CN108101937A - A kind of method for preparing L- α-glycerolphosphocholine - Google Patents
A kind of method for preparing L- α-glycerolphosphocholine Download PDFInfo
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- CN108101937A CN108101937A CN201711115959.XA CN201711115959A CN108101937A CN 108101937 A CN108101937 A CN 108101937A CN 201711115959 A CN201711115959 A CN 201711115959A CN 108101937 A CN108101937 A CN 108101937A
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- Prior art keywords
- glycerine
- protection object
- hydroxyl protection
- preparation
- double hydroxyl
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- 238000000034 method Methods 0.000 title abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 48
- 230000004224 protection Effects 0.000 claims abstract description 48
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical class OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000002360 preparation method Methods 0.000 claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 33
- 239000007864 aqueous solution Substances 0.000 claims abstract description 20
- 150000002148 esters Chemical class 0.000 claims abstract description 11
- 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 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- 150000001298 alcohols Chemical class 0.000 claims abstract description 9
- 230000003197 catalytic effect Effects 0.000 claims abstract description 6
- 238000007171 acid catalysis Methods 0.000 claims abstract description 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 238000010511 deprotection reaction Methods 0.000 claims description 15
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 12
- GPHXPYZYAPXTJR-UHFFFAOYSA-N [K+].P(=O)#C[N+](CCO)(C)C Chemical compound [K+].P(=O)#C[N+](CCO)(C)C GPHXPYZYAPXTJR-UHFFFAOYSA-N 0.000 claims description 12
- 239000003456 ion exchange resin Substances 0.000 claims description 12
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 235000011187 glycerol Nutrition 0.000 claims description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- 229940011051 isopropyl acetate Drugs 0.000 claims description 8
- 239000003223 protective agent Substances 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 6
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 6
- QKLTWTXYGRNBIX-GSVOUGTGSA-N [(2R)-2,3-dihydroxypropyl] hypobromite Chemical compound BrOC[C@@H](CO)O QKLTWTXYGRNBIX-GSVOUGTGSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- -1 choline mono-sodium salt Chemical class 0.000 claims description 4
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- FSGHEPDRMHVUCQ-UHFFFAOYSA-N 2-ethoxyprop-1-ene Chemical class CCOC(C)=C FSGHEPDRMHVUCQ-UHFFFAOYSA-N 0.000 claims description 3
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical class C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 3
- ZKJNETINGMOHJG-GGWOSOGESA-N (e)-1-[(e)-prop-1-enoxy]prop-1-ene Chemical compound C\C=C\O\C=C\C ZKJNETINGMOHJG-GGWOSOGESA-N 0.000 claims description 2
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical group OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 claims description 2
- 229960001231 choline Drugs 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical group CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 18
- 239000010410 layer Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical group COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 12
- 238000000605 extraction Methods 0.000 description 11
- 239000012535 impurity Substances 0.000 description 11
- YFGXUSPKPCTVCX-UHFFFAOYSA-N [Na+].P(=O)#C[N+](CCO)(C)C Chemical group [Na+].P(=O)#C[N+](CCO)(C)C YFGXUSPKPCTVCX-UHFFFAOYSA-N 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 230000006837 decompression Effects 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000009835 boiling Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000013517 stratification Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 6
- 229950004354 phosphorylcholine Drugs 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
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 239000008777 Glycerylphosphorylcholine Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-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
- 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
- FZGBADVTTLOFPU-UHFFFAOYSA-N 2-(2-dodecanoyloxyethoxy)ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCCOC(=O)CCCCCCCCCCC FZGBADVTTLOFPU-UHFFFAOYSA-N 0.000 description 1
- QOFLTGDAZLWRMJ-UHFFFAOYSA-N 2-methylpropane-1,1-diol Chemical compound CC(C)C(O)O QOFLTGDAZLWRMJ-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- BZCGWAXQDLXLQM-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O.ClP(Cl)(Cl)=O BZCGWAXQDLXLQM-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- CQBPOPVKDNHISM-UHFFFAOYSA-N propane-1,2,3-triol;propan-2-one Chemical compound CC(C)=O.OCC(O)CO CQBPOPVKDNHISM-UHFFFAOYSA-N 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000000126 substance Substances 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
- C07F9/10—Phosphatides, e.g. lecithin
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
It is as follows comprising step the present invention provides a kind of preparation method of the L α glycerolphosphocholines of high-content：(1) reaction under the catalysis of acid generates the double hydroxyl protection object I of halogenated glycerine to halogenated glycerine with ester；(2) double hydroxyl protection object II crude products of phosphorylcholine salt and the double hydroxyl protection object I reactions generation L α glycerolphosphocholines of halogenated glycerine；(3) double hydroxyl protection object II of L α glycerolphosphocholines are separated with the double hydroxyl protection object I of unreacted halogenated glycerine, double hydroxyl protection object II of the L α glycerolphosphocholines purified；(4) double hydroxyl protection object II aqueous solutions of the L α glycerolphosphocholines of purifying, which react to be deprotected under catalytic amount acid catalysis, obtains L α glycerolphosphocholine aqueous solutions; remove moisture under reduced pressure; it is crystallized with alcohols solvent, obtains L α glycerolphosphocholines.Technical scheme is compared with the prior art, and purity is high, and high income, technique is suitable for industrialized production.
Description
Technical field：
The present invention relates to pharmaceutical chemistry technical fields, and in particular to a kind of preparation method of L- α-glycerolphosphocholine.
Background technology：
L- α-glycerolphosphocholine (L-alpha-Glycerphosphatidylcholine, abbreviation GPC) is a kind of tool
Having improves the active material of brain function, has certain effect for prevention and auxiliary treatment senile dementia.
The known technological means for obtaining GPC is mainly by two kinds：One kind is to be extracted from natural products, such as from yolk
Egg yolk lecithin is extracted, soybean lecithin is lifted from soybean.Further obtained by chemical method or enzymatic hydrolysis separating-purifying
GPC (such as US5250719, US5315023, US6274362, EP217765 etc.).
Second method is that chemical synthesis obtains.
It is obtained from natural products since raw material sources, place of production difference have differences parameter, separates the complex process of impurity,
It is higher to industrialize cost.The distinct methods report of synthetic method is more in recent years, and synthetic method is compared to natural extraction method with work
Skill is relatively easy, Control of Impurities is good, and impurity is less.
Such as：European patent EP 0486100 is reported, using the isopropylidene glycerol-4-methanol of double hydroxyl protections, with diethylene glycol dilaurate list
Phosphoryl chloride phosphorus oxychloride reacts, and forms phosphotriester, then acetone glycerol choline phosphate is obtained by the reaction under elevated pressure with trimethylamine, finally
Hydrolysis deprotection obtains GPC crude products in dilute hydrochloric acid, and total recovery 50%, reaction equation is described as follows：
Japan Patent JP2007/269657 reports employ above-mentioned similar method.
What European patent EP 0502357 was reported is to protect double acetylating hydroxyl groups of glycerine, then route similar to the above
It carries out that GPC is prepared.
It reports that chiral glycidol is condensed with phosphatldylcholine in WO2007/145476, is obtained by purifying resin
GPC.This technique simplifies, but glycidol activity is strong, and polymerisation itself easily occurs, also can be with the hydroxyl of the product of generation into one
Step condensation, so impurity is more.
Chinese patent CN101544667A on the basis of the above, protects the hydroxyl of glycidol so that generation
Product further will not become impurity with glycidol reaction, there is certain effect.
Korean Patent KR2009/128631 is reacted using glycidol with phosphatidyl choline in sodium hydrate aqueous solution,
Water layer is washed with ethyl acetate again, after condensed water ethyl alcohol crystallization is added to obtain GPC products.It equally exists multiple caused by glycidol
The formation of impurity influences.
Chinese patent CN101967160A generates thick GPC and nothing using Phosphorylcholine inorganic salts and halogenated glycerine reaction
Machine salt halide filters out a large amount of inorganic salts, and crude product contains a small amount of inorganic salts, unreacted raw material and impurity, due to impurity
Water-soluble fine, acetone solubility is smaller, it is necessary to be washed with a large amount of acetone extracts, and actually also needing to purifying resin can just obtain
GPC sterlings.
Chinese patent CN103665028A discloses a kind of preparation method of L- α-Choline Glycerophosphate, with (2S) -3- it is halogenated -
1,2- propylene oxide is raw material with phosphorylcholine salt, obtains L- α-Choline Glycerophosphate after esterification, hydrolysis in a solvent
Crude product, then obtain L- α-Choline Glycerophosphate sterling through silica gel column chromatography, ion-exchange resin purification.But this method preparation L- α-
The Choline Glycerophosphate reaction time is longer, and yield is not high.
The content of the invention：
It is completed it is an object of the invention to provide a kind of easy industrialization, high income and easy purifying obtain high-purity
GPC new synthetic methods.
The invention is realized by the following technical scheme：
Double hydroxyl protection object II (Formula II) of L- α-glycerolphosphocholine (L- α-GPC) are anti-under catalytic amount acid catalysis
It should be deprotected to obtain L- α-glycerolphosphocholine,
Formula IIWherein R is alkyl.
Specifically, L- α-glycerolphosphocholine synthetic method includes the following steps：
(1) reaction under the catalysis of acid generates the double hydroxyl protection object I (formulas of the halogenated glycerine of (R) -3- to halogenated glycerine with protective agent
I), Formulas IWherein R is alkyl, and X is halogen；
(2) phosphorylcholine salt and the double hydroxyl protection object I reactions generation L- α-glycerophosphatide acyl courages of the halogenated glycerine of (R) -3-
Double hydroxyl protection object II (Formula II) crude products of alkali；
(3) by double hydroxyl protection object II of L- α-glycerolphosphocholine and the double hydroxyls of the halogenated glycerine of unreacted (R) -3-
Protection I is separated, double hydroxyl protection object II of the L- α-glycerolphosphocholine purified；
(4) double hydroxyl protection object II aqueous solutions of L- α-glycerolphosphocholine of purifying react under catalytic amount acid catalysis
Deprotection obtains L- α-glycerolphosphocholine aqueous solution, removes moisture under reduced pressure, is crystallized with alcohols solvent, obtains L- α-glycerine phosphorus
Phosphatidylcholine.
In step (1), the halogenated glycerine is (R) -3- glycerin chlorohydrins or (R) -3- bromo glycerine.
In step (1), the protective agent is selected from alkyl orthoformate, triethyl orthoformate, vinyl ethers, acrylic
The one or more of ether, 2- methoxyl groups propylene or 2- ethoxy propylenes.
In step (1), with molar amount, the protective agent inventory is more than or equal to 1.2 times of halogenated glycerine.
In step (1), acid is selected from p-methyl benzenesulfonic acid, anhydrous hydrogen chloride, the concentrated sulfuric acid, anhydrous oxalic acid, with molar amount, dosage
For the 1-10% of reactant.
In step (1), reaction temperature is 10-110 DEG C, is preferably 40-80 DEG C.
In step (1), react and carried out under negative pressure condition.
In step (1), reaction time control is in 1-15h, preferably 5-10h.
In step (1), after reaction, extra protective agent is recovered under reduced pressure.
(R) R=CH in the double hydroxyl protection object I of the halogenated glycerine of -3-3Or C2H5, X=Cl or Br；L- α-glycerophosphatide acyl courage
R=CH in double hydroxyl protection object II of alkali3Or C2H5。
In step (2), the phosphorylcholine salt is phosphorylcholine mono-sodium salt and/or phosphorylcholine monopotassium salt.
The step (2) is anti-in alcohols solvent for phosphorylcholine salt and the double hydroxyl protection object I of the halogenated glycerine of (R) -3-
Double hydroxyl protection object II of L- α-glycerolphosphocholine should be generated, alcohols solvent is recycled, is dissolved in water to obtain L- α-glycerine phosphorus
The crude product aqueous solution of double hydroxyl protection object II of phosphatidylcholine, wherein, with molar amount, the double hydroxyl protections of the halogenated glycerine of (R) -3-
The inventory of object I is 1.2 to 3.0 times of phosphorylcholine salt, is preferably 1.5 times.
In step (2), the alcohols solvent is selected from methanol, ethyl alcohol, isopropanol.
In step (2), reaction temperature is 50-90 DEG C, is preferably 65-85 DEG C.
Preferably, in step (2), reaction time 1min-5h is preferably 0.5-2h.
The step (3) for double hydroxyl protection object II of L- α-glycerolphosphocholine crude product aqueous solution with water-insoluble
Organic solvent extracts the double hydroxyl protection object I of the halogenated glycerine of unreacted (R) -3-, discards organic phase, the L- α-glycerine purified
Double hydroxyl protection object II of phosphatidyl choline.
In step (3), extractant is ether solvent such as methyl tertiary butyl ether(MTBE) or esters solvent such as ethyl acetate, acetic acid
Isobutyl ester, isopropyl acetate, n-propyl acetate.
In step (4), the acid is adjusted pH value of solution to 1-3 selected from dilute hydrochloric acid, dilute sulfuric acid.
In step (4), deprotection reaction temperature is 10-40 DEG C, is preferably 20-30 DEG C.
In step (4), after deprotection, L- α-glycerolphosphocholine aqueous solution is removed into hydrochloric acid by ion exchange resin
With remaining inorganic salts.
In step (4), the alcohols solvent is isobutanol.
Preferably, in step (4), reaction time 1min-5h is preferably 0.5-2h.
The product purity prepared by this method is more than 99.8%, is calculated with Phosphorylcholine salt, and overall yield of reaction is more than 88%.
The halogenated glycerine of (the R) -3-, phosphorylcholine list potassium (sodium) salt can be obtained from market purchasing.
The synthesis of GPC there are two difficult point needs to overcome, one is the control of inorganic salts, it is desirable that inorganic salts residual 0.01% with
Under, can inorganic salts be removed by resins exchange.Second difficult point is the removal of impurity.Second point is most crucial technology, on
The method for stating most introductions is to surround that deimpurity principle is gone to carry out highway route design.The present invention is by by the two of halogenated glycerine
A hydroxyl protection so that the intermediate polarity after protection becomes smaller, and solubility in water substantially becomes smaller, in common organic solvents
Solubility greatly enhance, so as to become very big with the polarity difference of product so that after the completion of reaction, it is only necessary to simply will production
Object is dissolved in the water, and carries out extracting and demixing with for example environment amenable solvent esters solvent of organic solvent, that is, realizes product
Purifying.And the ingredient proportion by increasing intermediate compound I, make another starting raw material phosphor acyl group choline list potassium (sodium) reactant salt complete
Entirely, the reaction was complete not only greatly improves its reaction yield for this raw material, and will not remain and form impurity in the product.By upper
Content can finally be obtained more than 99.8% by stating scheme, and the effect of molar yield more than 88% has reached the mesh of invention
's.
Specific reaction equation is as follows：
R=CH3、C2H5；X=Cl, Br (I)
R=CH3、C2H5；M=Na, K
In the present invention, the halogenated glycerine of (R) -3- is specially (R) -3- glycerin chlorohydrins or (R) -3- bromo glycerine, both are former
Material can be cheaper commercially to obtain.Protective agent is preferably trimethyl orthoformate or triethyl orthoformate.Also may be used
To select vinyl ethers, propenyl ether, 2- methoxyl groups propylene or 2- ethoxy propylenes, obtain being acetal or ketal class after protection
Compound, the main description trimethyl orthoformate of the present invention or triethyl orthoformate are as protectant technical solution.
During halogenated with the 3- glycerine reaction of trimethyl orthoformate or ethyl ester, since two kinds of reactants are liquid, during reaction not
With solvent, more than trimethyl orthoformate or the excessive 1.2 times of equivalents of ethyl ester, even if trimethyl orthoformate or ethyl ester substantially exceed
Amount needed for reaction, also has facilitation for reaction speed, shortens the time of reaction, and reaction charging sequence does not have any want
It asks, but the acid of catalytic amount is needed to carry out catalysis to accelerate reaction, sour dosage is generally the 1-10% equivalents of reactant,
Can be p-methyl benzenesulfonic acid, anhydrous hydrogen chloride, the concentrated sulfuric acid, anhydrous oxalic acid etc. for common inorganic acid.Reaction temperature is in 40-80
℃.Temperature is less than this scope, and the reaction time needs longer.Reaction preferably carries out under certain negative pressure condition, reaction process
The methanol or ethyl alcohol of middle generation are steamed by decompression, are conducive to the complete conversion of reaction, it is possible to reduce trimethyl orthoformate or second
The usage amount of ester.Reaction converts complete generally when 5-10 is small.Reaction finishes is recovered under reduced pressure extra raw material orthoformic acid three again
Methyl esters or ethyl ester, obtained product can be directly used for reacting in next step.
Another raw material of the present invention is Phosphorylcholine monopotassium salt and Phosphorylcholine mono-sodium salt.Due to sylvite and chloro thing
Reactivity is higher than sodium salt, and preferably Phosphorylcholine monopotassium salt is another synthesis segment in the present invention.
Solvent used in second step esterification is alcohols solvent, including methanol, ethyl alcohol, isopropanol.Reaction temperature 65-
85℃.(R) inventory of the double hydroxyl protection object I of the halogenated glycerine of -3- is 1.2 to 3.0 equivalents of Phosphorylcholine list potassium (sodium) salt, excellent
Select 1：1.5 equivalent.Make Phosphorylcholine list potassium (sodium) reactant salt complete by detection.Reaction finishes, and reaction dissolvent is recovered under reduced pressure, into
Row purifying, purification process are simple two-phase extraction.I.e.：Directly add water and extractant, extractant can be ether solvent
Such as methyl tertiary butyl ether(MTBE), esters solvent is such as ethyl acetate, isobutyl acetate, isopropyl acetate, n-propyl acetate.Extraction
Unreacted raw material and the double hydroxyl protection objects of impurity glycerine for decomposing generation.Organic phase is discarded, water mutually as purifies obtained II.
Second step reaction product abstraction purification finishes, and adds in catalytic amount diluted acid inorganic acid such as dilute hydrochloric acid, dilute sulfuric acid, dilute
Sour addition is to adjust aqueous solution to 1-3.Deprotection reaction temperature is room temperature.Reaction finishes, and the aqueous solution of obtained GPC leads to
Ion exchange resin removing hydrochloric acid and remaining inorganic salts are crossed, product steams moisture, adds in isobutanol alcohol crystallization and obtains white powder
Last shape solid is dried under reduced pressure solvent and obtains the GPC products that purity is more than 99.8%.It is calculated with Phosphorylcholine list potassium (sodium) salt, instead
It is more than 88% to answer total recovery.
Beneficial effects of the present invention：(1) using the method for the present invention preparation L- α-glycerolphosphocholine, its is simple for process, easily
In industrialized production；(2) L- α-glycerolphosphocholine prepared by the method for the present invention is used compared with the prior art, purity
Height, overall yield of reaction are high.
Specific embodiment
Here exemplary embodiment will be illustrated in detail.Embodiment described in following exemplary embodiment
Do not represent all embodiments consistent with the present invention.On the contrary, they be only with as being described in detail in the appended claims
, the examples of the apparatus and method that some aspects of the invention are consistent.
It is only merely for the purpose of description specific embodiment in terminology used in the present invention, is not intended to limit the invention.
It is also intended in " one kind " of singulative of the invention and used in the attached claims, " described " and "the" including majority
Form, unless context clearly shows that other meanings.It is also understood that term "and/or" used herein refers to and wraps
Containing one or more associated list items purposes, any or all may be combined.
It will be appreciated that though various information, but this may be described using term first, second, third, etc. in the present invention
A little information should not necessarily be limited by these terms.These terms are only used for same type of information being distinguished from each other out.For example, it is not departing from
In the case of the scope of the invention, the first information can also be referred to as the second information, and similarly, the second information can also be referred to as
One information.Depending on linguistic context, word as used in this " if " can be construed to " ... when " or " when ...
When " or " in response to determining ".
The present invention will be described in detail by way of examples below.
Comparative example 1
L- α-glycerolphosphocholine is prepared using the preparation method of EP0502357.
Comparative example 2
The preparation method of CN103665028A prepares L- α-glycerolphosphocholine.
Embodiment 1
(R) preparation of -2- methoxyl groups -4- chloromethyls -1,3- dioxo pentamethylene.
In 500mL vials, (R) -3- glycerin chlorohydrins 115.5g (1.0 moles), trimethyl orthoformate 138.0g are weighed
(1.3 moles), p-methyl benzenesulfonic acid 19.0g, after mixing, stirring is heated to 70-90 DEG C of reaction, is steamed in reaction process from still head
Go out low boiling material, predominantly methanol and a small amount of methyl formate.GC detect reaction process, about 6 it is small when the reaction was complete.It has reacted
Finish, be cooled to room temperature, add in sodium methoxide and be neutralized to pH=6-7.First heating low boiling point solvent is recovered under reduced pressure, then-
0.096Mpa collects 102-105 DEG C of fraction, obtains 143.4g products, yield 91%.
Embodiment 2
(R) preparation of -2- ethyoxyls -4- chloromethyls -1,3- dioxo pentamethylene.
In 500mL vials, (R) -3- glycerin chlorohydrins 115.5g (1.0 moles), triethyl orthoformate 192.5g are weighed
(1.3 moles), p-methyl benzenesulfonic acid 19.0g, after mixing, stirring is heated to 70-90 DEG C of reaction, is steamed in reaction process from still head
Go out low boiling material, predominantly ethyl alcohol and a small amount of Ethyl formate.GC detect reaction process, about 8 it is small when the reaction was complete.It has reacted
Finish, be cooled to room temperature, add in sodium ethoxide and be neutralized to pH=6-7.First heating low boiling point solvent is recovered under reduced pressure, then-
0.096Mpa collects 114-116 DEG C of fraction, obtains 154.5g products, yield 90%.
Embodiment 3
(R) preparation of -2- methoxyl groups -4- bromomethyls -1,3- dioxo pentamethylene.
In 500mL vials, (R) -3- bromo glycerine 199.0g (1.0 moles), trimethyl orthoformate 138.0g are weighed
(1.3 moles), p-methyl benzenesulfonic acid 19.0g, after mixing, stirring is heated to 70-90 DEG C of reaction, is steamed in reaction process from still head
Go out low boiling material, predominantly methanol and a small amount of methyl formate.GC detect reaction process, about 6 it is small when the reaction was complete.It has reacted
Finish, be cooled to room temperature, add in sodium methoxide and be neutralized to pH=6-7.First low boiling point solvent is recovered under reduced pressure in heating, then left in 100pa
68-73 DEG C of fraction of right collection, obtains 177.8g products, yield 88%.
Embodiment 4
(R) preparation of -2- ethyoxyls -4- bromomethyls -1,3- dioxo pentamethylene.
In 500mL vials, (R) -3- bromo glycerine 199.0g (1.0 moles), triethyl orthoformate 192.5g are weighed
(1.3 moles), p-methyl benzenesulfonic acid 19.0g, after mixing, stirring is heated to 70-90 DEG C of reaction, is steamed in reaction process from still head
Go out low boiling material, predominantly ethyl alcohol and a small amount of Ethyl formate.GC detect reaction process, about 8 it is small when the reaction was complete.It has reacted
Finish, be cooled to room temperature, add in sodium ethoxide and be neutralized to pH=6-7.First low boiling point solvent is recovered under reduced pressure in heating, then left in 100pa
118-121 DEG C of fraction of right collection, obtains 161.5g products, yield 87%.
