CN117384087A - 一种2-氯-n-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺的合成方法 - Google Patents
一种2-氯-n-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺的合成方法 Download PDFInfo
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- CN117384087A CN117384087A CN202311328371.8A CN202311328371A CN117384087A CN 117384087 A CN117384087 A CN 117384087A CN 202311328371 A CN202311328371 A CN 202311328371A CN 117384087 A CN117384087 A CN 117384087A
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 239000003446 ligand Substances 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 230000035484 reaction time Effects 0.000 claims abstract description 13
- 239000011572 manganese Substances 0.000 claims abstract description 8
- 239000007800 oxidant agent Substances 0.000 claims abstract description 8
- 230000001590 oxidative effect Effects 0.000 claims abstract description 5
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 claims abstract description 5
- VNNDVNZCGCCIPA-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;manganese Chemical compound [Mn].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O VNNDVNZCGCCIPA-FDGPNNRMSA-N 0.000 claims abstract description 4
- BKFAZDGHFACXKY-UHFFFAOYSA-N cobalt(II) bis(acetylacetonate) Chemical compound [Co+2].CC(=O)[CH-]C(C)=O.CC(=O)[CH-]C(C)=O BKFAZDGHFACXKY-UHFFFAOYSA-N 0.000 claims abstract description 4
- FJDJVBXSSLDNJB-LNTINUHCSA-N cobalt;(z)-4-hydroxypent-3-en-2-one Chemical compound [Co].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FJDJVBXSSLDNJB-LNTINUHCSA-N 0.000 claims abstract description 4
- HYZQBNDRDQEWAN-LNTINUHCSA-N (z)-4-hydroxypent-3-en-2-one;manganese(3+) Chemical compound [Mn+3].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O HYZQBNDRDQEWAN-LNTINUHCSA-N 0.000 claims abstract description 3
- LHKNFPQRVQCNQY-UHFFFAOYSA-N 4-methylsulfonylbenzamide Chemical compound CS(=O)(=O)C1=CC=C(C(N)=O)C=C1 LHKNFPQRVQCNQY-UHFFFAOYSA-N 0.000 claims abstract description 3
- 101100513612 Microdochium nivale MnCO gene Proteins 0.000 claims abstract description 3
- 229940071125 manganese acetate Drugs 0.000 claims abstract description 3
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 claims abstract description 3
- 230000015572 biosynthetic process Effects 0.000 claims abstract 4
- 238000003786 synthesis reaction Methods 0.000 claims abstract 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000005859 coupling reaction Methods 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 229910052763 palladium Inorganic materials 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000007112 amidation reaction Methods 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 235000011181 potassium carbonates Nutrition 0.000 claims description 8
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- -1 trifluoroacetoxy Chemical group 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000003863 ammonium salts Chemical class 0.000 claims description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- 239000005695 Ammonium acetate Substances 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- 235000019257 ammonium acetate Nutrition 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 2
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 claims description 2
- 239000001099 ammonium carbonate Substances 0.000 claims description 2
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 239000003513 alkali Substances 0.000 claims 1
- 125000002346 iodo group Chemical group I* 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 16
- 238000001228 spectrum Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 229930003231 vitamin Natural products 0.000 description 4
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- 235000013343 vitamin Nutrition 0.000 description 4
- 150000003722 vitamin derivatives Chemical class 0.000 description 4
- CLCPHXRHYYEUME-UHFFFAOYSA-N 2-chloro-4-methylsulfonylbenzoyl chloride Chemical compound CS(=O)(=O)C1=CC=C(C(Cl)=O)C(Cl)=C1 CLCPHXRHYYEUME-UHFFFAOYSA-N 0.000 description 3
- 206010004146 Basal cell carcinoma Diseases 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- AKVCBZWZBMTKMQ-UHFFFAOYSA-N 2-(2-chloro-5-nitrophenyl)pyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 AKVCBZWZBMTKMQ-UHFFFAOYSA-N 0.000 description 2
- HHNHWEOFIGWNRP-UHFFFAOYSA-N 2-(5-bromo-2-chlorophenyl)pyridine Chemical compound ClC1=CC=C(Br)C=C1C1=CC=CC=N1 HHNHWEOFIGWNRP-UHFFFAOYSA-N 0.000 description 2
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 description 2
- QWVLHTCIAZPQAY-UHFFFAOYSA-N 4-chloro-3-pyridin-2-ylaniline Chemical compound NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 QWVLHTCIAZPQAY-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052748 manganese Inorganic materials 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
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- 238000005406 washing Methods 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 description 1
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- NTBYINQTYWZXLH-UHFFFAOYSA-N 1,2-dichloro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(Cl)=C1 NTBYINQTYWZXLH-UHFFFAOYSA-N 0.000 description 1
- STTGYIUESPWXOW-UHFFFAOYSA-N 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline Chemical compound C=12C=CC3=C(C=4C=CC=CC=4)C=C(C)N=C3C2=NC(C)=CC=1C1=CC=CC=C1 STTGYIUESPWXOW-UHFFFAOYSA-N 0.000 description 1
- UPTFPFLOROPWKM-UHFFFAOYSA-N 2-(2-chloro-5-nitrophenyl)-1-oxidopyridin-1-ium Chemical compound [O-][N+](=O)c1ccc(Cl)c(c1)-c1cccc[n+]1[O-] UPTFPFLOROPWKM-UHFFFAOYSA-N 0.000 description 1
- FVZODFVCIDBDGS-UHFFFAOYSA-N 3-bromo-4-chloroaniline Chemical compound NC1=CC=C(Cl)C(Br)=C1 FVZODFVCIDBDGS-UHFFFAOYSA-N 0.000 description 1
- 102220645585 ADP-ribosylation factor-like protein 2_L7A_mutation Human genes 0.000 description 1
- 102220477582 Annexin A8_L2A_mutation Human genes 0.000 description 1
- 102220477583 Annexin A8_L3A_mutation Human genes 0.000 description 1
- 241000027355 Ferocactus setispinus Species 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 102220580228 Non-receptor tyrosine-protein kinase TYK2_L6A_mutation Human genes 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001869 cobalt compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- UZBHNSVUMGIKLU-UHFFFAOYSA-N cyclopenten-1-ylboronic acid Chemical compound OB(O)C1=CCCC1 UZBHNSVUMGIKLU-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
