CN111440079B - Synthesis method of DL-threo-p-chlorophenylserine - Google Patents

Synthesis method of DL-threo-p-chlorophenylserine Download PDF

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CN111440079B
CN111440079B CN202010356052.8A CN202010356052A CN111440079B CN 111440079 B CN111440079 B CN 111440079B CN 202010356052 A CN202010356052 A CN 202010356052A CN 111440079 B CN111440079 B CN 111440079B
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condensation
potassium
sodium
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CN111440079A (en
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李开波
程奇灵
余伟森
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Apeloa Pharmaceutical Co ltd
Shandong Puluohanxing Pharmaceutical Co ltd
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Apeloa Pharmaceutical Co ltd
Shandong Puluohanxing Pharmaceutical Co ltd
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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
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • 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
    • 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
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Abstract

The invention discloses a synthesis method of DL-threo-p-chlorophenylserine, which is divided into two steps; the first step: reacting p-chlorobenzaldehyde and glycine under a condensation condition a to prepare a condensation intermediate, and separating the condensation intermediate; and a second step of: the separated condensed intermediate reacts under the decomposition condition b to prepare DL-threo-p-chlorophenylserine. The method has the advantages of industrial production of all the raw materials, readily available raw materials, high yield, high selectivity, high product purity and low cost, and the process avoids the dilemma that the waste water is difficult to treat, is simple in subsequent operation, is environment-friendly and is suitable for industrial production.

Description

Synthesis method of DL-threo-p-chlorophenylserine
Technical Field
The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to synthesis of an antibiotic pharmaceutical intermediate, and belongs to the field of pharmaceutical chemicals.
Background
The synthesis of beta-amino alcohol drugs with two chiral centers has been a hotspot in the industry, such as chloramphenicol, thiamphenicol, florfenicol, and the like. The florfenicol is a broad-spectrum antibiotic special for veterinary drugs, has broad-spectrum activity against gram-negative bacteria and gram-positive bacteria, and is widely used for preventing and treating bacterial infection of animals. Recent reports indicate that bacterial resistance to florfenicol is becoming more and more severe. Therefore, there is an urgent need to develop a drug with the pharmaceutical activity of florfenicol while overcoming the drug resistance.
DL-threo-p-chlorophenylserine is an important medical intermediate, and the structure is shown as a formula (I):
there are few experimental methods available in the literature for the synthesis of compounds of formula (I). In Johannes Steinreiber et al (Tetrahedron, 2007, 63, 918-926), a bioconversion process is described wherein aldehyde and glycine are used as starting materials and, under specific conditions, aldol condensation reactions are directly carried out with specific enzymes as catalysts to produce a stereoselective phenylserine substituent. The method has harsh reaction conditions and is limited by factors such as selectivity, activity, stability and the like of the enzyme, and is in a laboratory research stage at present, and no report of amplification experiments and industrial production is seen.
In the Zhou Changyou et al (Synthetic Communications,1987, 17 (11), 1377-1382) the synthesis of ethyl p-chlorophenylserine is described. In a two-phase system with ethanol as a reaction solvent and potassium carbonate as alkali and in the presence of a phase transfer catalyst, the method for synthesizing p-chlorobenzenese serine ethyl ester with imine compounds and aldehydes as raw materials has the total yield of about 72 percent. The compound has a threo-red ratio of 1:1, is not optically active, and cannot meet the research requirements of medicines.
Copper salt method is also commonly used for synthesizing amino acid, and the synthesis method of DL-threo-p-methylsulfonylbenzylserine is described in detail in Dong Shunkang and other (Chinese journal of medicine, 1979,5,1-3) literature, and the method has high yield and good selectivity and is widely used in industrial production at present. The applicant has synthesized the compound of formula (1) by reference to this method in the initial stage of the study, but found during the experiment: the synthesis reaction is difficult to carry out, the reaction rate is very slow, the impurities are more, and the experimental molar yield is less than 20 percent (calculated by glycine). Presumably related to the nature of the substituent on the benzene ring, the methylsulfonyl increases the activity of the aldehyde, the reaction is easier to occur, the reaction is more thorough, and the yield is high; and the effect of the chlorine substituent is reversed.
