CN116655481A - Industrial synthesis method of levocarnitine - Google Patents

Industrial synthesis method of levocarnitine Download PDF

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CN116655481A
CN116655481A CN202310702693.8A CN202310702693A CN116655481A CN 116655481 A CN116655481 A CN 116655481A CN 202310702693 A CN202310702693 A CN 202310702693A CN 116655481 A CN116655481 A CN 116655481A
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ethyl ester
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levocarnitine
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CN116655481B (en
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李强
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Hainan Zhuoke 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
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
    • B01J31/2243—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/84—Metals of the iron group
    • B01J2531/847—Nickel
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • 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

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  • Crystallography & Structural Chemistry (AREA)
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Abstract

The invention provides a method for industrially synthesizing levocarnitine, which takes a sodium formate/ethanol mixed system as a hydrogen donor and a novel Ni complex as a catalyst, efficiently and rapidly reduces raw material ethyl 4-chloroacetoacetate into (R) -4-chloro-3-hydroxybutyrate with an ee value of more than 99.0 percent, has a simple catalyst synthesis process, avoids using hydrogen as a reducing agent, does not need to be carried out under high-temperature and high-pressure conditions, has low equipment requirements, greatly reduces the production cost and has good industrial production application prospect.

Description

Industrial synthesis method of levocarnitine
Technical Field
The invention relates to the field of medicine synthesis, in particular to a method for industrially synthesizing levocarnitine.
Background
Levocarnitine, also known as l-carnitine, chemical name: (R) -3-carboxyl-2-hydroxy-N, N, N-trimethyl-1-propylammonium hydroxide inner salt with structural formula of
Levocarnitine is a nutrient of "retinoid" necessary for human metabolism, and is an amino acid widely existing in the human body. In humans, levocarnitine has two sources, one is taken from the diet and the other is endogenously synthesized, and levocarnitine is synthesized from lysine and methionine under the action of a series of liver enzymes. Levocarnitine has many clinical applications, for example, it has therapeutic or adjuvant therapeutic effects on patients suffering from levocarnitine deficiency, cardiovascular diseases, hyperlipidemia, dialysis, renal disease, cirrhosis, diabetes, etc. The synthesis method of the levocarnitine reported in the current literature comprises the following steps: 1) extraction, 2) biosynthesis, 3) chemical synthesis. Extraction and biosynthesis methods have difficulty in mass production due to the large number of steps of extraction and purification and low yield. Most manufacturers currently use chemical synthesis to prepare levocarnitine.
The method comprises the steps of (A) synthesizing (Shen Dadong, zhu Jintao) L- (-) -carnitine, taking epichlorohydrin as a starting raw material, carrying out kinetic resolution by using an (S) -Salen Co catalyst to obtain dextro epichlorohydrin, reacting with trimethylamine hydrochloride to obtain quaternary ammonium salt, reacting with sodium cyanide, and carrying out hydrolysis to obtain the levocarnitine. However, the method has the advantages of long process route, large equipment investment, strong danger, environment friendliness, difficult three-waste treatment, low yield and high manufacturing cost due to the fact that the method uses the highly toxic sodium cyanide and needs to be split.
CN102952028A discloses that 4-chloroacetoacetic acid ethyl ester is used as raw material, under the action of chiral catalyst { [ Ru (p-cymene) I (+) TMBTP ] I }, the (R) -4-chloro-3-hydroxybutyric acid ethyl ester is prepared by high temperature catalytic hydrogenation, and then reacted with trimethylamine water solution with mass fraction of 45% at high temperature 24 h to convert into levocarnitine. However, the { [ Ru (p-cymene) I (+) TMBTP ] I } chiral catalyst adopted by the method has no industrial production, the preparation process is complex, the cost is extremely high, the method is not suitable for industrial production, in addition, the reduction reaction uses hydrogen, the reduction reaction needs to be carried out under a high-temperature and high-pressure environment, and the equipment requirement is high and the danger is strong.
