CN115636774B - Synthesis method of belisi - Google Patents
Synthesis method of belisi Download PDFInfo
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- CN115636774B CN115636774B CN202211525942.2A CN202211525942A CN115636774B CN 115636774 B CN115636774 B CN 115636774B CN 202211525942 A CN202211525942 A CN 202211525942A CN 115636774 B CN115636774 B CN 115636774B
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- 238000001308 synthesis method Methods 0.000 title claims description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 229960003094 belinostat Drugs 0.000 claims abstract description 19
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 16
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- 239000012467 final product Substances 0.000 claims abstract description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract 2
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 claims abstract 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 239000002798 polar solvent Substances 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- -1 acrylic ester Chemical class 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical group CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 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 claims description 6
- 125000002346 iodo group Chemical group I* 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 6
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical group [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 18
- 238000002360 preparation method Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000010499 C–H functionalization reaction Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- ZFLFWZRPMDXJCW-UHFFFAOYSA-N 2,5-dimethyl-1h-indole Chemical compound CC1=CC=C2NC(C)=CC2=C1 ZFLFWZRPMDXJCW-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000011734 sodium Substances 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 238000004896 high resolution mass spectrometry Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 102000003964 Histone deacetylase Human genes 0.000 description 3
- 108090000353 Histone deacetylase Proteins 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 101710134784 Agnoprotein Proteins 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000002332 glycine derivatives Chemical class 0.000 description 2
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 2
- 239000003276 histone deacetylase inhibitor 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
- 238000009987 spinning Methods 0.000 description 2
- 238000006277 sulfonation reaction Methods 0.000 description 2
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 2
- 150000003679 valine derivatives Chemical class 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910016509 CuF 2 Inorganic materials 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 241000764773 Inna Species 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 125000005396 acrylic acid ester group Chemical group 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
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- 230000014509 gene expression Effects 0.000 description 1
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- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002519 isoleucine derivatives Chemical class 0.000 description 1
- 150000002613 leucine derivatives Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000006772 olefination reaction Methods 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- PNXMTCDJUBJHQJ-UHFFFAOYSA-N propyl prop-2-enoate Chemical compound CCCOC(=O)C=C PNXMTCDJUBJHQJ-UHFFFAOYSA-N 0.000 description 1
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- 235000011150 stannous chloride Nutrition 0.000 description 1
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Abstract
The present invention relates to a chemical synthesis method of Bei Lisi. The preparation method comprises the steps of sequentially synthesizing intermediates I, II, III and IV by taking 2, 5-dimethylindole as a starting material, hydrolyzing in sodium hydroxide methanol solution, chloridizing by thionyl chloride to obtain sulfonyl chloride, and reacting with hydroxylamine hydrochloride to obtain the final product belinostat. The invention uses the method of C-H functionalization (C-H functionalization), improves the atom economy, has short overall reaction route and short time consumption, improves the reaction efficiency, enhances the production safety, reduces the environmental pollution and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a method for industrially synthesizing a drug Bei Lisi for treating recurrent refractory peripheral T cell lymphoma.
Background
Belinostat (belinostat) is a histone deacetylase inhibitor (histone deacetylase inhibitors, HDACI). Overexpression or deregulation of Histone Deacetylase (HDAC) causes excessive deacetylation of histone, remodelling of chromatin into a configuration inhibiting transcription, causing a decrease in expression of the corresponding gene, resulting in generation of canceration, and thus inhibition of HDAC is considered as an anticancer drug target with development prospect. Belinostat is a small molecule hydroxamate type HDACI, originally developed by topotargete Inc., chemical name:Nhydroxy-3- (3-phenylaminosulfonylphenyl) acrylamide, which was approved by the FDA for marketing in 7 of 2014, is currently recognized as an important drug for the treatment of T-cell lymphoma in the International market, and is also known for mesothelioma, B-cell lymphoma,Soft tissue sarcoma, colorectal cancer, liver cancer and the like also have single or combined treatment effects and have huge market potential, so that the development of a new technology of belisi has important significance.
The compound is disclosed in International patent WO0230879 for the first time, wherein the synthetic route of the compound is as follows:
in the first step of sulfonation reaction of the reaction route, fuming sulfuric acid is used, and is easy to cause explosion when meeting water, organic matters and oxidizing agents, has strong corrosiveness, has great danger and serious potential safety hazard in storage, transportation and use, and can also pollute the environment; the method has long route and multiple steps, and the total yield is only 1.3%, so that the industrialized production is difficult to realize.
The synthesis route II is as follows: the content of documents Synthetic Communication, 2009,40(17) 2520-2524 reports a synthetic route, which uses m-nitrobenzaldehyde as starting material, firstly makes olefination reaction, then reduces nitro group to amino group under the action of stannous chloride, then makes diazotization, sulfonation, amidation and hydroxylation successively so as to obtain belinostat.
In comparison to the first synthetic route, this route does not use highly corrosive raw materials such as fuming sulfuric acid and thionyl chloride. However, this route uses diazotisation reactions with a great risk of explosion, uses SO with a great environmental pollution 2 The gas, therefore, has great production safety hidden trouble and pollution source, and is difficult to realize large-scale industrialized production.
In summary, it is currently difficult to realize large-scale industrial production on the synthesis route of belinostat, either because of the use of highly polluting and corrosive reagents, or because of the dangerous diazotization reaction in the process route, or because of the long route and low yield. Therefore, the development of a green, environment-friendly, highly operable and safe belinostat synthesis method has important significance.
Disclosure of Invention
The invention provides a green synthesis method of belinostat, which adopts a method of C-H functionalization (C-H functionalization) in the first step of the route, improves the atom economy, has short integral reaction route and short time consumption, improves the reaction efficiency, enhances the production safety, reduces the environmental pollution and is suitable for industrial production.
The synthesis method of belinostat provided by the invention is characterized by comprising the following synthesis routes:
the method specifically comprises the following steps:
1) Dissolving intermediate I in proper amount of solvent, sequentially adding metal palladium catalyst, oxidant, amino acid derivative ligand and acrylic ester, heating to 80 o C, reacting 24 and h to obtain an intermediate II;
2) Dissolving the intermediate II in a polar solvent, adding a proper amount of alkaline reagent, and heating to reflux reaction. After the reaction, the solvent was dried by spinning, the mixture was separated with ethyl acetate and water, the aqueous phase was adjusted to pH 2-3 with acid, and then concentrated to dryness.
3) Dissolving the product of the last step in a polar solvent, adding a proper amount of alkaline reagent and methyl iodide, reacting at room temperature until the reaction is completed, and spin-drying the solvent to obtain an intermediate III;
4) And (3) dissolving the intermediate III in toluene, adding excessive thionyl chloride and a catalytic amount of DMF, heating to complete the reaction, and removing the solvent to obtain a product. Then dissolving in dichloromethane, adding aniline and pyridine, and reacting at room temperature to obtain an intermediate IV completely;
5) Intermediate IV is hydrolyzed in aqueous sodium hydroxide solution and then chlorinated by thionyl chloride to give sulfonyl chloride, and hydroxylamine hydrochloride is added to the mixture to give the final product Bei Lisi he.
Wherein the indole ring portion of template T is divided by m R 2 Substituted, the benzene ring being substituted by n R 3 Substitution;
R 1 、R 2 、R 3 specific ranges for substituents, m and n, are as follows:
R 1 =hydrogen, C 1 -C 4 Alkyl or halogen;
R 2 =hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy or halogen;
R 3 =hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy or halogen;
m is selected from integers from 0 to 4, when m is 0, the ring is unsubstituted; when m is greater than 1, R 2 May be the same or different;
n is an integer from 0 to 4, when n is 0, the ring is unsubstituted; when n is greater than 1, R 3 May be the same or different.
