CN115057791A - Industrial preparation method of levocarnitine - Google Patents
Industrial preparation method of levocarnitine Download PDFInfo
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- CN115057791A CN115057791A CN202210765087.6A CN202210765087A CN115057791A CN 115057791 A CN115057791 A CN 115057791A CN 202210765087 A CN202210765087 A CN 202210765087A CN 115057791 A CN115057791 A CN 115057791A
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- 229960001518 levocarnitine Drugs 0.000 title claims abstract description 81
- 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 75
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- -1 alkali metal salt Chemical class 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 23
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 19
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 19
- 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 claims abstract description 13
- 239000003729 cation exchange resin Substances 0.000 claims abstract description 13
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 12
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 52
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 238000001816 cooling Methods 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 239000003480 eluent Substances 0.000 claims description 20
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 12
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 12
- 238000000909 electrodialysis Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000002386 leaching Methods 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 238000010612 desalination reaction Methods 0.000 claims description 10
- 238000001291 vacuum drying Methods 0.000 claims description 10
- 235000010288 sodium nitrite Nutrition 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 239000005819 Potassium phosphonate Substances 0.000 claims description 3
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 3
- YXXXKCDYKKSZHL-UHFFFAOYSA-M dipotassium;dioxido(oxo)phosphanium Chemical compound [K+].[K+].[O-][P+]([O-])=O YXXXKCDYKKSZHL-UHFFFAOYSA-M 0.000 claims description 3
- 235000010289 potassium nitrite Nutrition 0.000 claims description 3
- 239000004304 potassium nitrite Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000007670 refining Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- NCPXQVVMIXIKTN-UHFFFAOYSA-N trisodium;phosphite Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])[O-] NCPXQVVMIXIKTN-UHFFFAOYSA-N 0.000 claims description 2
- 238000003795 desorption Methods 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 238000004321 preservation Methods 0.000 description 16
- 238000001514 detection method Methods 0.000 description 12
- 238000011068 loading method Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000010828 elution Methods 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 238000005070 sampling Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229960004203 carnitine Drugs 0.000 description 2
- 238000002242 deionisation method Methods 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 206010058892 Carnitine deficiency Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000235527 Rhizopus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- HGHAGJPXZLUPQV-FYZOBXCZSA-N [(2r)-3-carboxy-2-hydroxypropyl]-trimethylazanium;hydroxide Chemical group [OH-].C[N+](C)(C)C[C@H](O)CC(O)=O HGHAGJPXZLUPQV-FYZOBXCZSA-N 0.000 description 1
- MIOPJNTWMNEORI-OMNKOJBGSA-N [(4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-OMNKOJBGSA-N 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 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
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 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
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 208000016505 systemic primary carnitine deficiency disease Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
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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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- 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
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0239—Quaternary ammonium compounds
-
- 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
- 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
-
- 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
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
- B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to an industrial preparation method of levocarnitine. Adding alkali metal salt into the compound shown in the formula 2, adsorbing by cation exchange resin, and desorbing by ammonia water to obtain the compound shown in the formula 3. Compared with the prior art, the technical scheme of the invention can fully carry out the reaction, the reaction is thorough, no raw material is left, and the common impurity A in the preparation process of the levocarnitine is effectively removed, so that the finished levocarnitine product with high yield and high purity can be obtained, the yield can reach 99%, and the purity can reach 100%. In addition, the method has simple process and low cost of related raw materials, and can generate good economic benefit in industrial application.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to an industrial preparation method of levocarnitine.