US3733352 discloses a synthesis method of p-methylsulfonylbenzylserine, which comprises the steps of reacting glycine with p-methylsulfonylbenzaldehyde as an initial raw material, acidifying after the reaction, removing methanol by evaporation, adding water, filtering to recover raw material aldehyde, and neutralizing the water phase with ammonia water to pH 3-4 to obtain p-methylsulfonylbenzylserine. When the substrate is replaced by p-chlorobenzaldehyde by the p-methylsulfonyl benzaldehyde, the reaction result is not ideal, the yield is low, especially the erythro isomer content is large, and the purity of the product cannot meet the application requirement.
The invention can effectively avoid the defects in the method, and provides a method which has simple operation, good selectivity, high quality and high yield and can be used for industrial production for preparing DL-threo-p-chlorophenylserine.
Disclosure of Invention
The invention provides a synthesis method of DL-threo-p-chlorophenylserine, which has the advantages of simple process, good selectivity and high product purity and yield.
A synthesis method of DL-threo-p-chlorophenylserine comprises the following steps:
(1) Under the action of a base catalyst, performing condensation reaction on the p-chlorobenzaldehyde and glycine, and separating to obtain a condensation intermediate solid;
(2) And (3) decomposing the condensed intermediate solid obtained in the step (1) under the action of an acid catalyst, and after the reaction is finished, performing post-treatment to obtain the DL-threo-p-chlorobenzeneserine.
The synthesis method is shown as a formula (II):
a in the formula (II) represents condensation conditions, wherein the condensation conditions comprise a base catalyst A, a reaction medium A, a raw material ratio, a reaction temperature and a reaction time;
b in the formula (II) represents decomposition conditions including an acid catalyst B, a reaction medium B, an aldehyde recovery method and a product crystallization method.
In the prior art, the analogue of the condensed intermediate is not separated, but is directly hydrolyzed to synthesize DL-threo-p-methylsulfonyl phenylserine, but the inventor discovers that when p-chlorobenzaldehyde is taken as a substrate, the yield of the obtained DL-threo-p-chlorobenzeneserine is low and the purity is not high, and the inventor directly separates the condensed intermediate (II) under specific conditions, and discovers that the separation operation is added, so that the purity of the DL-threo-p-chlorobenzeneserine can be obviously improved, and the requirement of drug synthesis is met.
In the invention, the base catalyst A is an organic base or an inorganic base capable of reacting with glycine, and is at least one selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium (potassium) methoxide, sodium (potassium) ethoxide, liquid ammonia, ammonia water and the like, more preferably sodium hydroxide or potassium hydroxide, most preferably sodium hydroxide, and when sodium hydroxide is selected, the condensed intermediate solid can be separated out with higher yield and purity.
In the invention, the reaction medium A is required to have a certain solubility to p-chlorobenzaldehyde and a small solubility to condensation products, and is at least one selected from water, methanol, ethanol, isopropanol, acetonitrile and the like, more preferably methanol or a mixed solvent of methanol and water, and most preferably methanol, so that condensation intermediate solids are precipitated in high yield and purity.
In the present invention, the ratio of the raw materials in the condensation condition a is not strictly limited, and the raw materials are generally fed according to the stoichiometric ratio, and the molar ratio of the aldehyde to the glycine is preferably: 1.5 to 2.5:1, more preferably: 1.8-2.2:1, the conversion rate of the raw materials is the highest, and the quality and the yield of the obtained product are the best.
In the invention, the dosage of the catalyst A in the condensation condition a is a key factor, which can influence the pH value of a system, thereby influencing the conversion rate and the selectivity of the reaction. The optimal dosage of the catalyst A is as follows: the pH value of the system is controlled to be 12-14, more preferably: the pH value is 12.5-13.5. Too high or too low a pH will result in a decrease in the yield or purity of the precipitated intermediate product, thereby affecting the yield and purity of the final product.
