KR20100035897A - METHOD FOR PREPARING RACEMIC OR OPICALLY ACTIVE α-PHOSPHATIDYLCHOLINE DERIVATIVES - Google Patents
METHOD FOR PREPARING RACEMIC OR OPICALLY ACTIVE α-PHOSPHATIDYLCHOLINE DERIVATIVES Download PDFInfo
- Publication number
- KR20100035897A KR20100035897A KR1020080095276A KR20080095276A KR20100035897A KR 20100035897 A KR20100035897 A KR 20100035897A KR 1020080095276 A KR1020080095276 A KR 1020080095276A KR 20080095276 A KR20080095276 A KR 20080095276A KR 20100035897 A KR20100035897 A KR 20100035897A
- Authority
- KR
- South Korea
- Prior art keywords
- acid
- racemic
- derivative
- optically active
- reaction
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 46
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 33
- 239000000194 fatty acid Substances 0.000 claims abstract description 33
- 229930195729 fatty acid Natural products 0.000 claims abstract description 33
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 33
- 229950004354 phosphorylcholine Drugs 0.000 claims abstract description 28
- SUHOQUVVVLNYQR-MRVPVSSYSA-N choline alfoscerate Chemical class C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 18
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 11
- CTKINSOISVBQLD-GSVOUGTGSA-N (R)-Glycidol Chemical class OC[C@@H]1CO1 CTKINSOISVBQLD-GSVOUGTGSA-N 0.000 claims abstract description 9
- CTKINSOISVBQLD-VKHMYHEASA-N (S)-Glycidol Chemical compound OC[C@H]1CO1 CTKINSOISVBQLD-VKHMYHEASA-N 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000000872 buffer Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical compound [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002841 Lewis acid Substances 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 229940043279 diisopropylamine Drugs 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 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
- YWWVWXASSLXJHU-AATRIKPKSA-N (9E)-tetradecenoic acid Chemical compound CCCC\C=C\CCCCCCCC(O)=O YWWVWXASSLXJHU-AATRIKPKSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 4
- XMHIUKTWLZUKEX-UHFFFAOYSA-N hexacosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC(O)=O XMHIUKTWLZUKEX-UHFFFAOYSA-N 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 4
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical class F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 3
- 239000005639 Lauric acid Substances 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-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
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-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
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 2
- YWWVWXASSLXJHU-UHFFFAOYSA-N 9E-tetradecenoic acid Natural products CCCCC=CCCCCCCCC(O)=O YWWVWXASSLXJHU-UHFFFAOYSA-N 0.000 claims description 2
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 2
- 235000021353 Lignoceric acid Nutrition 0.000 claims description 2
- CQXMAMUUWHYSIY-UHFFFAOYSA-N Lignoceric acid Natural products CCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCC1=CC=C(O)C=C1 CQXMAMUUWHYSIY-UHFFFAOYSA-N 0.000 claims description 2
- 239000005642 Oleic acid Substances 0.000 claims description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000021314 Palmitic acid Nutrition 0.000 claims description 2
- 235000021319 Palmitoleic acid Nutrition 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
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 150000008064 anhydrides Chemical class 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
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 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
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 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
- 150000002148 esters Chemical class 0.000 claims description 2
- FARYTWBWLZAXNK-WAYWQWQTSA-N ethyl (z)-3-(methylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC FARYTWBWLZAXNK-WAYWQWQTSA-N 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-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
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 2
- XLQWJXJJLULKSL-UHFFFAOYSA-N n-methyl-n-(pentyliminomethylideneamino)methanamine;hydrochloride Chemical compound Cl.CCCCCN=C=NN(C)C XLQWJXJJLULKSL-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229960002446 octanoic acid Drugs 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
- 235000021313 oleic acid Nutrition 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
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 239000008117 stearic acid Substances 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
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 4
- 239000012042 active reagent Substances 0.000 claims 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- AJKLKFPOECCSOO-UHFFFAOYSA-N hydrochloride;hydroiodide Chemical compound Cl.I AJKLKFPOECCSOO-UHFFFAOYSA-N 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 150000002823 nitrates Chemical class 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 14
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract 5
- 238000006243 chemical reaction Methods 0.000 description 61
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 23
- 229910052799 carbon Inorganic materials 0.000 description 23
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 238000000746 purification Methods 0.000 description 14
- 239000000376 reactant Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 12
- 210000002969 egg yolk Anatomy 0.000 description 11
- 239000007795 chemical reaction product Substances 0.000 description 9
- 102000002322 Egg Proteins Human genes 0.000 description 8
- 108010000912 Egg Proteins Proteins 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 235000013345 egg yolk Nutrition 0.000 description 8
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 125000006239 protecting group Chemical class 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 150000008105 phosphatidylcholines Chemical class 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- 244000068988 Glycine max Species 0.000 description 3
- 235000010469 Glycine max Nutrition 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 235000004626 essential fatty acids Nutrition 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- QENHCSSJTJWZAL-UHFFFAOYSA-N magnesium sulfide Chemical compound [Mg+2].[S-2] QENHCSSJTJWZAL-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- JKXONPYJVWEAEL-YFKPBYRVSA-N [(2r)-oxiran-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1CO1 JKXONPYJVWEAEL-YFKPBYRVSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 150000001721 carbon Chemical class 0.000 description 2
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
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- 229960000443 hydrochloric acid Drugs 0.000 description 1
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
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- 239000000787 lecithin Substances 0.000 description 1
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- 235000008476 powdered milk Nutrition 0.000 description 1
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- 239000000047 product Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
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- 230000001172 regenerating effect Effects 0.000 description 1
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- 210000000582 semen Anatomy 0.000 description 1
- 238000010898 silica gel chromatography Methods 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- 239000003549 soybean oil Substances 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
Description
본 발명은 라세믹 또는 광학적으로 활성이 있는 α―포스파티딜콜린 유도체를 제조하는 방법에 관한 것으로, 보다 상세하게는, 간단한 제조공정과 저렴한 비용으로 순도가 높은 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 다양하게 제조할 수 있는 방법에 관한 것이다.The present invention relates to a process for preparing a racemic or optically active α-phosphatidylcholine derivative, and more particularly, to a highly purified racemic or optically active D or L- in a simple manufacturing process and at low cost. The present invention relates to a method for producing various α-phosphatidylcholine derivatives.
라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체는 하기 화학식 1로 표시되는 화합물로, 후술되는 다양한 기능을 가지고 있어 의약품, 건강기능식품, 분유, 화장품 등의 중요한 원료로 사용되고 있다.Racemic or optically active D or L-α-phosphatidylcholine derivatives are compounds represented by the following general formula (1), and have various functions described below, and thus are used as important raw materials such as pharmaceuticals, health functional foods, powdered milk, and cosmetics.
여기서, *는 키랄센터(chiral center)이고, 라세믹 및 광학적으로 활성이 있는 D 또는 L-α-광학 이성질체를 나타내며, R1 및 R2는 각각 독립적으로 치환 또는 비치환된 포화 또는 불포화 탄소수 2 내지 30의 아실기이며, 서로 동일하거나 상이하다.Where * is a chiral center and represents a racemic and optically active D or L-α-optical isomer, R 1 and R 2 are each independently substituted or unsubstituted saturated or unsaturated carbon atoms 2 To acyl groups of 30 to 30, the same or different from each other.
이러한, 라세믹 또는 광학활성이 있는 D 또는 L-α-포스파티딜콜린 유도체는 항산화작용, 뇌기능 활성화, 간 기능개선 등에 다양한 효과가 있어 의약품 또는 건강기능식품 등으로 널리 사용되어지고 있으며, 이러한 포스파디딜콜린 유도체들은 동물과 식물의 모든 인지질 중에서 가장 많고, 인지질 종류 중에 약 50%를 차지한다. Such D or L-α-phosphatidylcholine derivatives having racemic or optical activity have various effects such as antioxidant activity, brain function activation, liver function improvement, and are widely used as medicines or health functional foods. Choline derivatives are the largest of all phospholipids in animals and plants, accounting for about 50% of the phospholipid species.
특히, 두겹의 지질로 만들어진 세포막의 주된 성분이며, 계란 노른자위에서 얻은 난황유 속에는 약 30%나 들어 있으며, 간, 신경조직, 정액에 많이 들어 있다. 식물 중에는 특히, 식물 중에는 특히, 콩기름 속의 인지질 중에서 약 20%를 차지 한다. In particular, it is the main component of the cell membrane made of two-layered lipid, egg yolk oil obtained from about 30% is contained in the liver, nerve tissue, semen a lot. Among the plants, in particular, about 20% of the phospholipids in the soybean oil.
이러한, 포스파티딜콜린 유도체의 인체에서의 기능을 보면, 신경전달물질인 아세틸콜린의 양을 증가시켜 성인에게는 치매 등 각종 뇌질환에 대한 치료 및 예방효과를 높여 주고 기억력을 높여주며, 태아 및 유아에는 두뇌의 영양을 공급해 두 뇌를 집중개발 하는데 도움을 주어 현재 기능성 분유를 만드는데 많이 이용 되어지고 있다. Looking at the function of the phosphatidylcholine derivatives in the human body, the amount of acetylcholine, a neurotransmitter, increases the treatment and prevention effects for various brain diseases such as dementia and enhances memory in adults. It is used to make functional milk powder by nourishing and helping to concentrate the two brains.
그리고, 항 산화작용으로 인체조직에 유해한 작용을 하는 활성산소를 억제하는데 도움을 줌으로써 세포의 산화를 막아주고 건강하게 함으로써 인체건강에 도움을 주는 기능을 갖고 있다. 또한, 세포막의 주성분으로써, 영양의 흡수 및 노폐물의 배설 등 생명의 기초대사에 관여하고 세포의 수명을 연장시켜 노화방지에도 효과가 있으며, 세포를 재생시키고 치유함으로써 질병세포치료 및 질병예방에 도움을 주는 효과도 있다.In addition, the antioxidant action has the function to help the human health by preventing the oxidation of cells by helping to inhibit free radicals that have a harmful effect on human tissues. In addition, as a major component of cell membranes, it is involved in the basic metabolism of life, such as absorption of nutrients and excretion of waste products, and is effective in preventing aging by prolonging the lifespan of cells, and helping to treat disease cells and prevent diseases by regenerating and healing cells. Giving effect is also.
포스파티딜콜린의 또 하나의 주된 기능은 콜레스테롤 개선에 도움을 준다. 혈관벽의 잉여 콜레스테롤을 용해시켜 혈관벽을 깨끗하게 함으로써 혈액순환을 원활하게 하며, 세포내의 저밀도 콜레스테롤의 흡수를 통제시켜 체내의 나쁜 콜레스테롤의 양을 감소시켜 주는 기능을 갖고 있다. Another major function of phosphatidylcholine helps improve cholesterol. By dissolving excess cholesterol in the blood vessel wall to clean the blood vessel wall to facilitate blood circulation, and controls the absorption of low-density cholesterol in the cell has the function of reducing the amount of bad cholesterol in the body.
이밖에, 피부를 구성하는 성분의 하나로 피지와 땀을 유화시켜 각질층의 수분을 유지하는데 주요한 역할을 하는데 피부를 촉촉하게 유지시켜주는 주요성분이다. In addition, one of the components constituting the skin emulsifies sebum and sweat and plays a major role in maintaining the moisture of the stratum corneum is the main ingredient that keeps the skin moist.
이와 같은 다양한 기능을 가지고 있는 라세믹 또는 광학학적으로 활성이 있 는 D 또는 L-α-포스파티딜콜린 유도체의 제조방법은 합성방법뿐만 아니라, 식물(대두 등), 동물(난황 또는 소의 뇌)로부터 추출 및 분리 정제과정을 거쳐 제조할 수 있다. Such a method of preparing a racemic or optically active D or L-α-phosphatidylcholine derivative having various functions may be extracted from plants (such as soybeans), animals (eg yolk or bovine brain) as well as synthetic methods. It can be prepared through a separate purification process.
우선, 천연재료로부터 추출 및 분리 정제되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체의 제조방법은 오일을 함유하는 해바라기 또는 대두의 포스파티드를 C1~C2의 저급 알코올 및 이의 85~96% 수용성 용액을 사용하여 필수 지방산을 함유하는 조포스파티드로부터 필수 지방산을 함유하는 포스포파티드 추출물을 추출하여 산화알루미늄 흡착제 크로마토그래피 컬럼을 이용하여 흡착시키고, 이로부터 흡착된 포스파티딜콜린을 회수하여 필수지방산을 함유하는 포스파티딜콜린을 제조하는 방법이 개시되었으나(미국등록특허 제4,235,793), 이 방법은 회수과정에서 산화알루미늄 흡착제를 사용해야 하는 문제점이 있고, 순도가 64~70%로 낮다는 문제점이 있다.First, a method of preparing a racemic or optically active D or L-α-phosphatidylcholine derivative, which is extracted and separated and purified from a natural material, is a C 1 to C 2 lower alcohol containing sunflower or soybean phosphatide containing oil. And a phosphatidide extract containing essential fatty acids from crude phosphatides containing essential fatty acids using an 85-96% aqueous solution thereof and adsorbed using an aluminum oxide adsorbent chromatography column. Although a method of preparing phosphatidylcholine containing essential fatty acids by recovering the same has been disclosed (US Pat. No. 4,235,793), this method has a problem of using an aluminum oxide adsorbent in the recovery process, and has a low purity of 64 to 70%. There is this.
대한민국 등록특허 제450308호에는 난황을 저온에서 아세톤과 메틸렌클로라이드 등의 유기용매를 순차적으로 사용하여 난황유를 수득하고, 수득된 상기 난황유로부터 알코올 등의 유기용매를 사용하여 포스파티딜콜린 결정을 제조하는 방법이 개시되었으나, 이 방법 역시 순도가 85~95%로 낮다는 문제점이 있다.Korean Patent No. 450308 discloses a method of preparing egg yolk by using organic solvents such as acetone and methylene chloride at low temperature, and preparing phosphatidylcholine crystals using an organic solvent such as alcohol from the yolk obtained. However, this method also has a problem that the purity is low as 85 ~ 95%.
또한, 대한민국 등록특허 제472912호에서는 계란으로부터 난황을 분리하는 할란과정, 분리된 난황을 가열하여 반숙상태로 만드는 반숙과정, 반숙 처리된 난황을 건조하는 과정, 건조된 난황을 분쇄하는 과정, 분쇄된 난황을 추출용매를 이용하여 추출하는 과정 및 여러 번의 재추출과정과 여러 번의 농축과정으로 난황의 레시틴을 제조하는 방법이 개시되었으나, 이러한 방법은 제조과정이 복잡하고, 순도가 65~80%로 낮아 산업적으로 대량 생산하는데 많은 문제점이 있다.In addition, the Republic of Korea Patent No. 472912, the process of separating the egg yolk from the egg, the egg yolk process, heating the separated egg yolk to make it soft, the process of drying the egg yolk, the process of grinding the dried yolk, crushed The process of extracting egg yolk by using an extraction solvent and preparing a lecithin of egg yolk by several re-extracting processes and several concentration processes have been disclosed. However, these methods have a complicated manufacturing process and a low purity of 65-80%. There are many problems in mass production industrially.
이밖에 대두 및 천연으로부터 포스파티딜콜린을 제조하는 예를 보면, 미국 특허 제5,703,255호에서도 공지가 되어 있는데, 이 방법 역시 포스파티딜콜린의 순도가 낮거나 컬럼 크로마토그래피를 사용하여 정제를 하는 등 산업화하는 데는 많은 어려움이 있다.In addition, examples of preparing phosphatidylcholine from soybean and nature are also known from US Pat. No. 5,703,255. This method also has many difficulties in industrialization such as low purity of phosphatidylcholine or purification using column chromatography. have.
이와 같이, 천연으로부터 포스파티딜콜린을 제조하는 방법은 자연 친화적인 방법으로 제조할 수 있다는 장점은 있는 반면, 고순도 포스파티딜콜린을 제조하는데 많은 어려움이 있고, 또한 제조과정이 복잡하다는 단점이 있다.As such, the method of preparing phosphatidylcholine from nature has the advantage of being able to be produced in a natural manner, while it is difficult to produce high purity phosphatidylcholine, and also has the disadvantage of complicated manufacturing process.
한편, 합성적으로 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조하는 방법으로는 1, 2번 탄소위치의 지방산 유도체가 서로 같거나, 서로 다른 지방산 유도체를 가지는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체 제조방법으로 분류할 수 있다.On the other hand, synthetically racemic or optically active D or L-α-phosphatidylcholine derivatives to prepare a method for producing a fatty acid derivative at the carbon positions 1 and 2, the racemic or having a different fatty acid derivative or It can be classified as a method for preparing an optically active D or L-α-phosphatidylcholine derivative.
먼저, 1, 2번 탄소위치의 지방산 유도체가 서로 같은 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체 제조방법은 하기 반응식 1에 나타난 바와 같이 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린을 출발물질로 하고, 지방산 유도체, 지방산 클로라이드 유도체, 지방산 무수물 유도체 등을 사용하여 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조하는 방법이 개시된 바 있다(미국 등록특허 제4690784호, 미국 등록특허 제5000880호, 미국 등록특허 제5321145호).First, a method of preparing D or L-α-phosphatidylcholine derivatives in which the fatty acid derivatives at the carbon positions 1 and 2 are the same racemic or optically active D or L-α-phosphatidylcholine derivative is shown in Scheme 1 below. A method for producing racemic or optically active D or L-α-phosphatidylcholine derivatives using L-α-glycerophosphorylcholine as a starting material and using fatty acid derivatives, fatty acid chloride derivatives, fatty acid anhydride derivatives, and the like Has been disclosed (US Pat. No. 4,715,844, US Pat. No. 5000,880, US Pat. No. 5,321,145).
여기서, *는 키랄센터(chiral center)이고, 라세믹 및 광학적으로 활성이 있는 D 또는 L-α-광학 이성질체를 나타내며, R은 치환 또는 비치환된 포화 또는 불포화 탄소를 가지는 아실기를 의미한다.Where * is a chiral center and represents a racemic and optically active D or L-α-optical isomer, and R means an acyl group having a substituted or unsubstituted saturated or unsaturated carbon.
상기 반응식 1과 같이 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조할 경우에는 단일 스텝으로 제조되는 장점은 있으나, 출발물질인 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린의 가격이 매우 고가이고, 한쪽이 치환되지 않은 부생성물이 과량으로 존재하여 반응 수율이 떨어지며, 실리카겔 컬럼 크로마토그래피 등을 사용하여 정제해야 하 는 등 산업적으로 적용하기 어려운 단점이 있다.When preparing a racemic or optically active D or L-α-phosphatidylcholine derivative as in Scheme 1, there is an advantage of being prepared in a single step, but the starting material racemic or optically active D or L- α-glycerophosphorylcholine is very expensive, the reaction yield is low due to the presence of an excess of unsubstituted byproduct on one side, and difficult to apply industrially, such as purification using silica gel column chromatography. There is this.
또한, 1, 2번 탄소위치에 지방산 유도체가 서로 다른 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조하는 방법은 하기 반응식 2에 나타난 바와 같이, L-α-글리세로포스포릴콜린을 출발물질로 이용하여 1번 탄소위치를 트리페닐메틸클로라이드 유도체를 보호기로 도입하고, R2의 지방산 유도체를 2번 탄소위치에 도입한 다음, 1번 탄소위치의 보호기를 제거한 후에 1번 탄소위치에 R2의 다른 지방산 유도체를 도입함으로써, 1과 2번 탄소위치에 서로 다른 지방산 유도체가 치환된 L-α-포스파티딜콜린 및 그의 유도체를 제조하는 방법이 개시된 바 있었다(미국 등록특허 제4622180호).In addition, a method of preparing a racemic or optically active D or L-α-phosphatidylcholine derivative having different fatty acid derivatives at carbon positions 1 and 2 is shown in Scheme 2 below, L-α-glycerophosphate. Using polyylcholine as starting material, triphenylmethylchloride derivative was introduced at the carbon position 1 as a protecting group, fatty acid derivative of R 2 was introduced at carbon position 2, and then the protecting group at carbon position 1 was removed. By introducing another fatty acid derivative of R 2 at the carbon position, a method of preparing L-α-phosphatidylcholine and its derivatives substituted with different fatty acid derivatives at carbon positions 1 and 2 has been disclosed (US Patent No. 4462180). ).
여기서, *는 키랄센터(chiral center)이고, L-α-이성질체를 나타내며, T는 비치환되거나, 또는 C1~C6 알킬, C1~C6 알콕시 또는 할로겐으로 치환되거나, 또는 다치환된 트리페닐메틸기이고, R1 및 R2는 서로 상이하며, 서로 독립적으로 직쇄 또는 측쇄 C2~C24 알킬기이거나, 또는 할로겐 또는 알콕시로 일치환되거나, 다치환되거 나, 또는 비치환된 직쇄 또는 측쇄의 모노불포화 또는 폴리불포화된 C4~C24 알케닐 아실화기를 의미한다.Wherein * is a chiral center and represents an L-α-isomer, T is unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen, or polysubstituted Is a triphenylmethyl group, R 1 and R 2 are different from each other, and are each independently a linear or branched C 2 to C 24 alkyl group, mono-, poly-substituted, or unsubstituted straight or branched chain with halogen or alkoxy; Monounsaturated or polyunsaturated C 4 to C 24 alkenyl acyl groups.
전술된 반응식 2에서와 같은 제조방법은 출발물질을 보호기로 보호하고, 탈보호하는 제조공정이 있어 공정이 복잡하고, 고가의 L-α-글리세로포스포릴콜린을 출발물질로 사용하여 제조한다는 단점이 있다.The manufacturing method as in Scheme 2 described above has a manufacturing process that protects the starting material with a protecting group and deprotects it, which makes the process complicated, and uses the expensive L-α-glycerophosphorylcholine as a starting material. There is this.
그 밖에 1, 2번 탄소위치에 지방산 유도체가 서로 다른 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조하는 방법을 살펴보면, 하기 반응식 3에 나타난 바와 같이, 1과 2번 탄소위치에 동일한 지방산 유도체가 치환된 포스파티딜콜린 유도체를 포스포리파제 A2와 작용시켜 2번 탄소위치의 지방산 유도체를 제거하고, 여기에 1번 탄소위치의 지방산 유도체와 다른 새로운 지방산 유도체를 치환시킴으로써, L-α-포스파티딜콜린 유도체를 제조하는 방법이 개시되었다(Chemistry and Physics of Lipids, 50:11, 1989). 그러나, 이 방법은 출발물질 자체가 포스파티딜콜린 유도체를 사용함으로써 비효율적이고, 비경제적이며, 효소의 가수분해 속도 및 효능이 지방산 유도체의 형태에 따라 좌우된다는 문제점이 있다.In addition to the method of preparing a racemic or optically active D or L-α-phosphatidylcholine derivatives having different fatty acid derivatives at carbon positions 1 and 2, carbons 1 and 2, as shown in Scheme 3 below The phosphatidylcholine derivative substituted with the same fatty acid derivative at the position is reacted with phospholipase A 2 to remove the fatty acid derivative at the carbon position 2, and the fatty acid derivative at the carbon position 1 and other new fatty acid derivatives are substituted for L- A method for preparing α-phosphatidylcholine derivatives has been disclosed. and Physics of Lipids , 50:11, 1989). However, this method has a problem that the starting material itself is inefficient and economical by using a phosphatidylcholine derivative, and the rate and efficacy of the hydrolysis of the enzyme depend on the type of fatty acid derivative.
이에, 본 발명자들은 상기 종래기술의 문제점을 개선하고자 예의 노력한 결과, 라세믹 또는 광학적으로 활성이 있는 (S) 또는 (R)-글리시돌 유도체와 콜린포스페이트 또는 그의 염산 염을 제1 매질상에서 염기, 버퍼(buffer) 또는 루이스 에시드를 첨가시킨 고리열림 반응을 통한 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체를 제조한 다음, 제조된 상기 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체를 제2 매질 존재하에서 지방산 또는 그의 유도체와 치환반응시킨 경우, 1번 탄소위치와 2번 탄소위치에 서로 동일하거나 상이한 지방산 유도체가 치환된 다양한 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 고순도와 고수율로 경제적이면서 용이하게 제조할 수 있다는 것을 확인하고, 본 발명을 완성하게 되었다. Accordingly, the present inventors have made diligent efforts to improve the problems of the prior art, and as a result, racemic or optically active (S) or (R) -glycidol derivatives and cholinephosphate or hydrochloride salts thereof can be used as the base on the first medium. , To prepare a racemic or optically active D or L-α-glycerophosphorylcholine derivative via a ring opening reaction with the addition of a buffer or Lewis acid, and then the racemic or optically active When a D or L-α-glycerophosphorylcholine derivative having a substitution reaction with a fatty acid or a derivative thereof in the presence of a second medium, various fatty acid derivatives substituted with the same or different fatty acid derivatives at carbon positions 1 and 2 Racemic or optically active D or L-α-phosphatidylcholine derivatives can be produced economically and easily with high purity and high yield. It confirmed that, and thereby completing the present invention.
본 발명의 목적은 간단한 제조공정과 저렴한 비용으로 순도가 높은 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 다양하게 제조할 수 있는 방법을 제공하는데 있다.SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing a variety of highly purified racemic or optically active D or L-α-phosphatidylcholine derivatives at a simple manufacturing process and at low cost.
상기 목적을 달성하기 위하여, 본 발명은 (a) 하기 화학식 2로 표시되는 콜린포스페이트 또는 그의 염산염과 하기 화학식 3으로 표시되는 라세믹 또는 광학적으로 활성이 있는 (S) 또는 (R)-글리시돌 유도체를 제1 매질 존재하에서 고리열림 반응을 통하여 화학식 4로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체를 수득하는 단계; 및 (b) 상기 수득된 화학식 4로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체를 제2 매질 존재하에서 지방산 또는 그의 유도체와 치환반응시켜 화학식 1로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조하는 단계를 포함하는, 화학식 1로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조하는 방법을 제공한다.In order to achieve the above object, the present invention is (a) cholinephosphate represented by the following formula (2) or its hydrochloride salt and racemic or optically active (S) or (R)-glycidol represented by the following formula (3) Obtaining a racemic or optically active D or L-α-glycerophosphorylcholine derivative represented by Formula 4 through a ring opening reaction in the presence of a first medium; And (b) substituting the racemic or optically active D or L-α-glycerophosphorylcholine derivative represented by Formula 4 with a fatty acid or a derivative thereof in the presence of a second medium to represent the formula (1). A method of preparing a racemic or optically active D or L-α-phosphatidylcholine derivative represented by Formula 1, comprising the step of preparing a racemic or optically active D or L-α-phosphatidylcholine derivative To provide.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3](3)
[화학식 4][Formula 4]
상기 화학식에서, 상기 *는 키랄센터이고, 라세믹 및 광학적으로 활성이 있는 D 또는 L-α-광학 이성질체를 나타내며, R1 및 R2는 각각 독립적으로 치환 또는 비치환된 포화 또는 불포화 탄소수 2 내지 30의 아실기이며, 서로 동일하거나 상이하다.In the above formula, * represents a chiral center and represents racemic and optically active D or L-α-optical isomers, R 1 and R 2 are each independently substituted or unsubstituted saturated or unsaturated carbon atoms 2 to 30 acyl group and the same or different from each other.
본 발명에 따르면, 저가의 출발물질을 사용하여 경제적이고, 제조과정 중 지방산 유도체를 순차적으로 도입함으로써, 부생성물의 생성을 극소화할 수 있으며, 1번, 2번 탄소위치에 서로 동일하거나 상이한 지방산 유도체가 치환된 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린의 다양한 유도체를 특별한 정제과정, 보호기 도입과정 및 탈보호화 과정 없이 간편한 방법으로 대량생산할 수 있다.According to the present invention, it is economical using a low-cost starting material, and by sequentially introducing fatty acid derivatives during the manufacturing process, it is possible to minimize the production of by-products, and the same or different fatty acid derivatives at carbon positions 1 and 2 Various derivatives of the substituted racemic or optically active D or L-α-phosphatidylcholine can be mass-produced in a simple manner without special purification, protecting group introduction and deprotection.
본 발명은 (a) 하기 화학식 2로 표시되는 콜린포스페이트 또는 그의 염산염과 하기 화학식 3으로 표시되는 라세믹 또는 광학적으로 활성이 있는 (S) 또는 (R)-글리시돌 유도체를 제1 매질 존재하에서 고리열림 반응을 통하여 화학식 4로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체를 수득하는 단계; 및 (b) 상기 수득된 화학식 4로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체를 제2 매질 존재하에서 지방산 또는 그의 유도체와 치환반응시켜 화학식 1로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조하는 단계를 포함하는, 화학식 1로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조하는 방법에 관한 것이다.The present invention relates to (a) cholinephosphate represented by the following formula (2) or a hydrochloride thereof, and a racemic or optically active (S) or (R) -glycidol derivative represented by the following formula (3) in the presence of a first medium: Obtaining a racemic or optically active D or L-α-glycerophosphorylcholine derivative represented by Formula 4 through a ring-opening reaction; And (b) substituting the racemic or optically active D or L-α-glycerophosphorylcholine derivative represented by Formula 4 with a fatty acid or a derivative thereof in the presence of a second medium to represent the formula (1). A method of preparing a racemic or optically active D or L-α-phosphatidylcholine derivative represented by Formula 1, comprising the step of preparing a racemic or optically active D or L-α-phosphatidylcholine derivative It is about.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3](3)
[화학식 4][Formula 4]
상기 화학식에서, 상기 *는 키랄센터이고, 라세믹 및 광학적으로 활성이 있는 D 또는 L-α-광학 이성질체를 나타내며, R1 및 R2는 각각 독립적으로 치환 또는 비치환된 포화 또는 불포화 탄소수 2 내지 30의 아실기이며, 서로 동일하거나 상이하다.In the above formula, * represents a chiral center and represents racemic and optically active D or L-α-optical isomers, R 1 and R 2 are each independently substituted or unsubstituted saturated or unsaturated carbon atoms 2 to 30 acyl group and the same or different from each other.
보다 구체적으로, 본 발명에 따른 화학식 1로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체는 하기 반응식 4로 표시된 방법에 의해 제조할 수 있다.More specifically, the racemic or optically active D or L-α-phosphatidylcholine derivative represented by Formula 1 according to the present invention may be prepared by the method shown in Scheme 4 below.
상기 반응식 4에서, 상기 *, R1 또는 R2는 전술한 바와 같다. In Scheme 4, the *, R 1 or R 2 is as described above.
상기 반응식 4에 나타난 바와 같이, 화학식 2로 표시되는 콜린포스페이트 또는 그의 염산염과 화학식 3으로 표시되는 라세믹 또는 광학적으로 활성이 있는 (S) 또는 (R)-글리시돌 유도체를 제1 매질 존재하에 고리열림 반응을 통하여 화학식 4로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체를 제조할 수 있다. 이때, 고리열림 반응의 활성을 증가시키기 위해 염기, 버퍼(buffer), 루이스 에시드 및 이들의 혼합물로 구성된 군에서 선택되는 것을 첨가하여 반응을 진행한다.As shown in Scheme 4, cholinephosphate represented by formula (2) or hydrochloride thereof and racemic or optically active (S) or (R) -glycidol derivative represented by formula (3) in the presence of a first medium Through the ring opening reaction, a racemic or optically active D or L-α-glycerophosphorylcholine derivative represented by Formula 4 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.
이러한, 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체 제조방법은 이미 본 발명자에 의해 대한민국 특허 출원번호 제2008-34490호에 개시된 바 있다. Such a method for preparing racemic or optically active D or L-α-glycerophosphorylcholine derivatives has already been disclosed by Korean inventor in Korean Patent Application No. 2008-34490.
이와 같이 제조된 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체는 제2 매질 존재하에서 1번과 2번 탄소위치에 서로 동일하거나, 상이한 지방산 또는 그의 유도체와 치환반응시켜 최종 생산물인 화학식 1로 표시되는 1번과 2번 탄소위치에 서로 동일하거나, 상이한 지방산 유도체가 치환된 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 다양하게 제조할 수 있다.The racemic or optically active D or L-α-glycerophosphorylcholine derivatives thus prepared are substituted with the same or different fatty acids or their derivatives at the 1 and 2 carbon positions in the presence of a second medium. In this case, various racemic or optically active D or L-α-phosphatidylcholine derivatives substituted with the same or different fatty acid derivatives at the carbon positions 1 and 2 represented by the general formula (1) can be prepared in various ways. .
본 발명에 있어서, 화학식 3으로 표시되는 라세믹 또는 광학적으로 순도가 높은 (S) 또는 (R)-글리시돌 유도체는 반응에 첨가되는 화학식 2로 표시되는 콜린포스페이트 또는 그의 염산염을 기준으로 1~5당량 첨가시킬 수 있고, 바람직하게는 1~2 당량 사용하는 것이 바람직하다. 만약, 라세믹 또는 광학적으로 활성이 있는 (S) 또는 (R)-글리시돌 유도체를 콜린포스페이트 또는 그의 염산염을 기준으로 1 당량 미만으로 첨가시킬 경우 반응이 진행되지 않는 문제가 발생되고, 5당량을 초과하여 첨가시킬 경우에는 과량의 미반응 라세믹 또는 광학적으로 활성이 있는 (S) 또는 (R)-글리시돌 유도체가 남아 있어 비경제적이며, 이를 제거해야 하는 문제점이 있다.In the present invention, the racemic or optically pure (S) or (R) -glycidol derivative represented by the general formula (3) is 1 ~ based on the choline phosphate or hydrochloride thereof represented by the general formula (2) added to the reaction. 5 equivalents can be added, Preferably it is preferable to use 1-2 equivalents. If the racemic or optically active (S) or (R) -glycidol derivative is added less than 1 equivalent based on cholinephosphate or its hydrochloride salt, the reaction will not proceed, and 5 equivalents will occur. When added in excess of excess unreacted racemic or optically active (S) or (R)-glycidol derivatives remain uneconomical, there is a problem that must be removed.
본 발명에 있어서, 고리열림 반응의 활성을 증가시키기 위해 첨가되는 염기는 무기염기 및 유기염기로 구성된 군에서 선택되는 것으로, 상기 무기염기는 수산화나트륨, 수산화칼륨, 수산화칼슘, 수산화마그네슘, 수산화바륨, 소듐카보네이트, 소듐바이카보네이트, 포타슘카보네이트, 포타슘바이카보네이트 및 이들의 혼합물로 구성된 군에서 선택될 수 있고, 바람직하게는 수산화나트륨 또는 수산화칼륨일 수 있다.In the present invention, the base added to increase the activity of the ring opening reaction is selected from the group consisting of inorganic bases and organic bases, wherein the inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium It may be selected from the group consisting of carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and mixtures thereof, preferably sodium hydroxide or potassium hydroxide.
본 발명에 있어서, 무기염기가 첨가된 반응물의 pH는 3~10이고, 바람직하게는 6~8일 수 있다. 만약, 무기염기 첨가된 반응물의 pH가 3미만이면, 반응속도가 느리고, 미반응의 문제가 발생될 수 있으며, pH가 10을 초과하면, 부생성물이 생성되어 반응 수율이 감소할 뿐만 아니라, 별도의 정제과정이 필요하다. 이때 반응온 도는 0℃~100℃이고, 바람직하게는 20℃~40℃이며, 반응시간은 10~48시간이고, 바람직하게는 20~24시간일 수 있다. 만약, 반응온도가 0℃미만이면, 반응속도가 느려 반응이 잘 진행되지 않는 문제가 발생되고, 100℃를 초과하면, 부생성물이 증가하여 반응 수율을 감소시킬 뿐만 아니라, 별도의 정제과정이 필요하다.In the present invention, the pH of the reactant to which the inorganic base is added is 3 to 10, preferably 6 to 8. If the pH of the inorganic base-added reactant is less than 3, the reaction rate may be slow, and an unreacted problem may occur. If the pH exceeds 10, a by-product is generated to reduce the yield of the reaction. Purification process is required. In this case, the reaction temperature is 0 ° C to 100 ° C, preferably 20 ° C to 40 ° C, and the reaction time is 10 to 48 hours, preferably 20 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.
본 발명에 있어서, 고리열림 반응의 활성을 증가시키기 위해 첨가되는 유기염기는 트리메틸아민, 트리에틸아민, 이소프로필아민, 디이소프로필아민, 에틸디이소프로필아민, 피리딘, N,N-디메틸-4-아미노피리딘, 4-피롤리디노피리딘, 피콜린, 콜리딘 및 이들의 혼합물로 구성된 군에서 선택될 수 있고, 바람직하게는 트리에틸아민, 이소프로필아민 또는 디이소프로필아민일 수 있다.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 triethylamine, isopropylamine or diisopropylamine.
본 발명에 있어서, 유기염기가 첨가된 반응물의 pH는 3~10이고, 바람직하게는 6~8일 수 있다. 만약, 유기염기가 첨가된 반응물의 pH가 3미만이면, 반응속도가 느리고, 미반응의 문제가 발생될 수 있으며, pH가 10을 초과하면, 부생성물이 생성되어 반응 수율이 감소할 뿐만 아니라, 별도의 정제과정이 필요하다. 이때, 반응온도는 0℃~150℃이고, 바람직하게는 25℃~80℃이며, 반응시간은 2~48시간이고, 바람직하게는 20~24시간일 수 있다. 만약, 반응온도가 0℃미만이면, 반응속도가 느려 반응이 잘 진행되지 않는 문제가 발생되고, 150℃를 초과하면, 부생성물이 증가하여 반응수율을 감소시킬 뿐만 아니라, 별도의 정제과정이 필요하다.In the present invention, the pH of the reactant to which the organic base is added is 3 to 10, preferably 6 to 8. If the pH of the reactant to which the organic base is added is less than 3, 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. A separate purification process is needed. At this time, the reaction temperature is 0 ℃ ~ 150 ℃, preferably 25 ℃ ~ 80 ℃, the reaction time is 2 to 48 hours, preferably 20 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 exceeding 150 ℃, by-products are increased to reduce the reaction yield, and also requires a separate purification process Do.
본 발명에 있어서, 버퍼는 고리열림 반응을 활성화시킬 수 있고, 반응의 매질로도 사용할 수 있다. 상기 버퍼는 인산 버퍼, 카보네이트 버퍼, 초산 버퍼, 트리스 버퍼 및 이들의 혼합물로 구성된 군에서 선택될 수 있고, 바람직하게는 인산 버퍼일 수 있다. In the present invention, the buffer can activate the ring opening reaction and can also be used as the 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.
본 발명에 있어서, 버퍼가 사용될 경우 반응물의 pH는 3~10이고, 바람직하게는 6~8일 수 있다. 만약, 버퍼 사용될 경우 반응물의 pH가 3미만이면, 반응속도가 느리고, 미반응의 문제가 발생될 수 있으며, pH가 10을 초과하면, 부생성물이 생성되어 반응 수율이 감소할 뿐만 아니라, 별도의 정제과정이 필요하다. 또한, 반응온도는 0℃~100℃이고, 바람직하게는 20℃~40℃이며, 반응시간은 10~48시간이고, 바람직하게는 20~24시간일 수 있다. 만약, 반응온도가 0℃미만이면, 반응속도가 느려 반응이 잘 진행되지 않는 문제가 발생되고, 100℃를 초과하면, 부생성물이 증가하여 반응 수율을 감소시킬 뿐만 아니라, 별도의 정제과정이 필요하다.In the present invention, when a buffer is used, the pH of the reactant 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. In addition, the reaction temperature is 0 ° C to 100 ° C, preferably 20 ° C to 40 ° C, and the reaction time is 10 to 48 hours, preferably 20 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.
본 발명에 있어서, 루이스 에시드 또한, 고리열림 반응을 활성화시킬 수 있는 것으로, CuI, CuSO4, CuOTf2, SnSO4, AgPF6, AgBH4, Ag2SO4, BF3/Et2O, CsF, ZnOTf2 등이 사용될 수 있고, 바람직하게는 CuI 또는 CuSO4가 적당하며, 반응물을 기준으로 1~5 당량으로 첨가할 수 있고, 바람직하게는 1~2 당량을 첨가할 수 있다. 이는 반응물 기준으로 루이스 에시드를 1당량 미만으로 첨가시킬 경우, 미반응의 문제가 발생하고, 5당량을 초과하여 첨가시킬 경우에는 과량의 루이스 에시드를 제거하는데 어려운 문제가 발생될 수 있다.In the present invention, Lewis acid is also capable of activating the ring opening reaction, CuI, CuSO 4 , CuOTf 2 , SnSO 4 , AgPF 6 , AgBH 4 , Ag 2 SO 4 , BF 3 / Et 2 O, CsF, ZnOTf 2 or the like may be used, preferably CuI or CuSO 4 is suitable, and may be added in 1 to 5 equivalents, preferably 1 to 2 equivalents, based on the reactants. This may cause a problem of unreacted when adding less than 1 equivalent of Lewis acid on the basis of the reactant, and may be difficult to remove excess Lewis acid when added in excess of 5 equivalents.
