CN101484456B - 阿塞那平的制备方法和用于所述方法的中间产物 - Google Patents
阿塞那平的制备方法和用于所述方法的中间产物 Download PDFInfo
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- CN101484456B CN101484456B CN2007800254650A CN200780025465A CN101484456B CN 101484456 B CN101484456 B CN 101484456B CN 2007800254650 A CN2007800254650 A CN 2007800254650A CN 200780025465 A CN200780025465 A CN 200780025465A CN 101484456 B CN101484456 B CN 101484456B
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 229960005245 asenapine Drugs 0.000 title claims abstract description 36
- 230000008569 process Effects 0.000 title claims abstract description 11
- VSWBSWWIRNCQIJ-GJZGRUSLSA-N (R,R)-asenapine Chemical compound O1C2=CC=CC=C2[C@@H]2CN(C)C[C@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-GJZGRUSLSA-N 0.000 title claims 2
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 239000013067 intermediate product Substances 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 34
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical group [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- PJANXHGTPQOBST-VAWYXSNFSA-N trans-stilbene Chemical group C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 2
- BNHFWQQYLUPDOG-UHFFFAOYSA-N lithium;1,2,2,3-tetramethylpiperidine Chemical group [Li].CC1CCCN(C)C1(C)C BNHFWQQYLUPDOG-UHFFFAOYSA-N 0.000 claims description 2
- VSWBSWWIRNCQIJ-HUUCEWRRSA-N (S,S)-asenapine Chemical compound O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-HUUCEWRRSA-N 0.000 abstract description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 77
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000203 mixture Substances 0.000 description 40
- 239000000243 solution Substances 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000005406 washing Methods 0.000 description 17
- GMDCDXMAFMEDAG-CHHFXETESA-N (S,S)-asenapine maleate Chemical compound OC(=O)\C=C/C(O)=O.O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 GMDCDXMAFMEDAG-CHHFXETESA-N 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 11
- 229960001615 asenapine maleate Drugs 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 235000015320 potassium carbonate Nutrition 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 7
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000010949 copper Substances 0.000 description 6
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- -1 hydroxyl-phenyl Chemical group 0.000 description 6
- 238000004949 mass spectrometry Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 6
- 0 *c1cc(C=Cc2cc(*)ccc2*)c(*)cc1 Chemical compound *c1cc(C=Cc2cc(*)ccc2*)c(*)cc1 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 238000007872 degassing Methods 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 150000003233 pyrroles Chemical class 0.000 description 4
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 4
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 4
- NZNQDAWTGBTUOQ-UHFFFAOYSA-N 1-methoxy-n-methyl-n-trimethylsilylmethanamine Chemical compound COCN(C)[Si](C)(C)C NZNQDAWTGBTUOQ-UHFFFAOYSA-N 0.000 description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 3
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- UHEFACWYBYZURZ-UHFFFAOYSA-N 4-phenylnaphthalen-2-ol Chemical compound C=12C=CC=CC2=CC(O)=CC=1C1=CC=CC=C1 UHEFACWYBYZURZ-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical class [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- OOCUOKHIVGWCTJ-UHFFFAOYSA-N chloromethyl(trimethyl)silane Chemical compound C[Si](C)(C)CCl OOCUOKHIVGWCTJ-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000006352 cycloaddition reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 3
