CN116655481B - Industrial synthesis method of levocarnitine - Google Patents
Industrial synthesis method of levocarnitine Download PDFInfo
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- CN116655481B CN116655481B CN202310702693.8A CN202310702693A CN116655481B CN 116655481 B CN116655481 B CN 116655481B CN 202310702693 A CN202310702693 A CN 202310702693A CN 116655481 B CN116655481 B CN 116655481B
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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 27
- 229960001518 levocarnitine Drugs 0.000 title claims abstract description 27
- 238000001308 synthesis method Methods 0.000 title description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 10
- 239000004280 Sodium formate Substances 0.000 claims abstract description 8
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims abstract description 8
- 235000019254 sodium formate Nutrition 0.000 claims abstract description 8
- 239000000852 hydrogen donor Substances 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- AKDAXGMVRMXFOO-GSVOUGTGSA-N (3r)-4-chloro-3-hydroxybutanoic acid Chemical compound ClC[C@H](O)CC(O)=O AKDAXGMVRMXFOO-GSVOUGTGSA-N 0.000 claims abstract description 4
- 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 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000011347 resin Substances 0.000 claims description 18
- 229920005989 resin Polymers 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 14
- 125000002091 cationic group Chemical group 0.000 claims description 10
- 230000003287 optical effect Effects 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000006722 reduction reaction Methods 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 230000009466 transformation Effects 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- 238000010438 heat treatment Methods 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
- 239000008213 purified water Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000011403 purification operation Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000009987 spinning Methods 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 239000003638 chemical reducing agent Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 150000001768 cations Chemical class 0.000 description 4
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 4
- 230000006698 induction Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- IUNJCFABHJZSKB-UHFFFAOYSA-N 2,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1 IUNJCFABHJZSKB-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 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 2
- 239000013078 crystal Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- HOLGXWDGCVTMTB-UHFFFAOYSA-N 2-(2-aminophenyl)aniline Chemical compound NC1=CC=CC=C1C1=CC=CC=C1N HOLGXWDGCVTMTB-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 239000005703 Trimethylamine hydrochloride Substances 0.000 description 1
- HGHAGJPXZLUPQV-FYZOBXCZSA-N [(2r)-3-carboxy-2-hydroxypropyl]-trimethylazanium;hydroxide Chemical compound [OH-].C[N+](C)(C)C[C@H](O)CC(O)=O HGHAGJPXZLUPQV-FYZOBXCZSA-N 0.000 description 1
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000003426 co-catalyst Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229940078494 nickel acetate Drugs 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 description 1
- BJAARRARQJZURR-UHFFFAOYSA-N trimethylazanium;hydroxide Chemical compound O.CN(C)C BJAARRARQJZURR-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 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
-
- 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
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- 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
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- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Inorganic Chemistry (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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
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 1mol (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 732 type cation resin column into the reaction solution, controlling flow rate under the column to 5 ml/min, adding purified water into the resin column after the addition,controlling the flow rate under the column to be 10 ml/min, and ending when the pH value of the liquid discharged 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 (8)
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;
wherein, the structural general formula of the Ni catalyst in the step a) is as follows:
2. 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.
3. The method according to claim 2, characterized in that: the alcohol used in the post-treatment 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).
4. 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.
5. 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 4-chloroacetoacetic acid ethyl ester to the ethanol is 1mol (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.
6. The method according to claim 1, characterized in that: the cationic resin column in the step b) is 732 type cationic resin column.
7. 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 ℃.
8. 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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