CN115417802A - Preparation method of sepiatinib and intermediate thereof - Google Patents
Preparation method of sepiatinib and intermediate thereof Download PDFInfo
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- CN115417802A CN115417802A CN202110531186.3A CN202110531186A CN115417802A CN 115417802 A CN115417802 A CN 115417802A CN 202110531186 A CN202110531186 A CN 202110531186A CN 115417802 A CN115417802 A CN 115417802A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 159
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 57
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 125000006239 protecting group Chemical group 0.000 claims abstract description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 13
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 12
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims abstract description 11
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960004891 lapatinib Drugs 0.000 claims abstract description 11
- 238000006735 epoxidation reaction Methods 0.000 claims abstract description 9
- 238000007259 addition reaction Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 72
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 69
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 42
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 30
- -1 t-butoxycarbonyl Chemical group 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 25
- 239000002585 base Substances 0.000 claims description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 230000009615 deamination Effects 0.000 claims description 14
- 238000006481 deamination reaction Methods 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 13
- 238000006482 condensation reaction Methods 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 10
- 239000007818 Grignard reagent Substances 0.000 claims description 10
- 150000004795 grignard reagents Chemical class 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- 238000010511 deprotection reaction Methods 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 6
- 150000004967 organic peroxy acids Chemical class 0.000 claims description 6
- 125000002524 organometallic group Chemical group 0.000 claims description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 claims description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 5
- OKBMHIVCLCZGLA-UHFFFAOYSA-N 5-butyl-6-ethoxydec-5-ene;tin Chemical compound [Sn].CCCCC(CCCC)=C(CCCC)OCC OKBMHIVCLCZGLA-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 5
- 229960001701 chloroform Drugs 0.000 claims description 5
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 3
- OIXUJRCCNNHWFI-UHFFFAOYSA-N 1,2-dioxane Chemical compound C1CCOOC1 OIXUJRCCNNHWFI-UHFFFAOYSA-N 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 3
- VUIWJRYTWUGOOF-UHFFFAOYSA-N 2-ethenoxyethanol Chemical compound OCCOC=C VUIWJRYTWUGOOF-UHFFFAOYSA-N 0.000 claims description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 3
- 238000006757 chemical reactions by type Methods 0.000 claims description 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 3
- HFTNNOZFRQLFQB-UHFFFAOYSA-N ethenoxy(trimethyl)silane Chemical compound C[Si](C)(C)OC=C HFTNNOZFRQLFQB-UHFFFAOYSA-N 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 3
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 125000001979 organolithium group Chemical group 0.000 claims description 3
- 125000002734 organomagnesium group Chemical group 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 3
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- MZBSJLAGBUNNLH-UHFFFAOYSA-N 3,3,3-trifluoropropanamide Chemical group NC(=O)CC(F)(F)F MZBSJLAGBUNNLH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims 2
- 230000001681 protective effect Effects 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- 230000003595 spectral effect Effects 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- VBCYHQYCGGUMFM-UHFFFAOYSA-N BrC=1C(=[N+](C=CC=1)Br)Br Chemical class BrC=1C(=[N+](C=CC=1)Br)Br VBCYHQYCGGUMFM-UHFFFAOYSA-N 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 description 2
- 229960003750 ethyl chloride Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VRMVPBDYTFYKKL-UHFFFAOYSA-N n-(2,2,2-trifluoroethyl)formamide Chemical compound FC(F)(F)CNC=O VRMVPBDYTFYKKL-UHFFFAOYSA-N 0.000 description 1
- LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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Abstract
The invention provides a new synthetic method of an Upaginib intermediate. The synthesis method comprises the following steps: (1) The compound formula 1 is subjected to epoxidation reaction, addition reaction and protection reaction to prepare a compound formula 4; reacting the compound shown in the formula 4 with an acetyl reagent to obtain a compound shown in a formula 5; then reacting with a brominating reagent to obtain a compound shown as a formula 6; the reaction formula is shown as follows:
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of an ulpatinib intermediate, and further relates to a preparation method of ulpatinib.
Background
The chemical name of the Upatitinib is (3S, 4R) -3-ethyl-4- (3H-pyrazolo [1,2-a ] pyrrolo [2,3-e ] pyrazin-8-yl) -N- (2, 2-trifluoroethyl) pyrrolidine-1-carboxamide, and the structural formula is as follows:
it is a novel target JAK1 inhibitor, used for the treatment of atopic dermatitis.
At present, U.S. patents US2017129902A1 and WO20170667751A1 report synthetic routes to uppertinib for elbowe, a former company. It is clear from the above patent application that the construction of chiral key intermediate I is one of the cores of the synthetic route of uppertinib.
Meanwhile, many reports have been made on the preparation methods of chiral key intermediates I, such as patent documents CN 111217819A, WO 2020202183 Al, WO2020043033A2, etc., and the preparation methods of chiral key intermediates I disclosed in the patent documents are all optically pure intermediates obtained by chemical resolution
And then the intermediate is further converted into a chiral key intermediate I.
Chinese patent CN 109369659B reports a synthetic route to prepare chiral key intermediate I without chemical resolution. The route takes carbonyl intermediate A-1 as a starting material to react with Grignard reagent to obtain hydroxyl intermediate A-2. Then the intermediate A-4 is obtained by sulfuric acid dehydration and alkaline hydrolysis. Then the chiral carboxylic acid intermediate A-5 is directly obtained by hydrogenation of a chiral Ru metal catalyst, and a target intermediate I is obtained by chlorination, diazotization and bromination, wherein the reaction formula is as follows:
the diazo compound is used as a reaction material in the route, so that great potential safety hazards exist, and the used chiral Ru metal catalyst is high in price and cost and is not beneficial to industrial scale-up production.
In view of this, the invention is particularly proposed.
Disclosure of Invention
One of the purposes of the invention is to provide a new preparation method of an Upacitorib intermediate, so as to solve the problems of high preparation cost and potential safety hazard of the existing preparation method of the Upacitorib intermediate.
In order to achieve the above objects, the present invention provides, in a first aspect, a novel preparation method of an intermediate compound of uppertinib formula 6, comprising the steps of:
(1) The compound formula 1 is subjected to epoxidation reaction to prepare a compound formula 2;
(2) The compound formula 2 and an organic metal reagent are subjected to addition reaction to prepare a compound formula 3;
(3) The compound shown in the formula 3 is subjected to protection reaction to obtain a compound shown in the formula 4;
(4) Reacting the compound shown in the formula 4 with an acetyl reagent to obtain a compound shown in the formula 5;
(5) Reacting the compound shown in the formula 5 with a brominating reagent to obtain a compound shown in the formula 6;
the process route is as follows:
wherein G is a protecting group of nitrogen atom or trifluoroethylcarboxamido group, and R is a hydroxyl protecting group.
Preferably, the common oxidant for the epoxidation reaction in step (1) is organic peroxy acid, and the organic peroxy acid is any one of m-chloroperoxybenzoic acid, peroxyacetic acid, peroxyformic acid, peroxytrifluoroacetic acid, dimethyl copper peroxide and dimethyl dioxirane; commonly used solvents are inert solvents including, but not limited to, one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, xylene, nitrobenzene, acetonitrile, diethyl ether.
Preferably, the organometallic reagent in the step (2) is any one of a Grignard reagent, an organolithium reagent, an organoaluminum reagent, an organotitanium reagent, an organomagnesium reagent, an organozinc reagent, an organotin reagent and an organosamarium reagent, and the solvent is one or more of toluene, dichloromethane, trichloromethane, tetrahydrofuran, 1, 2-dichloroethane and 1, 4-dioxane; the organometallic reagent is preferably a grignard reagent, including but not limited to ethyl magnesium bromide, ethyl magnesium chloride; the molar ratio of the compound shown in formula 2 to the Grignard reagent is 1 to 1.5; the reaction temperature is 0 to 90 ℃.
Preferably, the solvent in step (3) is one or more of N, N-dimethylformamide, acetonitrile, toluene, dichloromethane, tetrahydrofuran, 1, 2-dioxane and acetone; the alkali is one or more of imidazole, pyridine, tetrabutylammonium fluoride, 2, 6-dimethylpyridine, sodium hydride, potassium carbonate, N, N-diisopropylethylamine, sodium carbonate and triethylamine; the molar ratio of the compound of formula 3 to the base is 1 to 3; the reaction temperature is-78 to 80 ℃.
Preferably, the acetyl reagent in the step (4) is one or more of vinyl n-butyl ether, acetic anhydride, tributyl (1-ethoxyethylene) tin, 2-vinyloxyethanol and vinyloxytrimethylsilane; the solvent is one or more of toluene, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane and acetonitrile; the base is N, N-diisopropylethylamine, triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane, preferably N, N-diisopropylethylamine; the addition amount of the base is 1 to 3 times of the equivalent of the compound shown in the formula 4; the catalyst is tetrakis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate and tris (dibenzylideneacetone) dipalladium, and the addition amount of the catalyst is 0.5-1% equivalent of the compound shown in the formula 4; according to the reaction type, a ligand can be added, wherein the ligand is 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1-bis (diphenylphosphino) ferrocene, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine, and the addition amount of the ligand is 1% -2% of the equivalent of the catalyst.
Preferably, the brominating reagent in the step (5) is tribromopyridinium salt, liquid bromine, bromosuccinimide, dibromohydantoin or cupric bromide; the solvent is ethyl acetate, dichloromethane, acetonitrile, toluene or tetrahydrofuran or their mixture.
As the protecting group for a nitrogen atom, various types of protecting groups known in the art may be selected, and the protecting group for a nitrogen atom includes, but is not limited to, alkoxycarbonyl groups, acyl groups, and alkyl groups. Preferably, the protecting group for nitrogen atom includes, but is not limited to, benzyloxycarbonyl, t-butyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsiloxyethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl. Preferred protecting groups for use herein are benzyl, benzyloxycarbonyl, allyloxycarbonyl.
As the hydroxyl protecting group, various types of protecting groups known in the art may be selected, and the hydroxyl protecting group includes, but is not limited to, alkyl groups, alkoxyalkyl groups, acyl groups, silyl ethers. Preferably, the hydroxyl protecting group includes, but is not limited to, methyl, methoxymethyl, tetrahydrofuranyl, benzyl, p-methoxybenzyl, trityl, acetyl, pivaloyl, trimethylsilyl, triisopropylsilyl, benzoyl, trifluoromethanesulfonyl.
The second aspect of the invention also provides an uppatinib intermediate compound shown as formula 6, wherein the uppatinib intermediate compound shown as formula 6 is prepared by the synthesis process.
The third aspect of the present invention also provides a preparation method of a novel urpactinib key parent nucleus compound, formula 8, which comprises the following steps: carrying out condensation reaction on the compound shown in the formula 6 and a compound a under proper conditions to obtain an intermediate compound shown in the formula 7; the compound shown in the formula 7 is subjected to cyclization reaction under the action of trifluoroacetic anhydride and organic base to obtain an intermediate compound shown in the formula 8; wherein the structural formulas of the compound a, the compound formula 7 and the compound formula 8 are shown as follows:
wherein G is a protecting group for a nitrogen atom or a trifluoroethylcarboxamido group.
Preferably, the base used in the condensation reaction is sodium carbonate, potassium phosphate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane, or benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate; further, the base is added in an amount of 3 times equivalent to that of the compound of formula 6; the reaction solvent is N, N-dimethylformamide, N-dimethylacetamide, toluene, acetonitrile, 1, 4-dioxane or tetrahydrofuran; the reaction temperature is-20 ℃ to 110 ℃.
Preferably, the base of the cyclization reaction is selected from triethylamine, N-diisopropylethylamine, pyridine or 2, 6-lutidine; the reaction solvent is selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; the reaction temperature is-20 ℃ to 110 ℃.
The fourth aspect of the invention also provides a key parent nucleus compound formula 8 of the empatinib, and the key parent nucleus compound formula 8 of the empatinib is prepared by the synthesis process.