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- 238000001556 precipitation Methods 0.000 description 3
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- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000005204 segregation Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- 125000006481 2-iodobenzyl group Chemical group [H]C1=C([H])C(I)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- WCGMYMAZQDIOMN-UHFFFAOYSA-N CC1C=C(C=CC1(F)Br)Cl Chemical compound CC1C=C(C=CC1(F)Br)Cl WCGMYMAZQDIOMN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- KUKCUROTFRBUNU-UHFFFAOYSA-N Daucic acid Chemical compound OC1C=C(C(O)=O)OC(C(O)=O)C1O KUKCUROTFRBUNU-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 238000010719 annulation reaction Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 238000007429 general method Methods 0.000 description 2
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- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- PGFPZGKEDZGJQZ-UHFFFAOYSA-N n,n-dimethylmethanamine oxide;dihydrate Chemical compound O.O.C[N+](C)(C)[O-] PGFPZGKEDZGJQZ-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical group C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-O triphenylphosphanium Chemical compound C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-O 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- YMHOBZXQZVXHBM-UHFFFAOYSA-N 2,5-dimethoxy-4-bromophenethylamine Chemical compound COC1=CC(CCN)=C(OC)C=C1Br YMHOBZXQZVXHBM-UHFFFAOYSA-N 0.000 description 1
- ZNOVTXRBGFNYRX-UHFFFAOYSA-N 2-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及制备阿塞那平,即反式-5-氯-2-甲基-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]-氧杂
Description
通常称为阿塞那平(asenapine)的反式-5-氟-2-甲基-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]氧杂并[4,5-c]吡咯是一种具有CNS-抑制活性且具有抗组胺和抗5-羟色胺活性的化合物(van den Burg的美国专利4,145,434)。已经有人综述了阿塞那平的药理学分布、其动力学和代谢作用以及在人志愿者和精神分裂症患者研究中第一安全性和功效(参见De Boer等,Drugs of the Future,18(12),1117-1123,1993)。已经证实,阿塞那平的马来酸盐(称作Org 5222)是一种广谱、高效能的5-羟色胺、去甲肾上腺素和多巴胺拮抗剂。
阿塞那平显示潜在的抗精神病活性并且可用于治疗抑郁症(参见国际专利申请WO 99/32108)。国际专利申请WO 95/23600(Akzo NobelN.V.)中已经描述过一种适用于阿塞那平马来酸盐的舌下或口腔给药的药物制剂。目前,阿塞那平马来酸盐是临床研究的主题,使该药物的大规模合成成为必要。
美国专利No.4,145,434中公开了制备阿塞那平的一般方法。药物(Org 5222)的理化性质已有报道(Funke等,Arzneim.-Forsch/Drug.Res.,40,536-539,1990)。还已描述了用于制备Org 5222及其放射性标记的衍生物的其它合成方法(Vader等,J.Labelled Comp.Radiopharm.,34,845-869,1994)。
仍需要阿塞那平的合成制备工序,该合成制备工序可以按工业规模可靠进行。
其特征在于使通式II的E-二苯乙烯衍生物
与偶氮甲碱叶立德反应以提供通式III的反式-吡咯烷衍生物,
在通式II和通式III中,R1是F、Br或I;
R2和R3不同并且各自选自H和Cl;和
R4是H或羟基保护基。随后当存在保护基时除去保护基,和在进行分子内闭环的条件下的处理产生通式I的化合物。
在通式II的定义中,R4可以是羟基保护基,它在反应条件下是稳定的,而产生通式III的反式-吡咯烷衍生物。此类保护基的实例是四氢吡喃基、甲硅烷基保护基或酰基。其它实例是本领域中已知的。参见例如,Wuts,P.G.M.和Greene,T.W.:Protective Groups in OrganicSynthesis,第三版,Wiley,New York,1999。优选的保护基是酰基,特别是乙酰基。
在本公开内容中,由具有一对粗体和散列楔形键(例如化合物(I)和(III)的通式中所示)的结构通式所表示的化合物是指“反式”非对映异构体。这些化合物中的每一种可以以单一对映异构体的形式或者以对映异构体的混合物(例如外消旋体)的形式存在,所述单一对映异构体具有由楔形键表示的绝对立体化学构型或者具有相反的绝对构型,所述对映异构体的混合物具有由楔形键表示的相对立体化学构型。
在本发明方法的第一反应步骤中,使通式II的E-二苯乙烯衍生物在[3+2]偶极环加成反应中与就地产生的偶氮甲碱叶立德反应以提供通式III的反式-吡咯烷衍生物。据认为该反应按其中所有键同时产生的协同方式进行。因此,立体化学在产物中得到保留。当从E-二苯乙烯衍生物开始反应时,唯一地形成反式吡咯烷环。在本发明方法中的偶极加成步骤的立体选择性在该方法的良好总产率方面代表大的优点。
可以由以下偶极结构表示的所需要的偶氮甲碱叶立德
可以例如,由三甲胺-N-氧化物二水合物(TMNO·2H2O)或三甲胺-N-氧化物脱水物(TMNO)与二异丙基氨基锂(LDA)或四甲基哌啶锂就地产生。可以通过添加LDA到通式II的E-二苯乙烯和TMNO在质子惰性溶剂例如四氢呋喃中的混合物中进行该偶极加成反应。优选地,缓慢地添加LDA以控制反应温度,优选控制到小于30℃,和实现该三甲胺-N-氧化物的溶解。
当通式II中的R1是Br或I时,使用TMNO的偶极加成以良好的产率和纯度产生通式III的吡咯烷,并且证明可能使所得的通式III的吡咯烷衍生物直接地从正戊烷/乙酸乙酯混合物或乙醇/水混合物结晶。
在一种优选的方法中,经由用三氟乙酸或氟化铯的活化就地由N-甲氧基甲基-N-三甲基甲硅烷基甲基-N-甲胺(下面通式3)产生所要求的偶氮甲碱叶立德(Hosomi,A.等,Chem.Lett.1117-1120,1984)。
新型氨基甲基醚(3)可以如下制备:通过(氯甲基)三甲基硅烷(1)将甲胺烷基化以产生仲胺(2),可以随后用甲醛在甲醇溶液中处理该仲胺:
反应试剂(3)的使用提供许多优点。例如,本发明的方法可以以更高的生产量进行,因为该氨基甲基醚反应试剂允许使用更小体积的溶剂。另外,反应试剂(3)的使用提供更安全的合成方法,因为产生偶氮甲碱叶立德的方法与使用三甲胺-N-氧化物的方法相比放热更少。此外,反应试剂(3)不以任何明显的程度与Z-二苯乙烯衍生物反应以致该合成可以容许更多Z-异构体。
在一个优选的实施方案中,使用其中R4代表保护基的通式II的二苯乙烯衍生物进行偶极加成反应。保护基例如乙酰基使用于亲电芳族取代反应的羟基-苯基钝化,该亲电芳族取代反应可能与产生通式II的吡咯烷的偶极加成反应竞争。结果,可以使副产物的出现最小化。
在该方法的第二步骤中,通式IIIA的反式-吡咯烷衍生物
形成阿塞那平的7元氧杂环的分子内闭环反应可以按乌尔曼(Ullmann)型反应进行,即在含铜(0)粉、铜(I)盐或铜(II)盐的溶剂中在碱存在下在高温下处理通式IIIA的化合物(Ma,D.,Cai,Q.,OrganicLetters,5,3799-3802,2003;Buck,E.等,Organic Letters4,1623-1626,202;Sawyer,J.S.,Tetrahedron 5045-5065,2002)。添加剂例如N,N-二甲基甘氨酸、N-甲基甘氨酸、2,2,4,4-四甲基-3,5-庚二酮(TMHD)或8-羟基喹啉可用来提高铜离子的溶解性。适合的碱包括Cs2CO3、K2CO3、吡啶、NaOH、KOH或CsF。有用的铜源包括Cu粉、CuI、CuBr、CuCl、Cu(CO)3(碳酸铜(II))、Cu(OAc)2(乙酸铜(II))、Cu(OTf)2(三氟甲烷磺酸铜(II))、Cu2O或CuSO4。
通式IIIA的化合物完全转化成阿塞那平的适合的条件是在回流的二氧杂环己烷中使用CuCl(0.25当量)、N,N-二甲基甘氨酸(0.25当量)和Cs2CO3(1.1当量)约24小时。在约80-110℃的温度下以工业规模的乌尔曼(Ullman)成环反应中使用的溶剂是二甲基甲酰胺(DMF)、二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、吡啶、二氧杂环己烷、甲苯、二甲苯、二乙二醇二甲基醚(二甘醇二甲基醚)、2-甲基四氢呋喃等。
工业规模的乌尔曼(Ullman)成环反应的优选的反应条件是使用二甲基乙酰胺或其与甲苯的混合物作为溶剂体系,使用Cs2CO3、NaOH、KOH或K2CO3作为碱,和使用与氯化铜(I)结合的二甲基甘氨酸作为催化剂。
本发明的一个尤其有用的实施方案是用于制备通式I的阿塞那平或其盐的方法,
其中使(E)-2-(2-溴苯乙烯基)-4-氯苯基乙酸酯
在惰性溶剂例如甲苯中与借助于三氟乙酸由N-甲氧基甲基-N-三甲基甲硅烷基甲基-N-甲胺就地产生的偶氮甲碱叶立德反应以提供反式-N-甲基-4-(2-溴苯基)-3-(2-乙酰氧基-5-氯苯基)-吡咯烷,
在碱性条件下,例如在碱水溶液中处理该吡咯烷衍生物,以除去乙酰基。在乌尔曼条件下借助于铜(I)盐后续处理该脱保护的吡咯烷衍生物以实现分子内闭环产生阿塞那平,可以任选地将它转变成药学上可接受的盐。
本发明的另一个方面提供此前所限定的通式III的新型反式-吡咯烷衍生物或其盐,
其中R1是F、Br或I;R2和R3不同并且各自选自H和Cl;和其中R4是H或羟基保护基。
本发明的又一个方面提供此前所限定的通式II的新型E-二苯乙烯-衍生物
其中R1是F、Br或I;R2和R3不同并且各自选自H和Cl;和其中R4是H或羟基保护基。这些二苯乙烯衍生物在工业上制备通式I的药物活性化合物,即阿塞那平中是有用的中间体。
通式II的E-二苯乙烯衍生物可以例如使用维悌希(Wittig)反应制备,其中使下面通式IV的卤化三苯基鏻与通式VI的合适的水杨醛在回流溶剂例如氯仿、四氢呋喃或其混合物中在当量用量的碱,例如二异丙基乙胺、DBU、DABCO、叔丁醇钾或乙醇钠存在下反应,其中R1、R2和R3各自如上面对通式II和III所限定。维悌希反应通常产生E-和Z-异构体的混合物,最佳的比例是约70∶30。可以通过色谱离析纯E-异构体(通式II)。
该通式IV的卤化三苯基鏻可以如下制备:在回流甲苯溶液中用三苯基膦处理通式V的化合物,其中Rl是F、Br或I,R2是H或Cl,和其中X代表卤素,优选Cl或Br。
通式II的E-二苯乙烯衍生物的优选合成方法使用下面通式VII的膦酸酯衍生物。可以通过将通式V的化合物与等摩尔量三乙基亚磷酸酯在无溶剂或使用溶剂例如甲苯的情况下加热制备该膦酸酯衍生物(Davidsen,S.K.;Phllips,G.W.;Martin,S.F.Organic Syntheses,Coll.Vol.8,p.451(1993);Vol.65,p.119)。
在随后的维悌希-霍纳尔(Wittig-Horner)反应(T.Kawasaki等,J.Org.Chem.,66,1200-1204,2001;Tet.Lett.43,2449,2001)中,在溶剂例如四氢呋喃中用碱例如叔丁醇钾、丁基锂、氢化钠或甲醇钠处理通式VII的膦酸酯,以产生中间体稳定化的膦酸根阴离子,该膦酸根阴离子与通式VI的水杨醛衍生物反应而选择性地产生通式II的E-二苯乙烯。
通式I的阿塞那平和通式III的反式-吡咯烷衍生物的适合的盐包括由与有机碱,例如三甲胺、三乙胺等组合获得的盐。适合的酸加成盐可以由无机酸例如盐酸、氢溴酸、磷酸和硫酸,或用有机酸例如抗坏血酸、柠檬酸、酒石酸、乳酸、马来酸、胡萝卜酸、富马酸、乙醇酸、琥珀酸、丙酸、乙酸和甲烷磺酸处理获得。通式I的阿塞那平的优选的酸加成盐是马来酸盐,即Org 5222。
本发明通过下面的实施例来说明。
实施例
如下实施例是说明性的和非限制性的并且代表本发明的具体实施方案。在下面实施例中的每一个中,化合物阿塞那平(通式I)和其前体通式III的反式-吡咯烷衍生物是外消旋体,并且在它们的结构通式中所用的粗体楔形键或粗体和散列楔形键对表示相对立体化学构型。
一般方法:
NMR谱图记录在Bruker DPX 400上。化学位移以份/百万份(ppm)报道。1H-NMR化学位移参照作为内标的TMS(s(单重峰);d(双重峰);t(三重峰);dd(双重双重峰);m(多重峰))。质谱记录在PE SCIEX API165上。使用装配了Restek RTX-柱的Agilent HP6890N气相色谱仪获得GC色谱。使用Agilent HP1100液相色谱仪获得HPLC色谱。
实施例1
A:(2-溴-苄基)-膦酸二乙酯
使2-溴苄基溴(1048g,4.2mol)在60℃的水浴中熔融并溶于二甲苯(xyleen)(734ml)。将该溶液加热到80℃。接下来在60分钟内按三等份将三乙基亚磷酸酯(766ml,4.46mol)添加到该反应混合物中。在110℃下搅拌该混合物一整夜。将该反应混合物与400ml二甲苯共蒸发两次。在真空中在60℃下除去二甲苯。在真空烘箱中在60℃下干燥该产物并在没有进一步纯化的情况下使用。
