WO2007139238A1 - Process for l-carnitine and acetyl l-carnitine hydrochloride - Google Patents
Process for l-carnitine and acetyl l-carnitine hydrochloride Download PDFInfo
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- WO2007139238A1 WO2007139238A1 PCT/KR2006/002002 KR2006002002W WO2007139238A1 WO 2007139238 A1 WO2007139238 A1 WO 2007139238A1 KR 2006002002 W KR2006002002 W KR 2006002002W WO 2007139238 A1 WO2007139238 A1 WO 2007139238A1
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- WIPO (PCT)
- Prior art keywords
- chloro
- carnitine
- formula
- preparing
- racemic
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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 50
- 238000000034 method Methods 0.000 title claims abstract description 37
- JATPLOXBFFRHDN-DDWIOCJRSA-N [(2r)-2-acetyloxy-3-carboxypropyl]-trimethylazanium;chloride Chemical compound [Cl-].CC(=O)O[C@H](CC(O)=O)C[N+](C)(C)C JATPLOXBFFRHDN-DDWIOCJRSA-N 0.000 title claims abstract description 23
- 230000008569 process Effects 0.000 title claims abstract description 9
- 229960001518 levocarnitine Drugs 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 claims abstract description 25
- 108090000790 Enzymes Proteins 0.000 claims abstract description 21
- 102000004190 Enzymes Human genes 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- LHBPNZDUNCZWFL-UHFFFAOYSA-N 4-chloro-3-hydroxybutanenitrile Chemical compound ClCC(O)CC#N LHBPNZDUNCZWFL-UHFFFAOYSA-N 0.000 claims abstract description 14
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 230000000707 stereoselective effect Effects 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 5
- 244000005700 microbiome Species 0.000 claims description 5
- 108090001060 Lipase Proteins 0.000 claims description 4
- 239000004367 Lipase Substances 0.000 claims description 4
- 102000004882 Lipase Human genes 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 235000019421 lipase Nutrition 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical group [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 3
- 108090000371 Esterases Proteins 0.000 claims description 2
- 108091005804 Peptidases Proteins 0.000 claims description 2
- 239000004365 Protease Substances 0.000 claims description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 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 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 9
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 230000003287 optical effect Effects 0.000 description 14
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 239000007795 chemical reaction product Substances 0.000 description 7
- ZAJNMXDBJKCCAT-UHFFFAOYSA-N ethyl 4-chloro-3-hydroxybutanoate Chemical compound CCOC(=O)CC(O)CCl ZAJNMXDBJKCCAT-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- ZAJNMXDBJKCCAT-RXMQYKEDSA-N ethyl (3r)-4-chloro-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@@H](O)CCl ZAJNMXDBJKCCAT-RXMQYKEDSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- JXXCENBLGFBQJM-UHFFFAOYSA-N (3-carboxy-2-hydroxypropyl)-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)CC(O)=O JXXCENBLGFBQJM-UHFFFAOYSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- FUDDLSHBRSNCBV-UHFFFAOYSA-N (+)-(R)-3-hydroxytetrahydrofuranone Natural products OC1COC(=O)C1 FUDDLSHBRSNCBV-UHFFFAOYSA-N 0.000 description 3
- FUDDLSHBRSNCBV-VKHMYHEASA-N (4s)-4-hydroxyoxolan-2-one Chemical compound O[C@@H]1COC(=O)C1 FUDDLSHBRSNCBV-VKHMYHEASA-N 0.000 description 3
- 108010084311 Novozyme 435 Proteins 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229960004203 carnitine Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 239000000126 substance Substances 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
- AKDAXGMVRMXFOO-GSVOUGTGSA-N (3r)-4-chloro-3-hydroxybutanoic acid Chemical compound ClC[C@H](O)CC(O)=O AKDAXGMVRMXFOO-GSVOUGTGSA-N 0.000 description 2
- PHIQHXFUZVPYII-LURJTMIESA-N (S)-carnitine Chemical compound C[N+](C)(C)C[C@@H](O)CC([O-])=O PHIQHXFUZVPYII-LURJTMIESA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 2
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003957 anion exchange resin Substances 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical class C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- RFMMMVDNIPUKGG-RXMQYKEDSA-N (2r)-2-acetamidopentanedioic acid Chemical compound CC(=O)N[C@@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-RXMQYKEDSA-N 0.000 description 1
- AKDAXGMVRMXFOO-VKHMYHEASA-N (3s)-4-chloro-3-hydroxybutanoic acid Chemical class ClC[C@@H](O)CC(O)=O AKDAXGMVRMXFOO-VKHMYHEASA-N 0.000 description 1
- GUYHPGUANSLONG-SNAWJCMRSA-N (E)-4-(trimethylammonio)but-2-enoate Chemical compound C[N+](C)(C)C\C=C\C([O-])=O GUYHPGUANSLONG-SNAWJCMRSA-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
- JHPNVNIEXXLNTR-UHFFFAOYSA-O 4-(trimethylammonio)butanoic acid Chemical compound C[N+](C)(C)CCCC(O)=O JHPNVNIEXXLNTR-UHFFFAOYSA-O 0.000 description 1
- SYUAOUMJFOLJHP-UHFFFAOYSA-N 4-chloro-2-ethyl-3-hydroxybutanenitrile Chemical compound CCC(C#N)C(O)CCl SYUAOUMJFOLJHP-UHFFFAOYSA-N 0.000 description 1