In the present invention, the temperature in the condensation conditions a is also a critical factor. The reaction temperature is preferably: the temperature is preferably 30 to 70 ℃, and more preferably: at 30-50 ℃, the amount of byproducts is the least, the yield and purity are the highest, and the reaction efficiency is reduced due to the excessively high and excessively low temperature.
In the present invention, the time in the condensation condition a is not strictly limited. The reaction rate of amino acid formation is high, and the reaction can be completed usually in a few hours, but the obtained amino acid contains a large amount of erythro isomers and has poor selectivity. The ratio of the threo and erythro contents is a certain value when the reaction conditions are certain, and the ratio of the threo and erythro contents is different when the reaction conditions are different. However, as the solubility of the threo configuration in the reaction medium is smaller than that of the erythro configuration, the reaction time is prolonged, the erythro configuration can be gradually converted into the threo configuration, the process is slower, the time is different from a few hours to a dozen hours, the longer the reaction time is, the more sufficient the conversion is, the better the quality of the obtained product is, and the higher the yield is. However, after a certain period of time, the reaction time was selected to be 10 hours or longer, and the end point of the reaction was determined by HPLC, since the effect of the time extension on the yield was small, and the amount of by-products was increased to adversely affect the purity and yield of the product.
In the invention, after the reaction in the first step is finished, filtering and washing are carried out to obtain the solid of the condensation intermediate, and the solid can be dried and then used for the reaction in the second step; or directly used for the second reaction without drying. The direct isolation of the condensed intermediate, rather than the direct hydrolysis of the reaction mixture, is critical for obtaining high purity DL-threo-p-chlorophenylserine.
In the present invention, the reaction medium B in the decomposition condition B is an aqueous solvent selected from at least one of water or a mixed solvent of the following solvents with water, such as methanol, ethanol, isopropanol, acetonitrile, etc., which can promote the decomposition of the condensation product, and further preferably water.
In the invention, the dosage of the reaction medium A and the reaction medium B is not strictly limited, and the dosage is determined according to the flowing condition of a reaction system; when the system is viscous and has poor fluidity, the reaction medium should be supplemented until the fluidity is good. The more the consumption is, the better the fluidity of the system is, but the dissolution amount of the product is increased, so that the loss is increased, the yield is reduced, and the post-treatment amount of the mother solution is increased, thereby bringing pressure to environmental protection. The amount of the reaction medium is thus chosen to be 5 to 20 times the amount of solid to be fed.
In the present invention, the acid catalyst B in the decomposition condition B is an organic acid or an inorganic acid capable of providing hydrogen ions, and is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, sulfurous acid, nitric acid, phosphoric acid, methanesulfonic acid, and the like. These catalysts have good catalytic effects on the reaction, and hydrochloric acid and sulfuric acid are more preferable. The selected catalyst and reaction medium have the advantages of easily available raw materials, low price and suitability for industrial production.
In the invention, the dosage of the acid catalyst B is not strictly limited, and the dosage is characterized by the pH value of a system; the dosage is large, the pH value is low, the decomposition speed is high, but the dosage is excessive, the dosage of alkali in the subsequent neutralization step is increased, the waste of raw materials is caused, and meanwhile, a large amount of inorganic salt is added, so that the method is economical and environmentally-friendly; the dosage is small, the pH value is high, the decomposition speed is low or the decomposition is incomplete, so that the products and the raw materials cannot be separated. The dosage of the catalyst B is as follows: the pH value of the system is controlled within the range of 0 to 2, more preferably 0.5 to 1.5, and the condensation product is completely decomposed at this time, so that the economic and environmental benefits are optimal.
In the present invention, the method for recovering aldehyde in the decomposition condition b comprises: filtering, extracting and other operations, the purity of the obtained aldehyde is good, and the recovery rate is high; the separated and recovered aldehyde is subjected to simple treatment and then is applied to the first-step reaction for condensation reaction, so that the recycling of raw materials is realized, the raw material unit consumption is reduced, and the economic benefit is improved. The extraction solvent used in the extraction operation is at least one selected from dichloromethane, chloroform, ethyl acetate, butyl acetate, toluene, n-butanol, n-octanol, isooctanol, pentanone and the like.
In the present invention, the DL-threo-p-chlorophenylserine can be obtained by crystallization. The crystallization method comprises the following steps: and (3) regulating the pH value of the filtrate remained after aldehyde separation to 5-7 by using alkali at a certain temperature to obtain a crystal product. The product obtained at this time has good purity and high yield. The temperature is not strictly limited, the temperature is high, the product has good crystal form and is easy to filter and wash, but the product decomposition is accelerated due to the excessive temperature, and the yield and purity of the product are unfavorable. The temperature is too low, the crystallization of the product is poor, impurities are easy to wrap, and the filtering and washing are not facilitated. The temperature is preferably 0 to 30 ℃. The alkali is generally inorganic alkali and is at least one selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonia water and the like; sodium hydroxide or ammonia is preferred.
Compared with the prior art, the invention has the advantages that: the method has the advantages of easily obtained reaction raw materials, mild reaction conditions, high selectivity, high product purity and yield, low cost, simple process and operation, easy post-treatment, environmental friendliness and suitability for industrial mass production.
Detailed Description
The present invention will be further described with reference to the following specific examples, which are provided for better understanding of the technical aspects of the present invention, but those skilled in the art will recognize that the present invention is not limited to these examples. Those skilled in the art will recognize that many modifications may be made thereto without departing from the spirit and scope of the invention, and that such modifications as fall within the scope of the invention.
In the present invention, both threo and erythro products were identified by HPLC and have been compared to standards.
Example 1:
4000g of water was put into a suitable reaction flask equipped with mechanical stirring, and placed in a water bath at 40-45℃under stirring, glycine (316 g,4.21 mol), copper sulfate pentahydrate (457 g,1.80 mol) were added, the solution was stirred and cleared, pH was adjusted to 9.0-9.5 with liquid alkali, p-chlorobenzaldehyde (457 g,3.25 mol) was added, and the reaction was carried out at constant temperature for 96 hours while maintaining the pH of the system unchanged. Filtering, washing with a large amount of water, pulping the wet product with ethanol after pumping, filtering, washing with a large amount of ethanol, pumping to obtain wet product, and drying to obtain copper salt dry product (346.7 g, p-chlorophenylserine external standard content: 48.3%,0.78 mol); the calculated yields were: 18.5% (calculated as glycine).
Example 2:
161g of 90% methanol aqueous solution by mass fraction is put into a proper reaction bottle equipped with mechanical stirring, placed in a water bath with 30 ℃ for stirring, glycine (6.12 g,0.082 mol) is added, and a methanol saturated solution of sodium hydroxide is slowly added to dissolve the glycine, and the pH value is adjusted to 12.5-13.5; adding p-chlorobenzaldehyde (22.9 g,0.163 mol) for reaction, keeping the system temperature at about 30 ℃ and the pH value between 12.5 and 13.5, detecting the reaction completely by HPLC after 40 hours of reaction, filtering and washing to obtain a wet product; drying to obtain a first-step finished product (18.58 g,0.052mol, the obtained finished product exists in the form of sodium salt of condensate); the calculated first step reaction molar yield is: 63.4% (calculated as glycine).