1H-NMR:(CDCl3):1.33(6H,t,2x CH3);3.43(1H,s,CH2-a);3.54(1H,s,CH2-b);4.12(4H,q,2x CH2O);7.17(1H,m,ArH);7.34(1H,m,ArH);7.55(1H,m,ArH),7.62(1H,m,ArH)。
31P-NMR:(CDCl3):23.81
质谱分析:发现M+1=307和309(Br-同位素)
B:反式-2-溴-5’-氨-2’-羟基二苯乙烯
在氮气下将5-氯水杨醛(188g,1.2mol)添加到(2-溴-苄基)-膦酸二乙酯(369g,1.2mol)在四氢呋喃(1500ml)中的溶液中。添加叔丁醇钾(300g,2.68mol)在四氢呋喃(3000ml)中的溶液,同时保持温度在33℃。在反应完成之后,添加水(1800ml)接着添加4N HCl(450ml)。用碳酸钠溶液(500ml)和饱和NaCl溶液洗涤该有机层。在50℃下在减压下蒸发该有机层获得反式-2-溴-5’-氯-2’-羟基二苯乙烯(301.9g,92%)。
1H-NMR(CDCl3):6.70(1H,d,H-7);7.12(1H,d,H-6);7,15(1H,t,H-2或H-3);7.21(1H,d,H-9);7.35(1H,t,H-2或H-3);7.46(1H,d,H-8);7.52(1H,d,H-5);7.58和7.68(2x2H,2xd,H-1和H-4)。
C:反式-N-甲基-2-(2-溴苯基)-3-(2-羟基-5-氯苯基)-吡咯烷
在环境温度下向反式-2-溴-5’-氯-2’-羟基二苯乙烯(81g,261mmol)在四氢呋喃(570ml)中的溶液中添加三甲胺-N-氧化物·二水合物(43.4g,390mmol)。然后在1小时的过程中添加在庚烷/THF中的二异丙基氨基锂(2M,1070ml,2140mmol),同时维持温度小于40℃。在反应完成之后,添加水(120ml)。将溶剂蒸发到小体积,之后添加乙酸乙酯(250ml)。用18%盐酸(~250ml)将pH值调节到pH值8并添加乙酸乙酯(250ml)。分离有机层并用乙酸乙酯(2×120ml)再次萃取水层。用水(325ml)和盐水洗涤合并的有机层,干燥(MgSO4),然后在真空中蒸发。从乙醇/水(1/1,v/v)使所得的油结晶而获得标题吡咯烷(62.0g,79%)。根据HPLC的纯度是99%a/a。
1H-NMR(MeOD):2.50(3H,s,CH3),2.52+3.09+3.10+3.45(4x1H,t,dd,t,t,Ha-5,Hb-5,Ha-6,Hb-6),3.62+4.14(2x 1H,2xm,H4+H7),6.72(1H,d,H-1),6.94(1H,d,H-3),6.98(1H,d,H-2),7.10+7.35(2x1H,2xt,H-10+H-9),7.52+7.58(2x1H,2xd,H-8+H-11)。
D+E:阿塞那平马来酸盐;Org 5222
方法1:
在氮气气氛下向反式-N-甲基-2-(2-溴苯基)-3-(2-羟基-5-氯苯基)-吡咯烷(103g;280.8mmol)和二氧杂环己烷(520ml)的混合物中添加碳酸铯(109.79g;1.2当量)、N,N二甲基甘氨酸(7.2g;0.25当量)和碘化亚铜(13.36g;0.25当量)。将该混合物加热到回流,在回流温度下搅拌68小时,然后在dicalite上过滤。用二氧杂环己烷(3×50ml)洗涤该dicalite。蒸发该二氧杂环己烷,之后将残余物溶于乙醇(1000ml)。在搅拌下将氢溴酸水溶液(48%;31.5ml)添加到该乙醇溶液中。搅拌该悬浮液16小时。收集该结晶的阿塞那平氢溴酸盐并在真空下干燥。在水(500ml)中搅拌该产物,于是通过添加氢氧化钠水溶液(2N)将pH值调节到8。用二氯甲烷萃取水层。用水(200ml)洗涤该有机层,在硫酸镁上干燥并蒸发。将残余物溶于乙醇(50ml)。向这一溶液中添加马来酸(16.6g;142.6mmol)在乙醇(20ml)和水(6ml)中的溶液。搅拌该反应混合物一整夜。将乙醇(20ml)添加到该粘稠物质中并再搅拌该悬浮液一个小时。收集该阿塞那平马来酸盐并在真空下在40℃下干燥,产量44g(39%)。根据HPLC的纯度是99.8%a/a。
1H-NMR(CDCl3):2.58(3H,s,1-N-CH3);3.14(2H,m,H-3和H-4);3.21和3.62(m,2x2H,2xH-2和2x H-5);6,24(2H,s,马来酸的乙烯属H’2),7.01-7.36(7H,m,芳族H)。
ESI_MSMS:在m/z 44,166,194,201,215,220,229观察到的碎片是[C2H6N]+,[C12H6O]+.,[C14H10O]+.,[C12H6ClO]+,[C13H8ClO]+,[C16H12O]+.,[C14H10ClO]。
熔点:140℃
方法2
将碳酸钾(6.24g;45.0mmol)和铜粉(0.96g;15.1mmol)悬浮在二甲基乙酰胺(25ml)中。使温度达到140℃并在30分钟的过程中引导氮气穿过该悬浮液。然后添加反式-N-甲基-2-(2-溴苯基)-3-(2-羟基-5-氯苯基)-吡咯烷(15g;40.9mmol)并搅拌该反应混合物29小时。在dicalite上过滤该悬浮液并蒸发溶剂。将残余物溶于甲苯(100ml)并用氨(50ml)和水(50ml)洗涤两次。在硫酸镁上干燥甲苯层并蒸发。将残余物溶于乙醇(18.2ml),于是在搅拌下添加马来酸(4.83g;41.4mmol)在乙醇(5.2ml)和水(1.82ml)中的溶液。在搅拌16小时之后,收集阿塞那平马来酸盐的晶体并在真空下在40℃下干燥,产生8.9g(54%)。根据HPLC的纯度是99.9%a/a。
1H-NMR(CDCl3):2.58(3H,s,1-N-CH3);3.14(2H,m,H-3和H-4);3.21和3.62(m,2x2H,2xH-2和2x H-5);6,24(2H,s,马来酸的乙烯属H’2),7.01-7.36(7H,m,芳族H)。
ESI_MSMS:在m/z 44,166,194,201,215,220,229观察到的碎片是[C2H6N]+,[C12H6O]+.,[C14H10O]+.,[C12H6ClO]+,[C13H8ClO]+,[C16H12O]+.,[C14H10ClO]。
熔点:140℃
方法3
向反式-N-甲基-2-(2-溴苯基)-3-(2-羟基-5-氯苯基)-吡咯烷(10g;27.3mmol)在甲醇(100ml)中的溶液中添加KOH(1.68g,29.9mmol)。在40℃下搅拌所获得的透明溶液15分钟。蒸发溶剂,添加甲苯(73ml)和DMA(18ml),接着添加CuCl(1.00g,10mmol)、二甲基甘氨酸(2.20g,21.3mmol)和碳酸钾(3.77g,27.3mmol)。在回流4小时之后,在真空中除去溶剂。将反应混合物溶于甲苯(55ml)并用5%氨溶液(3×55ml)萃取。在硫酸镁上干燥甲苯层并蒸发。将残余物溶于2-丙醇(10ml),于是在搅拌下添加马来酸(3.48g;30.0mmol)在2-丙醇(68ml)和水(1.82ml)中的溶液。在搅拌16小时之后,收集阿塞那平马来酸盐的晶体并在真空下在40℃下干燥,产生6.0g(55%)。根据HPLC的纯度是99%a/a。
1H-NMR(CDCl3):2.58(3H,s,1-N-CH3);3.14(2H,m,H-3和H-4);3.21和3.62(m,2x2H,2xH-2和2x H-5);6,24(2H,s,马来酸的乙烯属H’2),7.01-7.36(7H,m,芳族H)。
ESI MSMS:在m/z 44,166,194,201,215,220,229观察到的碎片是[C2H6N]+,[C12H6O]+.,[C14H10O]+.,[C12H6ClO]+,[C13H8ClO]+,[C16H12O]+.,[C14H10ClO]。
熔点:140℃
实施例2
A:(2-碘-苄基)-膦酸二乙酯