The preparation of embodiment 5L- α-GPC
In 500mL four-hole bottles, Phosphorylcholine monopotassium salt 44.2g (0.2mol), (R) -2- methoxyl group -4- chloromethanes are added in
Base -1,3- dioxo pentamethylene 45.7g (0.3mol), absolute ethyl alcohol 250mL, when back flow reaction 20 is small more than, HPLC detections are former
Expect that Phosphorylcholine monopotassium salt is less than less than 0.5%, stop being heated to reflux, etoh solvent is recovered under reduced pressure to dry, residue addition drink
With water 150mL and ethyl acetate 100mL, after ten minutes, stratification discards organic layer, and water layer uses ethyl acetate again for stirring
100mL is extracted 2 times, discards organic layer.Hydrochloric acid is added dropwise into the water layer after extraction, makes pH that it is small to be stirred to react 5 at room temperature for 1-2
When more than, after deprotection completely, the remaining inorganic salts of spent ion exchange resin removing, the aqueous solution decompression containing GPC steams water
Point, isobutanol 200mL is added in into residue, cooling and stirring crystallization filters, dry, obtains white powder GPC solids
45.2g, yield 88%.
The preparation of embodiment 6L- α-GPC
In 500mL four-hole bottles, Phosphorylcholine monopotassium salt 44.2g (0.2mol), (R) -2- methoxyl group -4- bromine first are added in
Base -1,3- dioxo pentamethylene 47.3g (0.24mol), absolute ethyl alcohol 250mL, when back flow reaction 10 is small more than, HPLC detections are former
Expect that Phosphorylcholine monopotassium salt is less than less than 0.5%, stop being heated to reflux, etoh solvent is recovered under reduced pressure to dry, residue addition drink
With water 150mL and isopropyl acetate 100mL, after ten minutes, stratification discards organic layer, and water layer uses isopropyl acetate again for stirring
Ester 100mL is extracted 2 times, discards organic layer.Hydrochloric acid is added dropwise into the water layer after extraction, pH is made to be stirred to react 5 at room temperature for 1-2
Hour or more, after deprotection completely, the remaining inorganic salts of spent ion exchange resin removing, the aqueous solution decompression containing GPC steams
Moisture adds in isobutanol 200mL into residue, and cooling and stirring crystallization filters, dry, obtains white powder GPC solids
46.7g, yield 91%.
The preparation of embodiment 7L- α-GPC
In 500mL four-hole bottles, Phosphorylcholine mono-sodium salt 41.0g (0.2mol), (R) -2- methoxyl group -4- chloromethanes are added in
Base -1,3- dioxo pentamethylene 45.7g (0.3mol), absolute ethyl alcohol 250mL, when back flow reaction 36 is small more than, HPLC detections are former
Expect that Phosphorylcholine mono-sodium salt is less than less than 0.5%, stop being heated to reflux, etoh solvent is recovered under reduced pressure to dry, residue addition drink
With water 150mL and ethyl acetate 100mL, after ten minutes, stratification discards organic layer, and water layer uses ethyl acetate again for stirring
100mL is extracted 2 times, discards organic layer.Hydrochloric acid is added dropwise into the water layer after extraction, makes pH that it is small to be stirred to react 5 at room temperature for 1-2
When more than, after deprotection completely, the remaining inorganic salts of spent ion exchange resin removing, the aqueous solution decompression containing GPC steams water
Point, isobutanol 200mL is added in into residue, cooling and stirring crystallization filters, dry, obtains white powder GPC solids
45.0g, yield 87.6%.
The preparation of embodiment 8L- α-GPC
In 500mL four-hole bottles, Phosphorylcholine mono-sodium salt 41.0g (0.2mol), (R) -2- methoxyl group -4- bromine first are added in
Base -1,3- dioxo pentamethylene 47.3g (0.24mol), absolute ethyl alcohol 250mL, when back flow reaction 20 is small more than, HPLC detections are former
Expect that Phosphorylcholine mono-sodium salt is less than less than 0.5%, stop being heated to reflux, etoh solvent is recovered under reduced pressure to dry, residue addition drink
With water 150mL and isobutyl acetate 100mL, after ten minutes, stratification discards organic layer, and water layer uses Sucrose Acetate again for stirring
Ester 100mL is extracted 2 times, discards organic layer.Hydrochloric acid is added dropwise into the water layer after extraction, pH is made to be stirred to react 5 at room temperature for 1-2
Hour or more, after deprotection completely, the remaining inorganic salts of spent ion exchange resin removing, the aqueous solution decompression containing GPC steams
Moisture adds in isobutanol 200mL into residue, and cooling and stirring crystallization filters, dry, obtains white powder GPC solids
45.3g, yield 88.4%.