Background
L-carnitine is also called L-carnitine, the chemical name is (R) -3-carboxyl-2-hydroxyl-N, N, N-trimethyl-1-propyl ammonium hydroxide inner salt, and the molecular formula is C 7 H 15 NO 3 Molecular weight of 161.2, and its chemical formula is as follows:
is discovered for the first time in meat extract by Russian chemists Gulewitsch and Krimberg in 1905, belongs to the vitamin class, and is widely present in animals, plants and microorganisms. Levocarnitine is mainly applied to (1) a series of complications of chronic renal failure long-term hemodialysis patients caused by carnitine deficiency, such as cardiomyopathy, skeletal myopathy, arrhythmia, hyperlipidemia, hypotension, dialysis muscle spasm and the like; (2) can be used together with erythropoietin for treating uremia anemia, and can be used for the adjuvant treatment of coronary atherosclerotic heart disease, angina pectoris, myocardial infarction, myocarditis, cardiac insufficiency, shock, ischemic cerebrovascular diseases, hepatitis, liver cirrhosis, diabetes, etc.; (3) and others: it also has therapeutic effect on infantile metabolic diseases, weight gain disorder, fatigue, obesity, etc.
The production method of the levocarnitine mainly comprises the following four steps: (1) and (4) an extraction method. Naturally occurring in various meats and milks, and thus can be extracted directly from beef and milk, however, the extraction process is costly and economically not reasonable. (2) A microbial fermentation method. Research shows that levocarnitine also exists in many microorganisms, and can be accumulated by submerged culture or solid fermentation of yeast, aspergillus, penicillium, rhizopus and other microorganisms. However, the screening work of the strains is more complicated, and the current fermentation level is lower. (3) A synthetic method. US4070394 is an earlier patent published in 1978 on epichlorohydrin as a starting material for the preparation of racemic carnitine by ammoniation, acidification, cyanation, hydrolysis and deionization. U.S. Pat. No. 3,3151149 uses D- (+) -camphorsulfonic acid and dibenzoyl-D-tartaric acid to resolve DL-carnitine, JP59231048A uses (-) -mandelic acid, and U.S. Pat. No. 4,493,3490 and DE3536093 use dibenzoyl-L-tartaric acid to resolve racemic carnitine to obtain levocarnitine. Although the method has low cost, the method uses the virulent sodium cyanide, and does not meet the current advocated development of green chemistry. Bellamy.F.D. et al (Tetrahedron Letters, 1990, 31 (50): 7323-. The method has a long route, and the D-malic acid is expensive and is not suitable for industrial amplification. (4) A biological enzyme method. 4-chloroacetoacetic acid ethyl ester is used as an initial raw material, and the levocarnitine is obtained through biological enzyme catalysis, quaternization, alkaline hydrolysis and deionization. The reaction process is simple and short, the product has high chiral purity, the reaction condition is friendly, the operation is easy, and the method has good industrial prospect. However, according to the disclosure of CN109053479B, the yield obtained by this method can only reach 88.7%, and the impurity a related to levocarnitine still remains.
Therefore, it is necessary to develop a method for preparing levocarnitine with high yield and high purity.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides an industrial preparation method of levocarnitine, which is characterized in that alkali metal salt is added into a compound in a formula 2, the compound is adsorbed by cation exchange resin and desorbed by ammonia water to obtain a compound in a formula 3 of the levocarnitine,
further, it comprises the following steps:
1) under the alkaline condition, mixing a trimethylamine aqueous solution and a dioxane solution of the compound shown in the formula 1, and then adding tetrabutylammonium bromide to fully react to obtain a compound shown in the formula 2;
2) adding alkali metal salt into the compound of the formula 2 obtained in the previous step, adsorbing by cation exchange resin, and desorbing by ammonia water to obtain a compound of a formula 3 of levocarnitine;
3) refining the crude product in an ethanol/acetone system to obtain a pure levocarnitine compound shown in the formula 3.
