CN111138492A - Alk抑制剂布格替尼的制备方法 - Google Patents
Alk抑制剂布格替尼的制备方法 Download PDFInfo
- Publication number
- CN111138492A CN111138492A CN202010008282.5A CN202010008282A CN111138492A CN 111138492 A CN111138492 A CN 111138492A CN 202010008282 A CN202010008282 A CN 202010008282A CN 111138492 A CN111138492 A CN 111138492A
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- China
- Prior art keywords
- acid
- sodium
- metal base
- solvent
- potassium
- Prior art date
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- Granted
Links
- 229950004272 brigatinib Drugs 0.000 title claims abstract description 20
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 13
- 239000000047 product Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 230000002378 acidificating effect Effects 0.000 claims abstract description 9
- 239000011230 binding agent Substances 0.000 claims abstract description 9
- 238000006467 substitution reaction Methods 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- HNYSXOZEEKWPNM-UHFFFAOYSA-N 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine Chemical compound C1=C([N+]([O-])=O)C(OC)=CC(N2CCC(CC2)N2CCN(C)CC2)=C1 HNYSXOZEEKWPNM-UHFFFAOYSA-N 0.000 claims abstract description 7
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- SEVCLCIAPQTBPN-UHFFFAOYSA-N 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperazin-1-yl]aniline Chemical compound COC1=C(N)C=CC(=C1)N1CCN(CC1)N1CCN(CC1)C SEVCLCIAPQTBPN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000004982 aromatic amines Chemical class 0.000 claims abstract description 5
- 239000012043 crude product Substances 0.000 claims abstract description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000004537 pulping Methods 0.000 claims abstract description 5
- MRYYJGQKVGZGSB-UHFFFAOYSA-N 1-methyl-4-piperidin-4-ylpiperazine Chemical compound C1CN(C)CCN1C1CCNCC1 MRYYJGQKVGZGSB-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 150000001412 amines Chemical group 0.000 claims abstract description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 3
- YOTZYFSGUCFUKA-UHFFFAOYSA-N dimethylphosphine Chemical compound CPC YOTZYFSGUCFUKA-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims abstract description 3