CN101875616a discloses that 4-chloroacetoacetic acid ethyl ester is used as a raw material, and is subjected to low-temperature hydrogenation reduction under the action of chiral catalyst L-tartaric acid modified Ni-B/SiO to obtain (R) -4-chloro-3-hydroxybutyric acid ethyl ester, and then reacted with trimethylamine with mass fraction of 33% to generate levocarnitine. However, this method has poor enantioselectivity, ethyl (R) -4-chloro-3-hydroxybutyrate has low purity, and hydrogen is used as well, and is required to be carried out under high pressure, and is highly required for equipment.
Aiming at the defects of the prior art, it is necessary to develop a method for synthesizing the levocarnitine, which has mild reaction conditions and is suitable for industrial production.
Disclosure of Invention
The invention aims to provide a method for industrially synthesizing levocarnitine.
In order to achieve the above purpose, the technical scheme adopted by the invention comprises the following steps:
a) Synthesis of ethyl (R) -4-chloro-3-hydroxybutyrate: 4-chloroacetoacetic acid ethyl ester is subjected to reduction reaction under the action of a hydrogen donor and a Ni catalyst to generate (R) -4-chloro-3-hydroxybutyric acid ethyl ester; the hydrogen donor is a sodium formate/ethanol mixed system, and the reaction formula is as follows:
b) Synthesis of levocarnitine: reacting (R) -4-chloro-3-hydroxybutyric acid ethyl ester with trimethylamine in the presence of alkali, adding dilute hydrochloric acid to regulate pH after the reaction, and purifying by adopting a cationic resin column to obtain levocarnitine;
in some embodiments, the Ni catalyst of step a) has the following structural formula:
in some embodiments, the post-processing of step a) comprises the steps of:
adding alcohol into the crude product of (R) -4-chloro-3-hydroxybutyric acid ethyl ester for heating and dissolving, then cooling to 0-10 ℃, adding the pure product of (R) -4-chloro-3-hydroxybutyric acid ethyl ester with the optical purity ee value of more than 99.0% for crystallization-induced asymmetric transformation, filtering and drying after crystallization to obtain the high-purity (R) -4-chloro-3-hydroxybutyric acid ethyl ester.
Preferably, the alcohol is selected from methanol or ethanol; the molar ratio of the ethyl 4-chloroacetoacetate to the (R) -4-chloro-3-hydroxybutyrate is 1 (0.01-0.02).
In some embodiments, the ethanol of step a) may be used as both a hydrogen donor and a reaction solvent, i.e., the reaction does not require additional addition of other organic solvents.
In some embodiments, in step a), the molar ratio of ethyl 4-chloroacetoacetate to Ni catalyst is 1 (0.1-0.2); the mol volume ratio of the ethyl 4-chloroacetoacetate to the ethanol is 1 mol (100-300 mL); the mol ratio of the 4-chloroacetoacetic acid ethyl ester to the sodium formate is 1 (1-1.2); the reaction temperature is 50-75 ℃, and the reaction time is 10-20 h.
In some embodiments, the base of step b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate. Sodium hydroxide is preferred.
In some embodiments, the cationic resin column of step b) is preferably a 732 type cationic resin column.
In some embodiments, the molar ratio of the ethyl (R) -4-chloro-3-hydroxybutyrate to trimethylamine in step b) is 1 (1.5-3.0); the mol ratio of the (R) -4-chloro-3-hydroxybutyric acid ethyl ester to the alkali is 1 (2.0-3.0); the reaction temperature is 0-30 ℃.
In some embodiments, step b) adjusts the pH to 6.
In some embodiments, the cationic resin column purification operation of step b) comprises:
adding the reaction solution into a cationic resin column, controlling the flow rate (5-10) ml/min under the column, adding purified water into the resin column after the addition, controlling the flow rate (10-20) ml/min under the column, and ending when the pH value of the discharged liquid under the column is 6; then dilute ammonia water is added, the flow rate (3-10) ml/min under the column is controlled, the liquid is started to be received when the pH value of the liquid discharged under the column is 7, the liquid is stopped to be received when the pH value is more than 8, the receiving liquid is combined, and the liquid is dried by spinning to obtain the white levocarnitine solid.
