JP6843765B2 - 両親媒性イミダゾリニウム化合物の製造方法 - Google Patents
両親媒性イミダゾリニウム化合物の製造方法 Download PDFInfo
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- JP6843765B2 JP6843765B2 JP2017557182A JP2017557182A JP6843765B2 JP 6843765 B2 JP6843765 B2 JP 6843765B2 JP 2017557182 A JP2017557182 A JP 2017557182A JP 2017557182 A JP2017557182 A JP 2017557182A JP 6843765 B2 JP6843765 B2 JP 6843765B2
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- carboxylic acid
- reaction mixture
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- -1 imidazolinium compound Chemical class 0.000 title claims description 53
- 238000004519 manufacturing process Methods 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims description 115
- 238000000034 method Methods 0.000 claims description 92
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 66
- 239000011541 reaction mixture Substances 0.000 claims description 50
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 38
- 239000003960 organic solvent Substances 0.000 claims description 35
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 27
- 239000000047 product Substances 0.000 claims description 27
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 20
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 19
- 239000012433 hydrogen halide Substances 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 19
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 18
- 125000001931 aliphatic group Chemical group 0.000 claims description 16
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 16
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 239000011780 sodium chloride Substances 0.000 claims description 15
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical class O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 13
- 150000002170 ethers Chemical class 0.000 claims description 12
- 150000002576 ketones Chemical class 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 125000005910 alkyl carbonate group Chemical group 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003377 acid catalyst Substances 0.000 claims description 6
- 238000004587 chromatography analysis Methods 0.000 claims description 6
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 6
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 6
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 6
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 6
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 6
- 239000011736 potassium bicarbonate Substances 0.000 claims description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000012024 dehydrating agents Substances 0.000 claims description 5
- 239000002808 molecular sieve Substances 0.000 claims description 5