- AKDAXGMVRMXFOO-UHFFFAOYSA-N 4-chloro-3-hydroxybutanoic acid Chemical compound ClCC(O)CC(O)=O AKDAXGMVRMXFOO-UHFFFAOYSA-N 0.000 description 1
- UCTNTYHJFWMUBD-UHFFFAOYSA-N 4-chloro-3-oxobutanoic acid Chemical class OC(=O)CC(=O)CCl UCTNTYHJFWMUBD-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 108010066477 Carnitine O-acetyltransferase Proteins 0.000 description 1
- 102100036357 Carnitine O-acetyltransferase Human genes 0.000 description 1
- 206010012289 Dementia 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
- 108010093096 Immobilized Enzymes Proteins 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- -1 alkyl (R)-4-chloro-3-hydroxybutyrate Chemical compound 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ZAJNMXDBJKCCAT-YFKPBYRVSA-N ethyl (3s)-4-chloro-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](O)CCl ZAJNMXDBJKCCAT-YFKPBYRVSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000004129 fatty acid metabolism Effects 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 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
- C07C227/14—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
-
- 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
-
- 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
- C07C227/16—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 not involving the amino or carboxyl groups
Definitions
- the present invention relates to a process for preparing L-carnitine of Formula 6 or acetyl L-carnitine hydrochloride of Formula 7. More specifically, the present invention relates to a process for preparing L-carnitine or acetyl L-carnitine hydrochloride, comprising sequentially synthesizing racemic 4-chloro-3-hydroxybutyronitrile of Formula 2 and racemic 4-chloro-3-hydroxy butyric acid alkyl ester of Formula 3 under specific reaction conditions, using racemic epichlorohydrin of Formula 1 as a starting material, preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester of Formula 4 from stereoselective hydrolysis of the racemic 4-chloro- 3 -hydroxy butyric acid alkyl ester in an aqueous solution using an enzyme, and preparing L-carnitine of Formula 6 or acetyl L-carnitine hydrochloride of Formula 7 from the (R)-4-chloro-3-hydroxy
- Carnitine exists as two distinct isomers, i.e. L-carnitine and D-carnitine, but it is known that only the L-isomer of carnitine is biologically active.
- L-carnitine sometimes referred to as Vitamin Bt, is present in the body and serves to help utilization of fatty acid as an energy source.
- D-carnitine is known as a competitive inhibitor against a physiological role of L-carnitine in vivo. Even though D, L-carnitine racemate has been conventionally used in the past, the use of optically pure L-carnitine alone is gradually increasing. In order to cope with such a trend, a great deal of research has been focused on preparation of optically pure L-carnitine.
- Acetyl L-carnitine hydrochloride is a stable form of acetyl L-carnitine, and is a compound prepared in the form of ester by reacting L-carnitine, which is incapable of passing through the blood brain barrier, with an acetyl group.
- Acetyl L-carnitine is synthesized from L-carnitine by the action of carnitine acetyltransferase in human brain, liver and kidney.
- Acetyl L-carnitine activates a variety of the intramitochondrial enzymes responsible for fatty acid and glucose metabolism to thereby facilitate brain energy metabolism, which consequently improves brain function.
- acetyl L-carnitine Due to having the activated acetyl group, acetyl L-carnitine also activates nerve growth factor receptors (NGFRs) to enhance the alibility of nerve cells. Further, acetyl L-carnitine promotes the production of the neurotransmitter acetylcholine to thereby induce smooth brain neurotransmission, which consequently improves the nerve cell function.
- NGFRs nerve growth factor receptors
- acetyl L-carnitine is clinically used to treat depression associated with the primary degenerative disease (Alzheimer's Dementia), is also prescribed to treat the secondary degenerative disease (vascular dementia), and is a broad-spectrum agent which can be used as a first-selective drug ex hibiting excellent ameliorating effects on early- stage dementia patients (The Journal of Applied Pharmacology (2001) 9:285-290).
- acetyl L-carnitine easily passes through the blood brain barrier and therefore can further effectively act on brain nerve cells.
- L-carnitine and acetyl L-carnitine are naturally-occurring substances found in living organisms and are therefore important compounds which attract a great deal of attention as safe drugs that exhibit substantially no adverse side effects even upon chronic administration thereof.
- Korean Patent No. 025039 discloses a method for preparing L-carnitine which includes ring opening and epoxidation of (S)-3-hydroxy-gamma-butyrolactone as a starting material, and a nu- cleophilic substitution with trimethylamine.
- this method suffers from a disadvantage associated with a difficulty of application thereof to a practical process due to a high cost of (S)-3-hydroxy-gamma-butyrolactone as the starting material.