The solvent in the step 1) comprises p-xylene, mesitylene, 1, 2-dichloroethane, chloroform, isopropanol, tertiary butanol, hexafluoroisopropanol, tetrahydrofuran or 1, 4-dioxane; the palladium catalyst comprises Pd (OPiv) 2 、Pd 2 (dba) 3 、Pd(OAc) 2 、PdCl 2 (PPh 3 ) 2 Or Pd (dppf) Cl 2 The method comprises the steps of carrying out a first treatment on the surface of the The oxidant comprises Ag 2 CO 3 、AgOAc、PhCO 2 Ag、AgNO 3 、AgTFA、Ag 2 O、AgSbF 6 、Ag 2 SO 4 、CuCl 2 、CuO、CuF 2 、Cu(OTf) 2 、Cu(OAc) 2 Or Cu (OAc) 2 (0.5 equiv)+O 2 The method comprises the steps of carrying out a first treatment on the surface of the Amino acid derivative ligands include valine derivatives, leucine derivatives, isoleucine derivatives, phenylalanine derivatives or glycine derivatives; the acrylic acid ester comprises methyl acrylate,Ethyl acrylate, propyl acrylate or butyl acrylate;
step 2) the polar solvent comprises methanol, ethanol, isopropanol, tertiary butanol or tetrahydrofuran; the alkaline reagent comprises potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or sodium hydride;
step 3) the polar solvent comprises acetonitrile, tetrahydrofuran, acetone or DMF; the alkaline reagent comprises sodium carbonate, potassium carbonate and cesium carbonate;
preferably, R 1 、R 2 、R 3 Specific ranges for substituents, m and n, are as follows:
R 1 =hydrogen, methyl, ethyl, fluoro, chloro, bromo or iodo;
R 2 =hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo or iodo;
R 3 =hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo or iodo;
m is selected from integers from 0 to 2, when m is 0, the ring is unsubstituted; when m is greater than 1, R 2 May be the same or different;
n is an integer from 0 to 2, and when n is 0, the ring is unsubstituted; when n is greater than 1, R 3 May be the same or different;
preferably, the solvent of step 1) comprises isopropanol, hexafluoroisopropanol or tetrahydrofuran; the palladium catalyst comprises Pd (OAc) 2 Or PdCl 2 (PPh 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the The oxidant comprises AgOAc and AgNO 3 、Cu(OAc) 2 Or Cu (OAc) 2 (0.5 equiv)+O 2 The method comprises the steps of carrying out a first treatment on the surface of the Amino acid derivative ligands include valine derivatives or glycine derivatives; the acrylic ester comprises methyl acrylate and ethyl acrylate;
step 2) the polar solvent comprises methanol or tetrahydrofuran; alkaline agents include potassium carbonate or sodium hydride;
step 3) the polar solvent comprises acetonitrile or DMF; the alkaline reagent comprises sodium carbonate or potassium carbonate;
R 1 、R 2 、R 3 specific ranges for substituents, m and n, are as follows:
R 1 =hydrogen, methyl, or fluoro; r is R 2 =hydrogen, methyl, methoxy or fluoro; r is R 3 =hydrogen, methyl, methoxy or fluoro;
m is selected from integers from 0 to 2, when m is 0, the ring is unsubstituted; when m is greater than 1, R 2 May be the same or different;
n is an integer from 0 to 2, and when n is 0, the ring is unsubstituted; when n is greater than 1, R 3 May be the same or different;
preferably, the solvent of step 1) is hexafluoroisopropanol and the palladium catalyst is Pd (OAc) 2 The oxidant is AgOAc or Cu (OAc) 2 (0.5 equiv)+O 2 The ligand of the amino acid derivative is Ac-Gly-OH, and the acrylic ester is ethyl acrylate; step 2) the polar solvent is methanol, and the alkaline reagent is potassium carbonate; step 3) the polar solvent is DMF, and the alkaline reagent is potassium carbonate;
R 1 、R 2 、R 3 specific ranges for substituents, m and n, are as follows:
R 1 =hydrogen or methyl; r is R 2 =hydrogen or methyl; r is R 3 =hydrogen or methoxy;
m is selected from 0 or 1, and when m is 0, the ring is unsubstituted;
n is an integer from 0 to 2, and when n is 0, the ring is unsubstituted; when n is greater than 1, R 3 May be the same or different.