The reaction route is as follows:
note: the compound shown in the formula 1 is (R) -4-chloro-3-hydroxy ethyl butyrate, the compound shown in the formula 2 is an intermediate 2, and the compound shown in the formula 3 is levocarnitine. The subsequent abbreviation is not described further
Preferably, the alkaline condition in step 1) is NaOH solution or KOH solution, and more preferably NaOH solution; the concentration of the trimethylamine aqueous solution is 30 percent;
preferably, the reaction temperature in the step 1) is controlled to be-5 ℃, further preferably, the reaction temperature in the step 1) is controlled to be 0-5 ℃, and most preferably, the reaction temperature in the step 1) is 5 ℃;
preferably, the reaction time of the step 1) is controlled to be 1.5-4 h, and further preferably, the reaction time of the step 1) is 2 h;
preferably, the molar charge ratio of trimethylamine to compound of formula 1 in step 1) is (4.6-6.1):1, more preferably, the molar charge ratio of trimethylamine to compound of formula 1 is (5.1-5.6):1, and most preferably, the molar charge ratio of trimethylamine to compound of formula 1 is 5.3: 1;
preferably, the molar ratio of tetrabutylammonium bromide to the compound of formula 1 in step 1) is (0.005-0.05):1, more preferably 0.01: 1;
preferably, after the reaction in step 1) is completed, the method further comprises a post-treatment process, specifically as follows: and (3) carrying out reduced pressure concentration at 5-15 ℃, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH to 5-6, adding dichloromethane, extracting and layering, collecting a water layer, and carrying out electrodialysis desalination.
Preferably, the alkali metal salt in step 2) is selected from one or a mixture of more than two of sodium nitrite, potassium nitrite, sodium phosphite, potassium phosphite, sodium thiosulfate and sodium metabisulfite, and further preferably, the alkali metal salt in step 2) is sodium nitrite;
preferably, the molar ratio of the alkali metal salt to the compound of formula 2 in step 2) is (0.5-0.7) to 1, and more preferably, the molar ratio of the alkali metal salt to the compound of formula 2 is 0.5: 1;
preferably, the concentration of the ammonia water used in the step 2) is 10-15%, and is preferably 12.5%; desorbing ammonia water in the step 2) to obtain the levocarnitine compound in the formula 3, specifically, desorbing the ammonia water to obtain an eluent, concentrating the eluent at 75-80 ℃ under reduced pressure until the pH of the system is 7-8, and cooling to 15-25 ℃ to obtain the levocarnitine compound in the formula 3.
Preferably, the refining in step 3) comprises the following operations: adding absolute ethyl alcohol into the levocarnitine compound of the formula 3, heating to 60-65 ℃, dissolving the system to be clear, slowly cooling to 20-30 ℃, slowly dripping acetone into the system, slowly cooling to 0-10 ℃ after dripping, keeping the temperature, crystallizing for 1-3 hours, filtering in three ways, leaching with acetone, and drying in vacuum at 45-55 ℃ to obtain a pure levocarnitine compound of the formula 3.
Further, the invention provides a detection method of levocarnitine, which comprises the following steps:
performing high performance liquid chromatography with silica gel as filler, column temperature of 40 deg.C, detection wavelength of 205nm, flow rate of 1.0ml/min, sample injection volume of 20ul, and ammonium acetate (pH 5) of 0.77 g/L: and the mobile phase is ACN 25:75, and the elution is carried out at the same temperature for 30 min. According to the HPLC detection method provided above, the finally synthesized levocarnitine is used as a test sample, and the content of the levocarnitine and the content of impurities such as impurity A can be detected.
The technical scheme of the invention has the following beneficial effects:
compared with the prior art, the technical scheme of the invention adds the phase transfer catalyst tetrabutylammonium bromide, promotes the quaternization reaction and fully performs the reaction. In addition, alkali metal salt is introduced for cation exchange, so that common impurity A in the preparation process of the levocarnitine is effectively removed, and a levocarnitine finished product with high yield and high purity is obtained, wherein the yield can reach 99%, and the purity can reach 100%. The invention has simple process and low cost of related raw materials, and can generate good economic benefit in industrialized application.
Drawings
FIG. 1 is an HPLC analytical profile of L-carnitine prepared according to the method described in example 1.
FIG. 2 is an HPLC analytical profile of L-carnitine prepared according to the method described in example 4.
Detailed Description
For better understanding of the technical solutions of the present invention, the technical solutions of the present invention are further described below with reference to specific examples, which are only for the purpose of facilitating understanding of the present invention and should not be construed as specifically limiting the present invention.