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 claims abstract 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 29
- 239000002585 base Substances 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 14
- 239000012535 impurity Substances 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 150000001340 alkali metals Chemical class 0.000 claims description 8
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 8
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 6
- 239000011736 potassium bicarbonate Substances 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 4
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical group C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 4
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- WLKUSVNHZXUEFO-UHFFFAOYSA-N 4-fluoro-2-methoxy-1-nitrobenzene Chemical group COC1=CC(F)=CC=C1[N+]([O-])=O WLKUSVNHZXUEFO-UHFFFAOYSA-N 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 2
- WLRIREROKRGVTD-UHFFFAOYSA-N 1,5-diazacycloundec-5-ene Chemical compound C1CCNCCCN=CCC1 WLRIREROKRGVTD-UHFFFAOYSA-N 0.000 claims description 2
- LUSVSIROXDVVOP-UHFFFAOYSA-N 2,5-dichloro-n-(2-dimethylphosphanylphenyl)pyrimidin-4-amine Chemical compound CP(C)C1=CC=CC=C1NC1=NC(Cl)=NC=C1Cl LUSVSIROXDVVOP-UHFFFAOYSA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 2
- 239000007836 KH2PO4 Substances 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 125000002524 organometallic group Chemical group 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- SHEQRWTUXYWGQS-UHFFFAOYSA-N 2-dimethylphosphanylaniline Chemical compound CP(C)C1=CC=CC=C1N SHEQRWTUXYWGQS-UHFFFAOYSA-N 0.000 claims 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract 2
- -1 dimethyl phospho Chemical class 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000008901 benefit Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 3
- OVDSPTSBIQCAIN-UHFFFAOYSA-N ap26113 Chemical compound COC1=CC(N2CCC(CC2)N(C)C)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O OVDSPTSBIQCAIN-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 3
- 229960005061 crizotinib Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 2
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- ABFQGXBZQWZNKI-UHFFFAOYSA-N 1,1-dimethoxyethanol Chemical compound COC(C)(O)OC ABFQGXBZQWZNKI-UHFFFAOYSA-N 0.000 description 1
- RLVROZLNYXBHFX-UHFFFAOYSA-N 4-fluoro-2-[(5-fluoro-2-nitrophenyl)methoxymethyl]-1-nitrobenzene Chemical compound FC=1C=CC(=C(COCC2=C(C=CC(=C2)F)[N+](=O)[O-])C1)[N+](=O)[O-] RLVROZLNYXBHFX-UHFFFAOYSA-N 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及药物技术领域,涉及药物ALK抑制剂AP26113的制备方法。所述的方法包括:(1)2,4,5‑三氯嘧啶与2‑(二甲基氧磷基)苯胺在敷酸剂的作用下进行芳香胺的取代反应,得到中间体1(2,5‑二氯‑N‑(2‑(二甲基膦)苯基)嘧啶‑4‑胺),打浆。(2)2‑硝基‑5‑氟苯甲醚与1‑甲基‑4‑(4‑哌啶基)‑哌嗪在敷酸剂作用下进行芳香胺的取代反应得到化合物1‑(1‑(3‑甲氧基‑4‑硝基苯基)哌啶‑4‑基)4‑甲基哌嗪,有机溶剂溶解,酸性溶剂萃取。(3)步骤(2)的产物经过钯碳催化氢化得到中间体2(2‑甲氧基‑4‑[4‑(4‑甲基‑1‑哌嗪基)‑1‑哌嗪基]‑苯胺)。(4)中间体1与中间体2在酸性催化条件下,进行胺的取代反应得到Brigatinib的粗品。本发明的Brigatinib收率达到50%以上,纯度达99.9%以上。
Description
技术领域
本发明涉及药物技术领域,涉及药物ALK抑制剂布格替尼AP26113(Brigatinib)的制备方法,还涉及制备过程中的中间体及杂质。
背景技术
Ariad公司发明的新药Brigatinib(AP26113)于2017年美国上市,该药属于第二代ALK抑制剂,批准的适应症为:间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌,且在克唑替尼(crizotinib)治疗后出现不耐受的患者。也就是说,这款新型靶向药,可以逆转克唑替尼的耐药性。在其发表的专利WO2016065028(A1),WO2017016410A1,WO2009070740(A2)中,介绍了该药物及其中间体的三条合成路线,有关Brigatinib合成方法,专利WO2016065028(A1)给出了原始工艺合成方法,因其合成路线简单,应用最广,但是每步反应收率低,最后产物收率只有不到25%,后处理一般为过柱,不适合工艺处理,也没有具体的提出工艺中可能出现的杂质(Scheme 1)。专利WO2017016410A1给出的合成方法第一个缺点是原料昂贵,在仿制药原料竞争激烈的今天不适合大规模或工业化生产,而且氰胺不稳定,与酸反应产生有毒气体;第二个缺点是最后一步的氯化反应往往产生大量副产物17(约11.7%),与产物结构相似,难以去除或避免。专利WO2009070740(A2)给出的合成方法第一个缺点是,由于在长期生产中使用了昂贵的试剂11,这一过程在竞争激烈的仿制药市场中是无利可图的。第二个缺点是化合物14与尿素发生缩合反应时,14上的氯原子很不稳定,容易被尿素上的胺基取代。第三个缺点是反应至少需要7个步骤,导致较低的产率(10.7%)。最后一步的后处理仍然是柱层析,这限制了商业的生产。因此,有必要开发一种新的制备方法,使其收率提高、成本降低、后处理操作简便,易于工业化生产,并且使其每步产生的杂质明确,便于工业控制检测。
Scheme 1.Ariad Synthetic Route of Brigatinib,WO2016065028(A1)
Scheme 2.SuZhou Miracpharma Technology Co.,Ltd Synthetic Route ofBrigatinib,WO2017016410A1
Scheme 3.Anqing Chico Phamaceutical Co.,Ltd Synthetic Route ofBrigatinib,WO2009070740(A2)
Ariad公司路线中有关杂质的发现与分离。
impurity A。
AP-4(0.5g 2.9mmol)溶解在DMF溶剂中,K2CO3(0.8g 5.8mol)条件下,加热反应4h,点板发现impurity B点出现,柱层析分离,得到白色产物impurity A。收率:3.5%,ESI-MS(m/z):197.1[M+H]+。
impurity B。
AP-4(0.5g 2.9mmol)在有机醇溶剂中,钯碳催化,5psi-20psi条件下震荡4.5h,点板反应完毕,产物点impurity B出现,收率:95.5%,ESI-MS(m/z):142.1[M+H]+。
impurity C。
中间体AP-3(0.5g 1.59mmol)有机溶剂中,酸性催化条件下,得到相应的杂质impurity C,收率:1.5%。ESI-MS(m/z):449.1[M+H]+。
上述所有路线大规模生产时存在着原料昂贵,产品收率低,杂质多,纯度低等缺点。因此有必要开发一种新的合成方法,从而降低合成成本,提高产品收率。
发明内容
为了克服现有技术的缺陷与相关杂质的出现,本发明提供一种新的Brigatinib的制备方法,该方法具有成本低、收率高、后处理简单的优点。
本发明的制备方法包括如下步骤:
(1)2,4,5-三氯嘧啶(AP-2)与2-(二甲基氧磷基)苯胺(AP-1)在敷酸剂的作用下进行芳香胺的取代反应,得到中间体1(2,5-二氯-N-(2-(二甲基膦)苯基)嘧啶-4-胺)(AP-3),打浆。
(2)2-硝基-5-氟苯甲醚(AP-4)与1-甲基-4-(4-哌啶基)-哌嗪(AP-5)在敷酸剂作用下进行芳香胺的取代反应得到化合物1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)4-甲基哌嗪(AP-6),有机溶剂溶解,酸性溶剂萃取。
(3)步骤(2)的产物经过钯碳催化氢化得到中间体2(2-甲氧基-4-[4-(4-甲基-1-哌嗪基)-1-哌嗪基]-苯胺)(AP-7)及相应的杂质impurity C。
(4)中间体1(AP-3)与中间体2(AP-7)在酸性催化条件下,进行胺的取代反应得到Brigatinib的粗品。
(5)Brigatinib粗品通过萃取,抽滤,干燥,浓缩,重结晶得到Brigatinib。
其中,
步骤(1)中,所述的敷酸剂选自碱金属碱、碱土金属碱,有机金属碱或有机碱;
进一步地,碱金属碱选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、氢化钠、氢化钾;
碱土金属碱选自氢化钙;
有机金属碱选自甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝;
有机碱选自二异丙基乙基胺、三乙胺、N-甲基吗啡啉、1,8-二氮杂-环十一碳-7-烯。
优选地,所述的敷酸剂选自K3PO4、K2HPO4、KH2PO4,反应溶剂DMF,反应条件50℃-100℃,原料比例最佳为AP-2:AP-1=1-3:1。
打浆溶剂为石油醚,乙酸乙酯或两者的混合溶剂。
步骤(2)中所述的敷酸剂选自碱金属碱、碱土金属碱、有机金属碱或有机碱,
进一步地,碱金属碱选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、氢化钠、氢化钾;
碱土金属碱选自氢化钙;
有机金属碱选自甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝,有机碱选自二异丙基乙基胺、三乙胺。
优选地,所述的敷酸剂选自:K2CO3、KHCO3、Na2CO3、NaHCO3,反应溶剂为乙腈,反应条件100℃-150℃,原料比例最佳为AP-4:AP-5=1-2:1。
后处理萃取中,酸性溶剂为1-2.5mol/L的盐酸溶液,有机溶剂为乙酸乙酯或二氯甲烷。萃取收集水层,水层用碳酸氢钠调PH为碱性,二氯甲烷萃取,最后收集有机层。
步骤(3)中反应的有机溶剂为C1-C4的一元醇溶液,选自甲醇、乙醇,所述压力优选为5psi-20psi。所述的催化剂为钯碳。
步骤(4)中的酸为乙酸、三氟乙酸、甲烷磺酸、三氟甲烷磺酸、对甲苯磺酸、樟脑磺酸、盐酸或硫酸;反应溶剂为C2-C5的醚类或二元醇溶液,选自乙二醇甲醚、乙二醇乙醚、乙二醇二甲醚、乙二醇二乙醚、乙二醇、丙二醇。
步骤(5)中所述的重结晶溶液为C1-C4的一元或二元醇溶液,选自甲醇、乙醇、丙醇、乙二醇。
本发明合成方法操作简单,反应原料易得,后处理方便,耗时短,避免了过柱,避免了Ariad公司合成路线中所有可能出现的杂质。Brigatinib收率可以达到50%以上,纯度达99.9%以上。有利于实现工业化最大效益生成。
本文报道了一种改进的Brigatinib的合成工艺,该工艺中确定了Ariad公司生产中可能出现的所有杂质,通过条件优化可以避免所有出现的杂质。提出了一种新颖的后处理方法,避免了过柱。最后收率高于55%,产物纯度大于99.9%。
具体实施方式
实施例1
中间体1(2,5-二氯-N-(2-(二甲基膦)苯基)嘧啶-4-胺)的合成。
将2,4,5-三氯嘧啶(AP-2)(15.2g,83mmol),2,4,5-三氯嘧啶和2-(二甲基氧磷基)苯胺(AP-1)(9.4g,55.6mmol,)和K2HPO4(15.3g,110mmol)在DMF中的悬浮液(55mL)中,65℃下搅拌4小时。冷却后,过滤反应混合物,用乙酸乙酯(20ml)洗涤滤饼,蒸发滤液。将残余物溶于乙酸乙酯(50ml)中,用饱和氯化钠溶液(3×100ml)萃取三次,合并有机物中心,旋转浓缩为黄白色固体,用PE(3×20ml)打浆三次,得到所需产物12.0g AP-3为黄白色固体。产率:90.3%,HPLC纯度>98.0%。ESI-MS(m/z):316.0[M+H]+,631.0[2M+H]+
实施例2
1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)4-甲基哌嗪的合成
2-硝基-5-氟苯甲醚(17.1g,0.1mol)和1-甲基-4-(4-哌啶基)-哌嗪(18.3g,0.1mol)在MeCN(65mL)溶剂中,碳酸钾(27.6g,0.2mol)作为敷酸剂,回流搅拌4.5小时,冷却至室温后抽滤,滤饼用DCM(20mL)洗涤。滤液合并浓缩,浓缩固体溶于DCM(50ml)中,用1mol/L HCl溶液(3×15ml)萃取三次,收集水层并用碳酸钾调节至pH=8.0,然后用DCM(3×20ml)萃取三次。用硫酸钠干燥,过滤,真空浓缩,得到所需产物AP-6,为亮黄色粉末29.34g,产率87.8%,HPLC纯度>99.8%。ESI-MS(m/z):335.2[M+H]+,669.4[2M+H]+
实施例3