The preparation of embodiment 9L- α-GPC
In 500mL four-hole bottles, Phosphorylcholine monopotassium salt 44.2g (0.2mol), (R) -2- ethyoxyl -4- chloromethanes are added in
Base -1,3- dioxo pentamethylene 50.0g (0.3mol), absolute ethyl alcohol 250mL, when back flow reaction 20 is small more than, HPLC detections are former
Expect that Phosphorylcholine monopotassium salt is less than less than 0.5%, stop being heated to reflux, etoh solvent is recovered under reduced pressure to dry, residue addition drink
With water 150mL and isopropyl acetate ester 100mL, after ten minutes, stratification discards organic layer, and water layer is different with acetic acid again for stirring
Propyl ester 100mL is extracted 2 times, discards organic layer.Hydrochloric acid is added dropwise into the water layer after extraction, pH is made to be stirred to react at room temperature for 1-2
5 it is small when more than, after deprotection completely, the remaining inorganic salts of spent ion exchange resin removing, the aqueous solution decompression containing GPC steams
Moisture adds in isobutanol 200mL into residue, and cooling and stirring crystallization filters, dry, obtains white powder GPC solids
45.3g, yield 88.2%.
The preparation of embodiment 10L- α-GPC
In 500mL four-hole bottles, Phosphorylcholine monopotassium salt 44.2g (0.2mol), (R) -2- ethyoxyl -4- bromine first are added in
Base -1,3- dioxo pentamethylene 50.7g (0.24mol), absolute ethyl alcohol 250mL, when back flow reaction 10 is small more than, HPLC detections are former
Expect that Phosphorylcholine monopotassium salt is less than less than 0.5%, stop being heated to reflux, etoh solvent is recovered under reduced pressure to dry, residue addition drink
With water 150mL and isopropyl acetate 100mL, after ten minutes, stratification discards organic layer, and water layer uses isopropyl acetate again for stirring
Ester 100mL is extracted 2 times, discards organic layer.Hydrochloric acid is added dropwise into the water layer after extraction, pH is made to be stirred to react 5 at room temperature for 1-2
Hour or more, after deprotection completely, the remaining inorganic salts of spent ion exchange resin removing, the aqueous solution decompression containing GPC steams
Moisture adds in isobutanol 200mL into residue, and cooling and stirring crystallization filters, dry, obtains white powder GPC solids
46.2g, yield 90%.
The preparation of embodiment 11L- α-GPC
In 500mL four-hole bottles, Phosphorylcholine mono-sodium salt 41.0g (0.2mol), (R) -2- ethyoxyl -4- chloromethanes are added in
Base -1,3- dioxo pentamethylene 50.0g (0.3mol), absolute ethyl alcohol 250mL, when back flow reaction 36 is small more than, HPLC detections are former
Expect that Phosphorylcholine mono-sodium salt is less than less than 0.5%, stop being heated to reflux, etoh solvent is recovered under reduced pressure to dry, residue addition drink
With water 150mL and isobutyl acetate ester 100mL, after ten minutes, stratification discards organic layer, and water layer is different with acetic acid again for stirring
Butyl ester 100mL is extracted 2 times, discards organic layer.Hydrochloric acid is added dropwise into the water layer after extraction, pH is made to be stirred to react at room temperature for 1-2
5 it is small when more than, after deprotection completely, the remaining inorganic salts of spent ion exchange resin removing, the aqueous solution decompression containing GPC steams
Moisture adds in isobutanol 200mL into residue, and cooling and stirring crystallization filters, dry, obtains white powder GPC solids
45.0g, yield 87.6%.
The preparation of embodiment 12L- α-GPC
In 500mL four-hole bottles, Phosphorylcholine mono-sodium salt 41.0g (0.2mol), (R) -2- ethyoxyl -4- bromine first are added in
Base -1,3- dioxo pentamethylene 63.3g (0.3mol), absolute ethyl alcohol 250mL, when back flow reaction 20 is small more than, HPLC detections are former
Expect that Phosphorylcholine mono-sodium salt is less than less than 0.5%, stop being heated to reflux, etoh solvent is recovered under reduced pressure to dry, residue addition drink
With water 150mL and isobutyl acetate 100mL, after ten minutes, stratification discards organic layer, and water layer uses Sucrose Acetate again for stirring
Ester 100mL is extracted 2 times, discards organic layer.Hydrochloric acid is added dropwise into the water layer after extraction, pH is made to be stirred to react 5 at room temperature for 1-2
Hour or more, after deprotection completely, the remaining inorganic salts of spent ion exchange resin removing, the aqueous solution decompression containing GPC steams
Moisture adds in isobutanol 200mL into residue, and cooling and stirring crystallization filters, dry, obtains white powder GPC solids
45.5g, yield 88.8%.
The detection of purity and the calculating of yield are carried out to the product of embodiment 5-12 and comparative example 1,2, as a result such as 1 institute of table
Show.According to table 1 as a result, L- α-GPC prepared by the method for the present invention, whether purity or yield, are higher than the prior art
Preparation method (comparative example 1, comparative example 2), and data have statistical significance (P ＜ 0.01).