The fifth aspect of the invention also provides a novel preparation method of Upatatin, which adopts the following technical scheme:
the compound formula 8 is subjected to deprotection reaction to obtain a compound formula 9, the compound formula 9 is subjected to condensation reaction with trifluoroethylamine in the presence of carbonyl diimidazole to obtain a chemical formula 10, the chemical formula 10 is subjected to deprotection reaction to obtain the lapatinib, wherein G in the compound formula 8 is a protecting group of a nitrogen atom, and the structural formula of the compound formula 9 and the compound formula 10 is shown as follows:
preferably, the compound of formula 8 is reacted under the action of a deamination protecting reagent to obtain the compound of formula 9, wherein the deamination protecting reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate or H 2 /Pd-C。
Preferably, the base of the condensation reaction is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane; the reaction solvent is selected from acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or toluene; the reaction temperature is-10 ℃ to 110 ℃.
Preferably, the compound of formula 10 is reacted under the action of a deamination protecting reagent, wherein the deamination protecting reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate or H 2 /Pd-C。
The sixth aspect of the invention also provides a second novel preparation method of empatinib, which adopts the following technical scheme:
carrying out deprotection reaction on the compound shown in the formula 8 to obtain the lapatinib, wherein the structural formula of the compound shown in the formula 8 is as follows:
。
preferably, the compound of formula 8 is reacted under the action of a deamination protecting reagent to obtain the lapatinib, wherein the deamination protecting reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate or H 2 /Pd-C。
The seventh aspect of the invention also provides empatinib, which is prepared by any one of the synthesis processes.
By applying the technical scheme of the invention, the trans-hydroxyl compound is generated through asymmetric epoxidation reaction, acetyl is attacked from the back to generate a cis-product under the catalysis of palladium, the chiral compound is directionally synthesized without chiral resolution, the use of expensive raw materials is avoided, the preparation cost of the lapatinib and the intermediate thereof is reduced, and the industrial popularization is facilitated.
Detailed Description
It should be noted that, in the present application, the embodiments and features of the embodiments may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As described in the background art, the existing preparation method of the intermediate of uppatinib has the problems of high preparation cost and potential safety hazard. In order to solve the above technical problems, the present application provides a preparation method of a new oupatinib intermediate compound formula 6, the preparation method comprising the steps of:
(1) The compound formula 1 is subjected to epoxidation reaction to prepare a compound formula 2;
(2) The compound formula 2 and an organic metal reagent are subjected to addition reaction to prepare a compound formula 3;
(3) The compound shown in the formula 3 is subjected to protection reaction to obtain a compound shown in the formula 4;
(4) Reacting the compound shown in the formula 4 with an acetyl reagent to obtain a compound shown in the formula 5;
(5) Reacting the compound shown in the formula 5 with a brominating reagent to obtain a compound shown in the formula 6;
the process route is as follows:
wherein G is a protecting group of nitrogen atom or trifluoroethyl carboxamide group, and R is a protecting group of hydroxyl group.
Preferably, the common oxidant for the epoxidation reaction in step (1) is organic peroxy acid, and the organic peroxy acid is any one of m-chloroperoxybenzoic acid, peroxyacetic acid, peroxyformic acid, peroxytrifluoroacetic acid, dimethyl copper peroxide and dimethyl dioxirane; commonly used solvents are inert solvents including, but not limited to, one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, xylene, nitrobenzene, acetonitrile, diethyl ether.
Preferably, the organometallic reagent in the step (2) is any one of a Grignard reagent, an organolithium reagent, an organoaluminum reagent, an organotitanium reagent, an organomagnesium reagent, an organozinc reagent, an organotin reagent and an organosamarium reagent, and the solvent is one or more of toluene, dichloromethane, trichloromethane, tetrahydrofuran, 1, 2-dichloroethane and 1, 4-dioxane; the organometallic reagent is preferably a grignard reagent, including but not limited to ethylmagnesium bromide, ethylmagnesium chloride; the molar ratio of the compound shown in formula 2 to the Grignard reagent is 1 to 1.5; the reaction temperature is 0 to 90 ℃.
Preferably, the solvent in step (3) is one or more of N, N-dimethylformamide, acetonitrile, toluene, dichloromethane, tetrahydrofuran, 1, 2-dioxane and acetone; the alkali is one or more of imidazole, pyridine, tetrabutylammonium fluoride, 2, 6-dimethylpyridine, sodium hydride, potassium carbonate, N, N-diisopropylethylamine, sodium carbonate and triethylamine; the molar ratio of the compound of formula 3 to the base is 1 to 3; the reaction temperature is-78 to 80 ℃.
Preferably, the acetyl reagent in the step (4) is one or more of vinyl n-butyl ether, acetic anhydride, tributyl (1-ethoxyethylene) tin, 2-vinyloxyethanol and vinyloxytrimethylsilane; the solvent is one or more of toluene, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane and acetonitrile; the base is N, N-diisopropylethylamine, triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane, preferably N, N-diisopropylethylamine; the addition amount of the base is 1-3 times of the equivalent of the compound shown in the formula 4; the catalyst is tetrakis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate and tris (dibenzylideneacetone) dipalladium, and the addition amount of the catalyst is 0.5-1% equivalent of the compound shown in the formula 4; according to the reaction type, a ligand can be added, wherein the ligand is 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1-bis (diphenylphosphino) ferrocene, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine, and the addition amount of the ligand is 1% -2% of the equivalent of the catalyst.
Preferably, the brominating reagent in the step (5) is tribromopyridinium salt, liquid bromine, bromosuccinimide, dibromohydantoin or cupric bromide; the solvent is ethyl acetate, dichloromethane, acetonitrile, toluene or tetrahydrofuran or their mixture.
As for the protecting group for a nitrogen atom, various types of protecting groups known in the art may be selected, and the protecting group for a nitrogen atom includes, but is not limited to, alkoxycarbonyl groups, acyl groups, and alkyl groups. Preferably, the protecting group for nitrogen atom includes, but is not limited to, benzyloxycarbonyl, t-butyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsiloxyethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl. Preferred protecting groups for use herein are benzyl, benzyloxycarbonyl, allyloxycarbonyl.