The invention has the following beneficial effects:
1) According to the invention, a sodium formate/ethanol mixed system is used as a hydrogen donor, a novel Ni complex is used as a catalyst, the raw material ethyl 4-chloroacetoacetate is efficiently and rapidly reduced into the (R) -4-chloro-3-hydroxybutyrate with an ee value of more than 99.0%, the catalyst preparation process is simple, the use of hydrogen as a reducing agent is avoided, the process is not required to be carried out under high temperature and high pressure conditions, the requirement on equipment is low, the production cost is greatly reduced, and the method has good industrial production prospect.
2) According to the invention, the (R) -4-chloro-3-hydroxybutyric acid ethyl ester pure product with the optical purity ee value more than 99.0% is added for crystallization induction asymmetric transformation, so that the optical purity of the product (R) -4-chloro-3-hydroxybutyric acid ethyl ester is greatly improved, and the post-treatment operation is simple and convenient.
Detailed Description
No endpoints of the ranges and any values recited herein are limited to the precise range or value, and such range or value should be understood to encompass values approaching those range or value. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
Step 1: synthesis of ligands
2, 4-dihydroxybenzaldehyde (290 g, 2.1 mol) and 2,2' -biphenyldiamine (184 g,1 mol) were added to methanol (200 mL), and the mixture was heated to 75℃to reflux for 6 hours. Cooled to room temperature, filtered and washed with methanol and dried in vacuo to afford the product 354.5 g as a pale yellow powder in 83.6% yield.
LC-MS (ESI): [M+H] + =425.3。
1 HNMR (500 MHz, DMSO-d 6 )：δ= 12.3 (s, 2H), 10.05(b, 2H), 8.61(s, 2H )，7.61-7.52 (m, 4H), 7.38- 7.29 (m, 4H), 7.05 (d, 2H), 6.55 (d, 2H)，6.21 (s, 2H)。
Step 2: synthesis of catalyst
The ligand (424.0 g,1.0 mol) prepared in step 1 above, nickel acetate (265.0 g, 1.5 mol) were added to methanol (300 mL), and the reaction was stirred at room temperature for 8 hours. After the reaction, the crude product is obtained by suction filtration, and then the crude product is separated and purified by silica gel column chromatography (the eluent is methylene dichloride and methanol (v/v) =8:1) to obtain 413.0g of yellow-green solid with the yield of 86.0 percent.
LC-MS (ESI): [M+H] + =481.4。
Examples
Ethyl 4-chloroacetoacetate (164.5 g,1.0 mol) was added to ethanol (200 mL), followed by sequential addition of the Ni catalyst prepared in example 1 (48.0 g, 0.1 mol), sodium formate (136.0 g,1 mol), and reaction was carried out at 60 ℃ for 15h. After the reaction, the mixture was filtered, water (300 mL) was added to the filtrate, chloroform (200 mL X3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude ethyl (R) -4-chloro-3-hydroxybutyrate, whose optical purity ee value was 73.1% as determined by gas chromatography.
Methanol (300) mL) is added into the crude product of the (R) -4-chloro-3-hydroxybutyric acid ethyl ester, heating is carried out for dissolution, then (R) -4-chloro-3-hydroxybutyric acid ethyl ester pure product (0.01 mol) with the optical purity ee value of 99.5% is added after the temperature is reduced to 10 ℃ for crystallization induction asymmetric transformation, crystals are separated out, and then the crystals are filtered and dried to obtain (R) -4-chloro-3-hydroxybutyric acid ethyl ester pure product 152.4 g with the yield of 91.5% and the optical purity ee value of 99.1%.