- the method of the present invention is characterized by preparation of high-quality
- L-carnitine at a low production cost, through the development of a production process of alkyl (R)-4-chloro-3-hydroxybutyrate which is used as an intermediate.
- the method of the present invention can achieve preparation of (R)-4-chloro-3-hydroxy butyric acid alkyl ester having an optical purity of more than 99%ee from the hydrolysis of the racemic 4-chloro-3-hydroxy butyric acid alkyl ester using the enzyme.
- the method of the present invention provides various advantages such as production of L-carnitine and acetyl L-carnitine hydrochloride with a high optical purity, environmental friendliness due to the use of immobilized lipase as an enzyme, and low production costs due to the feasibility of repeated use of enzyme.
- L-carnitine or acetyl L-carnitine hydrochloride having a high optical purity by a simplified process including 6 to 7 steps from an inexpensive material.
- the above and other objects can be accomplished by the provision of a process for preparing L-carnitine or acetyl L-carnitine hydrochloride, comprising preparing racemic 4-chloro-3-hydroxybutyronitrile of Formula 2 from racemic epichlorohydrin of Formula 1 in an aqueous hydrogen cyanide solution having a pH of 8 to 10; preparing racemic 4-chloro- 3 -hydroxy butyric acid alkyl ester of Formula 3 from the racemic 4-chloro-3-hydroxybutyronitrile of Formula 2 in the presence of an alcohol and a sulfuric acid catalyst; preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester of Formula 4 from stereoselective hydrolysis of the racemic 4-chloro-3-hydroxy butyric acid alkyl ester of Formula 3 in an aqueous solution using an enzyme or an enzyme- containing microorganism; and preparing L-carnitine of Formula 6 or ace
- the present invention provides a process for preparation of L- carnitine or acetyl L-carnitine hydrochloride.
- 4-chloro-3-hydroxybutyronitrile is synthesized from epichlorohydrin in an aqueous hydrogen cyanide solution
- 4-chloro-3-hydroxy butyric acid alkyl ester is then synthesized from the 4-chloro-3-hydroxybutyronitrile in the presence of an alcohol and a sulfuric acid catalyst
- the racemic 4-chloro-3 -hydroxy butyric acid alkyl ester is hydrolyzed in an aqueous solution using an enzyme, thereby preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester.
- the (R)-4-chloro-3-hydroxy butyric acid alkyl ester is reacted with trimethylamine, and the reaction product is treated with hydrochloric acid and passed through an anion-exchange resin column to thereby prepare L-carnitine.
- the (R)-4-chloro-3-hydroxy butyric acid alkyl ester is reacted with trimethylamine and then the reaction product is treated with hydrochloric acid to thereby prepare L-carnitine hydrochloride which is then reacted with acetic acid containing acetyl chloride to prepare acetyl L-carnitine hydrochloride.
- the enzyme used in the present invention was commercially available immobilized lipase Novozyme 435 (Novozymes). This enzyme can be repeatedly used several times. Further, the use of lipase PS or CRL (Amano) can also provide good results, instead of Novozyme 435. Further, good results can be achieved with the use of a microorganism, or esterase or protease, which has a hydrolytic capacity.
- FFAP FFAP (30 mm X 0.53 m, Agilent) which was then heated at 100 0 C for 5 min, elevated to 220 0 C at a rate of 20 °C/min, and maintained at 220 0 C for 15 min.
- Helium gas was used as a carrier.
- Detection was made using FID at 230 0 C while maintaining the column head pressure of 6 psi. A retention time was 14.32 min.
- a process for preparing L-carnitine or acetyl L-carnitine hydrochloride in accordance with the present invention employs a very inexpensive material as a starting material and involves a simplified reaction process in conjunction with a capability to prepare an intermediate having a high optical purity at a low production cost. Therefore, it is possible to achieve easy and inexpensive production of L-carnitine and acetyl L-carnitine hydrochloride having a high optical purity, as compared to a conventional preparation method. Further, the process of the present invention provides advantages, such as environmental friendliness due to the use of an immobilized enzyme in the preparation of the intermediate, and applicability thereof to industrial-scale production arising from decreased production costs due to the recyclability of the enzyme.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Provided is a process for preparing L-carnitine or acetyl L-carnitine hydrochloride. Specifically, the process comprises sequentially synthesizing racemic 4-chloro-3-hydroxybutyronitrile and racemic 4-chloro-3-hydroxy butyric acid alkyl ester under specific reaction conditions, using racemic epichlorohydrin as a starting material, preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester from stereoselective hydrolysis of the racemic 4-chloro-3-hydroxy butyric acid alkyl ester using an enzyme, and preparing L-carnitine or acetyl L-carnitine hydrochloride from the (R)-4-chloro-3-hydroxy butyric acid alkyl ester, according to the known method.