이때, 루이스 에시드가 첨가된 반응물의 pH는 3~10이고, 바람직하게는 6~8일 수 있다. 만약, 루이스 에시드 첨가된 반응물의 pH가 3미만이면, 미반응의 문제가 발생될 수 있고, pH가 10을 초과하면, 부생성물이 생성되어 반응 수율이 감소할 뿐만 아니라, 별도의 정제과정이 필요하다. 또한, 반응온도는 0℃~100℃이고, 바람직하게는 20℃~40℃이며, 반응시간은 10~48시간이고, 바람직하게는 20~24시간일 수 있다. 만약, 반응온도가 0℃미만이면, 반응속도가 느려 반응이 잘 진행되지 않는 문제가 발생되고, 100℃를 초과하면, 부생성물이 증가하여 반응 수율을 감소시킬 뿐만 아니라, 정제과정이 필요하다.In this case, the pH of the reactant to which the Lewis acid is added may be 3-10, preferably 6-8. If the pH of the reactant added to the Lewis acid is less than 3, an unreacted problem may occur. If the pH exceeds 10, by-products are generated to reduce the reaction yield and a separate purification process is required. Do. In addition, the reaction temperature is 0 ° C to 100 ° C, preferably 20 ° C to 40 ° C, and the reaction time is 10 to 48 hours, preferably 20 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, and if it exceeds 100 ℃, by-products increase to reduce the reaction yield, as well as the purification process is required.
본 발명에 있어서, 제1 매질은 물, 인산 버퍼, 카보네이트 버퍼, 초산 버퍼, 트리스 버퍼, 디메틸포름아미드, 디메틸아세트아미드, 디메틸설폭사이드, 아세톤, 아세토나이트릴, 메탄올,에탄올, 프로판올, 이소프로필알콜, 테트라하이드로퓨란, 다이옥산 및 이들의 혼합물로 구성된 군에서 선택되는 것을 사용할 수 있으며, 물, 버퍼 또는 극성 유기용매를 단독으로 사용하여 제조할 수 있고, 필요에 따라서는 유기 극성용매를 물 또는 버퍼와 함께 혼합용매 하에서 반응을 수행할 수도 있다.In the present invention, the first medium is water, phosphate buffer, carbonate buffer, acetic acid buffer, tris buffer, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, methanol, ethanol, propanol, isopropyl alcohol , Tetrahydrofuran, dioxane and mixtures thereof may be used, and may be prepared using water, a buffer, or a polar organic solvent alone. If necessary, the organic polar solvent may be mixed with water or a buffer. The reaction can also be carried out under mixed solvent.
본 발명에 있어서, 고리열림 반응 후에 생성되는 라세믹 또는 광학적으로 활 성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체를 함유한 반응물은 저급 알코올을 사용하여 층분리하고, 농축하여 고순도 및 고수율로 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체만을 추출할 수 있다. 이때 사용될 수 있는 저급 알코올은 탄소수가 1~5인 알코올일 수 있고, 바람직하게는 메탄올 또는 에탄올일 수 있다.In the present invention, the reactants containing the racemic or optically active D or L-α-glycerophosphorylcholine derivatives produced after the ring opening reaction are layered using a lower alcohol, concentrated to obtain high purity and It is possible to extract only racemic or optically active D or L-α-glycerophosphorylcholine derivatives in high yield. In this case, the lower alcohol that may be used may be an alcohol having 1 to 5 carbon atoms, preferably methanol or ethanol.
이와 같이 수득된 화학식 4로 표시되는 1번 탄소위치에 지방산 또는 그의 유도체가 치환된 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린은 제2 매질 존재하에서 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린의 2번 탄소위치에 1번 탄소위치의 지방산 유도체와 동일하거나, 상이한 지방산 또는 그의 유도체를 치환시켜 최종적으로 화학식 1로 표시되는 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 다양하게 제조할 수 있다.The racemic or optically active D or L-α-glycerophosphorylcholine substituted with a fatty acid or a derivative thereof at the carbon position represented by the formula (4) thus obtained is racemic or optical in the presence of a second medium. D 2 or L-α-glycerophosphorylcholine active with the same or different fatty acid derivatives at the carbon position 1 or the fatty acid derivatives at the carbon position 2, the racemic finally represented by the formula (1) Various optically active D or L-α-phosphatidylcholine derivatives can be prepared.
본 발명에 있어서, 지방산 또는 그의 유도체는 아세트산(acetic acid), 부티르산(butyric acid), 카프로산(caproic acid), 카프릴산(caprylic acid), 세로틴산(cerotic acid), 라우르산(lauric acid), 리그노세린산(lignoceric acid), 미리스트산(myristic acid), 미리스톨레인산(myristoleic acid), 올레산(oleic acid), 팔미트산(palmitic acid), 팔미톨레산(palmitoleic acid), 스테아르산(stearic acid) 등과 같은 탄소원자수가 2~30개를 갖는 치환되거나 치환되지 않은 포화 또는 불포화 탄소를 갖고 있는 지방산 또는 그의 지방산 유도체 구성된 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the fatty acid or a derivative thereof is acetic acid, butyric acid, caproic acid, caprylic acid, cerotic acid, lauric acid ), Lignoceric acid, myristic acid, myristoleic acid, oleic acid, palmitic acid, palmitoleic acid, It may be selected from the group consisting of fatty acids having a substituted or unsubstituted saturated or unsaturated carbon having 2 to 30 carbon atoms, such as stearic acid, or fatty acid derivatives thereof, but is not limited thereto.
상기 지방산 자체를 사용하여 치환반응시킬 경우에는 DCC(N,N-디사이클로헥실카르보디이미드), DIC(디이소프로필카르보디이미드), EDC(에틸(N,N-디메틸아미노)프로필카르보디이미드 하이드로클로라이드) 등을 단독으로 사용하거나 또는 N,N-디메틸-4-아미노피리딘과 혼합하여 반응을 활성화시킬 수 있다.In the case of the substitution reaction using the fatty acid itself, DCC (N, N-dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), EDC (ethyl (N, N-dimethylamino) propylcarbodiimide Hydrochloride) and the like can be used alone or mixed with N, N-dimethyl-4-aminopyridine to activate the reaction.
본 발명에 있어서, 지방산 유도체를 치환반응에 사용할 경우에는 무수물, 할라이드, 활성 에스테르, 이미다졸 형태 등의 활성화된 지방산 유도체를 사용할 수 있으며, 필요에 따라서는 반응의 활성화를 위하여 촉매 또는 유기염기와 함께 반응을 진행할 수 있다.In the present invention, when a fatty acid derivative is used in the substitution reaction, an activated fatty acid derivative such as anhydride, halide, active ester, or imidazole may be used, and if necessary, together with a catalyst or an organic base to activate the reaction. The reaction can proceed.
본 발명에 있어서, 촉매는 바람직하게 N,N-디메틸-4-아미노피리딘이고, 염기는 트리에틸아민, 트리에틸아민, 이소프로필아민, 디이소프로필아민, 에틸디이소프로필아민 등을 사용할 수 있다.In the present invention, the catalyst is preferably N, N-dimethyl-4-aminopyridine, and the base may be triethylamine, triethylamine, isopropylamine, diisopropylamine, ethyldiisopropylamine, or the like. .
본 발명에 있어서, 지방산 또는 그의 유도체는 반응물을 기준으로 1~5당량 첨가되는 것을 특징으로 할 수 있고, 바람직하게는 1~2당량을 사용할 수 있다. 만약, 첨가되는 지방산 또는 그의 유도체가 반응물을 기준으로 1당량 미만으로 첨가 될 경우, 반응이 진행되지 않는 문제가 발생하고, 5당량을 초과하여 첨가되는 경우에는 과량의 미반응의 지방산 또는 그의 유도체가 과량으로 남아 있어, 비경제적이며 제거해야하는 문제점이 있다. 이때, 반응온도는 0℃~100℃이고, 바람직하게는 20℃~50℃이며, 반응시간은 20~72시간이고, 바람직하게는 24~48시간일 수 있다. 만약, 반응온도가 0℃미만이면, 반응속독가 느려 반응이 잘 진행되지 않는 문제가 발생되고, 100℃를 초과하면, 부생성물이 증가하여 반응 수율을 감소시킬 뿐만 아니라, 부생성물이 증가하여 반응 수율을 감소시킬 뿐만 아니라, 별도의 정제과정이 필요할 수 있다.In the present invention, the fatty acid or derivatives thereof may be added in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents based on the reactants. If the added fatty acid or derivatives thereof is added in less than 1 equivalent based on the reactants, the reaction does not proceed, and when added in excess of 5 equivalents, the excess unreacted fatty acids or derivatives thereof There is a problem that it remains in excess, uneconomical and has to be eliminated. At this time, the reaction temperature is 0 ℃ ~ 100 ℃, preferably 20 ℃ ~ 50 ℃, the reaction time is 20 to 72 hours, preferably 24 to 48 hours. If the reaction temperature is less than 0 ° C, a problem arises in that the reaction speed is slow and the reaction does not proceed well. If the reaction temperature exceeds 100 ° C, the byproducts increase to reduce the reaction yield, and the byproducts increase to increase the reaction yield. In addition to the reduction, additional purification may be required.
본 발명에 있어서, 제2 매질은 아세트산에틸, 메틸렌클로라이드, 클로로포름, 1,2-디클로로에탄, 피리딘, 디메틸포름아미드, 디메틸아세트아미드, 디메틸설폭사이드, 아세톤, 아세토나이트릴, 에틸에스테르, 테트라하이드로퓨란, 다이옥산 등을 사용할 수 있다.In the present invention, the second medium is ethyl acetate, methylene chloride, chloroform, 1,2-dichloroethane, pyridine, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, ethyl ester, tetrahydrofuran , Dioxane and the like can be used.
본 발명에 있어서, 최종적으로 반응이 완결되면, 클로로포름, 메틸렌클로라이드, 아세트산에틸 등의 유기용매와 메탄올, 에탄올, 프로판올 등의 혼합용매로 추출하고, 감압 농축하여 상기 화학식 1로 표시되는 라세믹 및 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 고순도 및 고수율로 제조할 수 있다.In the present invention, when the reaction is finally completed, the organic solvent such as chloroform, methylene chloride, ethyl acetate and the like, extracted with a mixed solvent such as methanol, ethanol and propanol, concentrated under reduced pressure and racemic and optical represented by the formula (1) As active D or L-α-phosphatidylcholine derivatives can be prepared in high purity and high yield.