Example 1: preparation of levocarnitine
36.48g of sodium hydroxide and 685.44g of water are respectively added into a reaction kettle, stirring is started, the temperature is reduced to 5 ℃, 179.52g of trimethylamine aqueous solution (30%) is dropwise added into the system, after the addition is finished, 95.47g of the compound shown in the formula 1 is slowly dropwise added into the system, and after the addition is finished, the reaction is carried out for 2 hours at the temperature of 5 ℃. And (3) after the reaction is finished, performing reduced pressure concentration at 5-15 ℃ to remove trimethylamine, after the concentration is finished, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH of the system to 5-6, adding dichloromethane into the system for extraction and layering, collecting a water layer, and performing electrodialysis desalination to obtain the compound shown in the formula 2. And (3) loading cation exchange resin into the chromatographic column, loading the compound shown in the formula 2, washing with purified water until the pH of an effluent is 6-7, adding 12.5% ammonia water for elution, collecting an eluent, concentrating at 75-80 ℃ under reduced pressure until the pH of the system is 7-8, and cooling to 15-25 ℃ to obtain the levocarnitine. Adding 209.10g of absolute ethyl alcohol into the levocarnitine, heating to 60-65 ℃, dissolving the system to be clear, slowly cooling to 20-30 ℃, slowly dripping 627.30g of acetone into the system, slowly cooling to 0-10 ℃ after dripping, carrying out heat preservation and crystallization for 1-3 hours, carrying out three-in-one filtration, leaching with 34.85g of acetone, and carrying out vacuum drying at 45-55 ℃ to obtain a pure levocarnitine product, wherein the yield is 85%, and the purity of the levocarnitine is 99.13% and the impurity A is 0.87% through HPLC detection. HPLC integration data are shown in table 1 below:
TABLE 1
| Retention time (min) | Peak area | Percentage of Peak area (%) | Peak width (min) | Peak height |
| 9.734 | 4264.948 | 99.13 | 1.57 | 267.87 |
| 11.297 | 37.585 | 0.87 | 0.96 | 2.22 |
Example 2: preparation of levocarnitine
36.48g of sodium hydroxide and 685.44g of water are respectively added into a reaction kettle, stirring is started, the temperature is reduced to 5 ℃, 179.52g of trimethylamine aqueous solution (30%) is dropwise added into the system, after the addition is finished, 95.47g of the compound shown in the formula 1 is slowly dropwise added into the system, and after the addition is finished, the reaction is carried out for 2 hours at the temperature of 5 ℃. And (3) after the reaction is finished, performing reduced pressure concentration at 5-15 ℃ to remove trimethylamine, after the concentration is finished, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH of the system to 5-6, adding dichloromethane into the system for extraction and layering, collecting a water layer, and performing electrodialysis desalination to obtain the compound shown in the formula 2. And (3) loading cation exchange resin into the chromatographic column, adding 12.83g of sodium nitrite into the compound shown in the formula 2 for sampling, washing with purified water until the pH of an effluent is 6-7, adding 12.5% ammonia water for elution, collecting an eluent, concentrating the eluent at 75-80 ℃ under reduced pressure until the pH of the system is 7-8, and cooling to 15-25 ℃ to obtain the levocarnitine. Adding 209.10g of absolute ethyl alcohol into the levocarnitine, heating to 60-65 ℃, dissolving the system to be clear, slowly cooling to 20-30 ℃, slowly dropwise adding 627.30g of acetone into the system, slowly cooling to 0-10 ℃ after dropping, carrying out heat preservation and crystallization for 1-3 hours, carrying out three-in-one filtration, leaching with 34.85g of acetone, and carrying out vacuum drying at 45-55 ℃ to obtain a pure levocarnitine product, wherein the yield is 77%, the purity of the levocarnitine is 100% through HPLC detection, and no impurity A is detected.