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- 235000011148 calcium chloride Nutrition 0.000 claims description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 4
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- AGGIJOLULBJGTQ-UHFFFAOYSA-N sulfoacetic acid Chemical compound OC(=O)CS(O)(=O)=O AGGIJOLULBJGTQ-UHFFFAOYSA-N 0.000 claims description 3
- TZYLAVDLZMNCMQ-AWLASTDMSA-N [Cl-].CCCCCCCC\C=C/CCCCCCCC1N(CCO)CC[NH+]1CCOC(=O)CCCCCCC\C=C/CCCCCCCC Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC1N(CCO)CC[NH+]1CCOC(=O)CCCCCCC\C=C/CCCCCCCC TZYLAVDLZMNCMQ-AWLASTDMSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 238000005917 acylation reaction Methods 0.000 description 12
- GFIWSSUBVYLTRF-UHFFFAOYSA-N 2-[2-(2-hydroxyethylamino)ethylamino]ethanol Chemical compound OCCNCCNCCO GFIWSSUBVYLTRF-UHFFFAOYSA-N 0.000 description 11
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 11
- 230000010933 acylation Effects 0.000 description 10
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 9
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001450 anions Chemical class 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 125000002091 cationic group Chemical group 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000006462 rearrangement reaction Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 4
- UFQDKRWQSFLPQY-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-3-ium;chloride Chemical compound Cl.C1CN=CN1 UFQDKRWQSFLPQY-UHFFFAOYSA-N 0.000 description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- 239000005642 Oleic acid Substances 0.000 description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical class C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 229940049964 oleate Drugs 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000011027 product recovery Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000013603 viral vector Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- MLQBTMWHIOYKKC-KTKRTIGZSA-N (z)-octadec-9-enoyl chloride Chemical compound CCCCCCCC\C=C/CCCCCCCC(Cl)=O MLQBTMWHIOYKKC-KTKRTIGZSA-N 0.000 description 3
- 0 *C(OCCNCCNCCOC(*)=O)=O Chemical compound *C(OCCNCCNCCOC(*)=O)=O 0.000 description 3
- 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 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001476 gene delivery Methods 0.000 description 3
- 238000001415 gene therapy Methods 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- GIXSGMNJIPGMLG-CLFAGFIQSA-N 2-[2-[(z)-heptadec-8-enyl]-3-(2-hydroxyethyl)imidazolidin-1-yl]ethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC1N(CCO)CCN1CCOC(=O)CCCCCCC\C=C/CCCCCCCC GIXSGMNJIPGMLG-CLFAGFIQSA-N 0.000 description 2