The invention provides a green synthesis method of belinostat (belinostat), overcomes the defects of the prior art, and particularly develops a green, environment-friendly, high-operability and safe belinostat synthesis method. The method for functionalizing the C-H is used for the first step of the route, so that the atom economy is improved, the overall reaction route is short, the time consumption is short, the reaction efficiency is improved, the production safety is enhanced, the environmental pollution is reduced, and the method is suitable for large-scale industrial production.
Detailed Description
The present invention will be described in detail with reference to examples, but these examples are not intended to limit the present invention. The experimental methods for which specific conditions are not specified in the examples are generally as described in conventional conditions and handbooks, or as suggested by the manufacturer; the equipment, materials, reagents and the like used, unless otherwise indicated, are all commercially available.
Example 1 preparation of template T
2, 5-dimethylindole (5.0 g, 34.4 mmol) was dissolved in DMF (30 mL) at room temperature, then KOH (4.8 g, 86.1 mmol) was added thereto. After 15 minutes at room temperature, I is dissolved 2 (8.7. 8.7 g, 34.4 mmol) of DMF was added dropwise to the mixed reaction solution and the reaction was continued at 4.4 h. After the reaction was completed, the mixture was poured into Na 2 SO 3 (500. 500 mL, 0.1%) in ice water, a light orange precipitate formed. The mixture was filtered and the precipitate was dried in air to give a pale orange solid (8.8. 8.8 g) in 94.3% yield, melting point 134-135 o C。
2-Benzonitrile boronic acid pinacol ester (3.8 g, 16.6 mmol) was dissolved in 1, 4-dioxane (40 mL), followed by sequential addition of the intermediate 3-iodo-2, 5-dimethyl-1 obtained in the previous stepHIndole (2.5 g, 9.2 mmol), pd (dppf) Cl 2 (0.67 g, 0.9 mmol) cesium carbonate (7.5 g, 23.1 mmol) in water (4 mL) and the reaction was warmed to 80 o C, reacting 16 h under the protection of argon. After the reaction, the reaction mixture was quenched with aqueous ammonium chloride (80, mL), extracted with ethyl acetate (2X 60 mL), and the separated oil phase was driedNa 2 SO 4 Drying, filtering, concentrating, and column chromatography to obtain template T 1 (1.6 g, 70.5%) of a white solid, melting point 158-159 o C. Template T 2 、T 3 And T 4 All were prepared in the same manner and gave good yields.
1 H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.13 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 2.45 (s, 3H), 2.39 (s, 3H).
13 C NMR (100 MHz, Chloroform-d) δ 136.32, 134.11, 130.93, 129.90, 123.81, 119.92, 110.29, 58.47, 21.38, 14.36.
HR-MS (ESI) m/z calcd for C 10 H 10 INNa + [M+Na + ] 293.9750, found 293.9753.
1 H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.66 – 7.56 (m, 2H), 7.38 (td, J = 7.5, 1.4 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 2.40 (s, 3H), 2.35 (s, 3H).
13 C NMR (100 MHz, Chloroform-d) δ 139.78, 133.69, 133.52, 133.32, 132.49, 131.77, 129.41, 127.96, 126.56, 123.34, 119.24, 117.89, 113.13, 110.84, 110.29, 21.51, 12.88.
HR-MS (ESI) m/z calcd for C 17 H 14 N 2 Na + [M+Na + ] 269.1049, found 269.1046.
White solid, melting point 105-106 o C。
1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (s, 1H), 7.83 – 7.75 (m, 3H), 7.69 (d, J = 2.7 Hz, 1H), 7.66 (td, J = 7.7, 1.5 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.37 (td, J = 7.6, 1.3 Hz, 1H), 7.31 – 7.25 (m, 1H), 7.22 (td, J = 7.5, 7.0, 1.1 Hz, 1H).
13 C NMR (100 MHz, CDCl 3 ) δ 138.98, 136.25, 134.00, 132.74, 129.96, 126.22, 125.83, 124.43, 122.90, 120.81, 119.59, 119.25, 113.92, 111.68, 110.90.