Example 3: preparation of levocarnitine
36.48g of sodium hydroxide and 685.44g of water are respectively added into a reaction kettle, stirring is started, the temperature is reduced to 5 ℃, 179.52g of trimethylamine aqueous solution (30%) is dropwise added into the system, after the addition is finished, 95.47g of the compound shown in the formula 1 is slowly dropwise added into the system, 1.85g of tetrabutylammonium bromide is added, and the heat preservation reaction is carried out for 2 hours at the temperature of 5 ℃. And (3) after the reaction is finished, performing reduced pressure concentration at 5-15 ℃ to remove trimethylamine, after the concentration is finished, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH of the system to 5-6, adding dichloromethane into the system for extraction and layering, collecting a water layer, and performing electrodialysis desalination to obtain the compound shown in the formula 2. And (2) loading cation exchange resin into the chromatographic column, loading the compound shown in the formula 2, washing with purified water until the pH of an effluent is 6-7, adding 12.5% ammonia water for elution, collecting an eluent, concentrating under reduced pressure at 75-80 ℃, concentrating until the pH of the system is 7-8, and cooling to 15-25 ℃ to obtain the levocarnitine. Adding 209.10g of absolute ethyl alcohol into the levocarnitine, heating to 60-65 ℃, dissolving the system to be clear, slowly cooling to 20-30 ℃, slowly dripping 627.30g of acetone into the system, slowly cooling to 0-10 ℃ after dripping, carrying out heat preservation and crystallization for 1-3 hours, carrying out three-in-one filtration, leaching with 34.85g of acetone, and carrying out vacuum drying at 45-55 ℃ to obtain a pure levocarnitine product, wherein the yield is 96%, and the purity of the levocarnitine is 98.7% and the impurity A is 1.3% through HPLC detection.
Example 4: preparation of levocarnitine
36.48kg of sodium hydroxide and 685.44kg of water are respectively added into a reaction kettle, stirring is started, the temperature is reduced to 5 ℃, 179.52kg of trimethylamine aqueous solution (30%) is dropwise added into the system, 96.00kg of the compound shown in the formula 1 is slowly dropwise added into the system after the addition, 1.86kg of tetrabutylammonium bromide is simultaneously added, and the heat preservation reaction is carried out for 2 hours at the temperature of 5 ℃. And (3) after the reaction is finished, performing reduced pressure concentration at 5-15 ℃ to remove trimethylamine, after the concentration is finished, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH of the system to 5-6, adding dichloromethane into the system for extraction and layering, collecting a water layer, and performing electrodialysis desalination to obtain the compound shown in the formula 2. And (2) loading cation exchange resin into a chromatographic column, adding 16.58kg of sodium nitrite into the compound shown in the formula 2 for sampling, washing with purified water until the pH of an effluent liquid is 6-7, adding 12.5% ammonia water for elution, collecting an eluent, concentrating the eluent at 75-80 ℃ under reduced pressure until the pH of a system is 7-8, and cooling to 15-25 ℃ to obtain the levocarnitine. Adding 209.10kg of absolute ethyl alcohol into the levocarnitine, heating to 60-65 ℃, dissolving the system to be clear, slowly cooling to 20-30 ℃, slowly dripping 627.30kg of acetone into the system, slowly cooling to 0-10 ℃ after dripping, carrying out heat preservation and crystallization for 1-3 hours, carrying out three-in-one filtration, leaching with 34.85kg of acetone, and carrying out vacuum drying at 45-55 ℃ to obtain a pure levocarnitine product, wherein the yield is 99%, the purity of the levocarnitine is 100% through HPLC detection, and no impurity A is detected. HPLC integration data are shown in table 2 below:
TABLE 2
| Retention time (min) | Peak area | Percentage of Peak area (%) | Peak width (min) | Peak height |
