CN109824534B - 一种n-烷酰基美金刚的合成方法 - Google Patents
一种n-烷酰基美金刚的合成方法 Download PDFInfo
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- CN109824534B CN109824534B CN201910236412.8A CN201910236412A CN109824534B CN 109824534 B CN109824534 B CN 109824534B CN 201910236412 A CN201910236412 A CN 201910236412A CN 109824534 B CN109824534 B CN 109824534B
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- formic acid
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- 229960004640 memantine Drugs 0.000 title claims abstract description 19
- 238000001308 synthesis method Methods 0.000 title description 2
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229960000967 memantine hydrochloride Drugs 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 46
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- 235000019253 formic acid Nutrition 0.000 claims description 23
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 239000003495 polar organic solvent Substances 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 230000000442 meristematic effect Effects 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 12
- 239000012345 acetylating agent Substances 0.000 abstract description 5
- 238000004458 analytical method Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- 238000004817 gas chromatography Methods 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000523 sample Substances 0.000 description 23
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 22
- 239000012535 impurity Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- NYQWYYMEIBHRSB-UHFFFAOYSA-N n-(3,5-dimethyl-1-adamantyl)formamide Chemical compound C1C(C2)CC3(C)CC1(C)CC2(NC=O)C3 NYQWYYMEIBHRSB-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 14
- WVIRSYCDAYUOMJ-UHFFFAOYSA-N n-(3,5-dimethyl-1-adamantyl)acetamide Chemical compound C1C(C2)CC3(C)CC2(C)CC1(NC(=O)C)C3 WVIRSYCDAYUOMJ-UHFFFAOYSA-N 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 239000003480 eluent Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N Benzylformate Chemical compound O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 229940022663 acetate Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229940007550 benzyl acetate Drugs 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 150000007529 inorganic bases Chemical group 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- ZHWOKWSNUDXGNF-UHFFFAOYSA-N (2-nitrophenyl) formate Chemical compound [O-][N+](=O)C1=CC=CC=C1OC=O ZHWOKWSNUDXGNF-UHFFFAOYSA-N 0.000 description 1
