KR20100094004A - METHOD FOR PREPARING RACEMIC OR OPTICALLY ACTIVE α-GLYCEROPHOSPHORYL CHOLINE - Google Patents
METHOD FOR PREPARING RACEMIC OR OPTICALLY ACTIVE α-GLYCEROPHOSPHORYL CHOLINE Download PDFInfo
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- KR20100094004A KR20100094004A KR1020090013202A KR20090013202A KR20100094004A KR 20100094004 A KR20100094004 A KR 20100094004A KR 1020090013202 A KR1020090013202 A KR 1020090013202A KR 20090013202 A KR20090013202 A KR 20090013202A KR 20100094004 A KR20100094004 A KR 20100094004A
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- South Korea
- Prior art keywords
- racemic
- optically active
- buffer
- reaction
- mixtures
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 28
- 229960004788 choline alfoscerate Drugs 0.000 title abstract description 10
- SUHOQUVVVLNYQR-MRVPVSSYSA-O glycerylphosphorylcholine Chemical compound C[N+](C)(C)CCO[P@](O)(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-O 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- SUHOQUVVVLNYQR-MRVPVSSYSA-N choline alfoscerate Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 claims abstract description 41
- 239000000872 buffer Substances 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 16
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical compound [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002841 Lewis acid Substances 0.000 claims abstract description 10
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 10
- 239000002585 base Substances 0.000 claims abstract description 8
- 230000000694 effects Effects 0.000 claims abstract description 8
- 229950004354 phosphorylcholine Drugs 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 5
- 239000008363 phosphate buffer Substances 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 17
- 238000000746 purification Methods 0.000 abstract description 14
- 239000008777 Glycerylphosphorylcholine Substances 0.000 abstract description 9
- 229960004956 glycerylphosphorylcholine Drugs 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 7
- 239000007858 starting material Substances 0.000 abstract description 7
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 230000003412 degenerative effect Effects 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 2
- 208000024891 symptom Diseases 0.000 abstract description 2
- 208000011580 syndromic disease Diseases 0.000 abstract description 2
- 208000014644 Brain disease Diseases 0.000 abstract 1
- 230000002062 proliferating effect Effects 0.000 abstract 1
- 239000006227 byproduct Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 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 7
- 239000003456 ion exchange resin Substances 0.000 description 7
- 229920003303 ion-exchange polymer Polymers 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229960001231 choline Drugs 0.000 description 4
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- CTKINSOISVBQLD-GSVOUGTGSA-N (R)-Glycidol Chemical compound OC[C@@H]1CO1 CTKINSOISVBQLD-GSVOUGTGSA-N 0.000 description 3
- -1 acyl phospholipid Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000005947 deacylation reaction Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- VTDOEFXTVHCAAM-UHFFFAOYSA-N 4-methylpent-3-ene-1,2,3-triol Chemical compound CC(C)=C(O)C(O)CO VTDOEFXTVHCAAM-UHFFFAOYSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002996 emotional effect Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 235000019743 Choline chloride Nutrition 0.000 description 1
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- JGULOZKZZMBGFX-UHFFFAOYSA-L calcium;2-(trimethylazaniumyl)ethyl phosphate;chloride;tetrahydrate Chemical compound O.O.O.O.[Cl-].[Ca+2].C[N+](C)(C)CCOP([O-])([O-])=O JGULOZKZZMBGFX-UHFFFAOYSA-L 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- AWUCVROLDVIAJX-VKHMYHEASA-N sn-glycerol 1-phosphate Chemical compound OC[C@H](O)COP(O)(O)=O AWUCVROLDVIAJX-VKHMYHEASA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
- A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
-
- 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
- C07F9/113—Esters of phosphoric acids with unsaturated acyclic alcohols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
Abstract
The present invention relates to a process for preparing racemic or optically active α-glycerophosphoryl choline, and more particularly, to racemic or optically active (S) or (R) -epihalohi Secondary symptoms caused by cerebrovascular defects and proliferative or degenerative brain disorders through ring opening reactions in which the derivatives and cholinephosphate or salts thereof are added in the presence of a medium with a base, buffer, Lewis acid or mixtures thereof. The present invention relates to a method for producing a racemic or optically active D or L-α-glycerophosphoryl choline that is excellent in treating a syndrome.
The method for preparing racemic or optically active D or L-α-glycerophosphoryl choline according to the present invention is economical by using a low cost starting material, and is a one-pot reaction without a separate purification process. Highly pure racemic or optically active D or L-α without side reactions in the presence of the medium by using a base, buffer, Lewis acid or mixture thereof which not only simplifies the preparation process but also increases the activity of the reaction. -Glycerophosphoryl choline is effective in mass production.
Description
The present invention relates to a process for producing racemic or optically active α-glycerophosphoryl choline, wherein the high purity of the racemic or optically active D or L-α- in a simple manufacturing process and low cost Glycerphosphoryl choline is to be produced in large quantities.
Racemic or optically active D or L-α-glycerophosphoryl choline is a compound represented by the following formula (1), which is a secondary symptom due to cerebrovascular defects and senile perception such as degenerative or degenerative brain matrix mental syndrome It is known to have excellent effects in treating elderly caustic depression, such as disorders (low memory, confusion, disorientation, decreased motivation and spontaneity, decreased concentration), emotional and behavioral changes (emotional anxiety, irritability, lack of interest), By promoting the production of acetylcholine, a neurotransmitter in the brain, it is known as an excellent drug that normalizes the abnormality of the choline nerve transmission system due to the lack of acetylcholine and normalizes the function of damaged neurons.
[Formula 1]
Where * is a chiral center and refers to racemic and optically active D or L-α-optical isomers.
As such, racemic or optically active D or L-α-glycerophosphoryl choline with good pharmacological effects may be prepared by organic synthesis, It can also be prepared by deacylating acyl phospholipid, and the typical method is as follows.
First, Korean Patent No. 0262281 discloses a method of deacylating a phospholipid mixture obtained by natural or synthetic reaction by alcohol decomposition as in Scheme 1 below, and preparing glycerophosphoryl choline using a basic ion exchange resin. This is known. However, this method is a method of purifying phospholipids containing excessive impurities in the starting material by deacylation reaction to produce glycerophosphoryl choline, and the recovery rate of glycerophosphoryl choline is low. Since the basic ion exchange resin is used, there is a disadvantage that it is not suitable for mass production.
Scheme 1
Wherein R and R1 may be the same or different and are C13-C25 alkyl, C13-C25 mono or poly unsubstituted alkenyl.
U.S. Pat.No. 5,525,1919 discloses a process for preparing L-α-glycerophosphoryl choline by a method similar to Scheme 1, but this method also requires a purification process using an ion exchange resin. , L-α-glycerophosphoryl choline has the disadvantage of low recovery.
In addition, a method of preparing glycerophosphoryl choline through deacylation of lecithin extracted from plant material or animal organ is known (Biochim. Biophys . Acta , 488: 36, 1977; Biochim. Biophys. Acta, 1003: 277, 1989), depending on the reaction conditions (reaction time, temperature, base and solvent type) of the deacylation reaction, various by-products such as D-1,2-glycerophosphate are produced and purified. The disadvantages are complex and low yields.
As shown in the above known examples, in the preparation of L-α-glycerophosphoryl choline, methods using a substance such as lecithin extracted from a plant or animal may be used to prepare L-α-glycerophosphoryl choline. Although there is an advantage in that the necessary materials can be easily obtained in nature, since an excessive amount of impurities are included in the extraction process, it needs to be purified using ion exchange resin, etc., so that the purification process is complicated, difficult to manufacture with high purity, and low recovery rate. Not only is it uneconomical, but also unsuitable for industrial mass production.
On the other hand, looking at the conventional method for preparing glycerophosphoryl choline by the organic synthesis method, D, L-α-glycerophosphoryl choline using D, L-acetone glycerol as a starting material as shown in Scheme 2 below ( J. Org . Chem. , 26: 608, 1961), but since the reaction proceeds in a total of four steps, the reaction process is complicated and the reaction is carried out under anhydrous conditions. The disadvantage is that the process is difficult. In particular, the starting materials D and L-acetone glycerol are very expensive, and expensive compounds such as palladium and silver carbonate are used to remove phenyl groups and chlorine ions that act as protecting groups of the reaction, making them difficult to apply industrially. There are disadvantages.
Scheme 2
EP 468100 discloses a racemic or L-α-glycerophosphate from the substitution reaction of isopropylidene glycerol and 2-chloro-2-oxa-3,3,2-dioxophospholane, as shown in Scheme 3 below. A method of preparing foryl choline is disclosed. However, this method also uses expensive isopropylidene glycerol and 2-chloro-2-oxa-3,3,2-dioxophosphola as starting materials. There is a problem in that after the hydrolysis reaction, the racemic or L-α-glycerophosphoryl choline must be purified using an ion exchange resin.
Scheme 3
Here, * is chiral center and means racemic or L-form optical isomer.
In addition, Korean Patent Application Publication No. 2007-0119176 discloses calcium 2- (trimethylammonio) ethylphosphate chloride tetrahydrate by removing calcium ions under acid conditions to obtain cholinephosphate chloride, as shown in Scheme 4. L-α-glycerophosphoryl choline chloride was prepared by performing a ring opening reaction with (R) -glycidol on the chlorine, and then using the ion exchange resin, A method of removing ions and producing L-α-glycerophosphoryl choline is disclosed.
Scheme 4
However, this method is not only expensive in terms of (R) -glycidol, which is used as a key intermediate of the reaction, but also yields a high reaction yield because (R) -glycidol is unstable and easily decomposed during the ring opening reaction. Low and in particular, there is a disadvantage in that it is difficult to produce L-α-glycerophosphoryl choline with high purity because the method for purifying glycerol produced in large quantities as a byproduct is difficult. In addition, since the reaction proceeds in several stages, the manufacturing process is complicated and uneconomical. In the final stage, L-α-glycerophosphoryl choline is purified in a large amount by using an ion exchange resin to remove chlorine ions. There are many problems in manufacturing.
Accordingly, the present inventors have intensively tried to improve the problems of the prior art, and as a result, the racemic or optically active (S) or (R) -epihalohydrin derivatives and cholinephosphate or salts thereof are ringed in the presence of a medium. By carrying out the one-pot reaction through the opening reaction, it is possible to economically and easily prepare racemic or optically active D or L-α-glycerophosphoryl choline with high purity and high yield without a separate purification process. It was confirmed that this can be done, and the present invention has been completed.
It is an object of the present invention to provide a method for producing large amounts of racemic or optically active D or L-α-glycerophosphoryl choline with high optical purity at a simple manufacturing process and at low cost.
In order to achieve the above object, the present invention provides a choline phosphate represented by the following formula (2) or a salt thereof and a racemic or optically active (S) or (R)-epihalohydrin derivative represented by the formula (3) Provided is a method for preparing a racemic or optically active D or L-α-glycerophosphoryl choline represented by Formula 1 through a ring opening reaction in the presence of a medium.
[Formula 1]
[Formula 2]
(3)
* Denotes a chiral center and racemic and optically active D or L-α-optical isomer, X means fluorine, chlorine, bromine or iodine.
The method for preparing racemic or optically active D or L-α-glycerophosphoryl choline according to the present invention is economical by using a low cost starting material, and is a one-pot reaction without a separate purification process. Highly pure racemic or optically active D or L-α without side reactions in the presence of the medium by using a base, buffer, Lewis acid or mixture thereof which not only simplifies the preparation process but also increases the activity of the reaction. -Glycerophosphoryl choline is effective in mass production.
The present invention provides a cholimopening reaction of cholinephosphate represented by the following formula (2) or a salt thereof and racemic or optically active (S) or (R) -epihalohydrin derivative represented by the formula (3) in the presence of a medium. It relates to a method for producing a racemic or optically active D or L-α-glycerophosphoryl choline represented by the general formula (1).
[Formula 1]
[Formula 2]
*
(3)
* Denotes a chiral center and racemic and optically active D or L-α-optical isomer, X means fluorine, chlorine, bromine or iodine.
More specifically, the racemic or optically active D or L-α-glycerophosphoryl choline represented by Formula 1 according to the present invention may be prepared by the method shown in Scheme 5 below.
Scheme 5
In Scheme 5, the * or X is as described above.
As shown in Scheme 5, cholinephosphate represented by the formula (2) or a salt thereof and racemic or optically active (S) or (R) -epihalohydrin derivative represented by the formula (3) in the presence of a medium Through the ring opening reaction, racemic or optically active D or L-α-glycerophosphoryl choline represented by Formula 1 may be prepared. At this time, in order to increase the activity of the ring opening reaction, the reaction proceeds by adding one selected from the group consisting of a base, a buffer, a Lewis acid, and a mixture thereof.
Such a method for preparing racemic or optically active D or L-α-glycerophosphoryl choline has already been disclosed in Korean Patent Application No. 2008-34490 by the present applicant, but Korean Patent Application No. 2008 D or L-α at economical and low cost by using racemic or optically active (S) or (R) -epihalohydrin derivatives which are easier and cheaper to produce than the materials disclosed in -34490. As mass production of glycerophosphoryl choline becomes possible, it can be usefully used for the treatment of brain function improvement.
In the present invention, the racemic or optically pure (S) or (R) -epihalohydrin derivative represented by the formula (3) is based on the choline phosphate or salt thereof represented by the formula (2) added to the reaction. 1-5 equivalents can be added, Preferably it is preferable to use 1-2 equivalents. If the racemic or optically active (S) or (R) -epihalohydrin derivative is added to less than 1 equivalent based on cholinephosphate or its salts, the reaction will not proceed. When added in excess of 5 equivalents, an excess of unreacted racemic or optically active (S) or (R) -epihalohydrin derivative remains uneconomical, and there is a problem to remove it.
In the present invention, the base added to increase the activity of the ring opening reaction is an inorganic base or an organic base, the inorganic base is sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium carbonate, sodium bicarbonate, It may be selected from the group consisting of potassium carbonate, potassium bicarbonate and mixtures thereof, preferably sodium hydroxide or potassium hydroxide, such inorganic bases are 1 to 5 equivalents, preferably 1 to 3, based on the reactants Equivalent weight can be used. If it is added less than 1 equivalent on the basis of the reactants, the reaction rate is slow, and there may be a problem of unreacted. If it is added more than 5 equivalents, by-products are increased and a separate purification process is required. There is a problem that the yield is reduced. At this time, the reaction temperature of the ring opening reaction is 0 ° C ~ 100 ° C, preferably 25 ° C ~ 80 ° C, the reaction time is 2 to 48 hours, preferably 10 to 24 hours. If the reaction temperature is less than 0 ℃, the reaction rate is slow, the problem that the reaction does not proceed well, if it exceeds 100 ℃, the by-products increase to reduce the reaction yield, and also requires a separate purification process Do.
In the present invention, the organic base added to increase the activity of the ring opening reaction is trimethylamine, triethylamine, isopropylamine, diisopropylamine, ethyldiisopropylamine, pyridine, N, N-dimethyl-4 -Aminopyridine, 4-pyrrolidinopyridine, picoline, collidine and mixtures thereof, preferably isopropylamine and diisopropylamine, wherein the pH is 2 ~ 10, preferably 3-8. If the pH of the reactants is less than 2, the reaction rate may be slow, and an unreacted problem may occur. If the pH exceeds 10, byproducts are generated to reduce the reaction yield, and a separate purification process may be performed. need. At this time, the reaction temperature of the ring opening reaction is 0 ° C ~ 100 ° C, preferably 25 ° C ~ 80 ° C, the reaction time is 2 to 48 hours, preferably 10 to 24 hours. If the reaction temperature is less than 0 ℃, the reaction rate is slow, the problem that the reaction does not proceed well, if it exceeds 100 ℃, the by-products increase to reduce the reaction yield, and also requires a separate purification process Do.
In the present invention, Lewis acid may also be added to activate the ring opening reaction. The Lewis acid may be CuI, CuSO 4 , CuOTf 2 , SnSO 4 , AgPF 6 , AgBH 4 , Ag 2 SO 4 , BF 3 / Et 2 O, CsF, ZnOTf 2 , and the like, and preferably CuI or CuSO 4 Is suitable, it can be added in 1 to 5 equivalents, preferably 1 to 2 equivalents based on the reactants. This is because if the addition of less than 1 equivalent Lewis acid on the basis of the reactant, the problem of unreacted, if the addition of more than 5 equivalents by-product is increased to require a separate purification process, the reaction yield is reduced There is a problem. At this time, the reaction temperature of the ring opening reaction is 0 ° C to 100 ° C, preferably 25 ° C to 80 ° C, the reaction time is 2 to 24 hours, and preferably 10 to 24 hours. If the reaction temperature is less than 0 ℃, the reaction rate is slow, the problem that the reaction does not proceed well, if it exceeds 100 ℃, the by-products increase to reduce the reaction yield, and also requires a separate purification process Do.
In addition, in the present invention, the buffer can activate the ring-opening reaction and can also be used as a medium of the reaction. The buffer may be selected from the group consisting of phosphate buffer, carbonate buffer, acetic acid buffer, tris buffer and mixtures thereof, preferably phosphate buffer.
In the present invention, when a buffer is used, the pH of the reactants is 3-10, preferably 6-8. If the pH of the reactants is less than 3 when the buffer is used, the reaction rate may be slow and an unreacted problem may occur. If the pH exceeds 10, byproducts are generated to reduce the reaction yield, Purification is necessary. The reaction temperature is 0 ° C to 100 ° C, preferably 25 ° C to 80 ° C, and the reaction time is 10 to 48 hours, preferably 10 to 24 hours. If the reaction temperature is less than 0 ℃, the reaction rate is slow, the problem that the reaction does not proceed well, if it exceeds 100 ℃, the by-products increase to reduce the reaction yield, and also requires a separate purification process Do.
In the present invention, the medium is water, phosphate buffer, carbonate buffer, acetic acid buffer, tris buffer, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, methanol, ethanol, propanol, isopropanol, butanol, Isobutanol, tert-butanol, tetrahydrofuran, dioxane and mixtures thereof may be used, and may be prepared using water, a buffer or a polar organic medium alone, and organic polar if necessary. The reaction may be carried out under mixed medium with water or buffer.
The manufacturing method of the optically active D or L-α-glycerophosphoryl choline according to the present invention is economical using a low-cost starting material compared to the conventional method, one-pot without a separate purification process Reaction, which is not only easy to prepare, but also increases the activity of the reaction, by using base, Lewis acid, buffer and mixtures thereof, quantitatively racemic and optically active without side reactions in the presence of the medium. Or it is effective to mass-produce L-α-glycerophosphoryl choline.
Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.
Example 1: Preparation of racemic-α-glycerophosphoryl choline using inorganic base
Dissolve 100 g of phosphorylcholine chloride (1 equivalent, 450 mmol) in 500 ml of ethanol in a 1,000 ml three-necked round bottom flask equipped with a thermometer and agitator, and then add 75.52 g of potassium carbonate (1.2 equivalent, 540 mmol). The solution was slowly warmed up to 80 ° C. and stirred at isothermal for 30 minutes. 78.8 g of racemic epichlorohydrin (1.87 equivalents, 845.1 mmol) was slowly added to the stirred reaction, followed by reaction at 80 ° C. for 17 hours. After the reaction was completed, the reaction mixture was concentrated, the reaction mixture was diluted by adding 100 ml of water, stirred at room temperature for 1 hour, washed twice with ethyl acetate, and the aqueous layer was concentrated under reduced pressure to obtain racemic-α-. 107.2 g of glycerophosphoryl choline (yield 92%) were prepared. The NMR analysis results of the prepared racemic-α-glycerophosphoryl choline are as follows.