본 발명에 따른 라세믹 및 광학적으로 활성이 있는 D 또는 L-α-포스파티딜 콜린 유도체를 제조하는 방법은 종래의 방법과는 달리 저가의 출발물질을 사용하여 경제적이고, 반응 중간체로 1번 탄소위치에 지방산 유도체가 치환된 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-글리세로포스포릴콜린 유도체를 사용함으로써, 2번 탄소위치에 지방산 또는 그의 유도체를 순차적으로 도입할 수 있어 지방산 또는 그의 유도체가 치환되지 않은 부생성물의 생성을 극소화할 수 있어 특별한 정제과정이 불필요하고, 1번 탄소위치와 2번 탄소위치에 서로 다른 지방산 유도체가 치환된 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조할 경우에도 보호기 도입 및 탈보호화하는 과정 없이 간편하게 고순도, 고수율의 1번 탄소위치와 2번 탄소위치에 서로 다른 지방산 유도체가 치환된 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조할 수 있다. 여기서, 라세믹 또는 광학적으로 활성이 있는 그의 염 유도체로 제조될 수 있는데, 이들 염으로는 플로오르화 수소산, 요오드화 수소산, 브롬화 수소산, 염산, 질산, 황산, 메탄설폰산, 벤젠설폰산, 파라-톨루엔설폰산 등의 염으로 제조될 수 있으며, 이에 제한된 것은 아니다.The method for preparing the racemic and optically active D or L-α-phosphatidyl choline derivatives according to the present invention is economical using a low cost starting material, unlike the conventional method, at the carbon position 1 as a reaction intermediate. By using racemic or optically active D or L-α-glycerophosphorylcholine derivatives substituted with fatty acid derivatives, fatty acids or their derivatives can be introduced sequentially at carbon position so that the fatty acids or their derivatives It is possible to minimize the production of unsubstituted by-products, so that no special purification process is necessary, and racemic or optically active D or L-α- substituted with different fatty acid derivatives at carbon positions 1 and 2 Even in the preparation of phosphatidylcholine derivatives, high purity, high yield, carbon number 1 and 2, without the introduction of protecting groups and deprotection The carbon located in a different fatty acid derivatives substituted racemic or can be optically producing a D or L-α- phosphatidyl choline derivatives which are active. Here, they may be prepared with racemic or optically active salt derivatives thereof, such as hydrofluoric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, para-toluene It may be prepared with a salt such as sulfonic acid, but is not limited thereto.
이에, 본 발명에 따른 라세믹 또는 광학적으로 활성이 있는 D 또는 L-α-포스파티딜콜린 유도체를 제조하는 방법은 의약품 또는 건강기능식품 등에 중요한 원료로 사용될 수 있는 다양한 포스파티딜콜린 유도체 및 그의 염 유도체를 경제적이며, 저렴한 가격으로 산업적으로, 대량생산이 용이하게 생산할 수 있다.Accordingly, the method for preparing a racemic or optically active D or L-α-phosphatidylcholine derivative according to the present invention is economical to various phosphatidylcholine derivatives and salt derivatives thereof that can be used as important raw materials for medicines or health functional foods, Industrially, mass production can be easily produced at a low price.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어 자명할 것이다.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.
실시예 1: 라세믹 1,2-디아세틸-α-포스파티딜콜린의 제조Example 1 Preparation of Racemic 1,2-Diacetyl-α-Phosphatidylcholine
1-1: 1-1: 라세믹Racemic 1-아세틸-α- 1-acetyl-α- 글리세로Glycerol -3--3- 포스포릴콜린의Phosphorylcholine 제조 Produce
온도계, 교반기가 부착된 250ml의 3구 둥근 바닥 플라스크에 10g의 콜린포스페이트(1당량, 54.6mmol)를 넣고, 여기에 증류수 80ml와 메탄올 20ml을 첨가시켜 콜린포스페이트를 용해시켰다. 용해된 상기 혼합물에 22ml의 5N 수산화나트륨(2당량, 109.2mmol)를 천천히 가하여 상온에서 2시간 동안 교반 시키고, 이때 pH를 7~8로 유지한 후에 9.5g의 라세믹 글리시딜아세테이트(1.5당량, 81.9mmol)을 상기의 반응물에 천천히 적가한 다음, 상온에서 24시간 반응시켰다. 상기 반응이 완료되면, 반응물을 감압 농축하여 메탄올을 완전히 제거하고, 상기 반응액에 20ml의 아세트산에틸을 가하여 반응물을 3회 세척한 뒤에 수층을 감압 농축하였다. 농축된 상기 반응물에 20ml의 증류수를 사용하여 완전히 용해시킨 다음, 50ml의 에탄올을 첨가하여 에탄올 층을 얻고, 상기 에탄올 층을 감압 농축하여 라세믹-1-아세틸- α-글리세로-3-포스포릴콜린 11.38g(수율 70%)를 수득하였다. 수득된 상기의 라세믹-1-아세틸-α-글리세로-3-포스포릴콜린에 대한 NMR 분석결과는 하기와 같다. 10 g of cholinephosphate (1 equivalent, 54.6 mmol) was placed in a 250 ml three-necked round bottom flask equipped with a thermometer and a stirrer, and 80 ml of distilled water and 20 ml of methanol were added thereto to dissolve cholinephosphate. 22 ml of 5N sodium hydroxide (2 equivalents, 109.2 mmol) was slowly added to the dissolved mixture, followed by stirring at room temperature for 2 hours. At this time, after maintaining the pH at 7-8, 9.5 g of racemic glycidyl acetate (1.5 equivalents) was added. , 81.9 mmol) was slowly added dropwise to the reaction product, followed by reaction at room temperature for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to completely remove methanol, and 20 ml of ethyl acetate was added to the reaction mixture to wash the reaction mixture three times, and the aqueous layer was concentrated under reduced pressure. 20 ml of distilled water was completely dissolved in the concentrated reaction product, and then 50 ml of ethanol was added to obtain an ethanol layer, and the ethanol layer was concentrated under reduced pressure to obtain racemic-1-acetyl-α-glycero-3-phosphoryl. 11.38 g (70% yield) of choline were obtained. The NMR analysis results of the racemic-1-acetyl-α-glycero-3-phosphorylcholine obtained are as follows.
『1H NMR (D2O, 300MHz) : δ2.24(s, 3H), 3.23(s, 9H), 3.67(t, 2H), 3.94(m, 2H), 4.08~4.25(m, 3H), 4.32(m, 2H)』`` 1 H NMR (D 2 O, 300 MHz): δ 2.24 (s, 3H), 3.23 (s, 9H), 3.67 (t, 2H), 3.94 (m, 2H), 4.08-4.25 (m, 3H) , 4.32 (m, 2H) 』
1-2: 1-2: 라세믹Racemic 1-아세틸-α- 1-acetyl-α- 글리세로Glycerol -3--3- 포스포릴콜린의Phosphorylcholine 제조 Produce
온도계, 교반기가 부착된 250ml의 3구 둥근 바닥 플라스크에 10g의 콜린포스페이트(1당량, 54.6mmol)를 넣고, 여기에 pH 7.5의 인산 버퍼 100ml와 메탄올 20ml을 첨가시켜 콜린포스페이트를 용해시켰다. 용해된 상기의 반응물에 9.5g의 라세믹 글리시딜아세테이트(1.5당량, 81.9mmol)을 천천히 적가한 다음, 상온에서 24시간 반응시켰다. 상기 반응이 완료되면, 반응물을 감압 농축하여 메탄올을 완전히 제거하고, 상기 반응액에 20ml의 아세트산에틸을 가하여 반응물을 3회 세척한 뒤에 수층을 감압 농축하였다. 농축된 상기 반응물에 20ml의 증류수를 사용하여 완전히 용해시킨 다음, 50ml의 에탄올을 첨가하여 에탄올 층을 얻고, 상기 에탄올 층을 감압 농축하여 라세믹-1-아세틸-α-글리세로-3-포스포릴콜린 12.19g(수율 75%)를 수득하였다. 수득된 상기의 라세믹-1-아세틸-α-글리세로-3-포스포릴콜린에 대한 NMR 분석결과는 하기와 같다. 10 g of cholinephosphate (1 equivalent, 54.6 mmol) was added to a 250 ml three-necked round bottom flask equipped with a thermometer and a stirrer, and 100 ml of a pH 7.5 phosphoric acid buffer and 20 ml of methanol were added thereto to dissolve cholinephosphate. 9.5 g of racemic glycidyl acetate (1.5 equivalents, 81.9 mmol) was slowly added dropwise to the dissolved reaction product, followed by reaction at room temperature for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to completely remove methanol, and 20 ml of ethyl acetate was added to the reaction mixture to wash the reaction mixture three times, and the aqueous layer was concentrated under reduced pressure. 20 ml of distilled water was completely dissolved in the concentrated reactant, and then 50 ml of ethanol was added to obtain an ethanol layer, and the ethanol layer was concentrated under reduced pressure to obtain racemic-1-acetyl-α-glycero-3-phosphoryl. 12.19 g (75% yield) of choline were obtained. The NMR analysis results of the racemic-1-acetyl-α-glycero-3-phosphorylcholine obtained are as follows.
