CN108191908B - 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
- Publication number
- CN108191908B CN108191908B CN201711464511.9A CN201711464511A CN108191908B CN 108191908 B CN108191908 B CN 108191908B CN 201711464511 A CN201711464511 A CN 201711464511A CN 108191908 B CN108191908 B CN 108191908B
- Authority
- CN
- China
- Prior art keywords
- phosphate
- glycerophosphorylcholine
- glycerol
- preparing
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- SUHOQUVVVLNYQR-MRVPVSSYSA-N choline alfoscerate Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title abstract description 11
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims abstract description 12
- SSZWWUDQMAHNAQ-VKHMYHEASA-N (R)-3-chloro-1,2-propanediol Chemical compound OC[C@@H](O)CCl SSZWWUDQMAHNAQ-VKHMYHEASA-N 0.000 claims abstract description 6
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 5
- 229910000318 alkali metal phosphate Inorganic materials 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- -1 phosphoric acid alkali metal salt Chemical class 0.000 claims description 8
- 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
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000011033 desalting Methods 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 2
- CPWJKGIJFGMVPL-UHFFFAOYSA-K tricesium;phosphate Chemical compound [Cs+].[Cs+].[Cs+].[O-]P([O-])([O-])=O CPWJKGIJFGMVPL-UHFFFAOYSA-K 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 abstract description 5
- 239000010452 phosphate Substances 0.000 abstract description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- YHHSONZFOIEMCP-UHFFFAOYSA-N 2-(trimethylazaniumyl)ethyl hydrogen phosphate Chemical compound C[N+](C)(C)CCOP(O)([O-])=O YHHSONZFOIEMCP-UHFFFAOYSA-N 0.000 description 9
- 229950004354 phosphorylcholine Drugs 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 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 description 5
- 239000003456 ion exchange resin Substances 0.000 description 5
- 229920003303 ion-exchange polymer Polymers 0.000 description 5
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 4
- 229960003178 choline chloride Drugs 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- CTKINSOISVBQLD-GSVOUGTGSA-N (R)-Glycidol Chemical compound OC[C@@H]1CO1 CTKINSOISVBQLD-GSVOUGTGSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-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
- 239000012535 impurity Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000002351 wastewater Substances 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
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 235000019743 Choline chloride Nutrition 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 2
- 230000003930 cognitive ability Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229960004063 propylene glycol Drugs 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000001308 synthesis 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
- BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 1
- 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
- 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
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- SUHOOTKUPISOBE-UHFFFAOYSA-N O-phosphoethanolamine Chemical compound NCCOP(O)(O)=O SUHOOTKUPISOBE-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
- 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
- 239000002585 base Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000004880 explosion Methods 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
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 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
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000005228 liver tissue Anatomy 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- AIIAHNREQDTRFI-UHFFFAOYSA-N oxiran-2-ylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1CO1 AIIAHNREQDTRFI-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 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
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000008439 repair process 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
- 239000007787 solid Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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***。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***,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***-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 (5)
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;其中,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;
(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)中的反应温度为30-80℃,反应时间为9-10小时。
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(3)中的反应温度为室温,反应时间为5-6小时。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711464511.9A CN108191908B (zh) | 2017-12-28 | 2017-12-28 | 一种L-α-甘油磷酸胆碱的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711464511.9A CN108191908B (zh) | 2017-12-28 | 2017-12-28 | 一种L-α-甘油磷酸胆碱的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108191908A CN108191908A (zh) | 2018-06-22 |
CN108191908B true CN108191908B (zh) | 2020-04-21 |
Family
ID=62585354
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711464511.9A Active CN108191908B (zh) | 2017-12-28 | 2017-12-28 | 一种L-α-甘油磷酸胆碱的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108191908B (zh) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1245736B (it) * | 1990-11-15 | 1994-10-14 | Magis Farmaceutici | Processo per preparare alfa-glicerofosforilcolina |
KR100966627B1 (ko) * | 2006-06-14 | 2010-06-29 | 주식회사 대웅제약 | L-α-글리세로포스포릴 콜린의 제조방법 |
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 |
KR101616945B1 (ko) * | 2014-02-10 | 2016-04-29 | 엔자이텍 주식회사 | 라세믹 또는 광학적으로 활성이 있는 α―글리세로포스포릴 콜린의 제조방법 |
-
2017
- 2017-12-28 CN CN201711464511.9A patent/CN108191908B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
CN108191908A (zh) | 2018-06-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103304594B (zh) | 一种L-α-甘油磷酸胆碱的制备方法 | |
CN101967160B (zh) | 一步法制备外消旋体DL、D或L-α-甘油磷酰基胆碱的方法 | |
US8658401B2 (en) | Method for preparing high purity L-α glycerylphosphorylcholine | |
AU2008212060A1 (en) | Process for preparing water-soluble phosphonooxymethyl derivatives of alcohol and phenol | |
KR101132589B1 (ko) | 베타인 제조 방법 | |
US9617288B2 (en) | Method for preparing racemic or optically active α-glycerophosphorylcholine | |
CN108822149B (zh) | 一种富马酸替诺福韦艾拉酚胺关键中间体的制备方法 | |
CN108191908B (zh) | 一种L-α-甘油磷酸胆碱的制备方法 | |
CN110372749A (zh) | 一种丙酚替诺福韦关键中间体一苯基pmpa的制备方法 | |
CN108467410B (zh) | 一种taf中间体的制备方法及产品和应用 | |
US7687652B2 (en) | Sphingomyelin, intermediates thereof and methods for preparation of same | |
EP1650215A1 (en) | Process for preparing lysophoshatidylcholine | |
CN105601705B (zh) | 一种硼替佐米的制备方法 | |
CN108101937B (zh) | 一种制备L-α-甘油磷脂酰胆碱的方法 | |
US20080255386A1 (en) | Process for preparing ibandronate | |
CN101928301B (zh) | 从右旋磷霉素左旋苯乙胺盐合成左旋磷霉素右旋苯乙胺盐的方法 | |
CN104230987A (zh) | 一种[1-卤代-(2-丙氧基)]-甲基膦酸类化合物及其制备和应用 | |
CN110256484B (zh) | 一种米替福新的制备方法 | |
CN116813664A (zh) | 一种L-α-甘磷酸胆碱的高效制备方法 | |
CN114213458A (zh) | 环丁胺端基的二硬脂酰磷脂酰胆碱及其制备方法 | |
CN111004279A (zh) | 一种磷系阻燃剂乙基膦酸二乙酯制备方法 | |
CN110759942A (zh) | 一种工业化生产甘磷酸胆碱的方法 | |
TW202311214A (zh) | 萜類胺基醇衍生物的純化方法 | |
CN117143145A (zh) | 二油酰基磷脂酰乙醇胺的制备方法 | |
CN118047690A (zh) | 含氟长链脂质体类化合物及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |