CN103079571A - 降伊波加因碱组合物 - Google Patents
降伊波加因碱组合物 Download PDFInfo
- Publication number
- CN103079571A CN103079571A CN2011800381737A CN201180038173A CN103079571A CN 103079571 A CN103079571 A CN 103079571A CN 2011800381737 A CN2011800381737 A CN 2011800381737A CN 201180038173 A CN201180038173 A CN 201180038173A CN 103079571 A CN103079571 A CN 103079571A
- Authority
- CN
- China
- Prior art keywords
- noribogaine
- alkali
- ibogaine
- compositions
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- RAUCDOKTMDOIPF-UHFFFAOYSA-N hydroxyibogamine Natural products CCC1CC(C2)CC3C1N2CCC1=C3NC2=CC=C(O)C=C12 RAUCDOKTMDOIPF-UHFFFAOYSA-N 0.000 title claims abstract description 147
- RAUCDOKTMDOIPF-RYRUWHOVSA-N noribogaine Chemical compound N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC=C(O)C=C12 RAUCDOKTMDOIPF-RYRUWHOVSA-N 0.000 title claims abstract description 146
- 239000000203 mixture Substances 0.000 title claims abstract description 88
- AREITJMUSRHSBK-UHFFFAOYSA-N ibogamine Natural products CCC1CC2C3CC1CN2CCc4c3[nH]c5ccccc45 AREITJMUSRHSBK-UHFFFAOYSA-N 0.000 claims abstract description 94
- VOXIUXZAOFEFBL-UHFFFAOYSA-N Voacangin Natural products CCC1CC2CN3CC1C(C2)(OC(=O)C)c4[nH]c5ccc(OC)cc5c4C3 VOXIUXZAOFEFBL-UHFFFAOYSA-N 0.000 claims abstract description 93
- OLOCMRXSJQJJPL-UHFFFAOYSA-N ibogaine Natural products CCC1CC2CC3C1N(C2)C=Cc4c3[nH]c5ccc(OC)cc45 OLOCMRXSJQJJPL-UHFFFAOYSA-N 0.000 claims abstract description 93
- HSIBGVUMFOSJPD-CFDPKNGZSA-N ibogaine Chemical compound N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC=C(OC)C=C12 HSIBGVUMFOSJPD-CFDPKNGZSA-N 0.000 claims abstract description 88
- 239000003513 alkali Substances 0.000 claims description 101
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 58
- 239000007787 solid Substances 0.000 claims description 44
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- 150000001875 compounds Chemical group 0.000 description 20
- 238000000746 purification Methods 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- 125000003368 amide group Chemical group 0.000 description 15
- -1 noribogaine chemical compounds Chemical class 0.000 description 15
- 239000003957 anion exchange resin Substances 0.000 description 14
- 125000000524 functional group Chemical group 0.000 description 14