Description
Description
PROCESS FOR L-CARNITINE AND ACETYL L-CARNITINE
HYDROCHLORIDE
Technical Field
[1] The present invention relates to a process for preparing L-carnitine of Formula 6 or acetyl L-carnitine hydrochloride of Formula 7. More specifically, the present invention relates to a process for preparing L-carnitine or acetyl L-carnitine hydrochloride, comprising sequentially synthesizing racemic 4-chloro-3-hydroxybutyronitrile of Formula 2 and racemic 4-chloro-3-hydroxy butyric acid alkyl ester of Formula 3 under specific reaction conditions, using racemic epichlorohydrin of Formula 1 as a starting material, preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester of Formula 4 from stereoselective hydrolysis of the racemic 4-chloro- 3 -hydroxy butyric acid alkyl ester in an aqueous solution using an enzyme, and preparing L-carnitine of Formula 6 or acetyl L-carnitine hydrochloride of Formula 7 from the (R)-4-chloro-3-hydroxy butyric acid alkyl ester.
[2]
[3]
[4]
[5]
[6] [Reaction Scheme 1]
[7]
enzyme
[8] wherein R is an alkyl group (C H , n = 1 to 8). n 2n+l
Background Art [9] Carnitine exists as two distinct isomers, i.e. L-carnitine and D-carnitine, but it is known that only the L-isomer of carnitine is biologically active. L-carnitine, sometimes referred to as Vitamin Bt, is present in the body and serves to help utilization of fatty acid as an energy source. D-carnitine is known as a competitive inhibitor against a physiological role of L-carnitine in vivo. Even though D, L-carnitine racemate has been conventionally used in the past, the use of optically pure L-carnitine alone is gradually increasing. In order to cope with such a trend, a great deal of research has been focused on preparation of optically pure L-carnitine.
[10] Acetyl L-carnitine hydrochloride is a stable form of acetyl L-carnitine, and is a compound prepared in the form of ester by reacting L-carnitine, which is incapable of passing through the blood brain barrier, with an acetyl group. Acetyl L-carnitine is synthesized from L-carnitine by the action of carnitine acetyltransferase in human
brain, liver and kidney. Acetyl L-carnitine activates a variety of the intramitochondrial enzymes responsible for fatty acid and glucose metabolism to thereby facilitate brain energy metabolism, which consequently improves brain function. Due to having the activated acetyl group, acetyl L-carnitine also activates nerve growth factor receptors (NGFRs) to enhance the alibility of nerve cells. Further, acetyl L-carnitine promotes the production of the neurotransmitter acetylcholine to thereby induce smooth brain neurotransmission, which consequently improves the nerve cell function. Due to having the aforementioned pharmacological actions, acetyl L-carnitine is clinically used to treat depression associated with the primary degenerative disease (Alzheimer's Dementia), is also prescribed to treat the secondary degenerative disease (vascular dementia), and is a broad-spectrum agent which can be used as a first-selective drug ex hibiting excellent ameliorating effects on early- stage dementia patients (The Journal of Applied Pharmacology (2001) 9:285-290). Unlike L-carnitine, acetyl L-carnitine easily passes through the blood brain barrier and therefore can further effectively act on brain nerve cells.
[11] L-carnitine and acetyl L-carnitine are naturally-occurring substances found in living organisms and are therefore important compounds which attract a great deal of attention as safe drugs that exhibit substantially no adverse side effects even upon chronic administration thereof.
[12] The conventionally known process for preparing L-carnitine is as follows.
[13] As a first method, mention may be made of classical resolution which involves forming isomers of carnitine from racemates of D,L-carnitine or derivatives thereof, using L-tartaric acid (EP 157,315), dibenzoyl-D-tartaric acid (U.S. Patent No. 4,933,490), dibenzoyl-L-tartaric acid (U.S. Patent No. 4,610,828), D-mandelic acid (Japanese Unexamined Patent Publication No. Sho 59-231,048) or N- acetyl-D-glutamate (Japanese Unexamined Patent Publication No. Hei 1-131,143) as an optical resolution reagent, resolving to obtain a desired form of the carnitine isomer in a suitable solvent by taking advantage of a solubility difference between the isomers, and then hydrolyzing the thus-resolved isomer to thereby obtain L-carnitine only. However, the aforesaid method suffers from disadvantages such as a difficulty to perform recrystallization and high production costs due to the use of an expensive optical resolution reagent.
[14] As a second method, there is a biological method using microorganisms or enzymes.
[15] For example, mention may be made of a method for preparing L-carnitine via stereoselective hydroxylation of butyrobetaine as a starting material using an enzyme (U.S. Patent Nos. 4,371,618 and 5,187,039) and a method for preparing L-carnitine via stereoselective hydration of crotonobetaine as a starting material using a suitable
enzyme (U.S. Patent Nos. 4,650,759 and 5,248,601, and EP 457,735). However, these methods have also a disadvantage associated with a difficulty of application thereof to industrial-scale production due to a low concentration of reactants and a prolonged reaction time of 2 to 3 days.
[16] As a third method, there is a method for preparing L-carnitine, involving synthesis of a (R)-4-chloro-3-hydroxybutyrate derivate from 4-chloro-3-oxobutyrate derivative via the stereoselective reduction using a ruthenium catalyst, followed by preparation of L-carnitine by a conventional method (U.S. Patent No. 4,895,979, EP-A-339764, EP- B-295109, and Tetrahedron Letters, (1998) 29: 1555). However, this method has also a disadvantage such as high production costs of (R)-4-chloro-3-hydroxybutyrate derivate, and a difficulty of application thereof to industrial-scale production in that the reaction must be carried out under high- temperature and high-pressure conditions.
