CN113735725A - Preparation method of L-carnitine - Google Patents
Preparation method of L-carnitine Download PDFInfo
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- CN113735725A CN113735725A CN202111138336.0A CN202111138336A CN113735725A CN 113735725 A CN113735725 A CN 113735725A CN 202111138336 A CN202111138336 A CN 202111138336A CN 113735725 A CN113735725 A CN 113735725A
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- trimethylamine
- carnitine
- ethyl acetate
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- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims abstract description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 6
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000003197 catalytic effect Effects 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical group [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 claims description 4
- 229910000367 silver sulfate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- ZAJNMXDBJKCCAT-RXMQYKEDSA-N ethyl (3r)-4-chloro-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@@H](O)CCl ZAJNMXDBJKCCAT-RXMQYKEDSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- BJAARRARQJZURR-UHFFFAOYSA-N trimethylazanium;hydroxide Chemical compound O.CN(C)C BJAARRARQJZURR-UHFFFAOYSA-N 0.000 claims 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract description 8
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003456 ion exchange resin Substances 0.000 abstract description 5
- 229920003303 ion-exchange polymer Polymers 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000011780 sodium chloride Substances 0.000 abstract description 4
- -1 halogen ions Chemical class 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract 1
- 238000002242 deionisation method Methods 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 3
- 238000005956 quaternization reaction Methods 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- WHUSTVAXKRFVPD-RXMQYKEDSA-N ethyl 2-[(2r)-oxiran-2-yl]acetate Chemical compound CCOC(=O)C[C@@H]1CO1 WHUSTVAXKRFVPD-RXMQYKEDSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000020989 red meat Nutrition 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/24—Synthesis of the oxirane ring by splitting off HAL—Y from compounds containing the radical HAL—C—C—OY
- C07D301/26—Y being hydrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
-
- 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
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a preparation method of L-carnitine, which takes R-4-chloro-3-hydroxy ethyl butyrate as a raw material, generates (2R) -2-ethylene oxide ethyl acetate through catalytic cyclization under an alkaline condition, and then generates a ring-opening reaction with trimethylamine to prepare the L-carnitine. The invention adopts the technical scheme of ring closure and then ring opening, avoids the step of removing halogen ions in ion exchange resin, is convenient to remove byproducts such as sodium chloride and the like, and reduces the production cost; simple operation, low production cost, high purity of target products and high yield, and is suitable for application in industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of L-carnitine.
Background
L-carnitine (also known as L-carnitine or transliteration carnitine) is an amino-like acid for promoting fat to be converted into energy, and red meat is a main source of the L-carnitine and has no toxic or side effect on human bodies. L-carnitine with CAS number 541-15-1 and structural formula
The synthesis method of L-carnitine mainly comprises three methods:
1. racemate resolution method. Using epichlorohydrin as an initial raw material, and performing quaternization, cyanation, alkaline hydrolysis, chiral separation and deionization to obtain the L-carnitine, as shown in the scheme (1) (Chinese patent CN 106748843B).
The sodium cyanide used in the method is a highly toxic compound, the resolution effect is poor, the byproduct dextro-carnitine is more than half, the deionization process is carried out in ion exchange resin, the cost is high, and the method is not suitable for large-scale production.
2. A biological enzyme method. Taking ethyl 4-chloroacetoacetate as a starting material, and obtaining L-carnitine through biological enzyme catalysis, quaternization, alkaline hydrolysis and deionization, as shown in a route (2) (Chinese patents CN103709058B, CN106947752A and the like).
The method has the advantages of high chiral purity of the product, mild reaction conditions and the like, but the preparation process of the biological enzyme used in catalysis is complex and the conditions are harsh; and the step 2 is ammonolysis reaction of the chloride, byproducts such as sodium chloride and the like are generated in the reaction process, ion exchange resin is needed in the deionization process, and the cost is high.
3. Chemical synthesis method. Similar to the second method, 4-chloroacetoacetic acid ethyl ester is used as a starting material, and the L-carnitine is obtained through catalytic reduction, quaternization, alkaline hydrolysis and deionization, as shown in a route (3) (Chinese patent CN104030934B, European patent EP0339764B 1).
The yield of the L-carnitine prepared by the method is only about 50%, the reaction conditions need high temperature and high pressure, the yield is lower, and the ion exchange resin used in the deionization process has higher cost and is obviously not suitable for industrial production.