- 238000010520 demethylation reaction Methods 0.000 description 13
- 230000000903 blocking effect Effects 0.000 description 10
- 125000005647 linker group Chemical group 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 229910001873 dinitrogen Inorganic materials 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
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- 229940125782 compound 2 Drugs 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 0 CCC(C1)(C2*1CC1)C(C=C)=C[C@]2C(*2)=C1c1c2ccc(O)c1 Chemical compound CCC(C1)(C2*1CC1)C(C=C)=C[C@]2C(*2)=C1c1c2ccc(O)c1 0.000 description 4
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 3
- 150000003797 alkaloid derivatives Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 3
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- 238000005516 engineering process Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229920002401 polyacrylamide Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920002223 polystyrene Polymers 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000005587 carbonate group Chemical group 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- VLOWUTVRYMTRJO-HHNICDRHSA-N 12,13-dimethoxyibogamine Chemical compound N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC(OC)=C(OC)C=C12 VLOWUTVRYMTRJO-HHNICDRHSA-N 0.000 description 1
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
- SQDFWBUESZGRBR-UHFFFAOYSA-N 1h-azepine;1h-indole Chemical class N1C=CC=CC=C1.C1=CC=C2NC=CC2=C1 SQDFWBUESZGRBR-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- KEQJIWNXZVYKFH-UIVJTFTRSA-N CCC(C1)C2NCC1C[C@H]2C(C)N Chemical compound CCC(C1)C2NCC1C[C@H]2C(C)N KEQJIWNXZVYKFH-UIVJTFTRSA-N 0.000 description 1
- HOUYIYVTYLTLAF-MWJCJQSMSA-N CCC(C1)C2NCC1C[C@H]2C(N)=C Chemical compound CCC(C1)C2NCC1C[C@H]2C(N)=C HOUYIYVTYLTLAF-MWJCJQSMSA-N 0.000 description 1
- RAUCDOKTMDOIPF-YEDQSRJZSA-N CCC(CC(C[C@H]12)C3)C1N3CCc(c1c3)c2[nH]c1ccc3O Chemical compound CCC(CC(C[C@H]12)C3)C1N3CCc(c1c3)c2[nH]c1ccc3O RAUCDOKTMDOIPF-YEDQSRJZSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241001246918 Tabernanthe iboga Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
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- 125000003277 amino group Chemical group 0.000 description 1
