CN115636774A - Synthesis method of belinostat - Google Patents
Synthesis method of belinostat Download PDFInfo
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- CN115636774A CN115636774A CN202211525942.2A CN202211525942A CN115636774A CN 115636774 A CN115636774 A CN 115636774A CN 202211525942 A CN202211525942 A CN 202211525942A CN 115636774 A CN115636774 A CN 115636774A
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- hydrogen
- methyl
- acrylate
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- 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 title claims abstract description 25
- 229960003094 belinostat Drugs 0.000 title claims abstract description 25
- 238000001308 synthesis method Methods 0.000 title description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 21
- 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
- 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 4
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 claims abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 239000002798 polar solvent Substances 0.000 claims description 16
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-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
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 239000007800 oxidant agent Substances 0.000 claims description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 8
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 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 6
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 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
- 125000001246 bromo group Chemical group Br* 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
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000002346 iodo group Chemical group I* 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- 101710134784 Agnoprotein Proteins 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 4
- 101150003085 Pdcl gene Proteins 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 150000002332 glycine derivatives Chemical class 0.000 claims description 4
- -1 methoxy, ethoxy Chemical group 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 150000003679 valine derivatives Chemical class 0.000 claims description 4
- 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 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910016509 CuF 2 Inorganic materials 0.000 claims description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 claims description 2
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 150000002519 isoleucine derivatives Chemical class 0.000 claims description 2
- 150000002613 leucine derivatives Chemical class 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 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
- 150000002993 phenylalanine derivatives Chemical class 0.000 claims description 2
- PNXMTCDJUBJHQJ-UHFFFAOYSA-N propyl prop-2-enoate Chemical compound CCCOC(=O)C=C PNXMTCDJUBJHQJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 20
- 238000009776 industrial production Methods 0.000 abstract description 6
- 238000010499 C–H functionalization reaction Methods 0.000 abstract description 5
- 238000003912 environmental pollution Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 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
- 239000011734 sodium Substances 0.000 description 17
- 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 8
- 239000007787 solid Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 102000003964 Histone deacetylase Human genes 0.000 description 3
- 108090000353 Histone deacetylase Proteins 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 3
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 3
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 3
- 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution 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
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate 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
- 239000000463 material Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000006277 sulfonation reaction Methods 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
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-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
- 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
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 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
- 239000008346 aqueous phase Substances 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 Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 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
- 238000005260 corrosion Methods 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
- 238000002474 experimental method Methods 0.000 description 1
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- 238000006460 hydrolysis 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
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
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- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
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Abstract
The invention relates to a chemical synthesis method of belinostat. 2, 5-dimethylindole is used as a starting material to sequentially synthesize intermediates I, II, III and IV, the intermediates are hydrolyzed in sodium hydroxide methanol solution, then thionyl chloride is chlorinated to obtain sulfonyl chloride, and the sulfonyl chloride reacts with hydroxylamine hydrochloride to obtain a final product of belinostat. The method uses a C-H functionalization (C-H functionalization) method, improves atom economy, has short overall reaction route and short time consumption, improves reaction efficiency, enhances production safety, reduces environmental pollution, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to an industrial synthesis method of a peripheral T cell lymphoma drug belinostat difficult to relapse.
Background
Belinostat (belinostat) is a histone deacetylase inhibitor (HDACI). The overexpression or abnormal regulation of Histone Deacetylase (HDAC) can lead to the excessive deacetylation of histone, so that chromatin is remodeled into a transcription inhibiting configuration, the expression of corresponding genes is reduced, and canceration is caused, therefore, the inhibition effect on HDAC is considered to be a promising anticancer drug target. Belinostat is an HDACI of small molecule hydroxamates, originally developed by topotarget corporation, chemical name:N-hydroxy-3- (3-phenylaminosulfonylphenyl) acrylamide, which is approved by FDA to be on the market in 7 months in 2014, becomes an important drug for treating T cell lymphoma recognized in the international market at present, has a single or combined treatment effect on mesothelioma, B-cell lymphoma, soft tissue sarcoma, colorectal cancer, liver cancer and the like, and has great market potential, so that the method has important significance in developing a new process of Belinostat.
The compound is disclosed in international patent WO0230879 for the first time, wherein the synthetic route of the compound is as follows:
fuming sulfuric acid is used in the sulfonation reaction in the first step of the reaction route of the method, the fuming sulfuric acid is easy to explode when meeting water, organic matters and oxidants, and has strong corrosivity, great danger and serious potential safety hazards exist in storage, transportation and use, and meanwhile, the environment is also polluted; in addition, the method has long route, more steps and total yield of only 1.3 percent, so that the industrial production is difficult to realize.
The second synthetic route is as follows: the Synthetic Communication, 2009,40(17) 2520-2524 reports a synthetic route which uses m-nitrobenzaldehyde as a starting material,firstly, olefin alkylation reaction is carried out, nitro is reduced to amino under the action of stannous chloride, and then the belinostat is obtained through diazotization, sulfonation, amidation and hydroxylamination in sequence.
Compared with the first synthesis route, the method does not use high-corrosion raw materials such as fuming sulfuric acid and thionyl chloride. However, the route uses diazotization with great explosion risk and SO with great environmental pollution 2 Therefore, the route has great potential safety hazard and pollution source and is difficult to realize large-scale industrial production.
In conclusion, the existing synthesis route of the belinostat is difficult to realize large-scale industrial production because of the use of a highly polluting and corrosive reagent, or because of the hazardous diazotization reaction in the process route, or because of long route and low yield. Therefore, the method for synthesizing the belinostat has important significance in developing a green and environment-friendly method with strong operability and safety.
Disclosure of Invention
The invention provides a green synthesis method of belinostat, which uses a C-H functionalization (C-H functionalization) method in the first step of the route, improves atom economy, has short whole reaction route and short time consumption, improves reaction efficiency, enhances production safety, reduces environmental pollution and is suitable for industrial production.
The synthesis method of the belinostat is characterized by being prepared according to the following synthesis route:
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 acrylate, and heating to 80 DEG o C, reacting for 24 hours to obtain an intermediate II;
2) And dissolving the intermediate II in a polar solvent, adding a proper amount of alkaline reagent, and heating to reflux reaction. After the reaction is finished, the solvent is dried in a rotary manner, the mixture is separated by ethyl acetate and water, the pH value of the water phase is adjusted to 2-3 by acid, and then the water phase is concentrated and dried in a rotary manner.
3) Dissolving the product in 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 complete, and then spin-drying the solvent to obtain an intermediate III;
4) And dissolving the intermediate III in toluene, adding excessive thionyl chloride and a catalytic amount of DMF, heating until the reaction is completed, and removing the solvent to obtain the product. Dissolving in dichloromethane, adding aniline and pyridine, and reacting at room temperature to obtain an intermediate IV;
5) And hydrolyzing the intermediate IV in an aqueous solution of sodium hydroxide, chlorinating the hydrolyzed intermediate IV by thionyl chloride to obtain sulfonyl chloride, and adding hydroxylamine hydrochloride into the mixture to obtain the final product of the belinostat.