LC-MS (ESI): [M+H] + =167.7。
1 HNMR (500 MHz, CDCl 3 )：δ= 4.23 (q，2H), 4.33-4.16 (m，1H), 3.70 (d，2H), 3.3 (s，1H) ,2.70-2.61 (m，2H), 1.20 (t，3H)。
Sodium hydroxide (80.0 g,2.0 mol) was dissolved in 25% by mass aqueous trimethylamine (500 mL), then slowly added dropwise to a solution of ethyl (R) -4-chloro-3-hydroxybutyrate (166.5 g,1.0 mol) in chloroform (300 mL) at 0℃with a controlled dropping rate of 10 ml/min, followed by stirring at 0℃for 10 hours, then warmed to room temperature, and the reaction was continued for 20 hours. After the reaction, dilute hydrochloric acid is added to adjust the pH to 6, 732 type cation resin column is adopted for purification, and the operation is as follows:
adding the reaction solution into 732 type cation resin column, controlling flow rate under the column to be 5 ml/min, adding purified water into the resin column after the addition, controlling flow rate under the column to be 10 ml/min, and ending when pH value of discharged liquid under the column is 6; then adding 8% of diluted ammonia water by mass, controlling the flow rate under the column to be 4 ml/min, starting to receive when the pH value of the liquid discharged under the column is 7, stopping receiving when the pH value is more than 8, combining the receiving solutions, and spin-drying to obtain white levocarnitine solid 148.6 g, wherein the yield is 92.3%. The specific rotation was-30.8 ° (c=1, h 2 O)。
LC-MS (ESI): [M+H] + =162.3。
1 H NMR (500 MHz, D 2 O)：δ= 4.71-4.55 (m，1H), 3.60-3.48(d，2H), 3.31 (s，9H), 2.58-2.41 (dd，2H)。
Examples
Ethyl 4-chloroacetoacetate (164.5 g,1.0 mol) was added to ethanol (300 mL), followed by sequential addition of the Ni catalyst prepared in example 1 (72.0 g, 0.15 mol), sodium formate (204.0 g, 1.5 mol), and heating to 75 ℃ for reaction for 10h. After the reaction, the mixture was filtered, water (350. 350 mL) was added to the filtrate, chloroform (200. 200 mL X3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude ethyl (R) -4-chloro-3-hydroxybutyrate, whose optical purity ee value was 75.5% as measured by gas chromatography.
Methanol (400) mL) is added into the crude product of the (R) -4-chloro-3-hydroxybutyric acid ethyl ester, the temperature is raised for dissolution, then (R) -4-chloro-3-hydroxybutyric acid ethyl ester pure product (0.02 mol) with the optical purity ee value of 99.5% is added for crystallization induction asymmetric transformation after the temperature is reduced to 5 ℃, and the (R) -4-chloro-3-hydroxybutyric acid ethyl ester pure product 150.3 g with the yield of 90.3% and the optical purity ee value of 99.0% is obtained after the crystallization, filtration and drying.
LC-MS (ESI): [M+H] + =167.7。
1 HNMR (500 MHz, CDCl 3 )：δ= 4.23 (q，2H), 4.33-4.16 (m，1H), 3.70 (d，2H), 3.3 (s，1H) ,2.70-2.61 (m，2H), 1.20 (t，3H)。
Sodium hydroxide (80.0 g,2.0 mol) was dissolved in 25% by mass aqueous trimethylamine (500 mL), then slowly added dropwise to a solution of ethyl (R) -4-chloro-3-hydroxybutyrate (166.5 g,1.0 mol) in chloroform (300 mL) at 5℃with a controlled dropping rate of 5 ml/min, followed by stirring at 5℃for 15 hours, then warmed to room temperature, and the reaction was continued for 24 hours. After the reaction, dilute hydrochloric acid is added to adjust the pH to 6, 732 type cation resin column is adopted for purification, and the operation is as follows:
adding the reaction solution into 732 type cation resin column, controlling flow rate under the column to be 10 ml/min, adding purified water into the resin column after the addition, controlling flow rate under the column to be 15 ml/min, and ending when the pH value of the discharged liquid under the column is 6; then adding 8% of diluted ammonia water by mass, controlling the flow rate under the column to be 5 ml/min, starting to receive when the pH value of the liquid discharged under the column is 7, stopping receiving when the pH value is more than 8, combining the receiving solutions, and spin-drying to obtain white levocarnitine solid 147.3 g with the yield of 91.5%. The specific rotation was-30.9 ° (c=1, h 2 O)。
LC-MS (ESI): [M+H] + =162.3。
1 H NMR (500 MHz, D 2 O)：δ= 4.71-4.55 (m，1H), 3.60-3.48(d，2H), 3.31 (s，9H), 2.58-2.41 (dd，2H)。
The above examples are presented for clarity of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. And thus obvious variations or modifications to the disclosure are within the scope of the invention.