As the hydroxyl protecting group, various types of protecting groups known in the art may be selected, and the hydroxyl protecting group includes, but is not limited to, alkyl groups, alkoxyalkyl groups, acyl groups, silyl ethers. Preferably, the hydroxyl protecting group includes, but is not limited to, methyl, methoxymethyl, tetrahydrofuranyl, benzyl, p-methoxybenzyl, trityl, acetyl, pivaloyl, trimethylsilyl, triisopropylsilyl, benzoyl, trifluoromethanesulfonyl.
The compound of formula 1 can be obtained commercially or can be synthesized by referring to the prior art.
The second aspect of the invention also provides an uppatinib intermediate compound shown as formula 6, wherein the uppatinib intermediate compound shown as formula 6 is prepared by the synthesis process.
The third aspect of the invention also provides a preparation method of a novel key mother nucleus compound of Upacatinib, which is shown in the formula 8, and the preparation method comprises the following steps:
the preparation method comprises the following steps: carrying out condensation reaction on the compound shown in the formula 6 obtained by the synthesis and the compound a under proper conditions to obtain an intermediate compound shown in the formula 7; the compound shown in the formula 7 is subjected to cyclization reaction under the action of trifluoroacetic anhydride and organic base to obtain an intermediate compound shown in the formula 8, wherein G is a protective group of nitrogen atoms or trifluoroethyl formamide.
Preferably, the base used in the condensation reaction is sodium carbonate, potassium phosphate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane, or benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate; further, the base is added in an amount of 3 times equivalent to that of the compound of formula 6; the reaction solvent is N, N-dimethylformamide, N-dimethylacetamide, toluene, acetonitrile, 1, 4-dioxane or tetrahydrofuran; the reaction temperature is-20 ℃ to 110 ℃.
Preferably, the base of the ring formation reaction is selected from triethylamine, N-diisopropylethylamine, pyridine or 2, 6-lutidine; the reaction solvent is selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; the reaction temperature is-20 ℃ to 110 ℃.
The fourth aspect of the invention also provides a key parent nucleus compound formula 8 of the empatinib, and the key parent nucleus compound formula 8 of the empatinib is prepared by the synthesis process.
The fifth aspect of the invention also provides a novel preparation method of Upatatin, which comprises the following steps:
the preparation method comprises the following steps: the compound formula 8 is subjected to deprotection reaction to obtain a compound formula 9, the compound formula 9 is subjected to condensation reaction with trifluoroethylamine in the presence of carbonyldiimidazole to obtain a chemical formula 10, and the chemical formula 10 is subjected to deprotection reaction to obtain the lapatinib, wherein G is a protecting group of a nitrogen atom.
Preferably, the compound of formula 8 is reacted under the action of a deamination protecting reagent to obtain the compound of formula 9, wherein the deamination protecting reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate or H 2 /Pd-C。
Preferably, the base of the condensation reaction is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane; the reaction solvent is selected from acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or toluene; the reaction temperature is-10 ℃ to 110 ℃.
Preferably, the compound of formula 10 is reacted under the action of a deamination protecting reagent to obtain uppatinib, wherein the deamination protecting reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate or H 2 Pd-C, alkali.
The sixth aspect of the present invention also provides a second novel preparation method of empatinib, which comprises:
the preparation method comprises the following steps: and carrying out deprotection reaction on the compound shown in the formula 8 to obtain the lapatinib, wherein G is trifluoroethyl formamido.
Preferably, the compound of formula 8 is reacted under the action of a deamination protecting reagent to obtain the lapatinib, wherein the deamination protecting reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate or H 2 Pd-C, alkali.
The seventh aspect of the invention also provides empatinib, which is prepared by any one of the synthesis processes.
By applying the technical scheme of the invention, the trans-hydroxyl compound is generated through asymmetric epoxidation reaction, the acetyl group is attacked from the back side to generate a cis-product through palladium catalysis, the chiral compound is directionally synthesized without chiral resolution, the use of expensive raw materials is avoided, the preparation cost of the lapatinib and the intermediate thereof is reduced, and the industrial popularization is facilitated.
In the present application, DIPEA refers to N, N-diisopropylethylamine, and DMSO refers to thionyl chloride.
Example 1
40.6g of the compound of formula 1 (0.2 mol) was dissolved in 600mL of dichloromethane, the reaction temperature was controlled at 0 ℃, 41.6g of m-chloroperoxybenzoic acid (0.24mol, 1.2eq) was added in portions, after the addition, the temperature was raised to room temperature to complete the reaction, the reaction solution was concentrated to about 100mL, cooled to 0 ℃ and filtered, the filter cake was washed with 0 ℃ dichloromethane, and the filtrate was concentrated to obtain 40.4g of the product with a yield of 92.2%.
Mass spectral data for compound 2: [ M + H ]] + 220.0。
Example 2
32.9g of the compound of formula 2 (0.15 mol) were dissolved in a tetrahydrofuran (400 ml) solution of CuBr (3.0 g), and ethylmagnesium chloride [ prepared from ethylchloride (50 g) and magnesium (9.2 g) ] was added thereto at-78 ℃ under nitrogen atmosphere]. After the addition, the temperature is raised to room temperature, the stirring is continued for 2 hours, the reaction is completed, and the reaction liquid is extracted by ethyl acetate and water. The organic layer was washed with 1N HCl, water, saturated NaHCO 3 Washing, concentration and purification of the concentrate by silica gel chromatography gave 33.7g of the compound of formula 3 in 90.1% yield.
Mass spectral data for compound 3: [ M + H ]] + 251.1。
Example 3
29.9g of the compound of formula 3 (0.12 mol) was dissolved in 300mL of dichloromethane, the temperature was cooled to 0 ℃, 39.5g of trifluoromethanesulfonic anhydride (0.14 mol) was added in portions, after the addition was complete, the reaction was completed at room temperature, washed 3 times (100 mL/time) with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 41.1g of the product in 89.9% yield.
Mass spectral data for compound 4: [ M + H ]] + 382.1。
Example 4
Under nitrogen atmosphere, 38.1g of compound 4 (0.1 mol), 1% equivalent of palladium acetate, 2% equivalent of 1, 3-bis (diphenylphosphino) propane, 2 equivalent of DIPEA,1.2 equivalent of tributyl (1-ethoxyethylene) tin and 200mL of DMSO are added into a 500mL reaction vessel, the reaction is stirred at 100 ℃ for 3 hours, the completion of the reaction is detected, the reaction solution is cooled to room temperature, 6N hydrochloric acid is added into the reaction solution to adjust the pH value to 5 to 6, the reaction solution is stirred at room temperature for 1 hour, water and ethyl acetate are added for extraction, the organic phase is dried and concentrated, and 23.4g of compound formula 5 is obtained after purification, and the yield is 85.0%.