Wherein the indole ring moiety of template T is substituted by m R 2 Substituted by n R on the phenyl ring 3 Substitution;
R 1 、R 2 、R 3 specific ranges of substituents and m and n are as follows:
R 1 = hydrogen, C 1 -C 4 Alkyl or halogen;
R 2 = hydrogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or halogen;
R 3 = hydrogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or halogen;
m is selected from an integer of 0 to 4, and 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 selected from 0 to 4, and 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 paraxylene, mesitylene, 1, 2-dichloroethane,Chloroform, isopropanol, tert-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 (ii) a 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 (ii) a The amino acid derivative ligand comprises valine derivatives, leucine derivatives, isoleucine derivatives, phenylalanine derivatives or glycine derivatives; the acrylate comprises methyl acrylate, ethyl acrylate, propyl acrylate or butyl acrylate;
step 2) the polar solvent comprises methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran; the alkaline agent comprises potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or sodium hydride;
the polar solvent in the step 3) comprises acetonitrile, tetrahydrofuran, acetone or DMF; the alkaline agent comprises sodium carbonate, potassium carbonate and cesium carbonate;
preferably, R 1 、R 2 、R 3 Specific ranges of substituents and 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 an integer of 0 to 2, and 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 of 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 (ii) a The oxidant comprises AgOAc and AgNO 3 、Cu(OAc) 2 Or Cu (OAc) 2 (0.5 equiv)+O 2 (ii) a The amino acid derivative ligand comprises valine derivative or glycine derivative; the acrylate comprises methyl acrylate and ethyl acrylate;
step 2) the polar solvent comprises methanol or tetrahydrofuran; the alkaline agent comprises potassium carbonate or sodium hydride;
step 3) the polar solvent comprises acetonitrile or DMF; the alkaline agent comprises sodium carbonate or potassium carbonate;
R 1 、R 2 、R 3 specific ranges of substituents and m and n are as follows:
R 1 hydrogen, methyl or fluorine; r 2 = hydrogen, methyl, methoxy or fluoro; r 3 Hydrogen, methyl, methoxy or fluoro;
m is an integer of 0 to 2, and 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 in 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 amino acid derivative ligand is Ac-Gly-OH, and the acrylate is ethyl acrylate; step 2), the polar solvent is methanol, and the alkaline reagent is potassium carbonate; step 3), taking DMF as a polar solvent and potassium carbonate as an alkaline reagent;
R 1 、R 2 、R 3 specific ranges of substituents and m and n are as follows:
R 1 = hydrogen or methyl; r 2 = hydrogen or methyl; r is 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, strong-operability and safe belinostat synthesis method. The first step of the route of the invention uses a C-H functionalization method, which improves the atom economy, has short whole reaction route and short time consumption, improves the reaction efficiency, enhances the production safety and reduces the environmental pollution, and is suitable for large-scale industrial production.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. The experimental methods in the examples, in which specific conditions are not specified, are generally performed under the conventional conditions and the conditions described in the manual or under the conditions recommended by the manufacturer; the equipment, materials, reagents and the like used are commercially available unless otherwise specified.
EXAMPLE 1 preparation of template T
2, 5-Dimethylindole (5.0 g, 34.4 mmol) is dissolved in DMF (30 mL) at room temperature, to which is then added KOH (4.8 g, 86.1 mmol). After 15 minutes reaction at room temperature, I will dissolve 2 A solution of (8.7 g, 34.4 mmol) in DMF was added dropwise to the mixture and the reaction was continued for 4 h. After the reaction was completed, the mixture was poured with Na 2 SO 3 (500 mL, 0.1%) in ice-water solution, a light orange precipitate formed. Filtering the mixed solution, and precipitatingAfter air drying, a light orange solid (8.8 g) was obtained in 94.3% yield with a melting point of 134-135% o C。
2-Benzenecarbonitrile pinaborate (3.8 g, 16.6 mmol) was dissolved in 1, 4-dioxane (40 mL) and the intermediate 3-iodo-2, 5-dimethyl-1 from the previous step was added sequentiallyHIndole (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 temperature of the reaction was raised to 80 o And C, reacting for 16 h under the protection of argon. After completion of 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 purified over anhydrous Na 2 SO 4 Drying, filtering, concentrating, and performing column chromatography to obtain template T 1 (1.6 g, 70.5%) 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.
Grey solid, melting point 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 sodium hydride (60% wt, 97.6 mg, 2.44 mmol) was added to the solution under ice bath conditions. After the reaction mixture was stirred for 15 minutes, benzenesulfonyl chloride (286.81 mg, 1.62 mmol) was added, followed by warming to room temperature overnight for reaction. After the reaction was complete, quench with water (40 mL) and extract with ethyl acetate (2X 30 mL) and separate the oil phase over anhydrous Na 2 SO 4 Drying, filtering, concentrating, and column chromatography to give intermediate I (258 mg, 82.2%), a white solid, m.p. 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
Intermediate I (3.0 g, 7.8 mmol) dissolved in HFIP (40 mL) was charged to a 100 mL flask to which was added successively Pd (OAc) 2 (174.3 mg, 0.78 mmol), agOAc (3.9 g, 23.3 mmol), ac-Gly-OH (181.8 mg, 1.55 mmol) was stirred at room temperature for 15 minutes, ethyl acrylate (1.69 mL, 15.5 mmol) was added, and the temperature was raised to 80 o C, reacting for 24 hours. After the reaction was complete, it was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to give yellow oil II (1.7 g, 45%).