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- 150000001450 anions Chemical class 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical group NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-O benzylaminium Chemical compound [NH3+]CC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-O 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
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- 239000011575 calcium Substances 0.000 description 1
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- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- QMMTZDCUCDXHEW-UHFFFAOYSA-N chloromethylbenzene;formic acid Chemical class OC=O.ClCC1=CC=CC=C1 QMMTZDCUCDXHEW-UHFFFAOYSA-N 0.000 description 1
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- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种降伊波加因碱组合物,该组合物含有非常高水平的2(R),4(S),5(S),6(S)和18(R)对映异构体并且含有不超过相对于降伊波加因碱的总量的0.5wt%的伊波加因碱。
Description
相关申请的交叉引用
本申请要求2010年7月23日提交的美国临时申请第61/367,310号的优先权和2010年12月3日提交的美国临时申请第61/419,766号的优先权,这两个美国临时申请的全部内容在此通过引用并入本文。
技术领域
本发明涉及降伊波加因碱(noribogaine)组合物。在一种实施方式中,所述降伊波加因碱组合物含有至少95%的2(R),4(S),5(S),6(S)和18(R)对映异构体形式的降伊波加因碱,并且其中,所述组合物含有不超过相对于降伊波加因碱的总量的0.5wt%的伊波加因碱(ibogaine)。在另一实施方式中,所述组合物含有不超过相对于降伊波加因碱的总量的0.3wt%的伊波加因碱。在另一实施方式中,所述组合物含有不超过相对于降伊波加因碱的总量的0.1wt%的伊波加因碱。
背景技术
降伊波加因碱是生物碱伊波加因碱家族中熟知的成员并且有时将其称为12-羟基伊波加因碱。虽然美国专利第2,813,873号要求保护作为“12-O-去甲基伊波加因碱”的降伊波加因碱,但是该美国专利提供的伊波加因碱的结构式并不正确。降伊波加因碱的结构目前已被确定并且发现降伊波加因碱的结构合并了色胺、四氢哈维因(tetrahydrohavaine)和吲哚吖庚因(indolazepine)的特征。降伊波加因碱可由如下通式来表示:
其中,在2、4、5、6和18位置的原子的构型为2(R)、4(S)、5(S)、6(S)和18(R)。
最近,降伊波加因碱及其药学上可接受的盐受到明显关注,这是因为非成瘾性生物碱在治疗药物依赖(美国专利第6,348,456号)方面有用并且可用作强效镇痛剂(美国专利第7,220,737号)。这两个美国专利的全部内容通过引用并入本文。
降伊波加因碱一般通过对天然生成的伊波加因碱进行O-去甲基化来制备:
所述天然生成的伊波加因碱从伊波加木(Tabernanth iboga,一种非洲西部的灌木)中分离得到。去甲基化可通过常规技术来完成,所述常规技术例如,在室温下与三溴化硼/二氯甲烷反应,随后进行常规纯化。
伊波加因碱具有令人产生幻觉的性质并且在美国其为1类管制物质。因此,由伊波加因碱制备降伊波加因碱的方法需要高度确保避免不可接受的量的伊波加因碱污染。然而,没有报道称这样制备的降伊波加因碱基本不含伊波加因碱(例如,不超过相对于降伊波加因碱的0.5wt%)。充其量是美国专利第6,348,456号要求保护一种基本上纯的降伊波加因碱化合物,但该美国专利没有公开任何纯化方法,更别提公开词组“基本上纯的”包含哪些物质,而且也没有公开组合物中残留的伊波加因碱的水平。由伊波加因碱合成降伊波加因碱的方法在美国专利第2,813,873号中报道。然而,该‘873号专利也没有说明在其合成过程中获得的降伊波加因碱的纯度。
因此,本领域亟需提供一种对映异构体富集(超过95%的2(R),4(S),5(S),6(S)和18(R)对映异构体)的且基本不含伊波加因碱(例如,不超过相对于降伊波加因碱的量的0.5wt%的伊波加因碱)的降伊波加因碱。
发明内容
本发明提供降伊波加因碱组合物,所述组合物为对映异构体富集的并且基本不含伊波加因碱。因为所述组合物不含不可接受的量的伊波加因碱并且为对映异构体富集的,所以该组合物在治疗成瘾和/或疼痛方面取得了显著突破。
在本发明的组合物的一个方面,本发明涉及含有降伊波加因碱的组合物,其中,所述降伊波加因碱中的至少95%以2(R),4(S),5(S),6(S)和18(R)对映异构体存在,并且其中,所述组合物含有不超过相对于降伊波加因碱的总量的0.5wt%的伊波加因碱。
在本发明的组合物的另一方面,本发明涉及含有降伊波加因碱的组合物,其中,所述降伊波加因碱中的至少95%以2(R),4(S),5(S),6(S)和18(R)对映异构体存在,并且其中,所述组合物含有不超过相对于降伊波加因碱的总量的0.3wt%的伊波加因碱污染。
在一些实施方式中,所述降伊波加因碱组合物中所含的伊波加因碱的量为不超过相对于降伊波加因碱的总量的0.1wt%的伊波加因碱。
在一些实施方式中,降伊波加因碱中的至少98%,优选地至少99%,更加优选地至少99.5%以2(R),4(S),5(S),6(S)和18(R)对映异构体存在。
在一些实施方式中,本发明的降伊波加因碱任选地通过可裂解的连接体结合至固体载体。所述固体载体可为树脂或小珠。
具体实施方式
本发明涉及含有降伊波加因碱的组合物,具体而言,本发明涉及含有以2(R),4(S),5(S),6(S)和18(R)对映异构体形式存在的高纯度的降伊波加因碱的组合物。然而,在对本发明进行更加详细地描述之前,首先对下列术语进行定义。
应当理解的是,本发明不限于所描述的具体实施方式,因此,可对本发明的具体实施方式作出改变。还应当理解的是,本文使用的术语仅仅是为了描述具体实施方式,并无意限定本发明,本发明的范围仅由所附的权利要求来限定。
应当注意的是,除非另有明确说明,本文和所附的权利要求中使用的单数形式(“a”、“an”和“the”)包括复数指代物。因此,例如,关于“药学上可接受的赋形剂”包括多种这样的赋形剂。
定义
除非另有说明,本文使用的所有技术术语和科学术语均具有与本发明所属技术领域的普通技术人员通常理解的含义相同的含义。本文使用的下列术语具有如下含义。
本文使用的术语“含有”或“包含”是指组合物和方法包括所记载的要素,但是不排除其他要素。当使用“基本上由……构成”来界定组合物和方法时,是指排除对用于所述目的的组合而言具有任何本质的重要意义的其他要素。因此,基本上由本文定义的要素构成的组合物可不排除对要求保护的本发明的基本特征和新颖性特征不产生实质影响的其他物质或步骤。“由……构成”是指排除超过痕量要素的其他成分和实质性方法步骤。由这些连接术语中的每一个界定的实施方式在本发明的范围内。
本文使用的术语“降伊波加因碱”是指生物碱降伊波加因碱(包括其所有对映异构体),并且该术语“降伊波加因碱”还包括其各种药学上可接受的盐。尤其值得注意的是由下式表示的对映异构体:
其中,在2、4、5、6和18位置的原子的构型为2(R)、4(S)、5(S)、6(S)和18(R)。
术语“固体载体”是指具有刚性或半刚性表面的物质,该物质含有或可衍生为含有使降伊波加因碱通过可裂解的连接体共价连接至其表面的反应性官能团。这样的物质是本领域众所周知的,包括,例如,二氧化硅、合成的硅酸盐、生物活动生成的硅酸盐、多孔玻璃、水凝胶、含有硅酸盐的矿物质、合成的聚合物、聚苯乙烯、聚丙烯、聚丙烯酰胺、聚乙二醇、聚丙烯酰胺及其共聚物(包括聚苯乙烯/聚乙二醇的共聚物和聚丙烯酰胺/聚乙二醇的共聚物),等等。固体载体的其他非限定性的实例包括:阴离子交换树脂。这些树脂包含带一定量的正电荷的基团并且交换阴离子。阴离子交换树脂的非限定性的实例包括I型阴离子交换树脂、II型阴离子交换树脂、I型阴离子交换树脂和II型阴离子交换树脂。
本文使用的术语“可裂解的连接基团”是指一种连接基团,其为一端共价连接至固体载体且另一端共价连接至降伊波加因碱的化学基团或共价键。使降伊波加因碱连接至固体载体的可裂解的连接基团的共价键中的至少一个可易于通过特定的化学反应或酶反应断裂,从而提供不含固体载体的降伊波加因碱。所选择的用于使连接臂的共价键断裂的化学反应或酶反应对键的断裂具有特异性,从而避免在化合物的其他位置发生不期望的反应。对应于在固体载体上形成的降伊波加因碱来选择可裂解的连接基团,从而避免降伊波加因碱过早地从固体载体上断裂并且不干扰在载体上合成的过程中使用的任何步骤。合适的可裂解的连接基团是本领域众所周知的,并且可包括诸如碳酸酯基团、氨基甲酸酯基团、酰胺基团等等这样的基团。在优选的实施方式中,可裂解的连接基团含有不超过10个原子。更加优选地,可裂解的连接体含有1至4个碳原子和2至4个选自氧、氮、硫、S(O)和S(O)2的杂原子。
本文使用的术语“反应条件”是指进行化学反应的具体条件。反应条件的实例包括,但不限于下列条件中的一种或一种以上:反应温度、溶剂、pH、压力、反应时间、反应物的摩尔比、碱或酸或催化剂的存在,等等。已知反应的反应条件对于本领域技术人员而言通常是已知的。
本文使用的术语“还原剂”是指在氧化还原反应中可提供电子,使氢加至分子的试剂。合适的还原剂包括氢化铝锂、硼氢化钠、氰基硼氢化钠,等等。
本文使用的术语“还原胺化条件”是指胺和羰基化合物发生反应形成亚胺,随后使用还原剂将亚胺还原为胺的反应。中间体亚胺可在还原步骤之前分离并纯化,或者中间体亚胺可用于还原步骤而无需在先进行分离或纯化。
本文使用的术语“药学上可接受的盐”是指药学上可接受的、无毒的、由多种本领域熟知的有机和无机反离子衍生得到的盐,并且,例如,当分子含有酸性官能团时,所述反离子包括诸如钠、钾、钙、镁、铵、四烷基铵等的反离子,以及当分子含有碱性官能团时,所述反离子包括诸如氯化物、溴化物、酒石酸盐、甲磺酸盐、乙酸盐、马来酸盐、草酸盐等的反离子。
本文使用的术语“保护基团”或“Pg”是指众所周知的如下官能团:当将该官能团连接至某一官能团时,该官能团使得到的受到保护的官能团对待在化合物的其他部分进行的反应条件具有惰性,并且在合适的时间该官能团可在“脱保护条件”下发生反应重新生成原始的官能团。保护基团的一致性不是关键的并且选择与分子的剩余部分相容的保护基团。在一种实施方式中,保护基团为在本文所述的反应过程中保护伊波加因碱或降伊波加因碱的氨基官能团的“氨基保护基团”。常规的氨基保护基团的实例包括,例如,苄基、乙酰基、氧乙酰基、羰基氧苄基(Cbz),等等。在另一实施方式中,保护基团为保护降伊波加因碱的羟基官能团的“羟基保护基团”。羟基保护基团的实例包括,例如,苄基、对甲氧基苄基、对硝基苄基、烯丙基、三苯甲游基、二烷基甲硅烷基醚(例如,二甲基甲硅烷基醚)、三烷基甲硅烷基醚(例如,三甲基甲硅烷基醚、三乙基甲硅烷基醚和叔丁基二甲基甲硅烷基醚)、酯(例如,苯甲酰基、乙酰基、苯基乙酰基、甲酰基、单卤代、双卤代和三卤代乙酰基(例如,氯代乙酰基、二氯代乙酰基、三氯代乙酰基、三氟代乙酰基))以及碳酸酯(例如,甲基、乙基、2,2,2,-三氯代乙基、烯丙基、苄基和对硝基苯基)。羟基保护基团的额外的实例可在标准参考文献(例如,Greene和Wuts,Protective Groups in Organic Synthesis.,第二版,1991,John Wiley&Sons,和McOmie Protective Groups in Organic Chemistry,1975,Plenum Press)中找到。本文公开的化合物的酚羟基的保护和脱保护的方法可在本领域中找到,具体而言,可在上述Greene和Wuts的著作以及其中所引用的参考文献中找到。
基本不含伊波加因碱的降伊波加因碱的制备
本发明的降伊波加因碱组合物可由伊波加因碱制备。含有不超过0.5%ppm伊波加因碱的降伊波加因碱可使用如下所述的固体载体合成方法来制备。因为该化合物由天然产物伊波加因碱制备,并且下面所述的反应不涉及任何立体化学中心,所以,这样制备的降伊波加因碱可为至少95%的2(R)、4(S)、5(S)、6(S)和18(R)对映异构体并且可能为100%的那种对映异构体。
在使用降伊波加因碱的固体载体合成方法的情况下,本发明的降伊波加因碱组合物可使用如下常规方法和步骤,由易于获得的起始原料制备。可知晓的是,在给出了典型或优选的反应条件(即,反应温度、时间、反应物的摩尔比、溶剂、压力,等等)的情况下,也可使用其他反应条件,除非另有说明。最佳反应条件可随所使用的具体反应物或溶剂的不同而不同,但是这些条件可由本领域技术人员通过常规优化步骤确定。
此外,对于本领域技术人员而言显然的是,常用保护基团对于避免特定官能团发生不期望的反应而言是必要的。用于各种不同的官能团的合适的保护基团和用于对特定官能团进行保护和脱保护的合适的条件是本领域众所周知的。例如,许多保护基团在T.W.Greene和G.M.Wuts,Protecting Groups inOrganic Synthesis,第四版,Wiley,N.Y.,2007以及其所引用的参考文献中描述。
本发明发现降伊波加因碱可如下述方案中所示的那样通过使用固体载体,由伊波加因碱制备和/或纯化,其中,PG表示胺保护基团,LG表示离去基团(例如,卤素或甲磺酸酯、甲苯磺酸酯或者这样的其他基团),L表示可裂解的连接基团(例如,诸如碳酸酯或氨基甲酸酯之类的羰基化合物),实心圆表示固体载体。
在下列方案中,芳基甲氧基基团的O-去甲基化生成相应的酚可使用本领域已知的任何合适的方法完成。合适的试剂包括路易斯(Lewis)酸(例如,BBr3,AlCl3),亲核试剂(例如,RS-,N3-,SCN-),高pH(例如,pH为12)条件下的NaCN,等等。在一些实施方式中,O-去甲基化应当在不影响与固体载体的连接或不改变分子的立体化学中心的立体化学的条件下进行。合适的试剂可易于由本领域技术人员确定并且可在例如T.W.Greene和G.M.Wuts,Protecting Groups in Organic Synthesis,第四版,Wiley,N.Y.,2007(参见例如第1006页至第1008页和第1022页至第1032页中的反应性表格(reactivitychart))以及其所引用的参考文献中找到。
方案1
降伊波加因碱5可通过方案1所示的途径中的任何一种,由伊波加因碱10制备和纯化。降伊波加因碱(化合物5)与伊波加因碱的区别在于伊波加因碱的甲氧基基团转化为降伊波加因碱中的羟基基团。在一种实施方式中,伊波加因碱的吲哚胺可使用胺保护基团进行保护,从而生成化合物1,随后同时进行O-去甲基化和保护基团的除去(例如,使用),生成降伊波加因碱5,或者随后按顺序进行O-去甲基化和保护基团的除去,生成降伊波加因碱5。此外,在一种实施方式中,降伊波加因碱可使用本领域已知的方法通过伊波加因碱的O-去甲基化直接制备和纯化,随后通过如下步骤对降伊波加因碱进行纯化:将降伊波加因碱加至固体载体上(化合物12或13),洗涤除去污染物,使连接基团L断裂并回收降伊波加因碱5。在上述合成方法中,如上所示的降伊波加因碱或中间体中的一个或一个以上可使用本领域已知的标准纯化技术(例如,柱层析、HPLC,等等)进行纯化。式11的化合物为商业上可获得的或可通过商业上可获得的起始原料(参见,例如来自于Sigma的商售树脂)在一个或两个步骤中合成得到。