在250ml圆底烧瓶中将三乙基亚磷酸酯(约66.6ml;94%纯;约396.8mmol)和2-碘代苄基氯1(100g,400mmol;在使用之前熔融)与二甲苯(65ml)混合。将透明溶液加热到回流同时搅拌24小时。反应之后进行GC和1H-NMR(CDCl3)。在4.73ppm处2H,s,CH2I的消失的质子共振和在3.47ppm处新的2H,d,CH2PO(OEt)2是反应进展的指示。
1H-NMR(CDCl3):1.33(6H,t,2x CH3);3.47(2H,d,CH2PO(OEt)2);4.12(q,4H,2x CH2O);6.99(1H,m,ArH);7.35(1H,m,ArH);7.54(1H,m,ArH),7.89(1H,m,ArH)。
质谱分析:M+1=355(发现Cl-同位素),M-1=355(发现Cl-同位素)。
B:反式-2-碘-5’-氯-2’-羟基二苯乙烯
将粗(2-碘-苄基)-膦酸二乙酯的所得溶液冷却到室温,然后添加到5-氯水杨醛(62.14g,396.8mmol;1.0当量)在THF(1000ml)中的溶液中。用冰浴将该溶液冷却到约0℃。在5分钟内分成几份添加KOtBu(97.2g,868mmol,2.19当量)并获得橙色、几乎透明的溶液。添加附加的THF(100ml)。在再搅拌10分钟之后,移除冰浴并搅拌反应混合物同时回暖到室温。在1小时之后,添加水(250ml)并获得透明的橙色溶液。添加乙酸乙酯(400ml),接着添加饱和NaCl水溶液(100ml)。分离有机相并在真空下浓缩而获得155g(>100%)油。然后,添加2N HCl(水溶液;250ml)接着添加乙酸乙酯(250ml)。分离有机相,用Na2SO4干燥,并在真空下蒸发而获得127g固体。然后在正戊烷(500ml)中在室温下搅拌这种固体15分钟。在玻璃滤器上过滤该米色固体,用正戊烷(50ml)洗涤并在真空下在旋转蒸发器上干燥。标题二苯乙烯的产量是111g(79%)。在没有进一步纯化的情况下使用该产物。
质谱分析:M+1=356(发现Cl-异构体)。
1H-NMR(CDCl3):6.8.1(1H,d,H-7);7.05(1H,d,H-6);7,18(1H,t,H-2或H-3);7.22(1H,d H-9);7.34(1H,t,H-2或H-3);7.42(1H,d,H-8,);7.60(1H,d,H-5);7.52和7.98(2x 2H,2x d,H-1和H-4)
C:反式-N-甲基-2-(2-碘苯基)-3-(2-羟基-5-氯苯基)-吡咯烷
在室温下将反式-2-碘-5’-氯-2’-羟基二苯乙烯(56.1g,157.6mmol)和三甲胺N-氧化物二水合物(52.55g,472.8mmol)的混合物溶于THF(570ml),同时搅拌。不是所有三甲胺N-氧化物二水合物都溶解。用冰浴将该混合物冷却到约0℃。然后,用滴液漏斗在25分钟内逐滴添加约4℃的冷却LDA溶液(577.5ml,1.8M,在庚烷/THF/乙基苯中;1.04mol)。内部温度上升到约20-26℃。在添加完成之后,所得的橙色/黄色溶液的温度在10分钟内降低到约8℃。吸取样品,用一些水骤冷并通过LC分析显示>90%环加成物。移除冰浴并再搅拌该反应混合物4小时同时回暖到室温。添加水(140ml)并在室温下搅拌该混合物一整夜。然后添加2N HCl(200ml)接着添加乙酸乙酯(500ml)。分离有机层。用乙酸乙酯(100ml)再次萃取该水层,该水层仍是略微碱性的(pH值指示剂纸)。用Na2SO4干燥合并的有机萃取物。在真空下蒸发获得油。添加二乙醚(100ml)而产生溶液。在搅拌的同时添加正戊烷(300ml)到这一醚溶液后获得黄色沉淀。在玻璃滤器上过滤并用正戊烷(2×25ml)洗涤在真空下干燥之后获得为黄色固体的纯环加成物(46.5g,112.6mmol;LC>95%纯),产率72%。熔点:123.1℃(开始),126.9℃(峰值)。将滤液合并并在真空下蒸发而获得23g油,根据NMR分析,它含有大量产物。在硅胶上通过色谱纯化(用乙酸乙酯洗脱)获得第二收获物(17g;41.1mmol;26%)。总产率是约98%。
质谱分析:M+1=414(发现Cl-异构体),M-1=412(发现Cl-异构体),
1H-NMR(CDCl3):2.60(3H,s,CH3),2.30+2.96+3.77+3.42(4x1H,t,dd,t,t,Ha-5,Hb-5,Ha-6,Hb-6),3.22(2H,m,H4+H7),6.82(1H,d,H-1),6.92(1H,d,H-3),7.02(1H,d,H-2),7.32+7.15(2x1H,2xt,H-10+H-9),7.51+7.85(2x1H,2xd,H-8+H-11)。
D:阿塞那平
方法1
将反式-N-甲基-2-(2-碘苯基)-3-(2-羟基-5-氯苯基)-吡咯烷(46.5g,112.6mmol)和碳酸铯(100g,306.9mmol)在N,N-二甲基乙酰胺(DMA,350ml)的混合物加热到140℃(内部温度),同时搅拌。在2小时之后,通过小量样品的NMR分析没有观察到阿塞那平;仅存在起始材料。然后,再次添加碳酸铯(98g)(合计使用607.7mmol Cs2CO3)并加热该混合物一整夜(16小时)。根据NMR分析,获得起始材料和阿塞那平的混合物。让该产物经历色谱纯化处理。1H-NMR(CDCl3)完全一致。
方法2
将反式-N-甲基-2-(2-溴苯基)-3-(2-羟基-5-氯苯基)-吡咯烷(27g,65.4mmol)、碳酸铯(42.7g,131mmol)、CuI(4.98g,26.2mmol)和TMHD(2.39g,13.1mmol,20mol%)在NMP(250ml)中的混合物加热到160℃(内部温度)。在1小时之后,反应完成。在4小时之后,然后用Kugelrohr设备在真空下浓缩该混合物而除去大部分NMP。1H-NMR(CDCl3)完全一致。
实施例3
A+B:反式-2-乙酰氧基-2’-溴-5’-氯二苯乙烯
在三乙基亚磷酸酯(297g,1769mmol)中在115℃下加热2-溴-5-氯-苄基溴(462g,1625mmol)2小时。将该混合物冷却。
在-10℃下,逐份向四氢呋喃(4610ml)中的水杨醛(216g,1769mmol)中添加KOtBu(495g,4411mmol)。在-10℃下添加上述混合物。搅拌该反应混合物2小时,然后添加乙酸酐(461g,4516mmol)。在15分钟搅拌之后,添加氯化氢(2900ml,1N,2900mmol)。分离层并用盐水(2升)洗涤有机层。在真空下浓缩有机层。在20℃到-10℃下从乙醇(4250ml)中使产物结晶。通过过滤离析该产物并在真空下干燥24小时。标题二苯乙烯的产量514.8g(90%)。根据HPLC的纯度是>99.5%a/a。
1H-NMR(CDCl3):2.39(3H,s,CH3),7.03(1H,d,J=16Hz,烯烃H),7.10(2H,m,H3+H4),7.30+7.35(2x1H,t,t,H2+H3),7.39(1H,d,J=16Hz,烯烃H),7.49+7.56+7.68(3x1H,d,d,d,H4’+H3’+H6’)。
熔点:134-135℃:
质谱:M+1=351和353(发现Br-同位素)。
C:反式-N-甲基-2-(2-羟基苯基)-3-(2-溴-5-氯苯基)-吡咯烷
在33℃下将反式-2-乙酰氧基-2’-溴-5’-氯二苯乙烯(1189g,3381mmol)溶于甲苯(5350ml)和三氟乙酸(10.42ml,165mmol)。在1小时的过程中添加N-甲氧基甲基-N-三甲基甲硅烷基-N-甲胺(670g,4153mmol)。在真空下浓缩有机层为油。在30℃下将这种油溶于甲醇(4160ml)。添加在水(900ml)中的氢氧化钾(209g,3725mmol)。在30分钟之后,用3N HCl(约200ml)将pH值调节到8-9。搅拌该混合物30分钟并过滤。在真空下干燥产物24h,产生1188g(96%)标题吡咯烷。根据HPLC的纯度是>99.0%a/a。