EXAMPLE 4 preparation of intermediate II Process two
Intermediate I (3.0 g, 7.8 mmol) dissolved in HFIP (40 mL) was charged to a 100 mL flask to which was added successively Pd (OAc) 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 drawing a vacuum from the flask and passing O through 2 Repeating the reaction for three times, and heating to 80 DEG C o C, reacting for 24 hours. After the reaction was complete, it was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to give yellow oil II (1.6 g, 43%).
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), anhydrous potassium carbonate (0.97 g, 7.0 mmol) was added, and the mixture was stirred at 70 o Stirring overnight under 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 pH of the aqueous phase is adjusted to 2-3 with 1 mol/L hydrochloric acid aqueous solution, and then the water is dried by spinning. The mixture was then dissolved in DMF (20 mL), to which was added potassium carbonate (1.45 g, 10.5 mmol), methyl iodide (0.44 mL, 7 mmol, 2.0 equiv), and stirred at room temperature overnight. After the reaction is completed, the solvent is removed under vacuum to obtain a crude intermediate III which is directly fed into the next step without further purification, while the template T is removed 1 (0.76 g, 88%) was recovered.
EXAMPLE 6 preparation of intermediate IV
The intermediate III is dissolved in toluene, then excess thionyl chloride is added and a few drops of DMF are added as catalyst and the mixture is heated to 70 deg.C o And C, reacting overnight. After the reaction was completed, the excess reagent was distilled off, and then the residue was dissolved in methylene chloride (25 mL), and an excess of pyridine and aniline were added to the mixture to react at room temperature for 4 hours. After the reaction was complete, the excess dichloromethane was evaporated and extracted with ethyl acetate (2 × 30 mL) and the separated oil phase was passed over anhydrous Na 2 SO 4 Drying, filtering, concentrating, and performing column chromatography to obtain intermediate IV (780 mg, 2.45 mmol) as yellow solid with melting point of 144-145 o C, total 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
Dissolving IV (500 mg, 1.6 mmol) in 1 mol/L NaOH methanol solution, and heating to 40-50 oC The reaction was continued for 2 hours while maintaining the temperature, and after completion of the hydrolysis reaction by TLC monitoring, the reaction was stopped and the pH was adjusted to 2.2 with 1 mol/L aqueous hydrochloric acid solution, and a precipitate was formed. Cooling the system to 20-30 deg.C oC Then, the mixture is filtered, filter residues are washed for a plurality of times by water, and the filter residues are transferred into an oven to be dried, so that 0.45 g of crude intermediate acid is finally obtained.
A catalytic amount of DBU (3.7 mg, 0.024 mmol) was dissolved in isopropyl acetate (4 mL) followed by the addition of the intermediate acid from the previous step (0.45 g, 1.5 mmol), and thionyl chloride (0.13 mL, 1.8 mmol/L) in 20-30 oC Stirring was carried out overnight under the conditions. After no reaction material remained as monitored by TLC, the reaction was stopped.