- -1 1, 8-diazabicyclo undec-7-ene tertiary amine compound Chemical class 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AVMSWPWPYJVYKY-UHFFFAOYSA-N 2-Methylpropyl formate Chemical compound CC(C)COC=O AVMSWPWPYJVYKY-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- XQABVLBGNWBWIV-UHFFFAOYSA-N 4-methoxypyridine Chemical compound COC1=CC=NC=C1 XQABVLBGNWBWIV-UHFFFAOYSA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-M 4-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-M 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- SOGXBRHOWDEKQB-UHFFFAOYSA-N benzyl 2-chloroacetate Chemical compound ClCC(=O)OCC1=CC=CC=C1 SOGXBRHOWDEKQB-UHFFFAOYSA-N 0.000 description 1
- QUKGYYKBILRGFE-VJJZLTLGSA-N benzyl acetate Chemical class C[13C](=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-VJJZLTLGSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- YJRGMUWRPCPLNH-UHFFFAOYSA-N butyl 2-chloroacetate Chemical compound CCCCOC(=O)CCl YJRGMUWRPCPLNH-UHFFFAOYSA-N 0.000 description 1
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
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- 238000002347 injection Methods 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- DCKVFVYPWDKYDN-UHFFFAOYSA-L oxygen(2-);titanium(4+);sulfate Chemical compound [O-2].[Ti+4].[O-]S([O-])(=O)=O DCKVFVYPWDKYDN-UHFFFAOYSA-L 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- VODRWDBLLGYRJT-UHFFFAOYSA-N propan-2-yl 2-chloroacetate Chemical compound CC(C)OC(=O)CCl VODRWDBLLGYRJT-UHFFFAOYSA-N 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- QJZNRCWAXUGABH-UHFFFAOYSA-N propyl 2-chloroacetate Chemical compound CCCOC(=O)CCl QJZNRCWAXUGABH-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- QQKDTTWZXHEGAQ-UHFFFAOYSA-N propyl carbonochloridate Chemical compound CCCOC(Cl)=O QQKDTTWZXHEGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