Claims (10)

1. A method for industrially synthesizing levocarnitine, which is characterized by comprising the following steps:
a) Synthesis of ethyl (R) -4-chloro-3-hydroxybutyrate: 4-chloroacetoacetic acid ethyl ester is subjected to reduction reaction under the action of a hydrogen donor and a Ni catalyst to generate (R) -4-chloro-3-hydroxybutyric acid ethyl ester; the hydrogen donor is a sodium formate/ethanol mixed system, and the reaction formula is as follows:
b) synthesis of levocarnitine: reacting (R) -4-chloro-3-hydroxybutyric acid ethyl ester with trimethylamine in the presence of alkali, adding dilute hydrochloric acid to regulate pH after the reaction, and purifying by adopting a cationic resin column to obtain levocarnitine;
3. the method according to claim 1, characterized in that: the structural general formula of the Ni catalyst in the step a) is as follows:
4. the method according to claim 1, characterized in that: the post-treatment of step a) comprises the steps of:
adding alcohol into the crude product of (R) -4-chloro-3-hydroxybutyric acid ethyl ester for heating and dissolving, then cooling to 0-10 ℃, adding the pure product of (R) -4-chloro-3-hydroxybutyric acid ethyl ester with the optical purity ee value of more than 99.0% for crystallization-induced asymmetric transformation, filtering and drying after crystallization to obtain the high-purity (R) -4-chloro-3-hydroxybutyric acid ethyl ester.
5. A method according to claim 3, characterized in that: the alcohol is selected from methanol or ethanol; the molar ratio of the ethyl 4-chloroacetoacetate to the (R) -4-chloro-3-hydroxybutyrate is 1 (0.01-0.02).
6. The method according to claim 1, characterized in that: the base in step b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
7. The method according to claim 1, characterized in that: in the step a), the mol ratio of the 4-chloroacetoacetic acid ethyl ester to the Ni catalyst is 1 (0.1-0.2); the mol volume ratio of the ethyl 4-chloroacetoacetate to the ethanol is 1 mol (100-300 mL); the mol ratio of the 4-chloroacetoacetic acid ethyl ester to the sodium formate is 1 (1-1.2); the reaction temperature is 50-75 ℃, and the reaction time is 10-20 h.
8. The method according to claim 1, characterized in that: the cationic resin column in the step b) is 732 type cationic resin column.
9. The method according to claim 1, characterized in that: the molar ratio of the (R) -4-chloro-3-hydroxybutyric acid ethyl ester to trimethylamine in the step b) is 1 (1.5-3.0); the mol ratio of the (R) -4-chloro-3-hydroxybutyric acid ethyl ester to the alkali is 1 (2.0-3.0); the reaction temperature is 0-30 ℃.
10. The method according to claim 1, characterized in that: the cationic resin column purification operation of step b) comprises:
adding the reaction solution into a cationic resin column, controlling the flow rate (5-10) ml/min under the column, adding purified water into the resin column after the addition, controlling the flow rate (10-20) ml/min under the column, and ending when the pH value of the discharged liquid under the column is 6; then dilute ammonia water is added, the flow rate (3-10) ml/min under the column is controlled, the liquid is started to be received when the pH value of the liquid discharged under the column is 7, the liquid is stopped to be received when the pH value is more than 8, the receiving liquid is combined, and the liquid is dried by spinning to obtain the white levocarnitine solid.
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