『1H NMR (D2O, 300MHz) : δ2.24(s, 3H), 3.23(s, 9H), 3.67(t, 2H), 3.94(m, 2H), 4.08~4.25(m, 3H), 4.32(m, 2H)』`` 1 H NMR (D 2 O, 300 MHz): δ 2.24 (s, 3H), 3.23 (s, 9H), 3.67 (t, 2H), 3.94 (m, 2H), 4.08-4.25 (m, 3H) , 4.32 (m, 2H) 』
1-3: 라세믹 1,2-디아세틸-α-포스파티딜콜린의 제조1-3: Preparation of racemic 1,2-diacetyl-α-phosphatidylcholine
온도계, 교반기가 부착된 250ml의 3구 둥근 바닥 플라스크에 실시예 1-1 또는 1-2에서 제조된 5.8g의 라세믹 1-아세틸-α-글리세로-3-포스포릴콜린(1당량, 19.4mmol)를 넣고, 디메틸포름아마이드 100ml으로 용해시켰다. 용해된 상기 혼합물에 7.3ml의 무수아세트산(4당량, 77.6mmol)을 천천히 가하고, 여기에 촉매 N, N-디메틸-4-아미노피리딘 0.05g(0.02당량, 0.4mmol)을 가한 다음, 40℃에서 15시간 동안 교반하여 반응시켰다. 반응이 완료되면 반응물을 감압 농축하여 디메틸포름아마이드를 완전히 제거하고, 50ml의 0.2N HCl 수용액을 가한 다음, 150ml의 클로로포름/메탄올(2:1, v/v)을 사용하여 3회에 걸쳐 추출하여 클로로포름 층을 얻었다. 얻어진 상기 클로로포름 층을 무수황화마그네슘으로 건조시킨 다음, 감압 농축하여 라세믹1, 2-디아세틸-α-포스파티딜콜린 5.4g(수율 82%)를 제조하였다. 제조된 상기 라세믹 1,2-디아세틸-α-포스파티딜포릴콜린에 대한 NMR 분석결과는 하기와 같다. 5.8 g of racemic 1-acetyl-α-glycero-3-phosphorylcholine (1 equivalent, 19.4) prepared in Examples 1-1 or 1-2 in a 250 ml three-neck round bottom flask with thermometer and stirrer mmol) was added and dissolved in 100 ml of dimethylformamide. 7.3 ml of acetic anhydride (4 equivalents, 77.6 mmol) was slowly added to the dissolved mixture, and 0.05 g (0.02 equivalents, 0.4 mmol) of catalyst N, N-dimethyl-4-aminopyridine was added thereto at 40 ° C. The reaction was stirred for 15 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to completely remove dimethylformamide, 50 ml of 0.2N HCl aqueous solution was added thereto, and then extracted three times using 150 ml of chloroform / methanol (2: 1, v / v). A chloroform layer was obtained. The obtained chloroform layer was dried over anhydrous magnesium sulfide, and then concentrated under reduced pressure to prepare 5.4 g (yield 82%) of racemic 1 and 2-diacetyl-α-phosphatidylcholine. The NMR analysis results of the prepared racemic 1,2-diacetyl-α-phosphatidyl forylcholine are as follows.
『1H NMR (D2O, 300MHz) : δ2.15(d, 6H), 3.25(s, 9H), 3.70(t, 2H), 4.09(t, 2H), 4.27~4.42(m, 4H), 5.28(m, 1H)』`` 1 H NMR (D 2 O, 300 MHz): δ 2.15 (d, 6H), 3.25 (s, 9H), 3.70 (t, 2H), 4.09 (t, 2H), 4.27 to 4.42 (m, 4H) , 5.28 (m, 1H) 』
실시예Example 2: 2: 라세믹Racemic 1-아세틸-2- 1-acetyl-2- 부티릴Butyryl -α--α- 포스파티딜콜린의Phosphatidylcholine 제조 Produce
온도계, 교반기가 부착된 250ml의 3구 둥근 바닥 플라스크에 실시예 1-1 또는 1-2에서 제조된 9g의 라세믹 1-아세틸-α-글리세로-3-포스포릴콜린(1당량, 30.1mmol)을 넣고, 디메틸포름아마이드 93ml으로 용해시켰다. 용해된 상기 혼합물에 5.5ml의 부틸산(2당량, 60.2mmol)을 천천히 가하고, 여기에 12.4g의 N, N-디사이클로헥실카보디이미드(2당량, 60.2mmol)와 3.6g의 N, N-디메틸-4-아미노피리딘(1당량, 30.1mmol)을 가한 다음, 상온에서 48시간 동안 교반하여 반응시켰다. 반응이 완료되면 형성된 침전물을 필터링하여 제거한 다음, 상기 반응물을 감압 농축하여 디메틸포름아마이드를 완전히 제거하고, 50ml의 0.2N HCl수용액을 가한 후에 150ml의 클로로포름/메탄올(2:1, v/v)을 사용하여 3회에 걸쳐 추출하여 클로로포름층을 얻었다. 이렇게 얻어진 클로로포름층을 무수황화마그네슘으로 건조시킨 다음, 감압 농축하여 라세믹-1-아세틸-2-부티릴-α-포스파티딜콜린 9.4g(수율 85%)를 제조하였다. 제조된 상기 라세믹 1-아세틸-2-부티릴-α-포스파티딜콜린에 대한 NMR 분석결과는 하기와 같다. 9 g of racemic 1-acetyl-α-glycero-3-phosphorylcholine (1 equivalent, 30.1 mmol) prepared in Examples 1-1 or 1-2 in a 250 ml three-neck round bottom flask with thermometer and stirrer ) Was added and dissolved in 93 ml of dimethylformamide. 5.5 ml of butyric acid (2 equivalents, 60.2 mmol) was slowly added to the dissolved mixture, to which 12.4 g of N, N-dicyclohexylcarbodiimide (2 equivalents, 60.2 mmol) and 3.6 g of N, N -Dimethyl-4-aminopyridine (1 equivalent, 30.1 mmol) was added, followed by stirring at room temperature for 48 hours. After the reaction was completed, the formed precipitate was filtered off, and the reaction solution was concentrated under reduced pressure to completely remove dimethylformamide, and 50 ml of 0.2N HCl solution was added thereto, followed by 150 ml of chloroform / methanol (2: 1, v / v). Extraction was performed three times using to obtain a chloroform layer. The chloroform layer thus obtained was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to prepare 9.4 g (yield 85%) of racemic-1-acetyl-2-butyryl-α-phosphatidylcholine. The NMR analysis results of the prepared racemic 1-acetyl-2-butyryl-α-phosphatidylcholine are as follows.
『1H NMR (CD3OD, 300MHz) : δ0.95(t, 3H), 1.62(m, 2H), 2.05(s, 3H), 2.33(t, 2H), 3.24(s, 9H), 3.67(t, 2H), 4.09(m, 2H), 4.07~4.21(m, 2H), 4.29(m, 2H), 5.25(m, 1H)』`` 1 H NMR (CD 3 OD, 300 MHz): δ 0.95 (t, 3H), 1.62 (m, 2H), 2.05 (s, 3H), 2.33 (t, 2H), 3.24 (s, 9H), 3.67 (t, 2H), 4.09 (m, 2H), 4.07-4.21 (m, 2H), 4.29 (m, 2H), 5.25 (m, 1H)
실시예Example 3: 광학적으로 활성이 있는 L-1, 2- 3: optically active L-1, 2- 디아세틸Diacetyl -α--α- 포스파티딜콜린의Phosphatidylcholine 제조 Produce
3-1: 광학적으로 활성이 있는 L-1-아세틸-α-3-1: Optically Active L-1-acetyl-α- 글리세로Glycerol -3--3- 포스포릴콜린의Phosphorylcholine 제조 Produce
온도계, 교반기가 부착된 250ml의 3구 둥근 바닥 플라스크에 10g의 콜린포스페이트(1당량, 54.6mmol)를 넣고, 증류수 80ml와 메탄올 20ml로 용해시켰다. 용해 된 상기 혼합물에 22ml의 5N 수산화나트륨(2당량, 109.2mmol)를 천천히 가한 다음, 상온에서 2시간 동안 교반시켰다. 이때 pH를 7~8로 유지한 다음, 9.5g의 (R)-글리시딜 아세테이트(1.5당량, 81.9mmol)을 상기의 반응물에 천천히 적가하고, 상온에서 48시간 동안 반응시켰다. 반응이 완료되면 반응물을 감압 농축하여 반응물에 함유된 메탄올을 완전히 제거한 다음, 20ml의 아세트산에틸을 가하여 3회 세척한 뒤 수층을 감압 농축하였다. 감압 농축된 상기 반응물에 20ml의 증류수를 사용하여 완전히 용해시킨 다음, 50ml의 에탄올을 첨가하여 에탄올 층을 얻고, 얻은 상기 에탄올층을 감압 농축하여 L-1-아세틸-α-글리세로-3-포스포릴콜린 11.86g(수율 73%)를 수득하였다. 상기 수득된 L-1-아세틸-α-글리세로-3-포스포릴콜린에 대한 NMR 분석결과는 하기와 같다. 10 g of cholinephosphate (1 equivalent, 54.6 mmol) was added to a 250 ml three-necked round bottom flask equipped with a thermometer and a stirrer, and dissolved in 80 ml of distilled water and 20 ml of methanol. 22 ml of 5N sodium hydroxide (2 equivalents, 109.2 mmol) was slowly added to the dissolved mixture, followed by stirring at room temperature for 2 hours. At this time, the pH was maintained at 7-8, and then 9.5 g of (R) -glycidyl acetate (1.5 equivalents, 81.9 mmol) was slowly added dropwise to the reaction product, and reacted at room temperature for 48 hours. When the reaction was completed, the reaction was concentrated under reduced pressure to completely remove the methanol contained in the reaction, and then washed three times with 20 ml of ethyl acetate, and the aqueous layer was concentrated under reduced pressure. 20 ml of distilled water was completely dissolved in the reaction mixture concentrated under reduced pressure, and then 50 ml of ethanol was added to obtain an ethanol layer. The obtained ethanol layer was concentrated under reduced pressure to obtain L-1-acetyl-α-glycero-3-force. 11.86 g (73% yield) of polycholine were obtained. The NMR analysis of the obtained L-1-acetyl-α-glycero-3-phosphorylcholine is as follows.