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- 239000013558 reference substance Substances 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- KUYMVWXKHQSIAS-UHFFFAOYSA-N tert-butyl 2-chloroacetate Chemical compound CC(C)(C)OC(=O)CCl KUYMVWXKHQSIAS-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种制备N‑烷酰基美金刚的方法,包括(a)盐酸美金刚在反应溶剂中与甲酰基化试剂或乙酰化试剂反应;(b)反应结束后,分离获得目标产物。该方法操作简单,原料易得,并且制备收率及产品纯度较高,适合在分析实验室快速制备。
Description
技术领域
本发明涉及药物技术领域,特别涉及一种高纯度N-烷酰基美金刚的合成方法。
背景技术
盐酸美金刚(Menantine Hydrochloride),商品名为是由德国Merz公司研制的治疗痴呆症药物,是一种新型、低中度亲和力、电压依赖及非竞争性的N-甲基-D-天冬氨酸(NMDA)受体拮抗药。2002年2月,欧洲专利药品委员会(CPMP)批准其用于中、重度阿尔茨海默病患者的治疗,其化学名为3,5-二甲基-1-氨基-金刚烷盐酸盐(3,5-Dimethyl-1-Amino-Adamantane Hydrochloride),分子式为C12H22ClN,其结构式如下:
杂质研究是药品研发及商业化生产的重要研究内容,贯穿于整个药品生命周期研究中,杂质的存在直接影响药品的安全性、有效性以及质量可控性。我们在对盐酸美金刚片进行质量研究的过程中发现,在长期稳定性样品及加速稳定性样品中都都有可能产生N-烷酰基美金刚杂质,并且随着放置时间延长,这些杂质会有明显的增长趋势,将对盐酸美金刚片的疗效及安全性产生一定的影响,合成这些杂质对照品对盐酸美金刚片进行进一步的质量研究具有重要的意义。为此,本发明目的在于开发一种易操作、高收率合成N-烷酰基美金刚的方法来对此杂质展开深入的研究。
发明内容
本发明人对盐酸美金刚片进行处方研究发现,特别是制剂处方制备条件控制不好或稳定性条件设置参数不佳时,样品中会产生多个未知杂质,其单个杂质的含量可能会超过制剂产品单个杂质0.2%的限度指标,其含量甚至可以达到0.5%以上。经实验确认及进一步分析发现盐酸美金刚片中常见降解杂质为N-甲酰基美金刚(I)和N-乙酰基美金刚(II),它们的结构式如下所式:
本发明的第一方面是发现了盐酸美金刚片中常见降解杂质N-甲酰基美金刚和N-乙酰基美金刚的产生过程:
1、美金刚分子中含有伯氨基,在美金刚固体制剂长期储存及相对比较极端的高温或高湿条件下,美金刚的氨基容易与处方配伍中含有还原糖类辅料、或者含有纤维素或纤维素衍生物等辅料发生相互作用后产生N-甲酰基美金刚和/或N-乙酰基美金刚杂质,并且杂质的产生与处方或工艺中水分含量有密切关系。以该N-甲酰基美金刚杂质为例,其可能的产生来源分析如下:
因此开发一种快速、经济地制备杂质化合物的方法对美金刚固体制剂处方开发、稳定性研究及分析方法开发过程中具有非常大的实际意义。
本发明提供一种制备如下式所示的N-烷酰基美金刚的方法,包括以下步骤:
(a)盐酸美金刚在反应溶剂中与甲酰基化试剂或乙酰基化试剂反应;
(b)反应结束后,分离获得目标产物。
步骤(a)所述的反应溶剂为极性有机溶剂。
所述极性有机溶剂优选为N,N-二甲基甲酰胺、甲酰胺、甲酸、甲醇、乙醇、异丙醇、正丙醇、四氢呋喃或二甲基亚砜、N-甲基吡咯烷酮。
1、当R为甲基时:
步骤(a)所使用的乙酰化试剂选自:乙酸、乙酸酐、乙酰氯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸正丁酯、乙酸异丁酯、乙酸叔丁酯、乙酸苄酯、乙酸C1-C5取代苄酯、乙酸酚酯、乙酸C1-C5取代酚酯,或者选自下述的任一混合物:乙酸和乙酸钠、乙酸和乙酸酐、乙酸和三氟乙酸酐、乙酸和氯乙酸甲酯、乙酸和氯乙酸乙酯、乙酸和氯乙酸正丙酯、乙酸和氯乙酸异丙酯、乙酸和氯乙酸正丁酯、乙酸和氯乙酸叔丁酯、乙酸和氯乙酸苄酯。
优选的乙酰化试剂为乙酸酐、乙酰氯、乙酸和氯乙酸甲酯以及乙酸和氯乙酸乙酯。
所述的乙酰基化试剂与盐酸美金刚的摩尔比为0.2~50:1,优选为1~2:1。
所述盐酸美金刚与乙酰基化试剂反应优选在碱存在条件下反应。
所述碱选自无机碱和有机碱,或是两者之间的任意组合,其中无机碱优选乙酸钠、乙酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铯、氢氧化钙、四甲基氢氧化铵、磷酸钠、磷酸钾、磷酸氢二钠、磷酸氢二钾、氨水,更优选碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠;有机碱优选三乙胺、二异丙基乙基胺、N-甲基吗啉、N-甲基环戊胺、N-甲基环己胺、1,8-二氮杂二环十一碳-7-烯叔胺类化合物、吡啶、4-甲氧基吡啶、2,6-二甲基吡啶或4-二甲胺基吡啶。
所述碱与盐酸美金刚的摩尔比为0.2~20:1,优选为1~2:1。
2、当R为氢时:
步骤(a)所述所述的甲酰化试剂选自:甲酸、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、甲酸正丁酯、甲酸异丁酯、甲酸叔丁酯、甲酸苄酯、甲酸C1-C5取代苄酯、甲酸酚酯、甲酸C1-C5取代酚酯、N,N-二甲基甲酰胺、甲酰胺或者选自下述的任一混合物:甲酸和乙酸酐,甲酸和三氟乙酸酐、甲酸和氯甲酸甲酯、甲酸和氯甲酸乙酯、甲酸和氯甲酸正丙酯、甲酸和氯甲酸异丙酯、甲酸和氯甲酸正丁酯、甲酸和氯甲酸叔丁酯、甲酸和氯甲酸苄酯。
所述的甲酰化试剂优选为甲酸、甲酸酚酯、甲酸C1-C5取代酚酯、N,N-二甲基甲酰胺、甲酰胺以及甲酸和乙酸酐的混合物。
所述甲酰化试剂为甲酸、N,N-二甲基甲酰胺或甲酰胺时,其与美金刚体积质量比为0.1~100:1mL/g,优选为5~20:1mL/g;当甲酰化试剂为甲酸、N,N-二甲基甲酰胺或甲酰胺之外的其它试剂时,其与美金刚分子的摩尔比为0.2~50:1,优选为1~10:1。
另外,当R为氢时,在反应中加入路易斯酸能促进和加速盐酸美金刚与酰基化试剂反应。
与现有技术相比,本发明体系的技术优点体现在以下几个方面:
(1)本发明提供的N-甲酰基美金刚和N-乙酰基美金刚制备方法,所使用的反应原料盐酸美金刚原料药及试剂,极易获得,并且操作简单,常温或加热条件下即可快速、高产率得到目标产物,特别适合在分析实验室快速制备;
(2)常规的美金刚固体制剂降解样品杂质含量只有0.5%左右,分离较困难,本发明提供的制备方法得到的反应液中目标产物N-甲酰基美金刚收率可达77%到92%、而N-乙酰基美金刚含量可达87%至97%,其余的组分主要为未反应完的美金刚,分离难度大大降低。
(3)根据本发明制备得到的目标产物的纯度在99%以上。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚明白,以下列举实施例,对本发明进一步详细说明。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
在本发明的下述各实施例中,用GC方法对合成的N-乙酰基美金刚反应液及纯化后的固体进行检测,首先,对本发明下述实施例所采用的GC(气相色谱)测试方法进行说明。GC色谱条件及检测方法:
仪器:高效气相色谱仪
色谱柱:Agilent J&W HP-5,50m×0.32mm,0.52μm(5%苯基-甲基聚硅氧烷共聚物)
载气:氮气
线速度:2.5mL/min
进样口温度:220℃
检测器温度:300℃
进样体积:1.0μL
分流比:20:1
升温程序:
起始温度50℃,保持0分钟,以5℃/min的速率升至145℃,保持0分钟,以10℃/min的速率升至250℃,保持20分钟;
稀释液:R为H时,正己烷:二甲亚砜(1:1)
R为CH3时,二氯甲烷;
空白溶液:同稀释液;
反应液中N-烷酰基美金刚含量检测:
吸取适量待测反应液,再加入适量稀释液,混匀后作为样品检测溶液,最终样品溶液中N-烷酰基美金刚浓度约为20mg/mL。用上述的GC方法对供试品溶液进行检测,并用峰面积归一化法计算待测样品中N-烷酰基美金刚含量。
纯化后的样品中N-烷酰基美金刚含量检测:
称取400mg待测样品,精密称定于20mL顶空瓶中,加入10-15mL稀释液,振摇使溶解,接着定容至刻度,混匀,作为供试品溶液。用上述的GC方法对供试品溶液进行检测,并用峰面积归一化法计算待测样品中N-乙酰基美金刚含量。
实施例1
将10g盐酸美金刚及7.7mL三乙胺加入100mL二氯甲烷中,接着加入5.7g乙酸酐,室温下搅拌2.5小时,用GC方法对反应液进行监控,目标化合物的纯度为96%,接着用旋转蒸发仪蒸去二氯甲烷,剩余物用柱层析方法[HP-Silica正相硅胶,洗脱剂为二氯甲烷:甲醇=(10:1,V/V)]对目标产物进行分离得到获得高纯度的N-乙酰基美金刚样品11.5g,GC纯度99.8%,产率90%。
实施例2
将10g盐酸美金刚及7.7mL三乙胺加入100mL二氯甲烷中,接着加入4.0g乙酰氯,室温下搅拌3小时,用GC方法对反应液进行监控,目标化合物的纯度为97%,接着用旋转蒸发仪蒸去二氯甲烷,剩余物用柱层析方法[HP-Silica正相硅胶,洗脱剂为二氯甲烷:甲醇=(10:1,V/V)]对目标产物进行分离得到获得高纯度的N-乙酰基美金刚样品11.6g,GC纯度99.7%,产率91%。
实施例3
将7.6g乙酸钠及10mL乙酸加入100mL四氢呋喃中,冷却至-10℃后缓慢加入5.3g氯甲酸甲酯,搅拌30分钟后缓慢加入10g盐酸美金刚,搅拌30分钟后升温至室温继续反应1.5小时,用GC方法对反应液进行监控,目标化合物的纯度为89%,接着用旋转蒸发仪蒸去大部分乙酸后,接着用80mL水对剩余物稀释,用碳酸钠调节pH至9左右,这时可见有固体析出,固体用120mL乙酸乙酯:正己烷(10:1,V/V)重结晶即可得到获得高纯度的N-乙酰基美金刚样品9.48g,GC纯度99.6%,产率82%。
实施例4
将10g盐酸美金刚及7.7mL三乙胺加入100mL乙醇中,接着加入5.7g乙酸酐,室温下搅拌3小时,用GC方法对反应液进行监控,目标化合物的纯度为95%,接着用冻干仪去除二甲亚砜,剩余物用柱层析方法[HP-Silica正相硅胶,洗脱剂为二氯甲烷:甲醇=(12:1,V/V)]对目标产物进行分离得到获得高纯度的N-乙酰基美金刚样品11.4g,GC纯度99.7%,产率89%。
