CN108191908A - 一种L-α-甘油磷酸胆碱的制备方法 - Google Patents
一种L-α-甘油磷酸胆碱的制备方法 Download PDFInfo
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- 229960001231 choline Drugs 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 12
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000011187 glycerol Nutrition 0.000 claims abstract description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 10
- -1 phosphoric acid alkali metal salt Chemical class 0.000 claims abstract description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 8
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical compound CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 claims abstract description 7
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims abstract description 6
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- XFGDAPQOKJYPQP-UHFFFAOYSA-N 1-chloropropane-1,2-diol Chemical compound CC(O)C(O)Cl XFGDAPQOKJYPQP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 2
- 238000010612 desalination reaction Methods 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 238000005660 chlorination reaction Methods 0.000 abstract description 5
- 239000002351 wastewater Substances 0.000 abstract description 4
- 241000370738 Chlorion Species 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 abstract description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 abstract description 2
- OGPMUTIEFPDJAX-UHFFFAOYSA-M calcium;2-(trimethylazaniumyl)ethyl phosphate Chemical compound [Ca+2].C[N+](C)(C)CCOP([O-])([O-])=O OGPMUTIEFPDJAX-UHFFFAOYSA-M 0.000 abstract description 2
- 239000000460 chlorine Substances 0.000 abstract description 2
- 229910052801 chlorine Inorganic materials 0.000 abstract description 2
- 239000003456 ion exchange resin Substances 0.000 abstract description 2
- 229920003303 ion-exchange polymer Polymers 0.000 abstract description 2
- 239000001103 potassium chloride Substances 0.000 abstract description 2
- 235000011164 potassium chloride Nutrition 0.000 abstract description 2
- 229960004063 propylene glycol Drugs 0.000 abstract description 2
- 238000003911 water pollution Methods 0.000 abstract description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 abstract 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 abstract 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 abstract 1
- 238000000034 method Methods 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 229950004354 phosphorylcholine Drugs 0.000 description 8
- 230000008569 process Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical compound [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 description 6
- 238000006116 polymerization reaction Methods 0.000 description 5
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QNYBOILAKBSWFG-SNVBAGLBSA-N (2s)-2-(phenylmethoxymethyl)oxirane Chemical compound C([C@H]1OC1)OCC1=CC=CC=C1 QNYBOILAKBSWFG-SNVBAGLBSA-N 0.000 description 2
- CTKINSOISVBQLD-VKHMYHEASA-N (S)-Glycidol Chemical compound OC[C@H]1CO1 CTKINSOISVBQLD-VKHMYHEASA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000001743 benzylic group Chemical group 0.000 description 2
- SUHOQUVVVLNYQR-MRVPVSSYSA-N choline alfoscerate Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 description 2
- 230000003930 cognitive ability Effects 0.000 description 2
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- 238000005516 engineering process Methods 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
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- 238000009413 insulation Methods 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical group [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 1
- LRWZZZWJMFNZIK-NFJMKROFSA-N (2R)-2-chloro-3-methyloxirane Chemical compound CC1O[C@@H]1Cl LRWZZZWJMFNZIK-NFJMKROFSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- NJNWCIAPVGRBHO-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[(oxo-$l^{5}-phosphanylidyne)methyl]azanium Chemical class OCC[N+](C)(C)C#P=O NJNWCIAPVGRBHO-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- LYBMBLCMTLTCMP-UHFFFAOYSA-M CC(OCC[N+](C)(C)C)=O.[O-]P(O)(O)=O Chemical compound CC(OCC[N+](C)(C)C)=O.[O-]P(O)(O)=O LYBMBLCMTLTCMP-UHFFFAOYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 239000008777 Glycerylphosphorylcholine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000027418 Wounds and injury 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
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 229960004956 glycerylphosphorylcholine Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
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- 230000036541 health Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
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- 239000012074 organic phase Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 125000002525 phosphocholine group Chemical group OP(=O)(OCC[N+](C)(C)C)O* 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- WHJKYJBKWZOMMW-UHFFFAOYSA-M tetramethylazanium;2-(trimethylazaniumyl)ethyl phosphate Chemical compound C[N+](C)(C)C.C[N+](C)(C)CCOP([O-])([O-])=O WHJKYJBKWZOMMW-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
本发明涉及一种L‑α‑甘油磷酸胆碱的制备方法,包括:采用(R)‑3‑氯‑1,2‑丙二醇为起始原料,与磷酸碱金属盐制备(R)‑甘油磷酸酯;然后再与二溴乙烷反应制备(R)‑3‑甘油基环乙基磷酸酯;最后与三甲胺进行开环反应得到L‑α‑甘油磷酸胆碱。本发明避免了使用氯化磷酸胆碱钙盐或钾盐而造成的大量废水污染问题和最终产品必须过离子交换树脂柱除去氯离子的环节,产物纯度好,收率高,适于工业化生产,具有良好的应用前景。