Example 3:
184g of 90% methanol aqueous solution by mass fraction is put into a proper reaction bottle equipped with mechanical stirring, placed in a water bath at 40 ℃ for stirring, glycine (6.12 g,0.082 mol) is added, and a methanol saturated solution of sodium hydroxide is slowly added to dissolve the glycine, and the pH value is adjusted to 12.5-13.5; adding p-chlorobenzaldehyde (22.9 g,0.163 mol) for reaction, keeping the system temperature at about 35 ℃ and the pH value between 12.5 and 13.5, detecting the reaction completely by HPLC after the reaction for 35 hours, filtering and washing to obtain a wet product; drying to obtain a first-step finished product (21.53 g,0.060 mol); the calculated first step reaction molar yield is: 73.2% (calculated as glycine).
Example 4:
696g of 90% methanol aqueous solution by mass fraction is put into a proper reaction bottle equipped with mechanical stirring, placed in a water bath with 40 ℃ for stirring, glycine (23.3 g,0.31 mol) is added, and a methanol saturated solution of sodium hydroxide is slowly added to dissolve the glycine, and the pH value is adjusted to 12.5-13.5; then adding p-chlorobenzaldehyde (117 g, content: 74.7%,0.62 mol) recovered according to the method of example 8 for reaction, keeping the system temperature at about 40 ℃ and the pH value between 12.5 and 13.5, after 30 hours of reaction, detecting the reaction completely by HPLC, filtering and washing to obtain a wet product; drying to obtain a first-step finished product (86.8 g,0.24 mol); the calculated first step reaction molar yield is: 77.4% (calculated as glycine).
Example 5:
adding 1840g of methanol solution into a proper reaction bottle equipped with mechanical stirring, placing in a water bath at 40 ℃ for stirring, adding glycine (61.2 g,0.816 mol), slowly adding a methanol saturated solution of sodium hydroxide to dissolve glycine, and adjusting the pH value to 12.5-13.5; then adding p-chlorobenzaldehyde (229 g,1.629 mol) for reaction, keeping the system temperature at about 50 ℃ and controlling the pH value within the range of 12.5-13.5, after the reaction for 25 hours, detecting the reaction to be complete by HPLC, filtering and washing to obtain a wet product; drying to obtain a first-step finished product (214.2 g,0.595mol, wherein the first-step finished product exists in a sodium salt form); the calculated first step reaction molar yield is: 72.9% (calculated as glycine).
Example 6:
adding 1840g of methanol solution into a proper reaction bottle equipped with mechanical stirring, placing in a water bath at 40 ℃ for stirring, adding glycine (61.2 g, 0.815mol), slowly adding a methanol saturated solution of sodium hydroxide to dissolve glycine, and adjusting the pH value to 12.5-13.5; adding p-chlorobenzaldehyde (229 g,1.629 mol) for reaction, keeping the system temperature at about 65 ℃ and the pH value between 12.5 and 13.5, detecting the reaction by HPLC after 20 hours, filtering, not washing, and pumping to obtain a wet product; drying to obtain a first-step finished product (233.7 g,0.649 mol); the calculated first step reaction molar yield is: 79.5% (calculated as glycine).
Example 7:
800g of drinking water is put into a proper reaction bottle equipped with mechanical stirring, 83g of concentrated sulfuric acid is added under stirring, the temperature is reduced to 20-30 ℃, the product (214.2 g,0.595 mol) of the first step in the example 5 is slowly added, the pH value of the system is ensured to be=0-2 after the addition, the reaction is carried out for 2 hours under constant temperature, the filtration and the washing with a small amount of water are carried out, and the p-chlorobenzaldehyde recovery (wet weight: 99.2g, content: 82.0%,0.578 mol) is obtained after pumping, the recovery rate is: 97.1%. Collecting filtrate, stirring at 20-30deg.C, slowly neutralizing with ammonia water to pH=5-7, stirring at constant temperature for crystallization for more than 1 hr, filtering, washing, draining to obtain wet product, and oven drying to obtain DL-threo-p-chlorobenzeneserine product (115.5 g, threo HPLC purity: more than 99.5%,0.536 mol), with molar yield of: 90.1%.