To 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 lowered to 0-10 deg.C oC And starting stirring, slowly dropwise adding the acyl chloride reaction solution in the previous step while stirring, and then raising the temperature to room temperature to continue the reaction until the reaction is finished. And (3) after the reaction is stopped, demixing the system, removing the water phase, carrying out reduced pressure rotary evaporation on the oil phase to remove most of the solvent, adding isopropyl acetate (3 mL) into the oil phase to precipitate the system, adding heptane (5 mL), standing for a period of time, filtering, washing filter residues with heptane for a plurality of times, and drying in an oven to obtain a crude product. The crude product is then dissolved in a solvent mixture (EtOH: H) 2 Recrystallization from O = 1) to give the final product belinostat (0.33 g, 1.0 mmol), a light orange solid, m.p. 172-173 o C from IV-bThe total yield of elinostat 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 method for synthesizing the belinostat is characterized by comprising the following synthetic 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 acrylate, and heating to 80 DEG o C, reacting 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 is finished, the solvent is dried in a rotary manner, the mixture is separated by ethyl acetate and water, the pH value of a water phase is adjusted to 2-3 by acid, and then concentration and drying in a rotary manner are carried out;
3) Dissolving the product in 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 complete, and then 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 until the reaction is complete, and removing the solvent to obtain a product;
dissolving in dichloromethane, adding aniline and pyridine, and reacting at room temperature to obtain an intermediate IV;
5) Hydrolyzing the intermediate IV in a sodium hydroxide methanol solution, then chlorinating by thionyl chloride to obtain sulfonyl chloride, and adding hydroxylamine hydrochloride into the mixture to obtain a final product, namely belinostat;
wherein the indole ring moiety of template T is substituted by m R 2 Substituted by n R on the phenyl ring 3 Substitution;
R 1 、R 2 、R 3 specific ranges of substituents and m and n are as follows:
R 1 = hydrogen, C 1 -C 4 Alkyl or halogen;
R 2 = hydrogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or halogen;
R 3 = hydrogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or halogen;
m is an integer from 0 to 4, and 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, and when n is 0, the ring is unsubstituted; when n is greater than 1, R 3 May be the same or different.
2. The method of synthesizing belinostat according to claim 1, wherein:
the solvent in the step 1) comprises paraxylene, mesitylene, 1, 2-dichloroethane, chloroform, isopropanol, tert-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 (ii) a 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 (ii) a The amino acid derivative ligand comprises valine derivatives, leucine derivatives, isoleucine derivatives, phenylalanine derivatives or glycine derivatives; the acrylate comprises methyl acrylate, ethyl acrylate, propyl acrylate or butyl acrylate;
step 2) the polar solvent comprises methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran; the alkaline agent 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 agent comprises sodium carbonate, potassium carbonate and cesium carbonate;
R 1 、R 2 、R 3 specific ranges for substituents and m and n are as follows:
R 1 = hydrogen, methyl, ethyl, fluorine, chlorine, bromine or iodine;
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 an integer of 0 to 2, and 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 method of synthesizing belinostat according to claim 1, wherein:
the solvent in the step 1) comprises isopropanol, hexafluoroisopropanol or tetrahydrofuran;the palladium catalyst comprises Pd (OAc) 2 Or PdCl 2 (PPh 3 ) 2 (ii) a The oxidant comprises AgOAc and AgNO 3 、Cu(OAc) 2 Or Cu (OAc) 2 (0.5 equiv)+O 2 (ii) a The amino acid derivative ligand comprises valine derivative or glycine derivative; the acrylate comprises methyl acrylate and ethyl acrylate;
step 2) the polar solvent comprises methanol or tetrahydrofuran; the alkaline agent comprises potassium carbonate or sodium hydride;
step 3) the polar solvent comprises acetonitrile or DMF; the alkaline agent comprises sodium carbonate or potassium carbonate;
R 1 、R 2 、R 3 specific ranges for substituents and m and n are as follows:
R 1 hydrogen, methyl or fluorine;
R 2 hydrogen, methyl, methoxy or fluoro;
R 3 hydrogen, methyl, methoxy or fluoro;
m is selected from an integer of 0 to 2, and 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 method of synthesizing belinostat according to claim 1, wherein the method comprises the steps of:
the solvent in the 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 amino acid derivative ligand is Ac-Gly-OH, and the acrylate is ethyl acrylate;
step 2), the polar solvent is methanol, and the alkaline reagent is potassium carbonate;
step 3), taking DMF as a polar solvent and potassium carbonate as an alkaline reagent;
R 1 、R 2 、R 3 specific ranges for substituents and m and n are as follows:
R 1 = hydrogen or methyl; r is 2 = hydrogen or methyl; r is 3 = hydrogen or methoxy; m is selected from 0 or 1, and when m is 0, the ring is unsubstituted;
n is an integer of 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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