Description
技术领域
本发明属于手性药物的制备领域,特别涉及一种L-α-甘油磷酸胆碱的制备方法。
背景技术
L-α-甘油磷酸胆碱(L-α-Glycerophosphoryl Choline,简称L-α-GPC)为体内天然存在的水溶性磷脂代谢产物以及乙酰胆碱和磷脂酰胆碱合成的胆碱源,具有重要的营养保健功能和医学应用价值。L-α-GPC能够提高脑部的认知能力,甚至可以修复早期老年失智症患者已部分损伤的认知能力,能够保护肝组织免受有毒的四氯化碳和高脂蛋白类食品所产生的脂肪酸渗透,具有抗高血脂、保护血管的作用,并且可以促进青少年身体成长,提高记忆能力,因此在医药、保健品和功能性食品方面得到广泛的应用。L-α-GPC的化学结构式如下:
最早L-α-GPC是从牛胰脏提取纯化得到的(GSchmidt,J.Biochem.,1945,161,523)。英国专利GB2058792和美国专利US2864848报道了利用蛋黄卵磷脂水解提取制备L-α-GPC的技术工艺。日本专利(JP61158990)也报道了以大豆卵磷脂为原料水解提取制备L-α-GPC的方法。上述从天然物质提取L-α-GPC存在以下问题:因原材料来源途径不同差异很大,杂质成分也分部不均,使得后续分离纯化工艺繁缛复杂,造成产品质量很不稳定,加之操作工艺复杂,导致工业化生产成本具高不下。
通过化学合成L-α-GPC可以避免天然物质提取方法所存在的问题,因而广泛受到人们的关注。例如欧洲专利EP0486100采用D-甘油缩丙酮叉为原材料,与2-氧-2-氯-1,3,2-磷杂环氧戊环反应制得L-α-异亚丙基-3-甘油环己烷磷酰基酯,然后再与三乙胺在高压作用下缩合得到L-α-异亚丙基甘油磷酰胆碱,再经过稀盐酸开环得到L-α-GPC粗品。最后经离子交换树脂纯化得到L-α-GPC产品。工艺路线如下:
但该方法的缺点是:(1)原材料D-甘油缩丙酮叉原材料价格昂贵,不宜得到。(2)工艺复杂,废水排放量大,污染环境。(3)收率低,小于50%。
欧洲专利EP0502357提出用D-异亚丙基甘油对甲苯磺酸酯与磷酸胆碱四甲基铵盐进行缩合反应制备L-α-GPC。工艺路线如下:
其中A可以是Li+,Na+,k+或N+(CH3)。
该方法虽然比用D-甘油缩丙酮叉的工艺收率高,但原材料D-异亚丙基甘油对甲苯磺酸酯也是由D-甘油缩丙酮叉与对甲苯磺酰氯缩合而成,同样存在原材料价格昂贵,成本高等问题。
WO2007/145476采用R-缩水甘油为起始原材料,与磷酰胆碱缩合,再经离子交换树脂纯化得到L-α-GPC产品。工艺路线如下:
该方法简洁,收率高。但由于R-缩水甘油特别容易自身聚合。在生产的蒸馏纯化过程中,由于温度高,自身聚合特别快,不受控制且瞬间释放大量热量产生爆炸。所以R-缩水甘油根本无法通过工业化生产,因此原材料来源无法解决。
中国专利CN101544667A提出了用(S)-缩水甘油制成(2R)-对甲苯磺酸缩水甘油酯,然后再与磷酰基胆碱四烷基氢氧化铵加成物反应生成L-α-GPC氯化物,再通过离子交换树脂纯化得到产品。工艺路线如下:
其中,B=四丁基氢氧化铵;PC=磷酸胆碱。
同样的,(S)-缩水甘油也容易自身聚合,在蒸馏纯化过程中会瞬间聚合爆炸,原材料也不可能批量化得到。同时但该方法也存在磷酰基胆碱四烷基氢氧化铵与S-对甲苯磺酸缩水甘油酯产生开环的副反应,收率不高,且副反应杂质很难去除。
中国专利CN101967160A报道了采用3-卤代-1,2-丙二醇为原料,与磷酰基胆碱或磷酰基胆碱盐反应,制备DL、D或L-α-GPC的工艺。合成路线如下:
其中,X=F、Cl、Br、I;R=K、Na、Mg、Ca、Ba、Li或烷基。
该方法实际是3-卤代-1,2-丙二醇在磷酰基胆碱或磷酰基胆碱盐碱性条件作用下首先发生自身关环反应生成缩水甘油,继而缩水甘油再与磷酰基胆碱或磷酰基胆碱盐缩合得到α-GPC。由于反应过程中,缩水甘油还可以发生自身聚合的副反应,因此产生的杂质也很难去除。
中国专利CN101967160A提出了利用(R)-环氧氯丙烷与苄醇在强碱的作用下缩合制备(S)-苄基缩水甘油醚,然后将(S)-苄基缩水甘油醚与氯化磷酸胆碱反应制得L-α-氯化甘油磷酸胆碱苄基醚;再将所得到的L-α-氯化甘油磷酸胆碱苄基醚通过Pd/C加氢反应脱去苄基保护基,最后纯化即得L-α-GPC。合成路线如下:
该合成路线需要钯碳催化剂在高压下氢气脱苄基,成本高且危险性大。
发明内容
本发明所要解决的技术问题是提供一种L-α-甘油磷酸胆碱的制备方法,该方法避免了使用氯化磷酸胆碱钙盐或钾盐而造成的大量废水污染问题和最终产品必须过离子交换树脂柱除去氯离子的环节,产物纯度好,收率高,适于工业化生产,具有良好的应用前景。
本发明的一种L-α-甘油磷酸胆碱的制备方法,包括:
(1)将磷酸碱金属盐与(R)-3-氯-1,2-丙二醇按摩尔比1-2.5:1反应得到(R)-甘油磷酸酯碱金属盐,脱盐得到(R)-甘油磷酸酯;
(2)将(R)-甘油磷酸酯与二溴乙烷按摩尔比1:1-3反应得到(R)-3-甘油基环乙基磷酸酯;
(3)将(R)-3-甘油基环乙基磷酸酯与三甲胺按摩尔比1:1-3进行开环反应得到L-α-甘油磷酸胆碱。
所述步骤(1)中的磷酸碱金属盐为磷酸钾、磷酸钠或磷酸铯。
所述步骤(1)中的反应温度为45-50℃,反应时间为2-3小时。
所述步骤(2)中加入无水碳酸钾作为催化剂,与(R)-甘油磷酸酯的摩尔比为1-5:1。
所述步骤(2)中的反应温度为30-80℃,反应时间为9-10小时。
所述步骤(3)中的反应温度为室温,反应时间为5-6小时。
本发明针对现有L-α-GPC的合成方法的缺陷,提出了一种新的合成方法。本发明采用(R)-3-氯-1,2-丙二醇为起始原料,与磷酸碱金属盐作用合成制备(R)-甘油磷酸酯碱金属盐;然后再与二溴乙烷反应制备(R)-3-甘油基环乙基磷酸酯;最后与三甲胺进行开环反应得到L-α-甘油磷酸胆碱。
有益效果