Mass spectral data for compound 5: [ M + H ]] + 276.2。
Example 5
A500 mL three-necked flask was charged with 27.5g of the compound of formula 5 (0.1 mol), dissolved in 300mL of ethyl acetate and chloroform (1: 1 by volume), charged with 16.0g of copper bromide (0.11 mol), controlled at 50 to 60 ℃, reacted for 5 to 6 hours, checked for completion of the reaction on a dot plate, filtered, concentrated, dissolved in ethyl acetate, washed with an aqueous ammonium chloride solution until the aqueous phase became colorless, and the organic phase was concentrated and purified by drying to give 28.3g of a product in 79.9% yield.
Mass spectral data for compound 6: [ M + H ]] + 354.1。
Example 6
Adding 39.5g of the compound a (0.102 mol) into a 500mL three-necked flask, adding 180mL of N, N-dimethylacetamide, protecting with nitrogen, cooling to 5 ℃ in an ice-water bath, adding 8.96g (0.112 mol) of NaH, reacting for 30 minutes at 0-10 ℃, cooling to-15 ℃, dropwise adding 180mL of 39.1g of N, N-dimethylacetamide solution of the compound formula 6 (0.110 mol), controlling the dropwise adding temperature to be-20-10 ℃, completing the addition within about 45 minutes, reacting for 1 hour after the dropwise addition, detecting the reaction completion, adding 17.03g of acetic acid, stirring for 0.5 hour at room temperature, heating to 10-20 ℃, adding 600mL of water, adding 360mL of isopropyl acetate, stirring, separating, extracting the aqueous phase once with 180mL of isopropyl acetate, combining the organic phases, washing the organic phases twice with 180mL of 4% sodium bicarbonate solution, washing once with 180mL of water, purifying, and drying in vacuum to obtain 42.1g of the compound formula 7 with a yield of 62.6%.
Compound 7 nuclear magnetic data is as follows: 1 H-NMR(400MHz,d-DMSO) δ 8.76(s, 1H), 8.22-8.17(m,1H), 8.02-7.95(m,2H), 7.43-7.41(m,2H), 7.32-7.27(m,5H), 6.81-6.67(m,1H), 5.08-5.05(m,2H), 4.76(s,2H), 3.65-3.57(m,1H), 3.50-3.44(m,3H), 3.20-3.17(m,1H), 2.42-2.38(m,1H), 2.36(s, 3H), 1.42-1.29 (m,10H), 1.27-1.25 (m,1H), 0.90-0.86 (m,3H)。
example 7
Adding 10g of the compound shown as the formula 7 (15.1 mmol), 100mL of acetonitrile and 13.0g (61.9 mmol) of trifluoroacetic anhydride into a 250mL three-necked flask, heating to 70-80 ℃, reacting completely, cooling to room temperature, adding 500mL of water, adding 150mL of ethyl acetate, layering, extracting an aqueous phase with ethyl acetate for 2 times, washing an organic phase with 100mL of saturated saline solution, concentrating the organic phase, and purifying by a column to obtain 5.0g of a compound 8 with the yield of 61.0%.
Mass spectral data for compound 8: [ M + H ]] + 544.1。
Example 8
A500 mL three-necked flask was charged with 10g of Compound 8 (18.4 mmol), 150mL of methanol, 2.0g of Pd/C, hydrogen gas was replaced three times, and the reaction was carried out at room temperature to detect completion of the reaction, followed by filtration and concentration to obtain 5.3g of Compound 9 with a yield of 95.0%.
Compound 9 nuclear magnetic data are as follows: 1 H-NMR(400MHz,d-DMSO) δ 9.91(s, 1H), 8.78(s,1H), 8.05-7.99(m,3H), 7.91(s,1H), 7.46-7.43(m,3H), 4.46-4.43(m,1H), 3.70-3.62(m,3H), 3.17-3.13(m,1H), 2.60-2.57(m,1H), 2.33(s,3H), 0.92-0.87(m,2H), 0.60-0.56 (m,3H)。
mass spectral data for compound 9: [ M + H ]] + 410.2。
Example 9
Adding carbonyldiimidazole (22.70g, 140mmol) into a three-neck flask, adding N, N-dimethylformamide (150 mL) into the flask, stirring the mixture for dissolving, adding potassium carbonate (27.64g, 200mmol), cooling the mixture to 0 ℃, slowly adding trifluoroethylamine (14.86g, 150mmol) dropwise, stirring the mixture at room temperature for 30 minutes after the dropwise adding is finished, adding a compound 9 (35.54g, 100mmol) into the mixture, reacting the mixture at room temperature completely, adding reaction liquid into 1L of water, adding 500mL of ethyl acetate into the mixture, stirring the mixture for layering, extracting the aqueous phase for 2 times by using 300mL of ethyl acetate, combining organic phases, washing the mixture with 300mL of saturated common salt for 2 times, drying sodium sulfate, concentrating the organic phase to about 150mL, dropwise adding petroleum ether into the mixture under the stirring condition until crystals are separated out, slowly cooling the mixture to 0 ℃, continuing stirring the mixture at the temperature of 0 ℃ for crystallization for 2 hours, filtering, and using a filter cake in a volume ratio of 0 ℃ of 2:1, washed with petroleum ether and ethyl acetate, and dried to obtain a white solid intermediate 10, 44.68g, with a yield of 93%.