[17] As a fourth method, there is a method for preparing L-carnitine from a chiral material that is easily available from natural products. For example, U.S. Patent No. 4,413,142 discloses a method for preparing L-carnitine, involving a large number of reaction steps (10 steps) and using D-mannitol as a starting material. However, this method has problems associated with highly complicated reaction steps and the use of a heavy metal such as lead tetraacetate (Pb(CH COO) ). Further, even though preparation of L-carnitine from D-(R)-tartaric acid is also known (Tetrahedron Letters, (1990) 31:7323-7326), this method also presents problems such as long and complex production processes.
[18] As a fifth method, there is a method for preparing L-carnitine from
(S)-3-hydroxy-gamma-butyrolactone. For example, Korean Patent No. 025039 discloses a method for preparing L-carnitine which includes ring opening and epoxidation of (S)-3-hydroxy-gamma-butyrolactone as a starting material, and a nu- cleophilic substitution with trimethylamine. However, this method suffers from a disadvantage associated with a difficulty of application thereof to a practical process due to a high cost of (S)-3-hydroxy-gamma-butyrolactone as the starting material.
[19] As discussed above, even though various attempts have been made to find an efficient and economical method to prepare L-carnitine, conventional methods have various disadvantages and problems, such as great difficulty to achieve high yield and high optical purity, complicated production processes, and high production costs due to high-temperature and high-pressure reaction conditions, which consequently lead to a difficulty of practical application thereof.
[20]
Disclosure of Invention Technical Problem
[21] As a result of extensive investigations with the purpose of solving the above- described problems, the inventors of the present invention have prepared acetyl L- carnitine hydrochloride by sequentially synthesizing 4-chloro-3-hydroxybutyronitrile (Korean Patent Application No. 10-2005-0010935) and alkyl
4-chloro-3-hydroxybutyrate (Korean Patent Application No. 10-2004-0073342) under specific reaction conditions, using inexpensive epichlorohydrin as a starting material, preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester from hydrolysis of the resulting racemic 4-chloro-3-hydroxy butyric acid alkyl ester using an enzyme (Korean Patent Application No. 10-2004-0029791), preparing L-carnitine from the thus- obtained (R)-4-chloro-3-hydroxy butyric acid alkyl ester according to the known method (Journal of America Chemical Society, (1983) 105: 5925-5926; and Chemical Abstract, (1963) 59:2654c), and then preparing acetyl L-carnitine hydrochloride from L-carnitine according to the method known in the art (Journal of Organic Chemistry, (1967) 3989-3991).
[22] The method of the present invention is characterized by preparation of high-quality
L-carnitine at a low production cost, through the development of a production process of alkyl (R)-4-chloro-3-hydroxybutyrate which is used as an intermediate. In particular, unlike the conventional method, the method of the present invention can achieve preparation of (R)-4-chloro-3-hydroxy butyric acid alkyl ester having an optical purity of more than 99%ee from the hydrolysis of the racemic 4-chloro-3-hydroxy butyric acid alkyl ester using the enzyme. Therefore, the method of the present invention provides various advantages such as production of L-carnitine and acetyl L-carnitine hydrochloride with a high optical purity, environmental friendliness due to the use of immobilized lipase as an enzyme, and low production costs due to the feasibility of repeated use of enzyme.
[23] Therefore, it is an object of the present invention to provide a process for preparing
L-carnitine or acetyl L-carnitine hydrochloride having a high optical purity, by a simplified process including 6 to 7 steps from an inexpensive material.
[24]
Technical Solution
[25] In accordance with an aspect of the present invention, the above and other objects can be accomplished by the provision of a process for preparing L-carnitine or acetyl L-carnitine hydrochloride, comprising preparing racemic 4-chloro-3-hydroxybutyronitrile of Formula 2 from racemic epichlorohydrin of Formula 1 in an aqueous hydrogen cyanide solution having a pH of 8 to 10; preparing racemic 4-chloro- 3 -hydroxy butyric acid alkyl ester of Formula 3 from the racemic 4-chloro-3-hydroxybutyronitrile of Formula 2 in the presence of an alcohol and a
sulfuric acid catalyst; preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester of Formula 4 from stereoselective hydrolysis of the racemic 4-chloro-3-hydroxy butyric acid alkyl ester of Formula 3 in an aqueous solution using an enzyme or an enzyme- containing microorganism; and preparing L-carnitine of Formula 6 or acetyl L- carnitine hydrochloride of Formula 7 from the (R)-4-chloro-3-hydroxy butyric acid alkyl ester of Formula 4 according to the known method.