| 7.847 | 4266.159 | 100.00 | 1.66 | 354.14 |
Example 5: preparation of levocarnitine
36.48g of potassium hydroxide and 685.44g of water are respectively added into a reaction kettle, stirring is started, the temperature is reduced to 0 ℃, 179.52g of trimethylamine aqueous solution (30%) is dropwise added into the system, after the addition is finished, 95.47g of the compound shown in the formula 1 is slowly dropwise added into the system, 1.85g of tetrabutylammonium bromide is added, and the heat preservation reaction is carried out for 2 hours at the temperature of 0 ℃. And (3) after the reaction is finished, performing reduced pressure concentration at 5-15 ℃ to remove trimethylamine, after the concentration is finished, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH of the system to 5-6, adding dichloromethane into the system for extraction and layering, collecting a water layer, and performing electrodialysis desalination to obtain the compound shown in the formula 2. And (2) loading cation exchange resin into a chromatographic column, adding 16.5g of sodium nitrite into the compound shown in the formula 2 for sampling, washing with purified water until the pH of an effluent liquid is 6-7, adding 12.5% ammonia water for elution, collecting an eluent, concentrating the eluent at 75-80 ℃ under reduced pressure until the pH of a system is 7-8, and cooling to 15-25 ℃ to obtain the levocarnitine. Adding 209.10g of absolute ethyl alcohol into the levocarnitine, heating to 60-65 ℃, dissolving the system to be clear, slowly cooling to 20-30 ℃, slowly dropwise adding 627.30g of acetone into the system, slowly cooling to 0-10 ℃ after dropping, carrying out heat preservation and crystallization for 1-3 hours, carrying out three-in-one filtration, leaching with 34.85g of acetone, and carrying out vacuum drying at 45-55 ℃ to obtain a pure levocarnitine product, wherein the yield is 97%, the purity of the levocarnitine is 100% by HPLC (high performance liquid chromatography) detection, and no impurity A is detected.
Example 6: preparation of levocarnitine
36.48g of sodium hydroxide and 685.44g of water are respectively added into a reaction kettle, stirring is started, the temperature is reduced to 5 ℃, 179.52g of trimethylamine aqueous solution (30%) is dropwise added into the system, after the addition is finished, 95.47g of the compound shown in the formula 1 is slowly dropwise added into the system, 1.85g of tetrabutylammonium bromide is added, and the heat preservation reaction is carried out for 2 hours at the temperature of 5 ℃. And (3) after the reaction is finished, performing reduced pressure concentration at 5-15 ℃ to remove trimethylamine, after the concentration is finished, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH of the system to 5-6, adding dichloromethane into the system for extraction and layering, collecting a water layer, and performing electrodialysis desalination to obtain the compound shown in the formula 2. And (2) loading cation exchange resin into a chromatographic column, adding 17.88g of potassium nitrite into the compound shown in the formula 2 for sampling, washing with purified water until the pH of an effluent liquid is 6-7, adding 12.5% ammonia water for elution, collecting an eluent, concentrating the eluent at 75-80 ℃ under reduced pressure until the pH of a system is 7-8, and cooling to 15-25 ℃ to obtain the levocarnitine. Adding 209.10g of absolute ethyl alcohol into the levocarnitine, heating to 60-65 ℃, dissolving the system to be clear, slowly cooling to 20-30 ℃, slowly dropwise adding 627.30g of acetone into the system, slowly cooling to 0-10 ℃ after dropping, carrying out heat preservation and crystallization for 1-3 hours, carrying out three-in-one filtration, leaching with 34.85g of acetone, and carrying out vacuum drying at 45-55 ℃ to obtain a pure levocarnitine product with the yield of 87%, wherein the purity of the levocarnitine is 100% through HPLC detection, and no impurity A is detected.