Compound 10 nuclear magnetic data is as follows: 1 H-NMR(400MHz,d-DMSO) δ8.79(s, 1H), 8.09-8.4(m, 2H), 8.00-7.96(m,1H), 7.61(s,1H), 7.47-7.43(m,3H), 6.97-6.92(m,1H), 4.35-4.30(m,1H), 3.88-3.67(m,5H), 3.28-3.23(m,1H), 2.52-2.47(m,1H), 2.33(s,3H), 1.05-0.98 (m,1H), 0.82-0.79 (m,1H), 0.63-0.59 (m,3H)。
example 10
A250 mL three-necked flask was charged with 3g of compound 10 (5.61 mmol), 15mL of DMSO,1.5 equivalents of potassium tert-butoxide, reacted at room temperature until completion, 50mL of water was added, 50mL of ethyl acetate was extracted 3 times, the organic phases were combined, 50mL of saturated brine was washed once, the organic phase was concentrated, and column purification was performed to obtain 1.86g of uppertinib with a yield of 87.3%.
Example 11
A three-necked flask was charged with 6.9g of the starting material S1 (0.1 mol), 9.91g of trifluoroethylamine (0.1 mol), 21.2g of sodium carbonate (0.2 mol) and 150mL of tetrahydrofuran, and 17.84g of carbonyldiimidazole (0.11 mol) were added in portions, and the mixture was stirred at room temperature until the reaction was completed, and the reaction mixture was added to 100mL of water, and then 100mL of ethyl acetate was added, followed by stirring and layer separation, and the organic phase was washed with 50mL of saturated brine for 2 times, dried over sodium sulfate, concentrated and purified by column chromatography to obtain 17.49g of intermediate 1, which was obtained in 90.1% yield.
Mass spectral data for compound 1: [ M + H ]] + 195.1。
Example 12
38.8g of the compound of formula 1 (0.2 mol) is dissolved in 600mL of dichloromethane, the reaction temperature is controlled at 0 ℃, 41.6g of m-chloroperoxybenzoic acid (0.24mol, 1.2eq) is added in portions, after the addition is finished, the temperature is raised to room temperature for complete reaction, the reaction solution is concentrated to about 100mL, then cooled to 0 ℃ for filtration, a filter cake is washed by dichloromethane at 0 ℃, and the filtrate is concentrated to obtain 38.6g of a product, and the yield is 91.8%.
Mass spectral data for compound 2: [ M + Na ]] + 233.1。
Example 13
31.5g of the compound of formula 2 (0.15 mol) was dissolved in a solution of CuBr (3.0 g) in tetrahydrofuran (400 ml), and ethylmagnesium chloride [ prepared from ethylchloride (50 g) and magnesium (9.2 g) ] was added under nitrogen protection at-78 deg.C]. After the addition, the temperature was raised to room temperature, the reaction was continued for 1 hour with stirring, and the reaction solution was extracted with ethyl acetate and water. The organic layer was washed with 1N HCl, water, saturated NaHCO 3 Washing, concentration and purification of the concentrate by silica gel chromatography gave 32.8g of the compound of formula 3 in 91.1% yield.
Mass spectral data for compound 3: [ M + H ]] + 241.1。
Example 14
28.8g of the compound of formula 3 (0.12 mol) are dissolved in 300mL of dichloromethane, the temperature is cooled to 0 ℃, 39.5g of trifluoromethanesulfonic anhydride (0.14 mol) are added in portions, after the addition, the reaction is completed at 40 ℃, the temperature is cooled to room temperature, 100mL of saturated sodium chloride solution is added, the mixture is washed 3 times, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 40.2g of the product with a yield of 90.0%.
Mass spectral data for compound 4: [ M +18 ]] + 390.0。
Example 15
37.2g of compound 4 (0.1 mol), 1% equivalent of palladium acetate, 2% equivalent of 1, 3-bis (diphenylphosphino) propane, 2 equivalent of DIPEA,1.2 equivalent of tributyl (1-ethoxyethylene) tin and 200mL of DMSO are added into a 500mL reaction vessel, nitrogen is replaced for 3 times, the reaction vessel is heated to 100 ℃ and stirred until the reaction is completed, the reaction vessel is cooled to room temperature, 6N hydrochloric acid is added into the reaction solution to adjust the pH value to 5 to 6, the reaction vessel is stirred for 1 hour at the room temperature, water and ethyl acetate are added for extraction, an organic phase is dried by anhydrous sodium sulfate, filtered, concentrated and purified to obtain 22.2g of compound formula 5, and the yield is 83.6%.
Mass spectral data for compound 5: [ M + H ]] + 267.0。
Example 16
A500 mL three-necked flask was charged with 26.6g of the compound of formula 5 (0.1 mol), dissolved in 300mL of ethyl acetate and chloroform (1: 1 by volume), charged with 16.0g of copper bromide (0.11 mol), the temperature was controlled to 50 to 60 ℃, the reaction was carried out for 5 to 6 hours, the completion of the reaction was detected by spotting, filtration and concentration were carried out, the solution was dissolved in dichloromethane, the organic phase was washed with an aqueous ammonium chloride solution until the aqueous phase was colorless, and the organic phase was concentrated and purified by drying to obtain 28.3g of a product with a yield of 82.1%.
Mass spectral data for compound 6: [ M + H ]] + 345.1。
Example 17
Adding 39.5g of the compound a (0.102 mol) into a 500mL three-necked bottle, adding 180mL of N, N-dimethylacetamide, carrying out nitrogen protection, cooling to 5 ℃ in an ice-water bath, adding 8.96g (0.112 mol) of NaH, reacting at 0 to 10 ℃ for 30 minutes, cooling to-15 ℃, dropwise adding 180mL of 38.0g of the N, N-dimethylacetamide solution of the compound formula 6 (0.110 mol), controlling the dropwise adding temperature to be-20 to-10 ℃, completing about 45 minutes, reacting for 1 hour after the dropwise adding is completed, detecting the reaction is completed, adding 17.03g of acetic acid, stirring for 0.5 hour at room temperature, heating to 10 to 20 ℃, adding 600mL of water, adding 360mL of dichloromethane, stirring, separating, extracting the aqueous phase once with 180mL of dichloromethane, combining organic phases, washing the organic phase twice with 180mL of 4% sodium bicarbonate solution, washing with 180mL of saturated saline once, drying, concentrating, purifying by column chromatography to obtain 44.7g of the compound formula 7, and obtaining yield of 67.2%.