[26] [27] [Reaction Scheme 1] [28]
enzyme
[29] wherein R is an alkyl group (C H , n = 1 to 8). n 2n+l
Best Mode for Carrying Out the Invention
[30] Hereinafter, the present invention will be described in more detail. [31] As described above, the present invention provides a process for preparation of L- carnitine or acetyl L-carnitine hydrochloride. For this purpose,
4-chloro-3-hydroxybutyronitrile is synthesized from epichlorohydrin in an aqueous hydrogen cyanide solution, 4-chloro-3-hydroxy butyric acid alkyl ester is then synthesized from the 4-chloro-3-hydroxybutyronitrile in the presence of an alcohol and a sulfuric acid catalyst, and the racemic 4-chloro-3 -hydroxy butyric acid alkyl ester is hydrolyzed in an aqueous solution using an enzyme, thereby preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester. Then, the (R)-4-chloro-3-hydroxy butyric acid alkyl ester is reacted with trimethylamine, and the reaction product is treated with hydrochloric acid and passed through an anion-exchange resin column to thereby prepare L-carnitine. On the other hand, the (R)-4-chloro-3-hydroxy butyric acid alkyl ester is reacted with trimethylamine and then the reaction product is treated with hydrochloric acid to thereby prepare L-carnitine hydrochloride which is then reacted with acetic acid containing acetyl chloride to prepare acetyl L-carnitine hydrochloride.
[32] The enzyme used in the present invention was commercially available immobilized lipase Novozyme 435 (Novozymes). This enzyme can be repeatedly used several times. Further, the use of lipase PS or CRL (Amano) can also provide good results, instead of Novozyme 435. Further, good results can be achieved with the use of a microorganism, or esterase or protease, which has a hydrolytic capacity.
[33] In the present invention, reactants and reaction products were subjected to identification of materials using FT-NMR (Model No. DPX300, Burker Inc.). When (R)-4-chloro-3-hydroxy butyric acid alkyl ester was prepared by the hydrolysis of racemic 4-chloro- 3 -hydroxy butyric acid alkyl ester in an aqueous solution or an aqueous solution-containing solvent using immobilized lipase, the reaction product was extracted with ethyl acetate and analyzed by gas chromatography (Model No. DS6200, Donam Instruments, Inc., Korea).
[34] Racemic ethyl 4-chloro-3-hydroxybutyrate was loaded on a capillary column HP-
FFAP (30 mm X 0.53 m, Agilent) which was then heated at 100 0C for 5 min, elevated to 220 0C at a rate of 20 °C/min, and maintained at 220 0C for 15 min. Helium gas was used as a carrier. Detection was made using FID at 230 0C while maintaining the column head pressure of 6 psi. A retention time was 14.32 min.
[35] Optically active (R)- and (S)-4-chloro-3-hydroxybutyrates were loaded on a capillary column G-TA (30 m x 0.32 mm, Astec) which was then heated at 120 0C for 10 min, elevated to 170 0C at a rate of 10 °C/min, and maintained at 170 0C for 15 min. Helium gas was used as a carrier. Detection was made using FID at 170 0C while maintaining the column head pressure of 10 psi. Ethyl (R)-4-chloro-3-hydroxybutyrate was detected at 11.7 min, whereas ethyl (S)-4-chloro-3-hydroxybutyrate was detected at 12.1 min.
[36] Using a polarimeter (Model No. AP-100, ATAGO), the optical purity (specific
rotation) of L-carnitine and acetyl L-carnitine hydrochloride was analyzed following dissolution of these test compounds at a concentration of 1% (w/v) in pure water.
[37]
Mode for the Invention
[38] EXAMPLES
[39] Now, the present invention will be described in more detail with reference to the following Examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention.
[40]
[41] Example 1: Preparation of 4-chloro-3-hvdroxybutyronitrile (2)
[42] 185.2 g of potassium cyanide (KCN) was dissolved in 431 mL of water, and 171 mL of a 65 % sulfuric acid solution was slowly added dropwise thereto in an ice bath such that a pH value of the reaction solution was adjusted to a range of 8 to 10. The resulting potassium sulfate (K SO ) was filtered through a filter paper and an aqueous
2 4 hydrogen cyanide solution having a pH of 8 to 10 was recovered. 595 mL of the thus- prepared hydrogen cyanide solution was reacted with 35 g of epichlorohydrin at a temperature of less than 20 0C for 5 hours. The reaction product was extracted with ethyl acetate, and distilled under reduced pressure to obtain 35.87 g (yield: 80 %) of 4-chloro-3-hydroxybutyronitrile.
[43] Analysis results of 4-chloro-3-hydroxybutyronitrile are as follows:
[44] 1H-NMR(CDCl ): 2.79(2H, m), 3.65(2H, d), 3.86(1H, s), and 4.2O(1H, m) ppm
[45]
[46] Example 2: Preparation of ethyl 4-chloro-3-hydroxybutyrate (3)
[47] 35.37 g of 4-chloro-3-hydroxybutyronitrile was placed in 73.22 mL of 95 % ethanol to which 32.18 mL of cone, sulfuric acid was then gradually added. The mixture was stirred at a temperature of 80 to 85 0C for 16 to 24 hours, thereby obtaining 90.2 % ethyl 4-chloro-3-hydroxybutyronitrile. After the reaction was complete, the reaction product was washed with an equal amount of saturated sodium bicarbonate, and extracted with ethyl acetate three times. Thereafter, anhydrous sodium sulfate was added to remove moisture from the product which was then filtered and distilled under reduced pressure to remove ethyl acetate, followed by fractional distillation under reduced pressure (93-95 °C/5 mmHg) to obtain 40.4 g (yield: 80 %) of ethyl 4-chloro-3-hydroxybutyrate.