Disclosure of Invention
Aiming at the technical problems, the invention aims to provide the preparation method of the L-carnitine, which has the advantages of simple process, lower cost, higher yield and purity of target products, reduction of solid wastes and environmental protection.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of L-carnitine comprises the following steps: taking R-4-chloro-3-hydroxy ethyl butyrate as a raw material, catalyzing and cyclizing to generate (2R) -2-ethylene oxide ethyl acetate under an alkaline condition, and then performing ring-opening reaction with trimethylamine to synthesize the L-carnitine, wherein the reaction route is as follows:
the method specifically comprises the following steps:
(1) preparation of (2R) -2-Oxirane Ethyl acetate (Compound C)
Putting R-4-chloro-3-hydroxy ethyl butyrate (compound D), alkali, a silver sulfate catalyst and an organic solvent into a reaction bottle, carrying out cyclization reaction for 10-40h at 10-40 ℃ under a stirring state, cooling (or heating) the mixture to room temperature after the reaction is finished, filtering to remove the catalyst, excessive unreacted alkali and chloride salt, and distilling at normal pressure to remove the organic solvent to obtain the (2R) -2-ethylene oxide ethyl acetate.
(2) Preparation of L-Carnitine (Compound A)
And (3) mixing the aqueous solution of trimethylamine with the compound C, controlling the temperature to be-5 ℃, stirring for reaction for 1 hour, then heating to 10-40 ℃, and continuously stirring for 10-26 hours to generate ring-opening reaction. And after the reaction is finished, carrying out reduced pressure distillation to remove excessive unreacted trimethylamine, then dropwise adding concentrated hydrochloric acid to adjust the pH value to 5-6, and then carrying out crystallization and purification to obtain white crystal L-carnitine.
In the step (1), the catalyst is silver sulfate;
in the step (1), the alkali is any one of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;
in the step (1), the organic solvent is any one of dichloromethane, tetrahydrofuran and acetonitrile;
in the step (1), the cyclization reaction time is 10-40h, and can be but is not limited to 10h, 15h, 20h, 24h, 30h, 35h and 40 h; the reaction temperature is 10-40 deg.C, but not limited to 10 deg.C, 15 deg.C, 20 deg.C, 25 deg.C, 30 deg.C, 35 deg.C, 40 deg.C;
in the step (1), the molar ratio of the R-4-chloro-3-hydroxybutanoic acid ethyl ester to the alkali is 1: 0.5-1.8.
In the step (2), the trimethylamine and the compound C are mixed in a manner that a trimethylamine aqueous solution is slowly dripped into the compound C at a temperature of-5 to 5 ℃;
in the step (2), the feeding molar ratio of the compound C to the compound B is 1: 1.5-2.5, preferably 1:2, but can be not limited to 1:1.5, 1:1.8, 1:2, 1: 2.5;
in the step (2), the mass concentration of trimethylamine in the trimethylamine aqueous solution is 10-30%, preferably 20%.
Compared with the prior art, the invention has the beneficial effects that:
(1) the preparation method adopts the technical scheme of firstly cyclizing and then opening the ring, avoids the deionization process in the traditional process, is convenient for removing by-products such as sodium chloride and the like, thereby saving the step of removing halogen ions in ion exchange resin and reducing the production cost;
(2) the preparation method of the invention does not need special process conditions, has simple operation and low production cost, and is suitable for being applied to industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention will be 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 derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
(1) Preparation of (2R) -2-Oxirane Ethyl acetate (Compound C)
Ethyl R-4-chloro-3-hydroxybutyrate (0.1mol, 16.7g), sodium carbonate (0.11mol, 11.7g), silver sulfate (catalytic amount) and dichloromethane (20mL) were put into a reaction flask, the reaction temperature was 25 ℃, a cyclization reaction was carried out for 24 hours under stirring, after the reaction was completed, the mixture was cooled to room temperature, the catalyst and excess unreacted sodium carbonate and sodium chloride were removed by filtration, and dichloromethane was removed by atmospheric distillation to obtain 12.2g of ethyl (2R) -2-oxiraneacetate (theoretical value: 13g, yield: 93.8%).
(2) Preparation of L-Carnitine (Compound A)
At 0 ℃, a 20% trimethylamine (0.2mol, 59.1g) water solution is slowly dropped into the compound C (0.1mol, 13.0g), the temperature is controlled at 0 ℃, the reaction is stirred for 1 hour, the temperature is raised to 25 ℃, the stirring is continued, and the reaction is carried out for 14 hours. After the reaction is finished, the excessive unreacted trimethylamine is removed by reduced pressure distillation, concentrated hydrochloric acid is added dropwise to adjust the pH value to be 5-6, and then crystallization and purification are carried out, so that 15.5g of white crystal L-carnitine is obtained (the theoretical value is 16.1g, and the yield is 96.3%).