HR-MS (ESI) m/z calcd for C 15 H 10 N 2 Na + [M+Na + ] 241.0736, found 241.0732.
Gray solids, melting points 112-113 o C。
1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (s, 1H), 7.81 – 7.74 (m, 2H), 7.68 – 7.61 (m, 2H), 7.54 (s, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 2.46 (s, 3H).
13 C NMR (100 MHz, CDCl 3 ) δ 139.22, 134.60, 133.99, 132.73, 130.18, 129.97, 126.09, 126.07, 124.61, 124.49, 119.67, 118.81, 113.37, 111.37, 110.82, 21.65.
HR-MS (ESI) m/z calcd for C 16 H 12 N 2 Na + [M+Na + ] 255.0893, found 255.0898.
White solid, melting point 135-136 o C。
1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.67 – 7.57 (m, 2H), 7.46 – 7.38 (m, 2H), 7.30 (d, J = 7.9 Hz, 1H), 7.18 – 7.09 (m, 2H), 2.39 (s, 3H).
13 C NMR (100 MHz, CDCl 3 ) δ 139.62, 135.27, 133.62, 133.43, 132.58, 131.81, 127.80, 126.74, 121.95, 120.25, 119.26, 118.31, 113.25, 111.38, 110.66, 12.96.
HR-MS (ESI) m/z calcd for C 16 H 12 N 2 Na + [M+Na + ] 255.0893, found 255.0895.
Example 2 preparation of intermediate I
Template T 1 (200.00 mg, 0.81 mmol) was dissolved in THF (15 mL) and then sodium hydride (60% wt, 97.6 mg, 2.44 mmol) was added to the solution under ice-bath conditions. After the reaction solution was stirred for 15 minutes, benzenesulfonyl chloride (286.81 mg, 1.62 mmol) was added, followed by overnight reaction at room temperature. After the reaction was completed, it was quenched with water (40 mL), then extracted with ethyl acetate (2×30 mL), and the separated oil phase was extracted with anhydrous Na 2 SO 4 Drying, filtering, concentrating, and column chromatography to give intermediate I (258 mg, 82.2%) as a white solid with melting point 116-117 o C。
1 H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J = 8.5 Hz, 1H), 7.83 – 7.77 (m, 3H), 7.69 (t, J = 7.7, 1H), 7.55 – 7.47 (m, 3H), 7.43 (t, J = 7.7 Hz, 2H), 7.12 (d, J = 7.7 Hz, 1H), 6.96 (s, 1H), 2.57 (s, 3H), 2.35 (s, 3H).
13 C NMR (100 MHz, Chloroform-d) δ 138.72, 137.12, 135.46, 134.43, 133.73, 133.65, 133.33, 132.70, 131.58, 129.64, 129.36, 128.17, 126.40, 126.11, 119.48, 118.67, 117.94, 114.42, 114.19, 21.25, 14.26.
HR-MS (ESI) m/z calcd for C 23 H 18 N 2 NaO 2 S + [M+Na + ] 409.0981, found 409.0978.
Example 3 preparation of intermediate II Process one
Intermediate I (3.0 g, 7.8 mmol) was dissolved in HFIP (40 mL) and added to a 100 mL flask to which Pd (OAc) was added in sequence 2 (174.3 mg, 0.78 mmol), agOAc (3.9 g, 23.3 mmol), ac-Gly-OH (181.8 mg, 1.55 mmol), ethyl acrylate (1.69 mL, 15.5 mmol) was added after stirring at room temperature for 15 min, and the temperature was raised to 80 o C reaction 24 h. After the reaction was completed, it was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give yellow oil II (1.7 g, 45%) by column chromatography.