1H-NMR(CDCl3):2.25(1H,t,H1a),2.53(3H,s,CH3),2.86+3.25+3.31+3.67+4.05(5x1H,t,d,m,t,m,H1b+H4a+H3+H4b+H2),6.62+6.82+6.92+7.08+7.12+7.35+7.42(7x1H,t,d,d,t,t,d,d,芳族质子)。
熔点:167℃。
质谱:发现M+1366和368(溴-异构体)。
D+E:阿塞那平马来酸盐
方法1
在250mL圆底烧瓶中添加在N,N-二甲基乙酰胺(22ml)中的反式-N-甲基-2-(2-羟基苯基)-3-(2-溴-5-氯苯基)-吡咯烷(10.0g,27.3mmol)、碳酸铯(11.0g,33.8mmol)、氯化铜(I)(1.0g,10.10mmol)和N,N-二甲基甘氨酸(2.2g,21.33mmol)而获得褐色悬浮液。用氮气将该浆料脱气并加热到50℃。添加甲苯(88ml)并将该浆料加热到111℃保持12-14小时。当反应完成(通过HPLC监测)时,将该混合物冷却到20℃。添加90ml 3N氨并搅拌该混合物15分钟。摈弃水层。用2×60ml 3N氨洗涤该有机层。将该甲苯层与ECOSORB GL-793聚合物碳(1.0g)搅拌30分钟,然后过滤。通过真空蒸馏除去甲苯。添加2-丙醇(10.0ml)并真空蒸馏以除去溶剂而留下为淡黄油的阿塞那平。在45-50℃下将马来酸(3.5g,30.2mmol)溶于2-丙醇(55ml)。在45-50℃下将这一溶液添加到该黄色油中。在3小时内将该溶液冷却到10℃并在10℃下保持2小时。过滤固体并用40ml冷(0-5℃)2-丙醇洗涤。在40℃下干燥该固体而获得白色固体。重量:8.8g。通过在55-60℃下将该粗产物溶解在丙酮(51.5ml)中,然后缓慢地添加正庚烷(17.5ml)使该阿塞那平马来酸盐再结晶。添加种子晶体并搅拌该混合物一小时。在1小时的过程中再添加正庚烷(43ml),同时维持温度在55-60℃。在这一温度下搅拌该混合物一小时,然后在6小时内冷却到10℃。在10℃下搅拌至少1小时之后,通过过滤离析产物并用已经冷却到5-15℃的丙酮和正庚烷的1∶1混合物(9ml)洗涤。然后在真空烘箱中在60℃下干燥该材料。产生8.8g(88%)阿塞那平马来酸盐(斜方晶晶型)。根据HPLC的纯度:99.0%。
1H-NMR:(CDCl3)3.07(3h,s,CH3),3.94(6H,br s,吡咯烷质子),6.27(2H,s,马来酸盐质子),7.00-7.26(7H,m,芳族质子)。
熔点:140-141℃
方法2
向250mL烧瓶中加入反式-N-甲基-2-(2-羟基苯基)-3-(2-溴-5-氯苯基)-吡咯烷(5g,13.6mmol)、粉末Cs2CO3(0.8g,2.5mmol)、粉末碳酸钾(5.4g,29mmol)、CuCl(0.5g,5mmol)、N,N-二甲基甘氨酸(1.1g,10.6mmol)和N,N-二甲基乙酰胺(11mL)。用氮气将该浆料脱气并加热到50℃。向该反应混合物中添加脱气的甲苯(44mL)和水(1.5mL),然后将所得的浆料加热到110-112℃保持5-10小时。将反应冷却到室温并添加3N氨水(45mL)并搅拌15分钟。分离层并用3N氨水(2×30mL)洗涤有机层。在真空下除去甲苯而产生油。如上所述在2-丙醇中制备盐。
方法3
向500mL烧瓶中加入反式-N-甲基-2-(2-羟基苯基)-3-(2-溴-5-氯苯基)-吡咯烷(10g,27.2mmol)、CuCl(1.0g,10.2mmol)、碳酸钾(7.52g,54.4mmol)、N,N-二甲基甘氨酸(2.2g,21.3mmol)和22mL N,N-二甲基乙酰胺(22ml)。用氮气将该浆料脱气20分钟并加热到50℃。添加脱气的甲苯(90mL)接着添加2-甲基四氢呋喃(10mL)。在剧烈搅拌下将该混合物加热到110-115℃保持4-5小时。将反应混合物冷却到20℃。添加氢氧化铵(3N,90mL)。让该混合物滤过硅藻土。将甲基THF(20mL)添加到该滤液中。用氢氧化铵(3N,60mL)再洗涤该有机层两次。通过真空蒸馏在70-80℃下除去甲苯而获得油。如上所述在2-丙醇中制备盐。
方法4
向500mL烧瓶中加入反式-N-甲基-2-(2-羟基苯基)-3-(2-溴-5-氯苯基)-吡咯烷(10g,27.3mmol)、CuCl(1.0g,10.1mmol)、碳酸钾(7.52g,54.4mmol)、N,N-二甲基甘氨酸(2.2g,21.3mmol)和二甲基甲酰胺(50ml)。将该混合物加热到110-115℃保持3-4小时。通过HPLC监测反应直到起始材料小于2%。将反应混合物冷却到20℃。添加甲苯(50mL)接着添加3N NH4OH水溶液(90mL)并搅拌20分钟。分离层。用甲苯(3×50mL)洗涤水层。用3N NH4OH(3×60mL)洗涤合并的有机层。通过真空蒸馏在70-80℃下除去甲苯而获得油。如上所述在2-丙醇中制备盐。
实施例4
A:甲基-三甲基硅烷基甲基-胺
向耐压烧瓶(500ml)中加入氯甲基三甲基硅烷(100ml,716mmol)和40%甲胺水溶液(373ml,4.29mol)。将该反应物加热到85℃保持6小时,该反应引起小于690毫巴。将反应物冷却到20℃并分离层。将水层冷却到5℃并添加固体氢氧化钾(34g,0.607mol)。用1∶1戊烷:叔丁基甲基醚(200ml)洗涤水层。在真空中浓缩合并的有机物到约一半体积。在95-100℃下蒸馏产物;产生38g(50%)甲基-三甲基硅烷基甲基-胺(该产物包含10%mol/mol MTBE)。
1H-NMR:(CDCl3)0.00(9H,s,Si(Me3)),0.61(1H,s,NH),1.99(2H,s,CH2),2.42(3H,2,NMe)。
质谱:发现M+1118。
B:N-甲氧基甲基-N-三甲基甲硅烷基-N-甲胺
向甲醛(37%,在水中,8.5g)的冷溶液(0℃)中缓慢地添加甲基-三甲基硅烷基甲基-胺(205g,175mmol)的溶液,该反应混合物的温度低于5℃。添加甲醇(14ml),接着添加碳酸钾(12g)。在搅拌1小时之后,分离层。向有机层中添加碳酸钾(2g)并搅拌该有机物2小时。通过过滤除去碳酸钾并在45℃和20毫巴下蒸馏该产物。
1H-NMR:(CDCl3)0.00(9H,s,SiMe3),2.00(2H,s,CH2Si),2.30(3H,s,MeN),3.25(3H,s,OMe),3.88(2H,s,CH2O)。
质谱:发现M+1162。
实施例5
A+B:反式-2-溴-2’-乙酰氧基-5’-氯二苯乙烯
将2-溴苄基溴(25g,0.100mol)和甲苯(25ml)加热到100℃。接下来在30分钟内添加三乙基亚磷酸酯(19.3ml,0.108mol),同时保持温度小于116℃。在115℃下搅拌该混合物2小时,同时蒸馏甲苯。将该反应混合物冷却到室温并用THF(37.5mL)稀释。将KOtBu(30.5g,0.250mol)溶于THF(176ml)并冷却到-10℃。在5℃下添加(2-溴-苄基)-膦酸二乙酯溶液。接下来在5℃下添加在THF(62ml)中的氯水杨醛(17.2g,0.110mol)。在-5℃到0℃下搅拌该混合物1小时。当反应完成时,添加乙酸酐(28.3ml,0.301mol)并允许温度上升到20℃。反应在1小时内完成并将该混合物冷却到5℃。接下来迅速地添加250ml 1N HCl。用200ml饱和NaCl溶液洗涤有机层。在减压下在50℃下蒸发有机层,产生25.8g(73%)标题二苯乙烯。
1H-NMR(CDCl3):2.38(3H,s,H-11);6.87(1H,d,H-9),7.19+7.34(2x 1H,2x t,H-2+H-3),7.26(1H,d,H-6),7.46(1H,d,H-8),7.60(2H,dd,H-1+H-4),7.68(1H,d,H-5)。
C:反式-N-甲基-2-(2-溴苯基)-3-(2-羟基-5-氯苯基)-吡咯烷