Example 7: preparation of levocarnitine
36.48g of sodium hydroxide and 685.44g of water are respectively added into a reaction kettle, stirring is started, the temperature is reduced to 5 ℃, 179.52g of trimethylamine aqueous solution (30%) is dropwise added into the system, after the addition is finished, 95.47g of the compound shown in the formula 1 is slowly dropwise added into the system, 1.85g of tetrabutylammonium bromide is added, and the heat preservation reaction is carried out for 2 hours at the temperature of 5 ℃. And (3) after the reaction is finished, performing reduced pressure concentration at 5-15 ℃ to remove trimethylamine, after the concentration is finished, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH of the system to 5-6, adding dichloromethane into the system for extraction and layering, collecting a water layer, and performing electrodialysis desalination to obtain the compound shown in the formula 2. And (3) loading cation exchange resin into the chromatographic column, adding 35.53g of potassium phosphite into the compound shown in the formula 2 for sampling, washing with purified water until the pH of an effluent is 6-7, adding 12.5% ammonia water for elution, collecting an eluent, concentrating the eluent at 75-80 ℃ under reduced pressure until the pH of the system is 7-8, and cooling to 15-25 ℃ to obtain the levocarnitine. Adding 209.10g of absolute ethyl alcohol into the levocarnitine, heating to 60-65 ℃, dissolving the system to be clear, slowly cooling to 20-30 ℃, slowly dripping 627.30g of acetone into the system, slowly cooling to 0-10 ℃ after dripping, carrying out heat preservation and crystallization for 1-3 hours, carrying out three-in-one filtration, leaching with 34.85g of acetone, and carrying out vacuum drying at 45-55 ℃ to obtain a pure levocarnitine product with the yield of 93%, wherein the purity of the levocarnitine is 99.66% and the impurity A is 0.34% through HPLC detection.
Example 8: preparation of levocarnitine
36.48g of sodium hydroxide and 685.44g of water are respectively added into a reaction kettle, stirring is started, the temperature is reduced to 5 ℃, 179.52g of trimethylamine aqueous solution (30%) is dropwise added into the system, after the addition is finished, 95.47g of the compound shown in the formula 1 is slowly dropwise added into the system, 7.39g of tetrabutylammonium bromide is added, and the heat preservation reaction is carried out for 2 hours at the temperature of 5 ℃. And (3) after the reaction is finished, performing reduced pressure concentration at 5-15 ℃ to remove trimethylamine, after the concentration is finished, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH of the system to 5-6, adding dichloromethane into the system for extraction and layering, collecting a water layer, and performing electrodialysis desalination to obtain the compound shown in the formula 2. And (3) loading cation exchange resin into a chromatographic column, adding 16.58g of sodium nitrite into the compound shown in the formula 2 for sampling, washing with purified water until the pH of an effluent is 6-7, adding 12.5% ammonia water for elution, collecting an eluent, concentrating the eluent at 75-80 ℃ under reduced pressure until the pH of the system is 7-8, and cooling to 15-25 ℃ to obtain the levocarnitine. Adding 209.10g of absolute ethyl alcohol into the levocarnitine, heating to 60-65 ℃, dissolving the system to be clear, slowly cooling to 20-30 ℃, slowly dripping 627.30g of acetone into the system, slowly cooling to 0-10 ℃ after dripping, carrying out heat preservation and crystallization for 1-3 hours, carrying out three-in-one filtration, leaching with 34.85g of acetone, and carrying out vacuum drying at 45-55 ℃ to obtain a pure levocarnitine product, wherein the yield is 96.4%, the purity of the levocarnitine is 100% through HPLC detection, and no impurity A is detected.
Example 9: preparation of levocarnitine
36.48g of sodium hydroxide and 685.44g of water are respectively added into a reaction kettle, stirring is started, the temperature is reduced to 5 ℃, 179.52g of trimethylamine aqueous solution (30%) is dropwise added into the system, after the addition is finished, 95.47g of the compound shown in the formula 1 is slowly dropwise added into the system, 1.85g of tetrabutylammonium bromide is added, and the heat preservation reaction is carried out for 2 hours at the temperature of 5 ℃. And after the reaction is finished, concentrating under reduced pressure at 5-15 ℃ to remove trimethylamine, after the concentration is finished, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH of the system to 5-6, adding dichloromethane into the system, extracting and layering, collecting a water layer, and performing electrodialysis for desalting to obtain the compound shown in the formula 2. And (2) loading cation exchange resin into a chromatographic column, adding 19.65g of sodium nitrite into the compound shown in the formula 2 for sampling, washing with purified water until the pH of an effluent liquid is 6-7, adding 12.5% ammonia water for elution, collecting an eluent, concentrating the eluent at 75-80 ℃ under reduced pressure until the pH of a system is 7-8, and cooling to 15-25 ℃ to obtain the levocarnitine. Adding 209.10g of absolute ethyl alcohol into the levocarnitine, heating to 60-65 ℃, dissolving the system to be clear, slowly cooling to 20-30 ℃, slowly dripping 627.30g of acetone into the system, slowly cooling to 0-10 ℃ after dripping, carrying out heat preservation and crystallization for 1-3 hours, carrying out three-in-one filtration, leaching with 34.85g of acetone, and carrying out vacuum drying at 45-55 ℃ to obtain a pure levocarnitine product, wherein the yield is 98.3%, and the purity of the levocarnitine is 99.7% and the impurity A is 0.3% through HPLC detection.