The total yield of the two-step reaction is 90.3%, and the purity of the L-carnitine is 99.3%.
The specific adding mode of trimethylamine in the step (2) is not particularly limited, and the trimethylamine is added dropwise by adopting a adding mode known by persons skilled in the art according to the production scale of the reagent, and the internal temperature of the mixed solution is ensured not to exceed 0 +/-3 ℃.
Examples 2 to 13
Only the feed ratio or other conditions in step (1) were changed separately in the manner disclosed in example 1 and detailed in table 1.
Note: the white portion in the table represents that the conditions are the same as in example 1.
TABLE 1 reaction conditions and results for step (1) which differ
Examples 14 to 22
Only the feed ratio or other conditions in step (2) were changed separately in the manner disclosed in example 1 and detailed in table 2.
Note: the white portion in the table represents that the conditions are the same as in example 1.
TABLE 2 different reaction conditions and results of step (2)
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A preparation method of L-carnitine is characterized in that: the L-carnitine is prepared by using R-4-chloro-3-hydroxy ethyl butyrate as a raw material, performing catalytic cyclization under an alkaline condition to generate (2R) -2-ethylene oxide ethyl acetate, and performing ring-opening reaction with trimethylamine.
2. The method of claim 1, comprising the steps of:
(1) putting R-4-chloro-3-hydroxy ethyl butyrate, alkali, a catalyst and an organic solvent into a reaction bottle, carrying out catalytic cyclization reaction under a stirring state, cooling or heating the mixture to room temperature after the reaction is finished, filtering, and distilling at normal pressure to obtain (2R) -2-ethylene oxide ethyl acetate;
(2) mixing the aqueous solution of trimethylamine with (2R) -2-epoxyethane ethyl acetate, controlling the temperature, stirring for reaction for 1 hour, then heating and continuing stirring to enable the mixture to carry out ring-opening reaction; after the reaction is finished, carrying out reduced pressure distillation, adjusting the pH value, crystallizing and purifying to obtain the L-carnitine.
3. The method of claim 2, wherein the method comprises the steps of: in the step (1), the catalyst is silver sulfate; the alkali is any one of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; the organic solvent is any one of dichloromethane, tetrahydrofuran and acetonitrile.
4. The method of claim 2, wherein the method comprises the steps of: the molar ratio of the R-4-chloro-3-hydroxybutanoic acid ethyl ester to the alkali is 1: 0.5-1.8.
5. The method of claim 2, wherein the method comprises the steps of: in the step (1), the cyclization reaction time is 10-40 h; the reaction temperature is 10-40 ℃.
6. The method of claim 5, wherein the L-carnitine is prepared by: in the step (1), the cyclization reaction time is 24 h; the reaction temperature was 25 ℃.
7. The method of claim 2, wherein the method comprises the steps of: in the step (2), the trimethylamine and the (2R) -2-ethylene oxide ethyl acetate are mixed in a manner that a trimethylamine water solution is slowly dripped into the (2R) -2-ethylene oxide ethyl acetate at the temperature of-5 to 5 ℃.
8. The method of claim 2, wherein the method comprises the steps of: in the step (2), the feeding molar ratio of (2R) -2-ethylene oxide ethyl acetate to trimethylamine is 1: 1.5-2.5; the mass concentration of trimethylamine in the trimethylamine aqueous solution is 10-30%.
9. The method of claim 8, wherein the method comprises: in the step (2), the feeding molar ratio of (2R) -2-ethylene oxide ethyl acetate to trimethylamine is 1: 2; the mass concentration of trimethylamine in the trimethylamine aqueous solution is 20%.
10. The method of claim 2, wherein the method comprises the steps of: the reaction condition of the step (2) is that after the reaction is carried out for 1 hour at the temperature of minus 5 to 5 ℃, the temperature is increased to 10 to 40 ℃ and the reaction is carried out for 10 to 26 hours.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007108572A1 (en) * | 2006-03-22 | 2007-09-27 | Enzytech, Ltd. | Process for l-carnitine |
| CN102442927A (en) * | 2011-10-17 | 2012-05-09 | 黄冈华阳药业有限公司 | Preparation method of atorvastatin intermediate (R)-(-)-4-(cyano)-3-butyl hydroxyacetate |
| CN102952028A (en) * | 2011-08-16 | 2013-03-06 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of L-carnitine and its intermediate |
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