在另一实施方式中,降伊波加因碱可以下面的方案2所示的方式由伊波加因碱制备和纯化。
方案2
其中,Pg为氢或氨基保护基团,实心圆表示固体载体。
具体而言,在方案2中,氨基保护的伊波加因碱(化合物1)在本领域已知的条件下与三溴化硼或其他常用去甲基化试剂在例如,二氯甲烷中接触,生成氨基保护的降伊波加因碱(化合物2)。
在方案2中,将氨基保护的降伊波加因碱(化合物2)连接至固体载体通过在常规条件下使用氯甲酸酯/固体载体(化合物3)生成化合物4完成,其中,仅仅为了举例说明,显示了作为可裂解的连接基团的碳酸酯基团。其他可裂解的连接基团可同样用在方案2中。因为氨基保护的伊波加因碱不含与化合物3反应的官能团,所以,只有氨基保护的降伊波加因碱(化合物2)可与固体载体反应并生成化合物4。重复洗涤化合物4可除去一部分氨基保护的伊波加因碱,该氨基保护的伊波加因碱污染在该反应中使用的氨基保护的降伊波加因碱样品。此外,在任何时间,可除去一小部分固体载体,从而提供降伊波加因碱样品(在裂解和脱保护之后)。随后,可通过诸如GC/MS,NMR,C13-NMR等常用方法分析所述样品相对于存在的任何伊波加因碱的纯度。
在得到相对于任何产生污染的伊波加因碱的降伊波加因碱的期望的纯度水平之后,可通过可裂解的连接体的断裂以及随后的氨基基团的脱保护从固体载体中回收降伊波加因碱。断裂和脱保护均为本领域众所周知的。
正如所期望的那样,特别纯的降伊波加因碱(化合物5)可通过重复如下操作获得:形成氨基保护的降伊波加因碱(化合物2),使化合物2通过氨基保护的降伊波加因碱的羟基基团结合至固体载体,从固体载体上洗涤除去一部分产生污染的伊波加因碱。根据需要多次重复该操作并且优选地重复不超过5次,发现可制备含有不超过相对于组合物中存在的降伊波加因碱的量的0.5wt%的伊波加因碱的降伊波加因碱组合物、含有不超过相对于组合物中存在的降伊波加因碱的量的0.3wt%的伊波加因碱的降伊波加因碱组合物或含有不超过相对于组合物中存在的降伊波加因碱的量的0.1wt%的伊波加因碱的降伊波加因碱组合物。
在另一实施方式中,固体载体为阴离子交换树脂,其中,降伊波加因碱离子键合至所述阴离子交换树脂。这样的树脂使不带电荷的伊波加因碱通过简单洗脱而流过该树脂。阴离子交换树脂的非限定性实例包括,固体载体,优选地为从含有季铵的基团(例如,含有三烷基苄基铵的基团)衍生得到的固体载体。合适的三烷基苄基铵基团包括三甲基苄基铵、二甲基-2-羟乙基苄基铵,等等。商售的阴离子交换树脂的非限定性实例包括I型阴离子交换树脂、II型阴离子交换树脂、I型阴离子交换树脂和II型阴离子交换树脂。通过调节pH回收降伊波加因碱是本领域技术人员熟知的。
可选地,如下面方案3所示,降伊波加因碱盐酸盐通过如下步骤由伊波加因碱盐酸盐制备:首先将伊波加因碱盐酸盐转化为伊波加因碱游离碱,用甲醇处理,随后用诸如碳酸钾之类的碱在诸如二氯甲烷之类的溶剂中进行处理。然后,伊波加因碱通过如下步骤转化为降伊波加因碱氢溴酸盐:用三溴化硼或其他常用的去甲基试剂在诸如二氯甲烷之类的溶剂中进行处理,接着用甲醇淬灭,从而生成降伊波加因碱氢溴酸盐。降伊波加因碱氢溴酸盐随后通过用诸如碳酸钾之类的碱在诸如二氯甲烷之类的溶剂中进行处理,接着通过二氧化硅纯化而转化为游离碱,然后,使用HCl在诸如异丙醇之类的溶剂中转化为盐酸盐。
方案3
去甲基化的另一方法还如下面方案4所示的那样完成。
方案4
本发明发现使用BCl3代替BBr3除去甲基醚具有许多优势。例如,使用BCl3在一个步骤中生成降伊波加因碱盐酸盐,而无需将使用BBr3时得到的降伊波加因碱氢溴酸盐转化为盐酸盐。此外,本发明发现使用BCl3本质上降低了使用BBr3时得到的芳环的卤化作用。
在一种实施方式中,降伊波加因碱组合物中的伊波加因碱的量可通过开始在伊波加因碱上形成14C富集的甲氧基基团来确定。最终组合物中的相对于背景的14C的量可校正为降伊波加因碱组合物中伊波加因碱的量,该量随后可用于验证所使用的合成步骤是在所允许的降伊波加因碱组合物中伊波加因碱的最大量的条件下还是在低于所允许的降伊波加因碱组合物中伊波加因碱的最大量的条件下。伊波加因碱上14C富集的甲氧基可易于通过用14C富集的甲基化试剂对降伊波加因碱的12-羟基基团进行甲基化来制备。用于确定组合物中14C的量的技术是本领域众所周知的并且检测限低于1ppt。
对于本领域技术人员而言显然的是,可对上述示例性的方法(原料和方法这两者)作出许多改变,而不背离本发明的范围。
下面提供合成实例和生物学实例来举例说明本发明,所述合成实例和生物学实例不以任何方式被解释为对本发明的范围进行限定。除非另有说明,所有温度为摄氏度。
降伊波加因碱的组合物
本发明提供对映异构体富集的且基本不含伊波加因碱的降伊波加因碱组合物。
在一种实施方式中,本发明提供含有降伊波加因碱的组合物,其中,所述降伊波加因碱中的至少95%以2(R),4(S),5(S),6(S)和18(R)对映异构体存在,并且其中,所述组合物包含不超过相对于降伊波加因碱的总量的0.5wt%的伊波加因碱。在另一实施方式中,所述组合物包含不超过相对于降伊波加因碱的总量的0.3wt%的伊波加因碱。在另一实施方式中,所述组合物包含不超过相对于降伊波加因碱的总量的0.1wt%的伊波加因碱。