GPC purity and yield in 1 embodiment 5-12 of table
It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, may be used also
With to the present invention, some improvement and modification can also be carried out, these improvement and modification are also fallen into the protection domain of the claims in the present invention.
Claims (13)
1. a kind of preparation method of L- α-glycerolphosphocholine of high-content, it is characterised in that：Include the following steps：By L- α-
Double hydroxyl protection object II (Formula II) of glycerolphosphocholine react deprotection under catalytic amount acid catalysis and obtain L- α-glycerine phosphorus
Phosphatidylcholine,
Formula IIWherein R is alkyl.
2. according to the preparation method described in claim 1, it is characterised in that：Double hydroxyl protections of L- α-glycerolphosphocholine
The preparation method of object II includes the following steps：
(1) reaction under the catalysis of acid generates the double hydroxyl protection object I (Formulas I) of the halogenated glycerine of (R) -3- to halogenated glycerine with protective agent,
Formulas IWherein R is alkyl, and X is halogen；
(2) phosphorylcholine salt and the double hydroxyl protection object I reactions generation L- α-glycerolphosphocholines of the halogenated glycerine of (R) -3-
Double hydroxyl protection object II crude products；
(3) by double hydroxyl protection object II of L- α-glycerolphosphocholine and the double hydroxyl protections of the halogenated glycerine of unreacted (R) -3-
Object I is separated, double hydroxyl protection object II of the L- α-glycerolphosphocholine purified.
3. preparation method according to claim 2, it is characterised in that：In step (1), the halogenated glycerine is (R) -3- chlorine
For glycerine or (R) -3- bromo glycerine.
4. preparation method according to claim 2, it is characterised in that：In step (1), the protective agent is selected from orthoformic acid
Trialkyl ester, triethyl orthoformate, vinyl ethers, propenyl ether, one kind or several of 2- methoxyl groups propylene or 2- ethoxy propylenes
Kind.
5. preparation method according to claim 2, it is characterised in that：In step (1), with molar amount, the protective agent
Inventory is more than or equal to 1.2 times of halogenated glycerine.
6. preparation method according to claim 2, it is characterised in that：In step (1), acid is selected from p-methyl benzenesulfonic acid, anhydrous
Hydrogen chloride, the concentrated sulfuric acid, anhydrous oxalic acid, with molar amount, dosage is the 1-10% of reactant.
7. preparation method according to claim 2, it is characterised in that：(R) R in the double hydroxyl protection object I of the halogenated glycerine of -3-
=CH3Or C2H5, X=Cl or Br；R=CH in double hydroxyl protection object II of L- α-glycerolphosphocholine3Or C2H5。
8. preparation method according to claim 2, it is characterised in that：In step (2), the phosphorylcholine salt is phosphinylidyne
Base choline mono-sodium salt and/or phosphorylcholine monopotassium salt.
9. according to any preparation method in claim 2-7, it is characterised in that：The step (2) is phosphoryl courage
Alkali salt reacts double hydroxyls of generation L- α-glycerolphosphocholine with the double hydroxyl protection object I of the halogenated glycerine of (R) -3- in alcohols solvent
Base protection II recycles alcohols solvent, is dissolved in water to obtain the crude product of double hydroxyl protection object II of L- α-glycerolphosphocholine
Aqueous solution, wherein, with molar amount, the inventory of the double hydroxyl protection object I of the halogenated glycerine of (R) -3- is the 1.2 of phosphorylcholine salt
To 3.0 times.
10. according to the preparation method described in claim 2, it is characterised in that：The step (3) is L- α-glycerophosphatide acyl courage
The crude product aqueous solution of double hydroxyl protection object II of alkali extracts unreacted (R) -3- halogenated glycerine pair with water-insoluble organic solvent
Hydroxyl protection object I, discards organic phase, double hydroxyl protection object II of the L- α-glycerolphosphocholine purified.
11. preparation method according to claim 10, it is characterised in that：In step (3), extractant is ether solvent first
Base tertbutyl ether or esters solvent ethyl acetate, isobutyl acetate, isopropyl acetate or n-propyl acetate.
12. preparation method according to claim 1, it is characterised in that：The acid is selected from dilute hydrochloric acid, dilute sulfuric acid, by solution
PH is adjusted to 1-3.
13. preparation method according to claim 1, it is characterised in that：After deprotection, by L- α-glycerolphosphocholine water
Solution removes hydrochloric acid and remaining inorganic salts by ion exchange resin.
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| CN110128467A (en) * | 2019-05-07 | 2019-08-16 | 天津康巢生物医药股份有限公司 | A kind of process of purification of glycerol phosphatidyl choline crude product and its obtained glycerolphosphocholine |
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| CN110128467A (en) * | 2019-05-07 | 2019-08-16 | 天津康巢生物医药股份有限公司 | A kind of process of purification of glycerol phosphatidyl choline crude product and its obtained glycerolphosphocholine |
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