在甲苯(91ml)中在33℃下将反式-2-溴-2’-乙酰氧基-5’-氯二苯乙烯(26g,73mmol)制浆。添加三氟乙酸(200微升)。在90分钟内将N-甲氧基甲基-N-三甲基甲硅烷基-N-甲胺(14.5g;89.7mmol)添加到该反应混合物中。在添加之后,用水(25ml)洗涤该反应物。通过真空蒸馏除去甲苯。添加乙醇(30ml)并在减压下除去。将油溶于甲醇(90ml)。添加氢氧化钾(5g,在25ml水中)。该产物开始立即沉淀。在30分钟之后,用3N HCl(8ml)将pH值调节到8-9。添加水(10ml)并冷却到小于10℃。过滤并用1∶1甲醇∶水洗涤。在真空中干燥到26.0g(96%产率)。根据HPLC的纯度是98%a/a。
1H-NMR(MeOD):2.50(3H,s,CH3),2.52+3.09+3.10+3.45(4x1H,t,dd,t,t,Ha-5,Hb-5,Ha-6,Hb-6),3.62+4.14(2x 1H,2xm,H4+H7),6.72(1H,d,H-1),6.94(1H,d,H-3),6.98(1H,d,H-2),7.10+7.35(2x1H,2xt,H-10+H-9),7.52+7.58(2x1H,2xd,H-8+H-11)。
D+E:阿塞那平
参见实施例1或3步骤D+E
实施例6
A:5-氯-2-氟-苄基溴
在20℃下将5-氯-2-氟-甲苯(100g,692mmol)溶于乙酸乙酯(300ml)。向这一溶液中添加N-溴代琥珀酰亚胺(147.7g,830mmol)和过氧化二苯甲酰(2g,8.25mmol)。在80℃下搅拌该混合物3小时。添加庚烷(300ml)并将该溶液冷却到0℃,于是琥珀酰亚胺沉淀。在过滤并用庚烷洗涤之后,用水(1500ml)洗涤残余物。在真空中浓缩该滤液到干燥,产生162g粗5-氯-2-氟-苄基溴。在99℃和33毫巴下通过真空蒸馏纯化该粗产物(141g),得到5-氯-2-氟-苄基溴(99g,75%)。根据GC的纯度是87.1%a/a。
1H-NMR(CDCl3):4.44(2H,d,CH2),7.01(1H,t,H3),7.26(1H,m,H4),7.38(1H,m,H6)
B:(5-氯-2-氟-苄基)-膦酸二乙酯
在100℃下加热5-氯-2-氟-苄基溴(630g,根据GC的纯度72%a/a,2.42mol)并在1h 45中缓慢地添加三乙基亚磷酸酯(403g,2.42mol)。在100℃下搅拌该混合物2小时,并缓慢地添加THF(350ml)并蒸馏,直到通过NMR没有检测到乙基溴。为了离析该粗(5-氯-2-氟-苄基)-膦酸二乙酯,将该反应混合物冷却到室温,得到681g(100%)。
C:反式-5-氯-2-氟-2’-羟基二苯乙烯
向叔丁醇钾(1088g,9.69mol)在四氢呋喃(7升)中的溶液中在17分钟内在0℃下添加在四氢呋喃(3升)中的粗(5-氯-2-氟-苄基)-膦酸二乙酯(680g,2.42mmol)。向这一反应混合物中在1小时内添加水杨醛(325g,2.66mol)在四氢呋喃(3升)中的溶液。在0℃下搅拌3小时之后,反应完成。在0℃下添加HCl(2M,3升)而获得酸性溶液(pH值=4.5)。在20℃下离析有机相,在硫酸镁上干燥,过滤并在减压下浓缩。与庚烷(2×700ml)的共蒸发提供粗反式-5-氯-2-氟-2’-羟基二苯乙烯,通过添加在7.5升中的MTBE(6.5升)和NaOH(238g)将它纯化。在搅拌3.5小时之后,用HCl(1M,5升),接着用饱和NaCl溶液(4升)洗涤有机层。在减压下浓缩获得反式-5-氯-2-氟-2’-羟基二苯乙烯(460g,69%)。根据GC的纯度是84%a/a。
1H-NMR(CDCl3):6.79(1H,dd,H1),6.95(1H,m,H3),6.99(1H,dd,H7),7.15(1H,m,H6),7.17(1H,m,H2),7.21(1H,d,H8),7.44(1H,d,H9),7.54(1H,dd,H4),7.61(1H,dd,H5)。
质谱分析:[M+C3H5]+=289和291[M+C2H5]+=277和279,[M+H]+=249和251,(发现Cl-同位素),和[MH-HCl]+=213。
D:反式-N-甲基-2-(2-苯酚)-3-(2-氟-5-氯苯基)-吡咯烷
使用三甲胺-N-氧化物·二水合物的方法1
在5℃下向反式-5-氯-2-氟-2’-羟基二苯乙烯(451g,1.81mol)在四氢呋喃(2.5升)中的溶液中添加三甲胺-N-氧化物·二水合物(272.9g,2.45mol)。然后在1小时的过程中添加在环己烷(2M,3.6升,3.62mol)中的二异丙基氨基锂,同时维持温度处于5℃。在反应完成之后,在-10℃下在30min内添加饱和NH4Cl(1.8升)。蒸发有机溶剂并用乙酸乙酯(2升)萃取所获得的pH值为10的混合物。在减压下浓缩提供粗反式-N-甲基-2-(2-苯酚)-3-(2-氟-5-氯苯基)-吡咯烷,在80℃下将它溶于乙醇/水(855mL 3/7v/v),缓慢地冷却直到0℃以使反式-N-甲基-2-(2-苯酚)-3-(2-氟-5-氯苯基)-吡咯烷再结晶。离析晶体,并在减压下在干燥之后获得标题吡咯烷(207g,40%)。根据GC的纯度98.2%a/a。
1H-NMR(CDCl3):2.44(1H,m,H5),2.54(1H,s,CH3),2.90(1H,t,H6),3.19(1H,d,H6),3.33(1H,m,H7),3.56(1H,m,H5),3.61(1H,m,H4),6.65(1H,m,H10),6.79(1H,dd,H11),6.90(1H,dd,H8),6.98(1H,m,H1),7.12(1H,m,H9),7.17(1H,dd,H3),7.18(1H,m,H2)。
使用三甲胺-N-氧化物脱水物的方法2
通过水与甲苯的共蒸发就地由三甲胺-N-氧化物二水合物制备三甲胺-N-氧化物脱水物。向反式-5-氯-2-氟-2’-羟基二苯乙烯(80g,320mmol)在四氢呋喃(440ml)中的溶液中添加三甲胺-N-氧化物脱水物(48g,640mmol)。然后在5h 30小时的过程中添加在环己烷(1.5M,853ml,1.28mol)中的二异丙基氨基锂,同时维持温度处于5℃。在反应完成之后,在-10℃下在30min内添加饱和NH4Cl(320ml)。蒸发有机溶剂并用乙酸乙酯(355ml)萃取所获得的pH值为10的混合物。在减压下浓缩提供粗反式-N-甲基-2-(2-苯酚)-3-(2-氟-5-氯苯基)-吡咯烷,在80℃下将它溶于乙醇/水(855mL 3/7v/v),缓慢地冷却直到0℃以使反式-N-甲基-2-(2-苯酚)-3-(2-氟-5-氯苯基)-吡咯烷再结晶。离析晶体,并在减压下在干燥之后获得标题吡咯烷(90.2g,92%)。根据GC的纯度93.5%a/a。
1H-NMR(CDCl3):2.44(1H,m,H5),2.53(1H,s,CH3),2.90(1H,t,H6),3.19(1H,d,H6),3.34(1H,m,H7),3.56(1H,m,H5),3.61(1H,m,H4),6.64(1H,m,H10),6.79(1H,dd,H11),6.90(1H,dd,H8),6.98(1H,m,H1),7.12(1H,m,H9),7.17(1H,dd,H3),7.18(1H,m,H2)。
质谱分析:[M+C3H5]+=346和348,[M+C2H5]+=334和336,[M+H]+=306和308(发现Cl-同位素),
E和F阿塞那平马来酸盐