Example 4 preparation of intermediate II Process II
Intermediate I (3.0 g, 7.8 mmol) was dissolved in HFIP (40 mL) and added to a 100 mL flask to which Pd (OAc) was added in sequence 2 （174.3 mg, 0.78 mmol），Cu(OAc) 2 (708.4 mg, 3.9 mmol), ac-Gly-OH (181.8 mg, 1.55 mmol), stirring at room temperature for 15 minutes, adding ethyl acrylate (1.69 mL, 15.5 mmol), then briefly evacuating the flask and introducing O 2 Repeating for three times, and heating to 80 o C reaction 24 h. After the reaction was completed, it was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give yellow oil II (1.6 g, 43%) by column chromatography.
1 H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H), 7.80 (dd, J = 8.1, 1.4 Hz, 1H), 7.75 (dt, J = 8.1, 1.3 Hz, 1H), 7.70 (td, J = 7.7, 1.4 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 16.0 Hz, 1H), 7.51 (ddd, J = 8.1, 6.2, 1.4 Hz, 2H), 7.45 (t, J = 7.9 Hz, 1H), 7.14 (dd, J = 8.6, 1.8 Hz, 1H), 6.97 (s, 1H), 6.43 (d, J = 16.1 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 2.59 (s, 3H), 2.35 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).
13 C NMR (100 MHz, CDCl 3 ) δ 166.25, 142.11, 139.60, 137.00, 135.91, 135.44, 134.35, 133.92, 133.30, 132.72, 132.47, 131.52, 130.13, 129.74, 128.25, 127.49, 126.31, 125.77, 121.05, 119.88, 118.81, 117.91, 114.38, 114.26, 60.82, 21.25, 14.40, 14.28.
HR-MS (ESI) m/z calcd for C 28 H 24 N 2 NaO 4 S + [M+Na + ] 507.1349, found 507.1346.
EXAMPLE 5 preparation of intermediate III
Intermediate II (1.7 g, 3.5 mmol) was dissolved in methanol (50 mL) and anhydrous potassium carbonate (0.97 g, 7.0 mmol) was added thereto, and the mixture was stirred at 70 o Stirring overnight at C. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the mixture was separated by water (50 mL) and ethyl acetate (50 mL). Wherein the aqueous phase is adjusted to pH 2-3 with 1 mol/L aqueous hydrochloric acid solution, and the water is then dried by spinning. The mixture was then dissolved in DMF (20 mL), potassium carbonate (1.45 g, 10.5 mmol) was added thereto, methyl iodide (0.44 mL, 7 mmol, 2.0 equiv) and stirred overnight at room temperature. After the reaction is completed, the solvent is removed under vacuum to obtain a crude intermediate III, which is directly put into the next reaction without further purificationTemplate T to be removed simultaneously 1 (0.76 g, 88%) was recovered.
EXAMPLE 6 preparation of intermediate IV
Dissolving intermediate III in toluene, adding excessive thionyl chloride, and dripping a few drops of DMF as catalyst, heating the mixed solution to 70 o C overnight reaction. After completion of the reaction, the excess reagent was distilled off, and then the residue was dissolved in methylene chloride (25. 25 mL), and an excess of pyridine and aniline were added to the mixture to react at room temperature 4.4 h. After the reaction, the excess dichloromethane was distilled off, and then extracted with ethyl acetate (2X 30 mL), and the separated oil phase was subjected to anhydrous Na 2 SO 4 Drying, filtration, concentration and column chromatography give intermediate IV (780 mg, 2.45 mmol) as a yellow solid with melting point 144-145 o C, the overall yield from II-IV was 70%.
1 H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.66 – 7.58 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.23 (d, J= 7.2 Hz, 2H), 7.11 (d, J = 8.6 Hz, 3H), 6.42 (d, J = 16.0 Hz, 1H), 3.81 (s, 3H).
13 C NMR (100 MHz, Chloroform-d) δ 166.89, 142.62, 139.98, 136.16, 135.51, 132.24, 129.70, 129.45, 128.40, 126.35, 125.80, 121.99, 120.28, 52.01.
HR-MS (ESI) m/z calcd for C 16 H 15 NNaO 4 S + [M+Na + ] 340.0614 found 340.0617.