[48] Analysis results of racemic ethyl 4-chloro-3-hydroxybutyrate are as follows:
[49] 1H-NMR (CDCl3) = 1.28 (3H,t), 2.62 (2H,d), 3.53 (lH,br),
[50] 3.60 (2H,d), 4.20 (2H,q), 4.33 (lH,m)
[51]
[52] Example 3: Preparation of ethyl (RV4-chloro-3-hvdroxybutyrate (4)
[53] 40 g (10% w/v) of racemic ethyl 4-chloro-3-hydroxybutyrate was added to a flask containing 360 mL of 0.1M potassium phosphate buffer (pH 8.0) to which 4 g (1% w/ v) of immobilized lipase Novozyme 435 was then added, followed by reacting at 30 0C. After the reaction was carried out for 1 hour, the reaction product was extracted with an equal amount of ethyl acetate two times, and washed once with distilled water. Thereafter, anhydrous magnesium sulfate (MgSO ) was added to ethyl acetate to remove moisture, followed by distillation under reduced pressure to remove ethyl acetate, thus obtaining 12 g of ethyl (R)-4-chloro-3-hydroxybutyrate. The conversion was 70 % and the optical purity of ethyl (R)-4-chloro-3-hydroxybutyrate was 99.9 %ee.
[54]
[55] Example 4: Preparation of L-carnitine (6)
[56] 37 mL (0.156 mole) of an aqueous 30 wt/% trimethylamine solution was placed in
10 g (0.06 mole) of ethyl (R)-4-chloro-3-hydroxybutyrate, and the mixture was heated and stirred at a temperature of 80 to 90 0C for 3 hours. The conversion (%) of the substrate was confirmed by gas chromatography. After the reaction was complete, unreacted trimethylamine was removed by distillation under reduced pressure. 70 mL of 10 % HCl was added to the resulting concentrated solution which was then heated and stirred at a temperature of 80 to 90 0C for 2 hours, concentrated by distillation under reduced pressure, and dissolved in a small amount of water, followed by elution on a column packed with an anion exchange resin (Amberlite IRA 410, OH"). The eluted fractions were combined, concentrated by distillation under reduced pressure, and recrystallized from small amounts of anhydrous ethanol and acetone to afford 4.15 g (yield: 43 %) of L-carnitine. The optical purity of the product was measured using a polarimeter. The result is as follows:
[57] [α]25 = -30 °(C=l, H O)
[58]
[59] Example 5: Preparation of acetyl L-carnitine hydrochloride (7s)
[60] 37 mL (0.156 mole) of an aqueous 30wt/% trimethylamine solution was placed in
10 g (0.06 mole) of ethyl (R)-4-chloro-3-hydroxybutyrate, and the mixture was heated and stirred at a temperature of 80 to 90 0C for 3 hours. The conversion (%) of the substrate was confirmed by gas chromatography. After the reaction was complete, excessive trimethylamine was removed by distillation under reduced pressure. 70 mL of 10 % HCl was added to the resulting concentrated solution which was then heated and stirred at a temperature of 80 to 90 0C for 2 hours, concentrated by distillation under reduced pressure, and recrystallized from small amounts of anhydrous ethanol
and acetone to afford L-carnitine hydrochloride. The optical purity of the product was measured using a polarimeter. The specific rotation of L-carnitine hydrochloride is as follows: [61] [α]25 = -22 °(C=l, H O)
D 2
[62]
[63] The thus-obtained L-carnitine hydrochloride was dissolved in 20 mL of acetic acid, and 9 mL of acetyl chloride was slowly added dropwise thereto. The mixture was stirred at room temperature for about 40 min. 100 mL of ether was added to the reaction solution which was then stirred to obtain solids. The solids were recrystallized from small amounts of ethanol and acetone to give 4.5 g of acetyl L-carnitine hydrochloride having a high optical purity. The optical purity of the product was confirmed using a polarimeter. The specific rotation of acetyl L-carnitine hydrochloride is as follows:
[64] Specific rotation [α]25 = -28 ° (C=I, H O)
[65]
Industrial Applicability
[66] As can be seen from Examples 1 through 5, a process for preparing L-carnitine or acetyl L-carnitine hydrochloride in accordance with the present invention employs a very inexpensive material as a starting material and involves a simplified reaction process in conjunction with a capability to prepare an intermediate having a high optical purity at a low production cost. Therefore, it is possible to achieve easy and inexpensive production of L-carnitine and acetyl L-carnitine hydrochloride having a high optical purity, as compared to a conventional preparation method. Further, the process of the present invention provides advantages, such as environmental friendliness due to the use of an immobilized enzyme in the preparation of the intermediate, and applicability thereof to industrial-scale production arising from decreased production costs due to the recyclability of the enzyme.