在另一实施方式中,本发明提供含有降伊波加因碱的组合物,其中,所述降伊波加因碱中的至少98%以2(R),4(S),5(S),6(S)和18(R)对映异构体存在,并且其中,所述组合物包含不超过相对于降伊波加因碱的总量的0.5wt%的伊波加因碱。在另一实施方式中,本发明提供含有降伊波加因碱的组合物,其中,所述降伊波加因碱中的至少98%以2(R),4(S),5(S),6(S)和18(R)对映异构体存在,并且其中,所述组合物包含不超过相对于降伊波加因碱的总量的0.3wt%的伊波加因碱。在另一实施方式中,所述组合物包含不超过相对于降伊波加因碱的总量的0.1wt%的伊波加因碱。
实施例
在下面的实施例中,缩写具有其普遍接受的含义。
实施例1-由伊波加因碱合成和纯化降伊波加因碱
实施例1举例说明一种由伊波加因碱合成和纯化降伊波加因碱的方法,所述方法如下面方案5所示:
方案5
具体而言,在方案5中,伊波加因碱在诸如二氯甲烷之类的惰性溶剂中与化学计量过量的苄基氯甲酸酯接触。反应混合物还包含相对于伊波加因碱至少化学计量等量的二异丙基乙胺,从而除去反应过程中生成的酸。将反应保持在惰性气氛、室温条件下,直至由例如薄层色谱证实反应基本完成。这时,将O-去甲基化试剂(例如,三溴化硼或三氯化铝)或者优选地为化学计量过量的O-去甲基化试剂加至反应混合物中,随后将反应混合物保持在使伊波加因碱的甲氧基已转化为降伊波加因碱的羟基的条件(例如,室温条件)下。
上述生成的羟基随后用作连接固体载体的互补官能团。具体而言,结合至固体载体的过量的氯甲酸酯在使碳酸酯键形成的常规条件下与N-CBz-降伊波加因碱结合。结合至固体载体的氯甲酸酯可由带羟基的聚合物载体(例如,羟甲基聚苯乙烯或与聚合物结合的苄基醇,均可在商业上获自)和碳酰二氯制备。因为CBz-伊波加因碱不易于在这些O-去甲基化条件下反应,所以,其可保留在反应混合物的溶液相中并且可通过常规技术从反应混合物中洗涤除去,所述常规技术包括将固体载体放置于柱子中并且使过量的溶剂流过该柱。
在一个具体实施例中,将1kg含有CBz-降伊波加因碱的固体载体上样于柱上。使该柱的塞子部分地打开,从而使流过该柱的流速保持在0.5升/小时。将二氯甲烷连续加至柱顶部并在柱底部回收。将回收的二氯甲烷除去,得到残留的CBz-伊波加因碱。随后将固体载体的一部分与甲醇和催化量的钯-碳一同上样至氢化作用容器中。在高压条件下连续进行氢化作用大约5小时。随后停止反应,回收并除去甲醇,从而得到降伊波加因碱。降伊波加因碱的额外纯化可根据需要通过HPLC完成。
实施例2-由伊波加因碱盐酸盐合成和纯化降伊波加因碱盐酸盐
方案6
步骤1.纯化粗伊波加因碱盐酸盐并释放纯化的原料中的伊波加因碱游离碱
在氮气条件下向10L法兰反应器中装入伊波加因碱(428.5g)和乙醇(4.30L)。将得到的悬浮液加热至65℃至75℃持续1小时20分钟并在过夜搅拌的条件下冷却至室温。得到发白的浅黄色悬浮液。通过过滤收集固体并用二氯甲烷(DCM,2×0.5L)洗涤。将滤饼在氮气下干燥至恒重(279g)。将固体储存在氮气条件下并拒绝光照持续5天。高效液相色谱(HPLC)的过程控制(IPC)显示伊波加因碱(97.38%),伊波胺(ibogamine)(2.31%)且伊波灵(ibogaline)(0.31%)。在真空中浓缩滤液至干燥,得到淡棕色固体(72g)。HPLC的IPC显示伊波加因碱(59.49%),伊波胺(17.31%)且伊波灵(20.12%)以及未知物(总计3.04%)。将纯化的伊波加因碱盐酸盐(279g,97.38%)在氮气条件下悬浮于DCM(2.85L)中。加入25wt%的碳酸钾水溶液(470ml)并且用力地混合各相持续10分钟。分离各相。再用DCM(2×720ml)萃取水层。丢弃水层。用水(0.73L)洗涤合并的有机相,将洗涤后的有机相分成两个基本相等的部份并在真空中50℃下浓缩,得到浅棕色泡沫。将该泡沫在真空下干燥至恒重。HPLC的IPC显示伊波加因碱(93.15%),伊波胺(2.28%),伊波灵(0.31%)以及未知物(总计4.26%)。
步骤2.伊波加因碱游离碱转化为降伊波加因碱氢溴酸盐
在氮气条件下,向装配有温度计、气体气泡器、顶置搅拌仪、Schott加样瓶和洗涤器的3L法兰烧瓶中装入二氯甲烷(400ml)和BBr3的二氯甲烷溶液(1M,368ml)。在搅拌条件下,将混合物冷却至0℃至5℃。向Schott瓶中装入伊波加因碱游离碱(75g,MLR/629/73-1)和二氯甲烷(300ml),得到浅棕色溶液。将氮气通入瓶中,用箔盖住瓶子并通过压力加样管线将瓶子连接至法兰反应器。在110分钟内将溶液缓慢加至反应器中。加样之后,形成悬浮液。当加样完成时,使反应器的内含物升温至室温过夜。将混合物冷却至0℃至5℃并用甲醇淬灭,使混合物升温至室温并搅拌过夜。通过过滤收集固体,用DCM洗涤并干燥(产率:81%)。
0054发现伊波加因碱游离碱与BBr3的反应生成溴化的副产物,该副产物的形成可通过使用BCl3代替BBr3来避免,BCl3直接生成相应的HCl盐。
步骤3.降伊波加因碱氢溴酸盐转化为降伊波加因碱盐酸盐