Claims (10)
1. An industrial preparation method of levocarnitine is characterized in that alkali metal salt is added into a compound in a formula (2), the compound is adsorbed by cation exchange resin and desorbed by ammonia water to obtain a compound in a formula (3) of levocarnitine,
2. the method according to claim 1, wherein the alkali metal salt is selected from the group consisting of sodium nitrite, potassium nitrite, sodium phosphite, potassium phosphite, sodium thiosulfate and sodium metabisulfite, and preferably is sodium nitrite.
3. The process according to claim 1, wherein the molar ratio of the alkali metal salt to the compound of formula (2) is (0.5-0.7):1, preferably the molar ratio of the alkali metal salt to the compound of formula (2) is 0.5: 1.
4. The process according to claim 1, wherein the concentration of the aqueous ammonia is 10 to 15%, preferably 12.5%.
5. The preparation method according to claim 1, wherein the ammonia water desorption is carried out to obtain the levocarnitine compound of formula (3), and further the ammonia water desorption is carried out to obtain an eluent, the eluent is subjected to reduced pressure concentration at 75-80 ℃ until the pH of the system is 7-8, and then the temperature is reduced to 15-25 ℃ to obtain the levocarnitine compound of formula (3).
6. The method of claim 1, further comprising reacting an aqueous trimethylamine solution with a dioxane solution of the compound of formula (1) under basic conditions with tetrabutylammonium bromide to obtain the starting compound of formula (2), wherein the reaction formula is as follows:
7. the method of claim 6, wherein the alkaline condition is NaOH solution, KOH solution, preferably NaOH solution; the concentration of the trimethylamine aqueous solution is 30 percent; the molar charge ratio of the trimethylamine to the compound of the formula (1) is (4.6-6.1):1, preferably (5.1-5.6):1, more preferably 5.3: 1; the molar charge ratio of tetrabutylammonium bromide to the compound of formula (1) is (0.005-0.05):1, preferably 0.01: 1.
8. The preparation method according to claim 6, wherein the reaction temperature is controlled at-5 to 5 ℃, preferably 0 to 5 ℃, and more preferably 5 ℃; the reaction time is controlled to be 1.5-4 h, preferably 2 h; after the reaction is finished, the method further comprises a post-treatment process, which comprises the following specific steps: and (3) carrying out reduced pressure concentration at 5-15 ℃, slowly dropwise adding 18% hydrochloric acid into the system, adjusting the pH to 5-6, adding dichloromethane, extracting and layering, collecting a water layer, and carrying out electrodialysis desalination.
9. The preparation method according to claim 1, further comprising a purification method of the levocarnitine compound of formula (3), wherein the levocarnitine compound of formula (3) is purified in an ethanol/acetone system to obtain a pure levocarnitine compound of formula (3).
10. The production method according to claim 9, wherein the refining comprises the following operations: adding absolute ethyl alcohol into the levocarnitine compound of the formula (3), heating to 60-65 ℃, dissolving the system clearly, slowly cooling to 20-30 ℃, slowly dripping acetone into the system, slowly cooling to 0-10 ℃, preserving heat, crystallizing for 1-3 hours, filtering in three ways, leaching with acetone, and vacuum drying at 45-55 ℃ to obtain a pure levocarnitine compound of the formula (3).
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