1 H NMR (D 2 O, 300 MHz): δ 3.23 (s, 9H), 3.59-3.70 (m, 4H), 3.86-3.97 (m, 3H), 4.29 (m, 2H)
Example 2: Preparation of racemic-α-glycerophosphoryl choline using organic base
In a 500 ml three-necked round bottom flask equipped with a thermometer, a reflux condenser and a stirrer, 63.27 g of phosphorylcholine chloride (1 equivalent, 288.1 mmol) was dissolved in 189.8 ml ethanol and heated to reflux at 80 ° C. 49.86 g of racemic epichlorohydrin (1.87 equiv., 538.8 mmol) was slowly added to the reaction mixture, followed by reaction for 12 hours, followed by further reaction for 3 hours by adjusting the pH to 8.0 using isopropylamine. I was. The cooled solution was concentrated under reduced pressure and dissolved in 70 ml of 1N NaOH aqueous solution, and then stirred at room temperature for 1 hour and washed three times with 150 ml of isobutanol. The obtained aqueous layer was concentrated under reduced pressure, extracted with ethanol and concentrated under reduced pressure to prepare 66.7 g (90% yield) of racemic α-glycerophosphoryl choline. The NMR analysis result of the racemic α-glycerophosphoryl choline prepared above is the same as the analysis result of Example 1.
Example 3 Preparation of Optically Active L-α-Glycerphosphoryl Choline Using Inorganic Bases
Dissolve 100 g of phosphorylcholine chloride (1 equivalent, 450 mmol) in 500 ml of ethanol in a 1,000 ml three-necked round bottom flask equipped with a thermometer and agitator, and then add 75.52 g of potassium carbonate (1.2 equivalents, 540 mmol). After addition, the solution was slowly warmed to 80 ° C. and stirred at isothermal for 30 minutes. 78.8 g of (S) -epichlorohydrin (1.87 equiv, 845.1 mmol) was slowly added to the stirred reaction, followed by reacting at 80 ° C. for 17 hours. When the reaction was completed, the reaction solution was filtered and the filtrate was concentrated, 100 ml of water was added to dilute the reaction mixture, stirred for 1 hour at room temperature, washed twice with ethyl acetate, and the aqueous layer was concentrated under reduced pressure to L 108.3 g of -α-glycerophosphoryl choline (yield 93%) were prepared. The NMR analysis result of the prepared L-α-glycerophosphoryl choline is the same as the analysis result of Example 1.
Example 4 Preparation of Optically Active L-α-Glycerophosphoryl Choline Using Organic Bases
In a 500 ml three-necked round bottom flask equipped with a thermometer, a reflux condenser and a stirrer, 63.27 g of phosphorylcholine chloride (1 equivalent, 288.1 mmol) was dissolved in 189.8 ml ethanol and heated to reflux at 80 ° C. 49.86 g of (S) -epichlorohydrin (1.87 equivalents, 538.8 mmol) was added slowly thereto, followed by reaction for 12 hours, followed by further reaction for 3 hours by adjusting the pH to 8.0 using isopropylamine. I was. The cooled solution was concentrated under reduced pressure and dissolved in 70 ml of 1N NaOH aqueous solution, and then stirred at room temperature for 1 hour and washed three times with 150 ml of isobutanol. The obtained aqueous layer was concentrated under reduced pressure, extracted with ethanol, and concentrated under reduced pressure to prepare 66.0 g (yield 89%) of L-α-glycerophosphoryl choline. The NMR analysis result of the prepared L-α-glycerophosphoryl choline is the same as the analysis result of Example 1.
The specific parts of the present invention have been described in detail above, and it is apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. something to do. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (9)
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