向装配有氮气入口、气体气泡器、顶置搅拌器、温度计和滴液漏斗的10L法兰分液漏斗中装入降伊波加因碱氢溴酸盐(214.35g)、MeOH(1.95L)和二氯甲烷(4.18L),得到悬浮液。在搅拌和氮气条件下,在1小时内加入溶于水(1.65L)中的K2CO3(234g,3.0等量)。在加入过程中,内部温度从18.9℃上升至23.2℃。连续进行搅拌直至得到两相体系。分离下层的有机相。用二氯甲烷(2×1.46L)萃取上层的水相。用水(1×1.95L)洗涤合并的有机相。将有机层分成两份,将每一份在真空中浓缩至干燥,得到浅棕色固体(1×88.9g,1×79.3)。通过使用快速硅胶(7.20kg,43wt当量),用二氯甲烷/乙腈/三乙胺(1:1:0.5)进行洗脱,对固体进行层析纯化,收集到总共16个组份(每一组份5L),其中,第5组份至第16组份通过TLC和HPLC显示出期望的产物。基于对盐形成进行的测试工作的结果,合并第7组份至第11组份并浓缩至干燥,得到米色固体(136g)。将固体装入装配有氮气入口、气体气泡器、顶置搅拌器、滴液漏斗和温度计的5L法兰烧瓶中。加入异丙醇(3.27L)并在1小时内,在搅拌和氮气条件下将混合物加热至45℃至55℃,得到透明溶液。在1小时内加入异丙醇/HCl(5M,128.6ml,1.4当量)。观察到灰白色固体沉淀并在搅拌下将悬浮液冷却至室温过夜。再将混合物冷却至0℃至5℃。30分钟后,通过过滤收集固体并用二氯甲烷(2×0.49L)洗涤,在通氮气条件下抽吸干燥至恒重。在真空、60℃下再干燥固体4天。
降伊波加因碱游离碱的产量为168.2g(99%),降伊波加因碱游离碱(纯化的)的产量为136g(81%),降伊波加因碱盐酸盐的产量为150g(98%)。总产率(基于游离碱形成、纯化和盐形成步骤)为79%。分析结果如下:最终干燥前含有降伊波加因碱盐酸盐(99.3%)、副产物(0.5%)和伊波加因碱(0.1%)。干燥3天后含有降伊波加因碱盐酸盐(99.10%)、副产物(0.33%)、伊波加因碱(0.07%)、伊波胺(0.08%)和未知物(总计0.42%)。另一批含有降伊波加因碱盐酸盐(99.34%)、伊波加因碱(0.02%)、伊波胺(<0.01%)和伊波灵(0.02%)。
上述方法表明根据本发明制备了基本不含伊波加因碱的降伊波加因碱。虽然该方法提供基本不含伊波加因碱的降伊波加因碱,但是在通过伊波加因碱由此制备的降伊波加因碱中仍然观察到少量的伊波加因碱(占降伊波加因碱的大约0.02wt%或200ppm)。
Claims (12)
1.一种组合物,所述组合物含有降伊波加因碱,其中,所述降伊波加因碱中的至少95%以2(R),4(S),5(S),6(S)和18(R)对映异构体存在,并且其中,所述组合物含有不超过相对于降伊波加因碱的总量的0.5wt%的伊波加因碱。
2.如权利要求1所述的组合物,其中,所述组合物含有不超过相对于降伊波加因碱的总量的0.3wt%的伊波加因碱。
3.如权利要求1所述的组合物,其中,所述组合物含有不超过相对于降伊波加因碱的总量的0.1wt%的伊波加因碱。
4.如权利要求1所述的组合物,其中,所述组合物含有少于800ppm的伊波加因碱。
5.如权利要求1所述的组合物,其中,所述降伊波加因碱中的至少98%以2(R),4(S),5(S),6(S)和18(R)对映异构体存在。
6.一种组合物,所述组合物含有降伊波加因碱,其中,所述降伊波加因碱中的至少98%以2(R),4(S),5(S),6(S)和18(R)对映异构体存在,并且其中,所述组合物含有不超过相对于降伊波加因碱的总量的0.5wt%的伊波加因碱。
7.如权利要求6所述的组合物,其中,所述组合物含有不超过相对于降伊波加因碱的总量的0.3wt%的伊波加因碱。
8.如权利要求6所述的组合物,其中,所述组合物含有不超过相对于降伊波加因碱的总量的0.1wt%的伊波加因碱。
9.一种组合物,所述组合物含有降伊波加因碱盐酸盐和异丙醇。
10.一种组合物,所述组合物含有降伊波加因碱,浓度为5M的盐酸和异丙醇,其中,所述组合物的温度为45℃至55℃。
11.一种组合物,所述组合物含有降伊波加因碱、硅胶、二氯甲烷、乙腈和有机碱。
12.一种组合物,所述组合物含有固体降伊波加因碱盐酸盐和异丙醇。
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CN (1) | CN103079571A (zh) |
CA (1) | CA2806232A1 (zh) |
MX (1) | MX2013000733A (zh) |
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EP2595632A1 (en) | 2013-05-29 |
US9358237B2 (en) | 2016-06-07 |
JP2013532663A (ja) | 2013-08-19 |
US20130131046A1 (en) | 2013-05-23 |
MX2013000733A (es) | 2013-05-30 |
JP6049615B2 (ja) | 2016-12-21 |
JP6267776B2 (ja) | 2018-01-24 |
RU2586296C2 (ru) | 2016-06-10 |
CA2806232A1 (en) | 2012-01-26 |
UA111065C2 (uk) | 2016-03-25 |
RU2013102923A (ru) | 2014-08-27 |
US20190262351A1 (en) | 2019-08-29 |
WO2012012764A1 (en) | 2012-01-26 |
US20210275538A1 (en) | 2021-09-09 |
JP2017061532A (ja) | 2017-03-30 |
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