Mass spectral data for compound 6: [ M + H ]] + 653.4。
Example 18
Adding 3.3g of a compound shown as a formula 7 (5 mmol), 50mL of acetonitrile and 3.2g (15 mmol) of trifluoroacetic anhydride into a 100mL three-necked flask, heating to 70-80 ℃, reacting completely, cooling to room temperature, adding 150mL of water, adding 80mL of ethyl acetate, layering, extracting an aqueous phase with ethyl acetate for 2 times, washing an organic phase with saturated saline, concentrating the organic phase, and purifying by a column to obtain 1.9g of a compound 8 with the yield of 72.0%.
Mass spectral data for compound 8: [ M + H ]] + 535.1。
Compound 8 nuclear magnetic data is as follows: 1 H-NMR(400MHz,d-DMSO) δ8.78(s, 1H), 8.07-8.39(m, 2H), 8.01-7.96(m,1H), 7.61(s,1H), 7.47-7.44(m,3H), 6.96-6.92(m,1H), 4.34-4.29(m,1H), 3.89-3.65(m,5H), 3.28-3.24(m,1H), 2.51-2.47(m,1H), 2.34(s,3H), 1.03-0.98 (m,1H), 0.82-0.79 (m,1H), 0.63-0.60(m,3H)。
example 19
A500 mL three-necked flask was charged with 6g of Compound 8 (11.22 mmol), 20mL of DMSO, and 1.5 equivalents of potassium tert-butoxide, and the mixture was reacted at room temperature until completion, 80mL of water was added, and 50mL of ethyl acetate was extracted 3 times, the organic phases were combined, and 50mL of saturated saline was washed once, and the organic phase was concentrated and purified by column chromatography to obtain 3.82g of Upatinib, with a yield of 89.4%.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (14)
1. A process for the preparation of a novel oupatinib intermediate compound of formula 6, comprising the steps of:
(1) The compound formula 1 is subjected to epoxidation reaction to prepare a compound formula 2;
(2) The compound formula 2 and an organic metal reagent are subjected to addition reaction to prepare a compound formula 3;
(3) The compound shown in the formula 3 is subjected to protection reaction to obtain a compound shown in the formula 4;
(4) Reacting the compound shown in the formula 4 with an acetyl reagent to obtain a compound shown in the formula 5;
(5) Reacting the compound shown in the formula 5 with a brominating reagent to obtain a compound shown in the formula 6;
the process route is as follows:
wherein G is a protecting group of nitrogen atom or trifluoroethyl carboxamide group, R is a protecting group of hydroxyl group, the protecting group of nitrogen atom includes but is not limited to alkoxycarbonyl group, acyl group and alkyl group; protecting groups for nitrogen atoms include, but are not limited to, benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsiloxyethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl; preferred protecting groups are benzyl, benzyloxycarbonyl, allyloxycarbonyl; the hydroxyl protecting group includes, but is not limited to, alkyl, alkoxyalkyl, acyl, silyl ether; preferably, the hydroxyl protecting group includes, but is not limited to, methyl, methoxymethyl, tetrahydrofuranyl, benzyl, p-methoxybenzyl, trityl, acetyl, pivaloyl, trimethylsilyl, triisopropylsilyl, benzoyl, trifluoromethanesulfonyl.
2. The method according to claim 1, wherein the common oxidant for epoxidation in step (1) is organic peroxy acid, and the organic peroxy acid is any one of m-chloroperoxybenzoic acid, peroxyacetic acid, peroxyformic acid, peroxytrifluoroacetic acid, dimethyl copper peroxide, dimethyl dioxirane; commonly used solvents are inert solvents including, but not limited to, one or more of the group consisting of halogenated hydrocarbons, benzene, toluene, xylene, nitrobenzene, acetonitrile, diethyl ether.
3. The method according to claim 1, wherein in the step (2), the organometallic reagent is any one of a Grignard reagent, an organolithium reagent, an organoaluminum reagent, an organotitanium reagent, an organomagnesium reagent, an organozinc reagent, an organotin reagent, and an organosamarium reagent, and the solvent is one or more of toluene, dichloromethane, trichloromethane, tetrahydrofuran, 1, 2-dichloroethane, and 1, 4-dioxane; the organometallic reagent is preferably a grignard reagent, including but not limited to ethylmagnesium bromide, ethylmagnesium chloride; the molar ratio of the compound shown in formula 2 to the Grignard reagent is 1 to 1.5; the reaction temperature is 0 to 90 ℃.
4. The method according to claim 1, wherein the solvent in step (3) is one or more of N, N-dimethylformamide, acetonitrile, toluene, dichloromethane, tetrahydrofuran, 1, 2-dioxane, and acetone; the alkali is one or more of imidazole, pyridine, tetrabutylammonium fluoride, 2, 6-dimethylpyridine, sodium hydride, potassium carbonate, N, N-diisopropylethylamine, sodium carbonate and triethylamine; the molar ratio of the compound of formula 3 to the base is 1 to 3; the reaction temperature is-78 to 80 ℃.
5. The method according to claim 1, wherein the acetyl reagent in the step (4) is one or more of vinyl n-butyl ether, acetic anhydride, tributyl (1-ethoxyethylene) tin, 2-vinyloxyethanol, vinyloxytrimethylsilane; the solvent is one or more of toluene, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane and acetonitrile; the base is N, N-diisopropylethylamine, triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane, preferably N, N-diisopropylethylamine; the addition amount of the base is 1-3 times of the equivalent of the compound shown in the formula 4; the catalyst is tetrakis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate and tris (dibenzylideneacetone) dipalladium, and the addition amount of the catalyst is 0.5-1% equivalent of the compound shown in the formula 4; according to the reaction type, a ligand can be added, wherein the ligand is 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1-bis (diphenylphosphino) ferrocene, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine, and the addition amount of the ligand is 1% -2% of the equivalent of the catalyst.
6. The method according to claim 1, wherein the brominating agent in the step (5) is pyridinium tribromide, liquid bromine, bromosuccinimide, dibromohydantoin or copper bromide; the solvent is ethyl acetate, dichloromethane, acetonitrile, toluene or tetrahydrofuran or their mixture.