EXAMPLE 7 preparation of belinostat
IV (500 mg, 1.6 mmol) is dissolved in 1 mol/L NaOH in methanol and heated to 40-50 oC The reaction was continued at this temperature for 2 hours, and after completion of the hydrolysis reaction, TLC was monitored, the reaction was stopped, and the pH was adjusted to 2.2 with 1 mol/L aqueous hydrochloric acid, whereby precipitate was formed. Cooling the system to 20-30 deg.f oC Then filtering, washing the filter residue with water for several times, and transferring into an oven for drying to finally obtain the crude intermediate acid 0.45-g.
Catalytic amounts of DBU (3.7 mg, 0.024 mmol) were dissolved in isopropyl acetate (4 mL), followed by the addition of the last step of intermediate acid (0.45 g, 1.5 mmol) and thionyl chloride (0.13 mL, 1.8 mmol/L), at 20-30 oC Stirring was carried out overnight. After no reaction starting material remained as monitored by TLC, the reaction was stopped.
Into a 25 mL round bottom flask was added water (5 mL), THF (4 mL), and hydroxylamine hydrochloride (2.1 g, 30.8 mmol) and the temperature was reduced to 0-10 oC Stirring is started, the acyl chloride reaction liquid is slowly added dropwise while stirring, then the temperature is raised to room temperature, and the reaction is continued until the completion. After stopping the reaction, the system is layered, the water phase is removed, the oil phase is decompressed and distilled to remove most of the solvent, isopropyl acetate (3 mL) is added into the water phase, the system is precipitated, heptane (5 mL) is added into the water phase, the water phase is kept stand for a period of time, the water phase is filtered, and the filter residue is washed by the heptane for a plurality of times, and is dried in an oven to obtain a crude product. The crude product was then taken up in a mixed solvent (EtOH: H 2 O=1:1) to give the final product belinostat (0.33 g, 1.0 mmol), light orange solid, melting point 172-173 o The total yield from IV-belinostat was 65%.
1 H NMR (400 MHz, DMSO-d 6 ) δ 10.75−10.42 (m, 2H), 9.15 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),7.47 (d, J = 15.8 Hz, 1H), 7.24 (m, 2H), 7.10−7.01 (m, 3H), 6.51 (d, J = 15.8 Hz, 1H).
HR-MS (ESI) m/z calcd for C 15 H 14 N 2 NaO 4 S + [M+Na + ] 341.0566 found 341.0569。
Claims (4)
1. The synthesis method of belinostat is characterized by comprising the following synthesis routes:
the method specifically comprises the following steps:
1) Dissolving the intermediate I in a proper amount of solvent, sequentially adding a metal palladium catalyst, an oxidant, an amino acid derivative ligand and acrylic ester, and heating to 80 ℃ for reaction for 24 hours to obtain an intermediate II;
2) Dissolving the intermediate II in a polar solvent, adding a proper amount of alkaline reagent, and heating to reflux reaction; after the reaction, spin-drying the solvent, separating the mixture by ethyl acetate and water, adjusting the pH of the water phase to 2-3 by acid, and concentrating and spin-drying;
3) Dissolving the product of the last step in a polar solvent, adding a proper amount of alkaline reagent and methyl iodide, reacting at room temperature until the reaction is completed, and spin-drying the solvent to obtain an intermediate III;
4) Dissolving the intermediate III in toluene, adding excessive thionyl chloride and a catalytic amount of DMF, heating to react completely, and removing the solvent to obtain a product; then dissolving in dichloromethane, adding aniline and pyridine, and reacting at room temperature to obtain an intermediate IV completely;
5) Hydrolyzing the intermediate IV in a sodium hydroxide methanol solution, then chloridizing by using thionyl chloride and obtaining sulfonyl chloride in the presence of a catalytic amount of DBU, and adding hydroxylamine hydrochloride into the mixture to obtain a final product Bei Lisi;
the solvent in the step 1) is hexafluoroisopropanol, and the metal palladium catalyst is Pd (OAc) 2 The oxidant is AgOAc or 0.5equiv Cu (OAc) 2 And O 2 The amino acid derivative ligand is Ac-Gly-OH, and the acrylic ester is ethyl acrylate;
wherein the indole ring portion of template T is divided by m R 2 Substituted, the benzene ring being substituted by n R 3 Substitution;
R 1 、R 2 、R 3 specific ranges for substituents, m and n, are as follows:
R 1 =hydrogen, C 1 -C 4 Alkyl or halogen;
R 2 =hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy or halogen;
R 3 =hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy or halogen;
m is selected from integers from 0 to 4, when m is 0, the ring is unsubstituted; when m is greater than 1, R 2 May be the same or different;
n is an integer from 0 to 4, when n is 0, the ring is unsubstituted; when n is greater than 1, R 3 May be the same or different.