『1H NMR (D2O, 300MHz) : δ2.24(s, 3H), 3.23(s, 9H), 3.67(t, 2H), 3.94(m, 2H), 4.08~4.25(m, 3H), 4.32(m, 2H)』`` 1 H NMR (D 2 O, 300 MHz): δ 2.24 (s, 3H), 3.23 (s, 9H), 3.67 (t, 2H), 3.94 (m, 2H), 4.08-4.25 (m, 3H) , 4.32 (m, 2H) 』
3-2: 광학적으로 활성이 있는 L- 1-아세틸-α-3-2: Optically Active L-1-Acetyl-α- 글리세로Glycerol -3--3- 포스포릴콜린의Phosphorylcholine 제조 Produce
온도계, 교반기가 부착된 250ml의 3구 둥근 바닥 플라스크에 10g의 콜린포스페이트(1당량, 54.6mmol)를 넣고, 여기에 pH 7.5의 인산 버퍼 100ml와 메탄올 20ml을 첨가시켜 콜린포스페이트를 용해시켰다. 용해된 상기의 반응물에 9.5g의 (R)-글리시딜아세테이트(1.5당량, 81.9mmol)을 천천히 적가한 다음, 상온에서 24시간 반응시켰다. 상기 반응이 완료되면, 반응물을 감압 농축하여 메탄올을 완전히 제거하 고, 상기 반응액에 20ml의 아세트산에틸을 가하여 반응물을 3회 세척한 뒤에 수층을 감압 농축하였다. 농축된 상기 반응물에 20ml의 증류수를 사용하여 완전히 용해시킨 다음, 50ml의 에탄올을 첨가하여 에탄올 층을 얻고, 상기 에탄올 층을 감압 농축하여 L-1-아세틸- α-글리세로-3-포스포릴콜린 12.35g(수율 76%)를 수득하였다. 수득된 상기의 L-1-아세틸-α-글리세로-3-포스포릴콜린에 대한 NMR 분석결과는 하기와 같다. 10 g of cholinephosphate (1 equivalent, 54.6 mmol) was added to a 250 ml three-necked round bottom flask equipped with a thermometer and a stirrer, and 100 ml of a pH 7.5 phosphoric acid buffer and 20 ml of methanol were added thereto to dissolve cholinephosphate. 9.5 g of (R) -glycidyl acetate (1.5 equivalents, 81.9 mmol) was slowly added dropwise to the dissolved reaction product, followed by reaction at room temperature for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to completely remove methanol, and 20 ml of ethyl acetate was added to the reaction mixture to wash the reaction mixture three times, and the aqueous layer was concentrated under reduced pressure. 20 ml of distilled water was completely dissolved in the concentrated reaction product, and then 50 ml of ethanol was added to obtain an ethanol layer, and the ethanol layer was concentrated under reduced pressure to give L-1-acetyl-α-glycero-3-phosphorylcholine. 12.35 g (76% yield) were obtained. The NMR analysis results of the L-1-acetyl-α-glycero-3-phosphorylcholine obtained above are as follows.
『1H NMR (D2O, 300MHz) : δ2.24(s, 3H), 3.23(s, 9H), 3.67(t, 2H), 3.94(m, 2H), 4.08~4.25(m, 3H), 4.32(m, 2H)』`` 1 H NMR (D 2 O, 300 MHz): δ 2.24 (s, 3H), 3.23 (s, 9H), 3.67 (t, 2H), 3.94 (m, 2H), 4.08-4.25 (m, 3H) , 4.32 (m, 2H) 』
3-3: 광학적으로 활성이 있는 L-1, 2- 디아세틸 -α- 포스파티딜콜린의 제조 3-3: Preparation of optically L-1, 2- diacetyl -α- phosphatidylcholine which is active
온도계, 교반기가 부착된 250ml의 3구 둥근 바닥 플라스크에 실시예 3-1또는 3-2에서 제조된 5.8g의 L-1-아세틸-α-글리세로-3-포스포릴콜린(1당량, 19.4mmol)을 넣고, 디메틸포름아마이드 100ml로 용해시켰다. 용해된 상기 혼합물에 7.3ml의 무수아세트산(4당량, 77.6mmol)을 천천히 가하고, 여기에 촉매량의 N, N-디메틸-4-아미노피리딘 0.05g(0.02당량, 0.4mmol)을 가한 다음, 40℃에서 15시간 동안 교반하여 반응시켰다. 상기 반응이 완료되면, 상기 반응물을 감압 농축하여 디메틸포름아마이드를 완전히 제거하고, 50ml의 0.2N HCl 수용액을 가한 다음, 150ml의 클로로포름/메탄올(2:1, v/v)을 사용하여 3회에 걸쳐 추출하여 클로로포름층을 수득하였다. 이렇게 수득된 클로로포름 층을 무수황화마그네슘으로 건조시킨 다음, 감압 농축하여 L-1, 2-디아세틸-α-포스파티딜콜린 5.2g(수율 80%)를 제조하였다. 상기 제조된 L-1, 2-디아세틸-α-포스파티딜콜린에 대한 NMR 분석결과는 하기와 같다. 5.8 g of L-1-acetyl-α-glycero-3-phosphorylcholine (1 equivalent, 19.4) prepared in Example 3-1 or 3-2 in a 250 ml three-neck round bottom flask with thermometer and stirrer mmol) was added and dissolved in 100 ml of dimethylformamide. 7.3 ml of acetic anhydride (4 equivalents, 77.6 mmol) was slowly added to the dissolved mixture, and thereto was added 0.05 g (0.02 equivalents, 0.4 mmol) of N, N-dimethyl-4-aminopyridine in catalytic amount, and then 40 占 폚. The reaction was stirred for 15 hours at. When the reaction was completed, the reaction mixture was concentrated under reduced pressure to completely remove dimethylformamide, 50 ml of 0.2N HCl aqueous solution was added thereto, and then 150 ml of chloroform / methanol (2: 1, v / v) was added three times. Extraction over gave a chloroform layer. The chloroform layer thus obtained was dried over anhydrous magnesium sulfide, and then concentrated under reduced pressure to prepare 5.2 g (80% yield) of L-1 and 2-diacetyl-α-phosphatidylcholine. The NMR analysis results of the prepared L-1, 2-diacetyl-α-phosphatidylcholine are as follows.
『1H NMR (D2O, 300MHz) : δ2.15(d, 6H), 3.25(s, 9H), 3.70(t, 2H), 4.09(t, 2H), 4.27~4.42(m, 4H), 5.28(m, 1H)』`` 1 H NMR (D 2 O, 300 MHz): δ 2.15 (d, 6H), 3.25 (s, 9H), 3.70 (t, 2H), 4.09 (t, 2H), 4.27 to 4.42 (m, 4H) , 5.28 (m, 1H) 』
실시예Example 4: 광학적으로 활성이 있는 L-1, 2-아세틸-2- 4: optically active L-1, 2-acetyl-2- 부티릴Butyryl -α--α- 포스파티딜콜린의Phosphatidylcholine 제조 Produce
온도계, 교반기가 부착된 250ml의 3구 둥근 바닥 플라스크에 실시예 3-1 또는 3-2에서 제조된 9g의 L-1-아세틸-α-글리세로-3-포스포릴콜린(1당량, 30.1mmol)을 넣고, 디메틸포름아마이드 93ml으로 용해시켰다. 상기 혼합물에 5.5ml의 부틸산(2당량, 60.2mmol)을 천천히 가하고, 여기에 12.4g의 N, N-디사이클로헥실카보디이미드(2당량, 60.2mmol)와 3.6g의 N, N-디메틸-4-아미노피리딘(1당량, 30.1mmol)을 가한 다음, 상온에서 48시간 교반하여 반응시켰다. 반응이 완료되면 상시 반응물에 형성된 침전물을 필터링하여 제거하고, 반응물을 감압 농축하여 디메틸포름아마이드를 완전히 제거시킨 다음, 상기 반응물에 50ml의 0.2N HCl수용액을 가한 후에 150ml의 클로로포름/메탄올(2:1, v/v)을 사용하여 3회에 걸쳐 추출하였다. 이렇게 얻은 클로로포름층을 무수황화마그네슘으로 건조시킨 다음, 상기 반응물을 감압 농축하여 L-1-아세틸-2-부티릴-α-포스파티딜콜린 9.6g(수율 87%)를 제조하였다. 상기 제조된 L-1, 2-아세틸-2-부티릴-α-포스파티딜콜린에 대한 NMR 분석결과는 하 기와 같다. 9 g L-1-acetyl-α-glycero-3-phosphorylcholine (1 equivalent, 30.1 mmol) prepared in Example 3-1 or 3-2 in a 250 ml three-neck round bottom flask with thermometer and stirrer ) Was added and dissolved in 93 ml of dimethylformamide. 5.5 ml of butyric acid (2 equivalents, 60.2 mmol) was slowly added to the mixture, to which 12.4 g of N, N-dicyclohexylcarbodiimide (2 equivalents, 60.2 mmol) and 3.6 g of N, N-dimethyl were added. 4-aminopyridine (1 equivalent, 30.1 mmol) was added, followed by stirring for 48 hours at room temperature. When the reaction was completed, the precipitate formed in the reaction product was always removed by filtration, and the reaction product was concentrated under reduced pressure to completely remove dimethylformamide. Then, 50 ml of 0.2N HCl aqueous solution was added to the reaction product, followed by 150 ml of chloroform / methanol (2: 1). , v / v), extracted three times. The chloroform layer thus obtained was dried over anhydrous magnesium sulfide, and the reaction was concentrated under reduced pressure to prepare 9.6 g (yield 87%) of L-1-acetyl-2-butyryl-α-phosphatidylcholine. The NMR analysis results of the prepared L-1, 2-acetyl-2-butyryl-α-phosphatidylcholine are as follows.
『1H NMR (CD3OD, 300MHz) : δ0.95(t, 3H), 1.62(m, 2H), 2.05(s, 3H), 2.33(t, 2H), 3.24(s, 9H), 3.67(t, 2H), 4.09(m, 2H), 4.07~4.21(m, 2H), 4.29(m, 2H), 5.25(m, 1H)』`` 1 H NMR (CD 3 OD, 300 MHz): δ 0.95 (t, 3H), 1.62 (m, 2H), 2.05 (s, 3H), 2.33 (t, 2H), 3.24 (s, 9H), 3.67 (t, 2H), 4.09 (m, 2H), 4.07-4.21 (m, 2H), 4.29 (m, 2H), 5.25 (m, 1H)
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다. 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.
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| CN114478622A (en) * | 2022-03-17 | 2022-05-13 | 沈阳金久奇科技有限公司 | Preparation method of phosphatidylcholine |
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| US5886177A (en) | 1994-01-11 | 1999-03-23 | Isis Pharmaceuticals, Inc. | Phosphate linked oligomers |
| US6448373B1 (en) | 1994-01-11 | 2002-09-10 | Isis Pharmaceuticals, Inc. | Phosphate linked oligomers formed of monomeric diols and processes for preparing same |
| KR100966627B1 (en) * | 2006-06-14 | 2010-06-29 | 주식회사 대웅제약 | A process for preparation of L?glycerophosphoryl choline |
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| CN114478622A (en) * | 2022-03-17 | 2022-05-13 | 沈阳金久奇科技有限公司 | Preparation method of phosphatidylcholine |
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