实施例5
将10g盐酸美金刚及7.7mL三乙胺加入100mL四氢呋喃中,接着加入4.0g乙酰氯,室温下搅拌2.5小时,用GC方法对反应液进行监控,目标化合物的纯度为96%,接着用旋转蒸发仪蒸去二氯甲烷,剩余物用柱层析方法[HP-Silica正相硅胶,洗脱剂为二氯甲烷:甲醇=(10:1,V/V)]对目标产物进行分离得到获得高纯度的N-乙酰基美金刚样品11.5g,GC纯度99.7%,产率90%。
实施例6
将1g盐酸美金刚加入10mL甲酸中,加热升温至90℃反应16小时,用GC方法对反应液进行监控,目标化合物的纯度为82%,接着用冻干仪除去甲酸,剩余物用薄层层析方法[HP-Silica正相硅胶,洗脱剂为丙酮:正己烷=(1:12,V/V)]对目标产物进行分离得到获得高纯度的N-甲酰基美金刚样品0.74g,GC纯度99.3%,产率77%。
实施例7
将1g盐酸美金刚加入12mL甲酸中,接着加入0.35g氧化锌,加热升温至70℃反应16小时,用GC方法对反应液进行监控,目标化合物的纯度为92%,接着用冻干仪除去甲酸,剩余物用柱层析方法[HP-Silica正相硅胶,洗脱剂为乙酸乙酯:正己烷=(1:10,V/V)]即可得到获得高纯度的N-甲酰基美金刚样品0.84g,GC纯度99.7%,产率87%。
实施例8
将1g盐酸美金刚加入10mL甲酸中,接着加入0.1g硫酸钛,加热升温至80℃反应5小时,用GC方法对反应液进行监控,目标化合物的纯度为95%,接着用旋转蒸发仪蒸去甲酸,剩余物用柱层析方法[HP-Silica正相硅胶,洗脱剂为丙酮:正己烷=(1:12,V/V)]对目标产物进行分离得到获得高纯度的N-甲酰基美金刚样品0.86g,GC纯度99.8%,产率90%。
实施例9
将1g盐酸美金刚加入9mL N,N-二甲基甲酰胺中,接着加入4g硅胶,加热升温至105℃反应6小时,用GC方法对反应液进行监控,目标化合物的纯度为92%,接着用冻干仪除去N,N-二甲基甲酰胺,剩余物固体用柱层析方法[HP-Silica正相硅胶,洗脱剂为乙酸乙酯:正己烷=(1:10,V/V)]纯化即可得到获得高纯度的N-甲酰基美金刚样品0.84g,GC纯度99.8%,产率87%。
实施例10
将1g盐酸美金刚加入10mL N,N-二甲基甲酰胺中,接着加入1.2g二氧化钛,加热升温至105℃反应3小时,用GC方法对反应液进行监控,目标化合物的纯度为96%,接着用冻干仪除去N,N-二甲基甲酰胺,剩余物用柱层析方法[HP-Silica正相硅胶,洗脱剂为乙酸乙酯:正己烷=(1:10,V/V)]对目标产物进行分离得到获得高纯度的N-甲酰基美金刚样品0.86g,GC纯度99.2%,产率90%。
实施例11
将1g盐酸美金刚加入12mL甲酰胺中,接着加入0.42g二水合氯化铜,加热升温至40℃反应4小时,用GC方法对反应液进行监控,目标化合物的纯度为93%,接着用冻干仪除去甲酰胺,剩余物用柱层析方法[HP-Silica正相硅胶,洗脱剂为乙酸乙酯:正己烷=(1:12,V/V)]对目标产物进行分离得到获得高纯度的N-甲酰基美金刚样品0.83g,GC纯度99.2%,产率86%。
实施例12
将1g盐酸美金刚加入20mL四氢呋喃中,接着加入0.5g碳酸钾及0.84g甲酸邻硝基苯酯,室温下搅拌反应18小时,用GC方法对反应液进行监控,目标化合物的纯度为84%,接着用旋转蒸发仪蒸去溶剂,接着用80mL水对剩余物稀释,用碳酸钠调节pH至9左右,这时可见有固体析出,固体再用柱层析方法[HP-Silica正相硅胶,洗脱剂为乙酸乙酯:正己烷=(9:1,V/V)]对目标产物进行分离得到获得高纯度的N-甲酰基美金刚样品0.74g,GC纯度99.4%,产率77%。
实施例13
将1g盐酸美金刚加入15mL 1,4-二氧六环中,接着加入0.5g碳酸钾及0.93g甲酸对硝基苯酯,30℃下搅拌反应10小时,用GC方法对反应液进行监控,目标化合物的纯度为86%,接着用旋转蒸发仪蒸去溶剂,接着用80mL水对剩余物稀释,用碳酸钠调节pH至9左右,这时可见有固体析出,固体再用柱层析方法[HP-Silica正相硅胶,洗脱剂为乙酸乙酯:正己烷=(10:1,V/V)]对目标产物进行分离得到获得高纯度的N-甲酰基美金刚样品0.75g,GC纯度99.6%,产率78%。
Claims (3)
1.一种如下式所示的N-烷酰基美金刚的制备方法,其特征在于包括以下步骤:
其中R为H,
(a)盐酸美金刚在反应溶剂中与甲酰化试剂反应;所述甲酰化试剂为甲酸、N,N-二甲基甲酰胺或甲酰胺,并且在反应中加入路易斯酸;
(b)反应结束后,分离获得目标产物,
所述步骤(a)中的反应溶剂为极性有机溶剂,所述的极性有机溶剂选自N,N-二甲基甲酰胺、甲酰胺、甲酸。
2.根据权利要求1所述的制备方法,其特征在于,甲酰化试剂与美金刚体积质量比为0.1~100:1mL/g。
3.根据权利要求2所述的制备方法,其特征在于,甲酰化试剂与美金刚体积质量比为5~20:1mL/g。
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