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- DCLDUCYKOSZRHW-UHFFFAOYSA-N 2-hydroxyethyl-[2-(2-hydroxyethylazaniumyl)ethyl]azanium dibromide Chemical compound [Br-].[Br-].OCC[NH2+]CC[NH2+]CCO DCLDUCYKOSZRHW-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 125000006847 BOC protecting group Chemical group 0.000 description 2
- 239000005639 Lauric acid Substances 0.000 description 2
- 235000021360 Myristic acid Nutrition 0.000 description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 238000005349 anion exchange Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000003841 chloride salts Chemical class 0.000 description 2
- 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 2
- 150000005690 diesters Chemical class 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XEZVDURJDFGERA-UHFFFAOYSA-N tricosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCCC(O)=O XEZVDURJDFGERA-UHFFFAOYSA-N 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- WCRDEBWGJPQSIW-UHFFFAOYSA-N 2-(4,5-dihydro-1h-imidazol-3-ium-3-yl)ethanol;chloride Chemical compound [Cl-].OCC[NH+]1CCN=C1 WCRDEBWGJPQSIW-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 208000037919 acquired disease Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- HDFXRQJQZBPDLF-UHFFFAOYSA-L disodium hydrogen carbonate Chemical compound [Na+].[Na+].OC([O-])=O.OC([O-])=O HDFXRQJQZBPDLF-UHFFFAOYSA-L 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 125000002669 linoleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002479 lipoplex Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003431 steroids Chemical group 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- MBDNRNMVTZADMQ-UHFFFAOYSA-N sulfolene Chemical compound O=S1(=O)CC=CC1 MBDNRNMVTZADMQ-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
- C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
- C07D233/12—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D233/14—Radicals substituted by oxygen atoms
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
当該方法における第1段階は、N,N′−ビス(2−ヒドロキシエチル)エチレンジアミンのハロゲン化水素塩(式(III))の製造である。これは、代表的には好適な溶媒を含む反応混合物中、N,N′−ビス(2−ヒドロキシエチル)エチレンジアミン(式(II))をハロゲン化水素(HX)(XはCl、BrまたはIである。)と反応させることで行う。各種の好ましい実施形態において、ハロゲン化水素は、塩化水素(XはClである。)または臭化水素(XはBrである。)。各種の特に好ましい実施形態において、ハロゲン化水素は臭化水素である。概して、ハロゲン化水素は、N,N′−ビス(2−ヒドロキシエチル)エチレンジアミンを含む反応混合物中に導入される。これは、例えば、代表的には有機溶媒に溶かしたN,N′−ビス(2−ヒドロキシエチル)エチレンジアミンの溶液の形態である反応混合物にハロゲン化水素を気体として導入することで行うことができる。あるいは、ハロゲン化水素の有機溶媒中溶液(例えば、非水系HBr/酢酸、またはHClのメタノール、エタノール、ジオキサンもしくはまたはジエチルエーテル中溶液)を反応混合物に加えることができる。一般には、液相での反応混合物へのハロゲン化水素の導入が好ましい。
ハライド塩として保護されたN,N′−ビス(2−ヒドロキシエチル)エチレンジアミンの2級アミノ基で、式(III)の化合物の1級ヒドロキシル基をアシル化して、ジエステルを製造する。