2. The synthesis method of belinostat according to claim 1, wherein:
step 2) the polar solvent is methanol, ethanol, isopropanol, tertiary butanol or tetrahydrofuran; the alkaline reagent is potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or sodium hydride;
step 3) the polar solvent is acetonitrile, tetrahydrofuran, acetone or DMF; the alkaline reagent is sodium carbonate, potassium carbonate and cesium carbonate; r is R 1 、R 2 、R 3 Specific ranges for substituents, m and n, are as follows:
R 1 =hydrogen, methyl, ethyl, fluoro, chloro, bromo or iodo;
R 2 =hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo or iodo;
R 3 =hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo or iodo;
m is selected from integers from 0 to 2, when m is 0, the ring is unsubstituted; when m is greater than 1, R 2 May be the same or different;
n is an integer from 0 to 2, and when n is 0, the ring is unsubstituted; when n is greater than 1, R 3 May be the same or different.
3. The synthesis method of belinostat according to claim 1, wherein:
step 2) the polar solvent is methanol or tetrahydrofuran; the alkaline reagent is potassium carbonate or sodium hydride;
step 3) the polar solvent is acetonitrile or DMF; the alkaline reagent is sodium carbonate or potassium carbonate;
R 1 、R 2 、R 3 specific ranges for substituents, m and n, are as follows:
R 1 =hydrogen, methyl, or fluoro;
R 2 =hydrogen, methyl, methoxy or fluoro;
R 3 =hydrogen, methyl, methoxy or fluoro;
m is selected from integers from 0 to 2, when m is 0, the ring is unsubstituted; when m is greater than 1, R 2 May be the same or different;
n is an integer from 0 to 2, and when n is 0, the ring is unsubstituted; when n is greater than 1, R 3 May be the same or different.
4. The synthesis method of belinostat according to claim 1, wherein:
step 2) the polar solvent is methanol, and the alkaline reagent is potassium carbonate;
step 3) the polar solvent is DMF, and the alkaline reagent is potassium carbonate;
R 1 、R 2 、R 3 specific ranges for substituents, m and n, are as follows:
R 1 =hydrogen or methyl; r is R 2 =hydrogen or methyl; r is R 3 =hydrogen or methoxy; m is selected from 0 or 1, and when m is 0, the ring is unsubstituted; n is an integer from 0 to 2, and when n is 0, the ring is unsubstituted; when n is greater than 1, R 3 May be the same or different.
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| CN104478769A (en) * | 2014-12-22 | 2015-04-01 | 深圳万乐药业有限公司 | Belinostatsynthesis method suitable for industrial production |
| CN105367455A (en) * | 2015-12-18 | 2016-03-02 | 深圳万乐药业有限公司 | Preparation method of Belinostat isomer |
| CN105732444A (en) * | 2016-03-28 | 2016-07-06 | 大连理工大学 | Synthesis method of belinostat |
| WO2017199264A1 (en) * | 2016-05-17 | 2017-11-23 | Biophore India Pharmaceuticals Pvt. Ltd. | Novel process for the preparation of belinostat |
| CN109496210A (en) * | 2016-07-26 | 2019-03-19 | 费森尤斯卡比肿瘤学有限公司 | His polymorphic and preparation method thereof of Baily department |
| CN109336788A (en) * | 2018-10-31 | 2019-02-15 | 安徽省庆云医药股份有限公司 | A kind of his preparation method of Baily department |
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