在6.5-7，待所述D-对羟基苯甘氨酸甲酯拆分剂盐滴加完毕后继续滴加碱性金属氢氧化物至体系的pH值为7.5-8，然后在温度为10-15℃、pH值为7.5-8的条件下进行养晶，之后将得到的结晶液过滤，得到D-对羟基苯甘氨酸甲酯晶体和母液。
  2. 根据权利要求1所述的方法，其中，相对于1mol的D-对羟基苯甘氨酸拆分剂盐，所述甲醇的用量为15-25mol，所述氯化亚砜的用量为1-1.5mol。
  3. 根据权利要求1所述的方法，其中，相对于1mol的D-对羟基苯甘氨酸拆分剂盐，所述甲醇的用量为17-20mol，所述氯化亚砜的用量为1.1-1.2mol。
  4. 根据权利要求1-3中任意一项所述的方法，其中，所述D-对羟基苯甘氨酸拆分剂盐为D-对羟基苯甘氨酸苯基乙磺酸盐、D-对羟基苯甘氨酸溴代樟脑磺酸盐、D-对羟基苯甘氨酸酒石酸盐中的至少一种。
  5. 根据权利要求1-3中任意一项所述的方法，其中，所述D-对羟基苯甘氨酸拆分剂盐为D-对羟基苯甘氨酸苯基乙磺酸盐。
  6. 根据权利要求5所述的方法，其中，所述D-对羟基苯甘氨酸拆分剂盐通过在100-110℃下，将DL-对羟基苯甘氨酸与苯基乙磺酸钠在盐酸和水杨醛存在下反应8-12小时得到；优选地，相对于100重量份的苯基乙磺酸钠，所述DL-对羟基苯甘氨酸的用量为75-90重量份，所述盐酸的用量为50-60重量份，所述水杨醛的用量为2-3重量份。
  7. 根据权利要求1-6中任意一项所述的方法，其中，步骤(1)中所述的酯化反应在回流条件下进行，且酯化反应的时间为1-5小时。
  8. 根据权利要求1-7中任意一项所述的方法，其中，所述碱性金属氢氧化物选自氢氧化钠、氢氧化钾和氢氧化锂中的至少一种；优选地，所述碱性金属氢氧化物以其水溶液的形式使用，且浓度为5-10重量％。
  9. 根据权利要求1-8中任意一项所述的方法，其中，步骤(2)中所用的D-对羟基苯甘氨酸甲酯水溶液的浓度为1-5重量％。
  10. 根据权利要求1-9中任意一项所述的方法，其中，相对于100重量份的D-对羟基苯甘氨酸拆分剂盐，所述D-对羟基苯甘氨酸甲酯水溶液中D-对羟基苯甘氨酸甲酯的用量为0.5-2重量份。
  11. 根据权利要求1-10中任意一项所述的方法，其中，所述养晶的条件包括养晶温度为10-14℃，pH值为7.6-7.8，养晶时间为1-5小时。
  12. 根据权利要求1-11中任意一项所述的方法，其中，该方法还包括步骤(3)，将步骤(2)得到的D-对羟基苯甘氨酸甲酯晶体进行水洗，然后将得到的洗液与所述母液合并后依次进行甲醇回收和浓缩，之后往得到的 浓缩液中加入DL-对羟基苯甘氨酸、盐酸和水杨醛，然后将温度升至100-110℃反应8-12小时，反应结束后去除水杨醛并将产物过滤，得到D-对羟基苯甘氨酸拆分剂盐，将该D-对羟基苯甘氨酸拆分剂盐作为原料返回至步骤(1)中；优选地，相对于100重量份的所述浓缩液中的拆分剂盐，所述DL-对羟基苯甘氨酸的用量为75-90重量份，所述盐酸的用量为50-60重量份，所述水杨醛的用量为2-3重量份。
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