クロライドは式(I)の最終生成物における対イオンであることから、式(IV)の化合物が塩酸塩以外のハロゲン化水素塩である場合(例えば、式(III)の化合物をカルボン酸ハライドRC(O)Y(YはClではない)と反応させる場合)には、追加の洗浄段階が必要である。しかしながら、塩酸塩(IVb)を式(III)の化合物から製造する場合には、洗浄は必要ない。
転位反応を行うため、式(IVb)の化合物を、好適な溶媒を含む反応混合物に溶かし、この反応混合物を加熱し、撹拌すると、その際にアシル基移動とそれに続く縮合が生じ、結果的に式(I)のイミダゾリニウム化合物が生成する。
下記の非限定的実施例は、本発明をさらに説明するために提供されるものである。
N,N′−ビス(2−ヒドロキシエチル)エチレンジアミン(20g、0.135mol)を酢酸100mLに溶かした(発熱)。この溶液を冷却して約20℃とした後、臭化水素酸(0.283mol;50.3mL、33%酢酸中溶液)を、反応混合物に、反応混合物の温度が30℃を超えないように45分の期間をかけてゆっくり加えた。臭化水素酸の反応混合物への添加中に、白色沈殿が生成した。添加完了後、反応混合物を30分間撹拌してから、沈殿を濾過した。次に、その沈殿をアセトニトリルで洗浄し(25mLで2回)、30℃で真空乾燥して(5mbar)、N,N′−ビス(2−ヒドロキシエチル)エタン−1,2−ジアミニウムジブロミド40.58g(0.131mol、収率97%)を白色固体として得た。生成物の構造を、NMRスペクトル測定によって確認した。1H−NMR(DMSO−d6、400MHz)δ=8.62(4H、bs)、5.34(2H、bs)、3.67(4H、bs)、3.29(4H、bs)、および3.07(4H、bs)ppm。
N,N′−ビス{2−[(9Z)−オクタデカ−9−エンオイルオキシ]エチル}エタン−1,2−ジアミニウムジブロミドを、調製したばかりのオレイン酸クロライドでN,N′−ビス(2−ヒドロキシエチル)エタン−1,2−ジアミニウムジブロミドをアシル化することで製造した。
N,N′−ビス{2−[(9Z)−オクタデカ−9−エンオイルオキシ]エチル}エタン−1,2−ジアミニウムジブロミド(42g、0.050mol)をクロロホルム(500mL)に溶かした。この溶液に20℃で、水250mLおよび濃塩化ナトリウム水溶液500mLを加えた。反応混合物を1時間撹拌することで撹拌し、有機層を水層から分離した。代表的には、反応混合物を事前に遠心(3000から5000RPM)することで、より良好な相分離が行われた。有機層を、再度同様にして塩化ナトリウム水溶液によって処理した(2回)。最後に、有機層を水で洗浄し、塩化カルシウム2gで脱水し、減圧下に(500mbar、徐々に20mbarとする)40℃で濃縮して、N,N′−ビス{2−[(9Z)−オクタデカ−9−エンオイルオキシ]エチル}エタン−1,2−ジアミニウムジクロライド31.9g(0.0425mol、85%)をオフホワイト固体として得た。生成物の構造をNMRスペクトル測定によって確認した。1H−NMR(CDCl3、400MHz)δ=10.10(4H、bs)、5.35(4H、m)、4.49(4H、m)、3.69(4H、bs)、3.38(4H、m)、2.45(4H、m)、1.99(8H、m)、1.61(4H、m)、1.29(40H、m)、および0.88(6H、m)ppm。
N,N′−ビス{2−[(9Z)−オクタデカ−9−エンオイルオキシ]エチル}エタン−1,2−ジアミニウムジクロライド(20g、0.0266mol)をクロロホルム(160mL)およびメタノール(40mL)の混合物に溶かし、この混合物に、3Åモレキュラーシーブス(5g)を加えた。反応混合物を加熱して約54℃とし、24時間撹拌した。反応混合物を冷却して室温とし、濾過して固体を除去した。濾液を減圧下に(500mbar、徐々に5mbarとする)40℃で濃縮して、黄色様ロウ状固体を得た。粗生成物をアセトン30mLで処理し、40℃で30分間撹拌した。得られたスラリーを濾過し、濾液を減圧下に再度濃縮して、1−[2−(9(Z)−オクタデセノイルオキシ)エチル]−2−(8(Z)−ヘプタデセニル)−3−(2−ヒドロキシエチル)イミダゾリニウムクロライド14.4g(0.0207mol、収率78%)を無色ロウ状固体として得た。生成物の構造をNMRスペクトル測定によって確認した。1H−NMR(CDCl3、400MHz)δ=6.12(1H、bs)、5.34(4H、m)、4.34(2H、m)、4.09(4H、s)、3.87(2H、m)、3.77(2H、m)、3.52(2H、m)、2.78(2H、m)、2.32(2H、m)、2.00(8H、m)、1.59(4H、m)、1.30(40H、m)、および0.88(6H、m)ppm。
N,N′−ビス{2−[(9Z)−オクタデカ−5−エンオイルオキシ]エチル}エタン−1,2−ジアミニウムジクロライド(140g、0.186mol)および重炭酸ナトリウム(炭酸水素ナトリウム)(15.68g、0.205mol)をクロロホルム(1120mL)およびメタノール(280mL)の混合物に20℃で懸濁させた。反応混合物を加熱して約50から52℃の温度とし、5時間撹拌した。次に、混合物を減圧下に濃縮して(40℃;150mbar)、溶媒を除去し、残留物(196g)を得た。粗生成物の残留物をアセトン(1120mL)に溶かし、次に活性炭(28g、120℃で乾燥させたもの)を加え、懸濁液を室温で30分間撹拌した。得られたスラリーを濾過し、フィルターケーキをアセトン(150mL)で洗浄した。合わせた透明黄色濾液を減圧下に濃縮して(40℃;4mbar)、(1−[2−(9(Z)−オクタデセノイルオキシ)エチル]−2−(8(Z)−ヘプタデセニル)−3−(2−ヒドロキシエチル)イミダゾリニウムクロライド)120.3g(0.173mol、収率92.7%)を得た。
さらに説明するため、本開示のさらなる非限定的実施形態を、下記で説明する。
有機溶媒および塩基を含む反応混合物中で式(IV)の化合物を加熱して、式(I)の化合物を提供すること
を含む方法である。
Claims (25)
- 式(I)の化合物:
(式中、Rは、炭素原子11から29個の直鎖脂肪族飽和もしくは不飽和ヒドロカルビル基である。)の製造方法であって、