[67]
[68]
Claims
[1] A process for preparing L-carnitine, comprising: preparing racemic 4-chloro-3-hydroxybutyronitrile of Formula 2 from racemic epichlorohydrin of Formula 1 in an aqueous hydrogen cyanide solution having a pH of 8 to 10; preparing racemic 4-chloro- 3 -hydroxy butyric acid alkyl ester of Formula 3 from the racemic 4-chloro-3-hydroxybutyronitrile of Formula 2 in the presence of an alcohol and a sulfuric acid catalyst; preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester of Formula 4 from stereoselective hydrolysis of the racemic 4-chloro-3-hydroxy butyric acid alkyl ester of Formula 3 in an aqueous solution using an enzyme or an enzyme- containing microorganism; and preparing L-carnitine of Formula 6 from the (R)-4-chloro-3-hydroxy butyric acid alkyl ester of Formula 4 according to the known method. [Reaction Scheme 1]
enzyme
[2] A process for preparing acetyl L-carnitine hydrochloride, comprising: preparing racemic 4-chloro-3-hydroxybutyronitrile of Formula 2 from racemic epichlorohydrin of Formula 1 in an aqueous hydrogen cyanide solution having a pH of 8 to 10; preparing racemic 4-chloro- 3 -hydroxy butyric acid alkyl ester of Formula 3 from the racemic 4-chloro-3-hydroxybutyronitrile of Formula 2 in the presence of an alcohol and a sulfuric acid catalyst; preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester of Formula 4 from stereoselective hydrolysis of the racemic 4-chloro-3-hydroxy butyric acid alkyl ester of Formula 3 in an aqueous solution using an enzyme or an enzyme- containing microorganism; and preparing acetyl L-carnitine hydrochloride of Formula 7 from the (R)-4-chloro-3-hydroxy butyric acid alkyl ester of Formula 4 according to the known method.
[3] The process according to claim 1 or 2, wherein the inorganic acid used in the preparation of the aqueous hydrogen cyanide solution is sulfuric acid or hydrochloric acid, and the cyanide salt is potassium cyanide or sodium cyanide.
[4] The process according to claim 1 or 2, wherein the enzyme is lipase, esterase or protease having a hydrolytic capacity, which is used directly or is immobilized prior to use.
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| CN102557972A (en) * | 2011-12-31 | 2012-07-11 | 南京海辰药业有限公司 | Polycrystal substance of acetyl chloride levocarnitine |
| CN102579370A (en) * | 2011-12-31 | 2012-07-18 | 南京海辰药业有限公司 | Drug combination containing levocarnitine derivatives and preparation method of drug combination |
| CN102627580A (en) * | 2012-03-20 | 2012-08-08 | 河北临港化工有限公司 | New preparation technology of atorvastatin intermediate ethyl-4-cyan -3-hydroxybutyate |
| CN103044278A (en) * | 2012-12-07 | 2013-04-17 | 沈阳化工大学 | Method for synthesizing levocarnitine by taking D-(-)-tartaric acid as raw material |
| TWI466850B (en) * | 2009-02-05 | 2015-01-01 | Lonza Ag | Process for the production of a fatty acid/l-carnitine derivative |
| CN105481709A (en) * | 2015-08-19 | 2016-04-13 | 广西壮族自治区化工研究院 | Method for purifying and desalting crude product of L-carnitine |
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| CN114181101A (en) * | 2021-11-26 | 2022-03-15 | 开原亨泰营养科技有限公司 | Preparation method of L-carnitine tartrate capable of controlling crystal form of product |
| US11555008B2 (en) | 2020-06-05 | 2023-01-17 | Fudan University | Method for preparing L-carnitine using micro-reaction system |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI466850B (en) * | 2009-02-05 | 2015-01-01 | Lonza Ag | Process for the production of a fatty acid/l-carnitine derivative |
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| CN102579370A (en) * | 2011-12-31 | 2012-07-18 | 南京海辰药业有限公司 | Drug combination containing levocarnitine derivatives and preparation method of drug combination |
| CN102627580A (en) * | 2012-03-20 | 2012-08-08 | 河北临港化工有限公司 | New preparation technology of atorvastatin intermediate ethyl-4-cyan -3-hydroxybutyate |
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| CN105481709A (en) * | 2015-08-19 | 2016-04-13 | 广西壮族自治区化工研究院 | Method for purifying and desalting crude product of L-carnitine |
| CN108912022A (en) * | 2018-07-26 | 2018-11-30 | 湖北吉和昌化工科技有限公司 | A kind of method of purification of sodium polydithio-dipropyl sulfonate |
| US11555008B2 (en) | 2020-06-05 | 2023-01-17 | Fudan University | Method for preparing L-carnitine using micro-reaction system |
| CN114181101A (en) * | 2021-11-26 | 2022-03-15 | 开原亨泰营养科技有限公司 | Preparation method of L-carnitine tartrate capable of controlling crystal form of product |
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