(1)本发明原材料易得,并且生产过程废水排放少,环保压力小,产物纯度好,收率高;(2)本发明生产工艺节省了必须过离子交换树脂柱除去氯离子的环节,生产效率高,大幅度降低生产成本,适于工业化生产,具有良好的应用前景。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
(R)-甘油磷酸酯的制备
取磷酸钾212.3克(1mol),纯净水1000毫升,搅拌溶解,加热至45-50℃,滴加(R)-3-氯-1,2-丙二醇110克(1.0mol)。滴毕,保温反应2-3小时。冷却至室温,稀盐酸调pH值至4~5。蒸馏除去水分至干。加入500毫升乙醇加热回流,热过滤除去无机盐。蒸馏乙醇至干,得产物149.53克,收率87.43%。
实施例2
(R)-甘油磷酸酯的制备
取磷酸钠164克(1mol),纯净水1000毫升,搅拌溶解,加热至45-50℃,滴加(R)-3-氯-1,2-丙二醇100克(0.9mol)。滴毕,保温反应2-3小时。冷却至室温,稀盐酸调pH值至4~5。蒸馏除去水分至干。加入500毫升乙醇加热回流,热过滤除去无机盐。蒸馏乙醇至干,得产物130.86克,收率83.23%。
实施例3
(R)-3-甘油基环乙基磷酸酯的制备
取实施例1的(R)-甘油磷酸酯172克(1.0摩尔),无水乙醇1500毫升,室温下搅拌溶解,加入无水碳酸钾276.5克(2.0摩尔),苄基三乙基溴化铵5克(0.02摩尔;作用为相转移催化剂),二溴乙烷188克(1.0摩尔),加热至回流反应6小时,再次补加二溴乙烷94克(0.5摩尔),继续回流反应3小时。冷却至室温,过滤。蒸馏溶剂至干。加水500毫升,乙酸乙酯萃取。合并有机相,无水硫酸钠干燥,过滤。蒸馏溶剂至干,得白色固体产物130.02克,收率66.17%。
实施例4
L-α-GPC的制备
取实施例3的(R)-3-甘油基环乙基磷酸酯198克(1.0摩尔)与1500毫升无水乙醇混合,加入三甲胺177克(3.0摩尔),室温下反应5小时。TLC检查反应完全。展开剂为乙醚-石油醚(3:1),Rf=0.42。反应毕,减压浓缩,除去溶剂和过量的三甲胺,析出固体产物,无水乙醇:异丙醇=3:1重结晶(W/W),抽滤,50℃真空干燥4h,得白色固体236.76克,收率92.11%;纯度HPLC:99.68%,mp:145~147℃,[α]25D=-2.7°(c=2.7,H2O)。
核磁确认结构正确HNMR(d6-DMSO):δ3.20(s,9H,CH3);3.56~3.67(m,4H,J1=5.6;J2=6.0;J3=11.2;J4=5.2;J5=1.6;J6=2.4Hz,CH2);3.82~3.94(m,3H,J7=5.6;J8=3.2;J9=4.4;J10=4.0;J11=2.8;J12=3.6;J13=2.4Hz,CH2,CH);4.30(s,2H,CH2);4.79(br.,2H,OH)。
Claims (6)
1.一种L-α-甘油磷酸胆碱的制备方法,包括:
(1)将磷酸碱金属盐与(R)-3-氯-1,2-丙二醇按摩尔比1-2.5:1反应得到(R)-甘油磷酸酯碱金属盐,脱盐得到(R)-甘油磷酸酯;
(2)将(R)-甘油磷酸酯与二溴乙烷按摩尔比1:1-3反应得到(R)-3-甘油基环乙基磷酸酯;
(3)将(R)-3-甘油基环乙基磷酸酯与三甲胺按摩尔比1:1-3进行开环反应得到L-α-甘油磷酸胆碱。
2.根据权利要求1所述的一种L-α-甘油磷酸胆碱的制备方法,其特征在于:所述步骤(1)中的磷酸碱金属盐为磷酸钾、磷酸钠或磷酸铯。
3.根据权利要求1所述的一种L-α-甘油磷酸胆碱的制备方法,其特征在于:所述步骤(1)中的反应温度为45-50℃,反应时间为2-3小时。
4.根据权利要求1所述的一种L-α-甘油磷酸胆碱的制备方法,其特征在于:所述步骤(2)中加入无水碳酸钾作为催化剂,与(R)-甘油磷酸酯的摩尔比为1-5:1。
5.根据权利要求1所述的一种L-α-甘油磷酸胆碱的制备方法,其特征在于:所述步骤(2)中的反应温度为30-80℃,反应时间为9-10小时。
6.根据权利要求1所述的一种L-α-甘油磷酸胆碱的制备方法,其特征在于:所述步骤(3)中的反应温度为室温,反应时间为5-6小时。
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EP0486100A1 (en) * | 1990-11-15 | 1992-05-20 | MAGIS FARMACEUTICI S.p.A. | Process for preparing alpha-glycerophosphorylcholine |
WO2007145476A1 (en) * | 2006-06-14 | 2007-12-21 | Kim, Hyun Joo | A process for preparation of l-alpha-glycerophosphoryl choline |
CN101544667A (zh) * | 2008-03-27 | 2009-09-30 | 南京莱尔生物化工有限公司 | 一种L-α-甘油磷酸胆碱的合成方法 |
CN106459106A (zh) * | 2014-02-10 | 2017-02-22 | 酶科技株式会社 | 外消旋的或光学活性的α‑甘油磷酸胆碱的制备方法 |
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EP0486100A1 (en) * | 1990-11-15 | 1992-05-20 | MAGIS FARMACEUTICI S.p.A. | Process for preparing alpha-glycerophosphorylcholine |
WO2007145476A1 (en) * | 2006-06-14 | 2007-12-21 | Kim, Hyun Joo | A process for preparation of l-alpha-glycerophosphoryl choline |
CN101544667A (zh) * | 2008-03-27 | 2009-09-30 | 南京莱尔生物化工有限公司 | 一种L-α-甘油磷酸胆碱的合成方法 |
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