中间体2(2-甲氧基-4-[4-(4-甲基-1-哌嗪基)-1-哌嗪基]-苯胺)的合成
将1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)4-甲基哌嗪(AP-6)(20g,0.06mol)溶解在EtOH(800mL)中后,25℃条件振荡中用钯碳(3g,15%)催化氢化(10psi H2)2.5小时。混合物通过硅藻土过滤,浓缩滤液,得到紫色固体。产量:17.3g,产率95%,纯度>99.8%。ESI-MS(m/z):305.2[M+H]+609.4[2M+H]+
实施例4
终产物brigatinib(AP26113)的合成
向AP-3(17.0g,54.0mmol)和AP-7(18.0g,59.0mmol)的二甲氧基乙醇(50mL)溶液中加入2.5M TEA的乙醇(20mL)溶液。在搅拌下将所得混合物在密封管中120℃下加热5小时。冷却后,在旋转上除去挥发性组分,将得到的半固体溶于水(50mL)中。用EtOAc(50mL)洗涤后,水层用K2CO3碱化至pH=8.用DCM(3×50mL)萃取,然后浓缩合并有机物,得到黑色固体。用乙酸乙酯洗涤两次,得到粗产物Brigatinib灰白色固体(20.4g,89.5%产率)。
将粗产物(20.4g)在55℃下溶解在无水甲醇溶液(30mL)中,冷却结晶。将分离的结晶固体在40℃条件下干燥一夜,然后在真空干燥器中60℃下干燥2小时,得到精制纯品,为灰白色粉末47.7g,收率:80.3%,ESI-MS(m/z):583.3[M+H]+,HPLC纯度>99.9%。
Claims (10)
1.ALK抑制剂布格替尼的制备方法,其特征在于,包括如下步骤:
(1)2,4,5-三氯嘧啶与2-(二甲基氧磷基)苯胺在敷酸剂的作用下进行芳香胺的取代反应,得到2,5-二氯-N-(2-(二甲基膦)苯基)嘧啶-4-胺,打浆;
(2)2-硝基-5-氟苯甲醚与1-甲基-4-(4-哌啶基)-哌嗪在敷酸剂作用下进行芳香胺的取代反应得到化合物1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)4-甲基哌嗪,有机溶剂溶解,酸性溶剂萃取;
(3)步骤(2)的产物经过钯碳催化氢化得到2-甲氧基-4-[4-(4-甲基-1-哌嗪基)-1-哌嗪基]-苯胺及相应的杂质impurity C;
(4)2,5-二氯-N-(2-(二甲基膦)苯基)嘧啶-4-胺与2-甲氧基-4-[4-(4-甲基-1-哌嗪基)-1-哌嗪基]-苯胺在酸性催化条件下,进行胺的取代反应得到Brigatinib的粗品;
(5)Brigatinib粗品通过萃取,抽滤,干燥,浓缩,重结晶得到Brigatinib。
2.如权利要求1所述的制备方法,其特征在于,
步骤(1)所述的敷酸剂选自碱金属碱、碱土金属碱、有机金属碱或有机碱;
碱金属碱选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、氢化钠、氢化钾;
碱土金属碱选自氢化钙;
有机金属碱选自甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝;
有机碱选自二异丙基乙基胺、三乙胺、N-甲基吗啡啉、1,8-二氮杂-环十一碳-7-烯。
3.如权利要求1所述的制备方法,其特征在于,
步骤(2)中所述的敷酸剂选自碱金属碱、碱土金属碱、有机金属碱或有机碱,
碱金属碱选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、氢化钠、氢化钾;
碱土金属碱选自氢化钙;
有机金属碱选自甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝;
有机碱选自二异丙基乙基胺、三乙胺。
4.如权利要求1所述的制备方法,其特征在于,
步骤(1)中所述的敷酸剂选自K3PO4、K2HPO4、KH2PO4,反应溶剂DMF,反应温度50℃-100℃,原料比例最佳为2,4,5-三氯嘧啶:2-(二甲基氧磷基)苯胺=1-3:1。
5.如权利要求1所述的制备方法,其特征在于,
步骤(1)的打浆溶剂为石油醚,乙酸乙酯或两者的混合溶剂。
6.如权利要求1所述的制备方法,其特征在于,
步骤(2)所述的敷酸剂选自:K2CO3、KHCO3、Na2CO3、NaHCO3,反应溶剂为乙腈,反应温度为100℃-150℃,2-硝基-5-氟苯甲醚:1-甲基-4-(4-哌啶基)-哌嗪=1-2:1。
7.如权利要求1所述的制备方法,其特征在于,
步骤(2)的酸性溶剂为1-2.5mol/L的盐酸溶液,有机溶剂为乙酸乙酯或二氯甲烷。
8.如权利要求1所述的制备方法,其特征在于,
步骤(3)中反应的有机溶剂为C1-C4的一元醇溶液,选自甲醇、乙醇。
9.如权利要求1所述的制备方法,其特征在于,
步骤(4)中的酸为乙酸、三氟乙酸、甲烷磺酸、三氟甲烷磺酸、对甲苯磺酸、樟脑磺酸、盐酸或硫酸;反应溶剂为C2-C5的醚类或二元醇溶液,选自乙二醇甲醚、乙二醇乙醚、乙二醇二甲醚、乙二醇二乙醚、乙二醇、丙二醇。
10.如权利要求1所述的制备方法,其特征在于,
步骤(5)中所述的重结晶溶液为C1-C4的一元或二元醇溶液,选自甲醇、乙醇、丙醇、乙二醇。
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