在150℃下在氮气下加热反式-N-甲基-2-(2-苯酚)-3-(2-氟-5-氯苯基)-吡咯烷(205g;0.67mol)和氢氧化钾(44g;0.78mol)在N-甲基吡咯烷酮(2升)中的混合物6小时。在反应完成之后,将该混合物冷却到20℃。添加水(7.2升)并用乙酸乙酯(2×3升)萃取。用水和饱和NaCl洗涤有机层,在减压下浓缩而获得187g产量的粗阿塞那平。通过结晶纯化为HBr-盐:将粗阿塞那平溶于丙酮(930ml)。缓慢地添加在水中的47%HBr(77ml)。将该悬浮液加热到36℃而获得透明溶液并在冷却,过滤和在真空下在50℃干燥后,离析143g产量(58%)的阿塞那平溴化物盐。根据GC的纯度是94.8%。为了获得Org 5222,用氨在水中的28%水溶液(700ml)中和该溴化物盐(134g,0.36mol)。用乙酸乙酯(2×500ml)萃取游离碱并用饱和NaCl洗涤有机层。并在减压下浓缩而产生104g为游离碱的阿塞那平。将该游离碱溶于乙醇(208ml)并加热到60℃。添加马来酸(46.5g,0.40mol)并在-15℃下搅拌该混合物2h,于是马来酸盐沉淀。通过过滤收集晶体,用乙醇(208ml)和二异丙醚(208ml)洗涤。为了获得所需的多形晶,在55℃下将离析的晶体溶于乙醇(180ml)和水(20ml)。将温度降低到20℃并在48h内使所需的多形晶沉淀。过滤该晶体,用乙醇(100ml)洗涤并在减压下在40℃下干燥。产量92g(36%)。根据HPLC的纯度99.8%a/a。
1H-NMR(MeOD):3.14(3H,s,CH3),3.79+4.08(2x2H,2xm,H2+H5),3.93(2H,m,H4+H7),6.24(2H,s,马来酸的乙烯属H),7.35-7.13(7H,m,芳族H)。
Claims (10)
2.权利要求1的方法,其中R1是Br或I。
3.权利要求2的方法,其中R1是Br,R2是H,R3是Cl。
4.权利要求1-3中任一项的方法,其中该偶氮甲碱叶立德由三甲胺-N-氧化物或由N-甲氧基甲基-N-三甲基甲硅烷基甲基-N-甲胺就地产生。
5.权利要求4的方法,其中该偶氮甲碱叶立德由与二异丙基氨基锂或四甲基哌啶锂结合的三甲胺-N-氧化物就地产生。
6.权利要求4的方法,其中该偶氮甲碱叶立德由N-甲氧基甲基-N-三甲基甲硅烷基甲基-N-甲胺借助于三氟乙酸产生。
8.通式IIIA的反式-吡咯烷衍生物或其盐,
其中
R1是F、Br或I;和
R2和R3不同并且各自选自H和Cl。
9.权利要求8的反式-吡咯烷衍生物,它是反式-N-甲基-2-溴苯基-3-(2-羟基-5-氯苯基)-吡咯烷。
10.通式II的E-二苯乙烯-衍生物,
其中
R1是F、Br或I;
R2和R3不同并且各自选自H和Cl;和
R4是H或羟基保护基。
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US7875729B2 (en) * | 2007-01-05 | 2011-01-25 | Synthon Bv | Process for making asenapine |
MX2010007404A (es) * | 2008-01-04 | 2010-10-05 | Organon Nv | Procedimiento para la preparacion de asenapina y productos intermediarios utilizados en dicho procedimiento. |
AR077225A1 (es) | 2009-06-24 | 2011-08-10 | Organon Nv | Formulaciones inyectables que contienen asenapina y metodo de tratamiento que las utiliza |
WO2012123325A1 (en) | 2011-03-11 | 2012-09-20 | Medichem S.A. | NEW CRYSTAL FORMS OF THE SALT OF TRANS-5-CHLORO-2-METHYL-2,3,3A,12b-TETRAHYDRO-1H-DIBENZO[2,3:6,7]OXEPINO[4,5-c]PYRROLE WITH MALEIC ACID |
CN102229613B (zh) * | 2011-04-27 | 2013-08-07 | 上海华升生物科技有限公司 | 阿森纳平的合成工艺 |
ITMI20110734A1 (it) * | 2011-05-02 | 2012-11-03 | Olon Spa | Sali cristallini di asenapina |
EP2524919A1 (en) * | 2011-05-17 | 2012-11-21 | Sandoz AG | Novel crystalline salts of Asenapine with organic Di-acids and Tri-acids |
EP2524921A1 (en) * | 2011-05-17 | 2012-11-21 | Sandoz AG | Novel Crystalline Salts of Asenapine |
CN102952144A (zh) * | 2011-08-29 | 2013-03-06 | 上海华拓医药科技发展股份有限公司 | 阿森纳平马来酸盐的晶型、制备方法及其药物组合物 |
WO2013041604A1 (en) | 2011-09-21 | 2013-03-28 | Sandoz Ag | Crystal form of asenapine maleate |
EP2572703A1 (en) | 2011-09-21 | 2013-03-27 | Hexal AG | Compressed oral dosage form for asenapine maleate |
GB201121124D0 (en) * | 2011-12-08 | 2012-01-18 | Dow Corning | Hydrolysable silanes |
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CN103183680A (zh) * | 2011-12-27 | 2013-07-03 | 上海华拓医药科技发展股份有限公司 | 阿森那平的制备方法 |
WO2013190481A1 (en) * | 2012-06-21 | 2013-12-27 | Alembic Pharmaceuticals Limited | Process for preparing asenapine and salts of intermediates thereof |
CN103772402A (zh) * | 2014-01-07 | 2014-05-07 | 万特制药(海南)有限公司 | 一种新的阿塞那平马来酸盐粗品精制方法 |
CN104974167B (zh) * | 2014-04-02 | 2019-01-04 | 洋浦慧谷医药有限公司 | 阿塞那平的制备方法以及用于制备阿塞那平的中间体 |
US10056563B2 (en) | 2016-04-08 | 2018-08-21 | Samsung Electronics Co., Ltd. | Synthetic method of fused heteroaromatic compound and fused heteroaromatic compound, and intermediate thereof |
US10707424B2 (en) | 2016-11-08 | 2020-07-07 | Samsung Electronics Co., Ltd. | Synthetic method of fused heteroaromatic compound and fused heteroaromatic compound and intermediate therefor and synthetic method of intermediate |
AU2017384392B2 (en) | 2016-12-20 | 2023-05-25 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
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