7. A novel preparation method of a key mother nucleus compound of Upacatinib shown in formula 8 is characterized by comprising the following steps: carrying out condensation reaction on a compound shown in formula 6 obtained by the preparation method of claims 1-6 and a compound a under a proper condition to obtain an intermediate compound shown in formula 7; the compound shown in the formula 7 is subjected to cyclization reaction under the action of trifluoroacetic anhydride and organic base to obtain an intermediate compound shown in the formula 8; wherein the structural formulas of the compound a, the compound formula 7 and the compound formula 8 are shown as follows:
wherein G is a protecting group for a nitrogen atom or a trifluoroethylcarboxamido group.
8. The method according to claim 7, wherein the base used in the condensation reaction is sodium carbonate, potassium phosphate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecene-7-ene or 1, 4-diazabicyclo [2.2.2] octane, or benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate; further, the base is added in an amount of 3 times equivalent to that of the compound of formula 6; the reaction solvent is N, N-dimethylformamide, N-dimethylacetamide, toluene, acetonitrile, 1, 4-dioxane or tetrahydrofuran; the reaction temperature is-20 ℃ to 110 ℃.
9. The process according to claim 7, wherein the base of the cyclization reaction is selected from triethylamine, N-diisopropylethylamine, pyridine or 2, 6-lutidine; the reaction solvent is selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; the reaction temperature is-20 ℃ to 110 ℃.
10. A novel preparation method of Upatinib is characterized in that a compound formula 8 obtained by the preparation method of claims 7 to 9 is subjected to deprotection reaction to obtain a compound formula 9, the compound formula 9 is subjected to condensation reaction with trifluoroethylamine in the presence of carbonyldiimidazole to obtain a chemical formula 10, the chemical formula 10 is subjected to deprotection reaction to obtain Upatinib, wherein G is a protecting group of a nitrogen atom, the compound formula 9 is shown in the specification, and the structural formula of the compound formula 10 is shown as follows:
11. the process of claim 10, wherein the compound of formula 8 is reacted with a deaminating protecting agent selected from the group consisting of hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate, and H to form the compound of formula 9 2 /Pd-C。
12. The process according to claim 10, wherein the base of the condensation reaction is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene or 1, 4-diazabicyclo [2.2.2] octane; the reaction solvent is selected from acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or toluene; the reaction temperature is-10 ℃ to 110 ℃.
13. The process of claim 10, wherein the compound of formula 10 is reacted with a deaminating protecting agent selected from the group consisting of hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate, and H 2 Pd-C or a base.
14. A novel preparation method of Upaltinib, which is characterized in that the Upaltinib is prepared by carrying out deprotection reaction on a compound formula 8 obtained by the preparation method of claims 7 to 9, wherein the structural formula of the compound formula 8 is shown as follows:
the compound formula 8 is reacted under the action of a deamination protective reagent to prepare the lapatinib, wherein the deamination protective reagent is hydrobromic acid and acetic acid, dichloromethane and trifluoroacetic acid, hydrochloric acid and methanol, hydrochloric acid and ethyl acetate, and H 2 Pd-C or a base.
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| PCT/CN2022/080533 WO2022242278A1 (en) | 2021-05-16 | 2022-03-13 | Preparation methods for upadacitinib and intermediate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117285535A (en) * | 2023-11-27 | 2023-12-26 | 中节能万润股份有限公司 | Preparation method of Marpatinib intermediate and salified intermediate |
| CN117304194A (en) * | 2023-11-27 | 2023-12-29 | 中节能万润股份有限公司 | Synthesis method of lapatinib |
| CN117603117A (en) * | 2023-11-22 | 2024-02-27 | 江苏海洋大学 | Preparation method of chiral 3- (2-haloacetyl) -4-ethylpyrrolidine |
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| CN115947679B (en) * | 2022-12-16 | 2024-06-07 | 杭州澳赛诺生物科技有限公司 | Synthesis method of 6, 6-dimethyl-3-hetero-nitrogen-bicyclo [3.1.0] hexane-2-carboxylic acid methyl ester |
| CN116082351B (en) * | 2023-01-19 | 2024-09-17 | 宁波礼达先导生物技术有限公司 | Synthesis method and application of photoaffinity probe reagent 3- (3-ethanol-3H-biaziridine) propiolactone |
| HUP2300099A1 (en) * | 2023-03-23 | 2024-09-28 | Egis Gyogyszergyar Zartkoerueen Muekoedoe Reszvenytarsasag | Process for the preparation of active agent upadacitinib and intermediers |
| HUP2300098A1 (en) * | 2023-03-23 | 2024-09-28 | Egis Gyogyszergyar Zartkoerueen Muekoedoe Reszvenytarsasag | Process for the preparation of upadacitinib |
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| US20060183763A1 (en) * | 2004-12-31 | 2006-08-17 | Pfizer Inc | Novel pyrrolidyl derivatives of heteroaromatic compounds |
| EP2968591A1 (en) * | 2013-03-15 | 2016-01-20 | Novartis AG | Cell proliferation inhibitors and conjugates thereof |
| US11926633B2 (en) * | 2018-08-31 | 2024-03-12 | Suzhou Pengxu Pharmatech Co., Ltd | Synthesis methods for upadacitinib and intermediate thereof |
| CN111217819B (en) * | 2018-11-27 | 2021-05-14 | 杭州科巢生物科技有限公司 | Synthetic method of sepiatinib |
| CN110615753A (en) * | 2019-09-02 | 2019-12-27 | 南京新酶合医药科技有限公司 | Synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117603117A (en) * | 2023-11-22 | 2024-02-27 | 江苏海洋大学 | Preparation method of chiral 3- (2-haloacetyl) -4-ethylpyrrolidine |
| CN117285535A (en) * | 2023-11-27 | 2023-12-26 | 中节能万润股份有限公司 | Preparation method of Marpatinib intermediate and salified intermediate |
| CN117304194A (en) * | 2023-11-27 | 2023-12-29 | 中节能万润股份有限公司 | Synthesis method of lapatinib |
| CN117285535B (en) * | 2023-11-27 | 2024-02-02 | 中节能万润股份有限公司 | Preparation method of Marpatinib intermediate and salified intermediate |
| CN117304194B (en) * | 2023-11-27 | 2024-02-23 | 中节能万润股份有限公司 | Synthesis method of lapatinib |
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