Example 8:
800g of drinking water is put into a proper reaction bottle equipped with mechanical stirring, 91g of concentrated sulfuric acid is added under stirring, the temperature is reduced to 20-30 ℃, after the product (233.7 g,0.649 mol) of the first step in the example 6 is slowly added, the pH value of the system is ensured to be=0-2, the reaction is carried out for 2 hours under constant temperature, filtration and washing with a small amount of water are carried out, and the p-chlorobenzaldehyde recovery product (wet weight: 117.3g, content: 74.7%,0.623 mol) is obtained after pumping, the recovery rate is: 96.0%. Collecting filtrate, stirring at 20-30deg.C, slowly neutralizing with ammonia water to pH=5-7, stirring at constant temperature for crystallization for more than 1 hr, filtering, washing, draining to obtain wet product, and oven drying to obtain DL-threo-p-chlorobenzeneserine product (124.4 g, threo purity > 99.5%,0.577 mol), with molar yield: 88.9%.
Comparative example 1 (US 3733352)
250mL of methanol solution, 15g (0.2 mol) of glycine and 12.21g of potassium hydroxide solid (content: 91.9%) are put into a proper reaction bottle equipped with mechanical stirring, stirred and dissolved, and the temperature is controlled between 10 and 13 ℃; then, 56.3g of p-chlorobenzaldehyde (0.4 mol) was added, followed by addition of 20g of anhydrous potassium carbonate, and the pH was found to be >14.0, followed by stirring at 10 to 13℃for 32 hours, then, the pH was adjusted to 0.5 with concentrated hydrochloric acid, methanol was removed under reduced pressure, and then, 150mL of water was added, and p-chlorobenzaldehyde (wet: 43.38g, content: 75.5%,0.23 mol) was recovered by filtration. The filtrate was neutralized with ammonia water to pH 5-7 to give a solid (note: neutralization to 3-4 according to patent information, not largely precipitated), and dried to give a DL-threo-p-chlorobenzeneserine finished product (21.81 g, threo purity: 81.6%; erythro purity: 15.7%, molar amount of threo product: 0.083mol, molar amount of erythro product: 0.016 mol), molar yield of threo product was: 41.3%.
The result of comparative example 1 shows that although the method of US3733352 can be applied to the synthesis of p-methylsulfonylbenzylserine, the yield and purity of threo product are significantly reduced when used for the synthesis of DL-threo-p-chlorophenylserine.

Claims (5)

1. The synthesis method of DL-threo-p-chlorophenylserine is characterized by comprising the following steps:
(1) Under the action of an alkali catalyst, performing condensation reaction on p-chlorobenzaldehyde and glycine, and separating to obtain a condensation intermediate solid;
in the step (1), the pH value of the condensation reaction is 12-14; the temperature of the condensation reaction is 35-70 ℃;
the reaction time is more than 10 hours;
in the step (1), the condensation reaction solvent is selected from methanol or a mixed solvent of methanol and water;
(2) The condensation intermediate solid obtained in the step (1) is subjected to decomposition reaction under the action of an acid catalyst, and after the reaction is finished, the DL-threo-p-chlorobenzeneserine is obtained through post-treatment;
in step (2), the acid catalyst is selected from sulfuric acid;
in the step (2), the decomposition reaction is carried out in water;
in the step (2), the post-treatment method comprises the following steps: adding alkali into the obtained filtrate to adjust the pH value to be 5-7 for crystallization operation, and then filtering, washing and drying to obtain DL-threo-p-chlorobenzeneserine product.
2. The method for synthesizing DL-threo-p-chloroserine according to claim 1, wherein in the step (1), the separation method is filtration.
3. The method for synthesizing DL-threo-p-chloroserine according to claim 1, wherein in step (1), the base catalyst is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.
4. The method for synthesizing DL-threo-p-chloroserine according to claim 1, wherein in the step (2), the pH of the decomposition reaction is 0 to 2.
5. The method for synthesizing DL-threo-p-chloroserine according to claim 1, wherein the alkali used for adjusting the pH value is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and ammonia water;
the crystallization temperature is 0-30 ℃.
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