式(II)の化合物をハロゲン化水素(HX)と反応させて、式(III)(ここでXはCl、BrまたはIである。)の化合物を提供すること;
式(III)の化合物をカルボン酸ハライド[RC(O)Y](ここでYはCl、Br、FおよびIからなる群から選択される。)、またはカルボン酸無水物[RC(O)OC(O)R2](ここでRは式(I)について上記で定義の通りであり、R2は炭素原子1から29個の直鎖もしくは分岐の脂肪族飽和もしくは不飽和ヒドロカルビル基である。)
と反応させて、式(IV)の化合物を提供すること;
および
式(IV)の化合物を加熱して、式(I)の化合物を提供すること
を含む方法。 - 式(III)の化合物をカルボン酸無水物[RC(O)OC(O)R2]またはカルボン酸ハライド[RC(O)Y]と反応させ、X=Clである場合、式(IVb)の化合物が提供される請求項1に記載の方法。
- 式(III)の化合物を、酸触媒の非存在下にカルボン酸ハライドまたはカルボン酸無水物と反応させる、請求項2または3に記載の方法。
- 式(III)の化合物を、p−トルエンスルホン酸、ベンゼンスルホン酸、スルホ酢酸、リン酸、および三塩化リンからなる群から選択される酸触媒の非存在下に、カルボン酸ハライドまたはカルボン酸無水物と反応させる請求項2または3に記載の方法。
- 式(II)の化合物を、C2−C6カルボン酸類、C2−C6ニトリル類、C1−C6アルコール類、C2−C10エーテル類、C3−C6アルキルアセテート類、C3−C10ケトン類、C5−C8脂肪族炭化水素類、C1−C6塩素化炭化水素類、C3−C8アルキルカーボネート類、スルホラン、ジメチルスルホキシド、トルエン、クロロベンゼンおよびそれらの組み合わせから選択される有機溶媒をさらに含む反応混合物中、ハロゲン化水素(HX)と反応させる、請求項1から5のいずれか1項に記載の方法。
- 式(II)の化合物を0℃から60℃の温度でハロゲン化水素と反応させる、請求項1から6のいずれか1項に記載の方法。
- R2がC1−C10直鎖もしくは分岐の脂肪族炭化水素である請求項1から7のいずれか1項に記載の方法。
- 式(III)の化合物をカルボン酸ハライド[RC(O)Y](ここでRはC11−C29直鎖ヒドロカルビル基であり、YはClまたはBrである。)と反応させる、請求項1から8のいずれか1項に記載の方法。
- 式(III)の化合物をカルボン酸無水物[RC(O)C(O)R2](ここでRはC11−C29直鎖飽和または不飽和脂肪族ヒドロカルビル基であり、R2はC1−C10直鎖もしくは分岐の脂肪族炭化水素である。)と反応させる、請求項1から8のいずれか1項に記載の方法。
- 式(III)の化合物を、C2−C6ニトリル類、C2−C10エーテル類、C3−C6アルキルアセテート類、C3−C10ケトン類、C5−C8脂肪族炭化水素類、C1−C6塩素化炭化水素類、C3−C8アルキルカーボネート類、スルホラン、ジメチルスルホキシド、トルエン、クロロベンゼンおよびそれらの組み合わせからなる群から選択される有機溶媒をさらに含む反応混合物中、カルボン酸無水物[RC(O)OC(O)R2]、またはカルボン酸ハライド[RC(O)Y]と反応させる、請求項1から10のいずれか1項に記載の方法。
- 式(III)の化合物を、0℃から120℃の温度でカルボン酸無水物またはカルボン酸ハライドと反応させる、請求項1から11のいずれか1項に記載の方法。
- 式(IVa)の化合物を塩化ナトリウム水溶液と接触させて、式(IVb)の化合物を提供する、請求項2から12のいずれか1項に記載の方法。
- 式(IVa)の化合物を、C2−C6ニトリル類、C2−C10エーテル類、C3−C6アルキルアセテート類、C3−C10ケトン類、C5−C8脂肪族炭化水素類、C1−C6塩素化炭化水素類、トルエン、クロロベンゼンおよびそれらの組み合わせからなる群から選択される有機溶媒をさらに含む反応混合物中、塩化ナトリウムの水溶液と接触させる、請求項13に記載の方法。
- 式(IVa)の化合物を、0℃から60℃の温度で塩化ナトリウム水溶液と接触させる、請求項14に記載の方法。
- 式(IVb)の化合物を、式(IVb)の化合物およびC2−C6ニトリル類、C1−C6アルコール類、C2−C10エーテル類、C3−C6アルキルアセテート類、C3−C10ケトン類、C5−C8脂肪族炭化水素類、C1−C6塩素化炭化水素類、C3−C8アルキルカーボネート類、スルホラン、ジメチルスルホキシド、トルエン、クロロベンゼンおよびそれらの組み合わせからなる群から選択される有機溶媒を含む反応混合物中で加熱する、請求項2から15のいずれか1項に記載の方法。
- 式(IVb)の化合物を含む前記反応混合物が、重炭酸ナトリウム、重炭酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム、3級アミンまたはそれらの混合物からなる群から選択される弱塩基をさらに含む請求項16に記載の方法。
- 式(IVb)の化合物および有機溶媒を含む前記反応混合物が、モレキュラーシーブス、塩化カルシウム、硫酸マグネシウム、硫酸ナトリウム、活性炭またはこれらの組み合わせからなる群から選択される脱水剤をさらに含む請求項16または17に記載の方法。
- 式(IVb)の化合物および有機溶媒を含む前記反応混合物を、20℃から100℃の温度に加熱する請求項16から18のいずれか1項に記載の方法。
- 式(IV)の化合物を加熱することで、式(I)の化合物を含む生成物混合物を形成し、前記方法が、前記生成物混合物を濾過することで固体分画および式(I)の化合物を含む濾液を形成することをさらに含む、請求項1から19のいずれか1項に記載の方法。
- 式(I)の化合物を前記生成物混合物濾液から回収し、溶媒による洗浄、再結晶またはクロマトグラフィー法によって精製する、請求項20に記載の方法。
- 前記塩基が、重炭酸ナトリウム、重炭酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム、3級アミンまたはそれらの混合物から選択される弱塩基である請求項23または24に記載の方法。
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