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- KDCMHGOCDYEERH-UHFFFAOYSA-N n-(4-chloro-3-pyridin-2-ylphenyl)benzamide Chemical compound C1=C(C=2N=CC=CC=2)C(Cl)=CC=C1NC(=O)C1=CC=CC=C1 KDCMHGOCDYEERH-UHFFFAOYSA-N 0.000 description 1
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- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
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Abstract
本发明公开了一种2‑氯‑N‑[4‑氯‑3‑(2‑吡啶基)苯基]‑4‑(甲基磺酰基)苯甲酰胺的合成方法,其包括使式V所示的化合物叠氮基三甲基硅烷与氧化剂,在催化剂和配体的存在下,在溶剂中进行反应,制备得到目标产物的步骤,催化剂选自MnCl2、乙酰丙酮锰Mn(acac)2、醋酸锰Mn(OAc)2、MnBr2、MnCO3、MnF2、Mn2(CO)10、CoCl2和乙酰丙酮钴Co(acac)2中的一种或多种的组合。该合成方法反应路线短,反应条件温和,反应速率快,反应时间短,产率高,产品纯度较高,绿色环保成本较低。
Description
技术领域
本发明涉及一种2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺的合成方法。
背景技术
维莫德吉(Vismodegib),商品名为:Erivedge;是Genentech有限公司申请开发的并于2012年01月30日被美国食品药品监督管理局(FDA)第一个批准上市用于治疗晚期皮肤基底细胞癌(BCC)的抗肿瘤新药之一。维莫德吉是首个口服、具有高选择性的Hedgehog通路小分子抑制剂,主要用于已经不能开刀或化疗治疗的局部晚期基底细胞癌或癌变已扩散至身体其他器官的基底细胞癌患者的治疗。自2012年10月以来,Erivedge已获欧盟、瑞士、澳大利亚、以色列、韩国、墨西哥、厄瓜多尔批准。
维莫德吉CAS号:879085-55-9,中文名称:2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺,英文名称:2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide。其结构式如下所示:
对于维莫德吉(Vismodegib)的制备,主要有以下几种合成方案:
1、原研专利WO2006028958A1采用合成路线1(如下所示)制备维莫德吉。该路线以3-卤素-4-氯硝基苯和2-卤素吡啶为原料,先将2-卤素吡啶在ZnCl2和正丁基锂的作用下,制备有机锌试剂,该试剂经钯催化偶联反应制备2-(2-氯-5-硝基苯基)吡啶,后经还原反应将硝基还原为氨基,最后进行缩合反应得到维莫德吉。该合成路线涉及有机锌试剂的制备,该步反应需要严格的无水无氧反应条件,且使用的正丁基锂易燃易爆,在工业生产中较为危险,难以工业化生产。
2、中国专利CN103910671A通过2-氯-5-硝基氯苯与吡啶-N-氧化物的钯催化偶联反应,生成2-(2-氯-5-硝基苯基)吡啶-N-氧化物,然后经过三氯氧磷脱氧还原得到2-(2-氯-5-硝基苯基)吡啶,再使用铁粉还原硝基生成2-(2-氯-5-氨基苯基)吡啶,最后与2-氯-4-甲砜基苯甲酰氯经酰胺化反应得到维莫德吉(反应式如下所示)。该方案第一步的钯催化偶联反应时间需要2天,产率为60%,原料成本高,反应时间长,产率较低,且第二步使用三氯氧磷,会产生大量含磷废水,不利于环保。
3、中国专利CN104926714A通过对2-苯基吡啶采用一锅法依次完成Ru试剂催化的溴代反应与铜催化的氯代反应,生成2-(2-氯-5-溴苯基)吡啶,然后N2保护下经铜催化与苯甲酰胺反应生成2-(2-氯-5-苯甲酰胺基苯基)吡啶,再经过20%硫酸水解制备2-(2-氯-5-氨基苯基)吡啶,最后与2-氯-4-甲砜基苯甲酰氯经酰胺化反应得到维莫德吉(合成路线如下所示)。该方案采用酰胺水解的方式引入氨基,该步反应产率较高。但是第一步中,一锅法进行催化溴代与催化氯代需要3天,反应时间长,反应速率慢,且氯代溴代反应位点较多,该步骤较易发生副反应,生成的2-(2-氯-5-溴苯基)吡啶纯度较低,且Ru催化剂昂贵成本较高,不利于工业化生产。
发明内容
针对现有技术的缺点和不足,本发明提供了一种2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺(维莫德吉)的合成方法,该合成方法反应路线短,反应条件温和,反应速率快,反应时间短,产率高,产品纯度较高,绿色环保成本较低。
为达到上述目的,本发明采用的技术方案如下:
一种2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺的合成方法,所述合成方法包括使式V所示的化合物叠氮基三甲基硅烷与氧化剂,在催化剂和配体的存在下,在溶剂中进行反应,制备得到所述2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺/>的步骤,所述催化剂选自MnCl2、乙酰丙酮锰Mn(acac)2、醋酸锰Mn(OAc)2、MnBr2、MnCO3、MnF2、Mn2(CO)10、CoCl2和乙酰丙酮钴Co(acac)2中的一种或多种的组合。
现有技术中合成2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺(维莫德吉)时,通常以含有吡啶基团的化合物为原料,或者在反应路线中引入吡啶基团,而本发明与传统吡啶基团的引入方式不同,本发明通过采用锰化合物或者钴化合物作为催化剂,催化叠氮基三甲基硅烷,氧化剂与式V所示的化合物进行反应,叠氮基三甲基硅烷在氧化剂和催化剂的作用下,先生成叠氮自由基,同时催化剂被氧化为相应的三价化合物,叠氮自由基与式V所示的化合物中的环戊烯基团进行加成,之后释放氮气后,氮自由基部分与环戊基部分进行重排反应,得到含有吡啶基团及自由基的中间体,中间体再与催化剂对应的三价化合物进行反应,得到最终产物,同时催化剂恢复二价形态,该反应步骤将N原子“插入”式V所示的化合物中的环戊烯基团中,是合成维莫德吉目标产物的一种全新的反应路线。该反应路线的反应条件温和,采用的催化剂成本较低,且反应收率较高。并且,本发明采用锰化合物作为该步骤的催化剂时,其反应速率比钴化合物作为催化剂时更快。
在一些实施方式中,所述反应在铵盐的存在下进行,所述铵盐选自醋酸铵、碳酸铵、氯化铵、四丁基碘化铵、四丁基溴化铵和四丁基氯化铵中的一种或多种的组合。
优选地,所述铵盐为醋酸铵。
本发明人通过研究发现,通过在上述反应中加入铵盐,可以进一步提高目标产物维莫德吉的收率。
在一些实施方式中,所述铵盐与所述式V所示的化合物的摩尔比为0.5-2.0:1。
在一些实施方式中,所述配体为选自如下结构所示化合物:
其中,
Ph为苯环。
本发明人通过研究发现,采用上述L1-L8化合物作为催化剂的配体,可以明显提高目标产物的收率。
在一些实施方式中,所述氧化剂选自氧气、碘单质、醋酸碘苯、[双(三氟乙酰氧基)碘]苯、二叔丁基过氧化物、过硫酸钾、醋酸铜和2-碘酰基苯甲酸中的一种或多种的组合。
优选地,所述氧化剂为氧气。
在一些实施方式中,所述溶剂选自甲苯、1,4-二氧六环、二氯甲烷、乙二醇二甲醚、N,N-二甲基甲酰胺、四氢呋喃、乙腈、甲基叔丁基醚和水中的一种或多种的组合。
优选地,所述溶剂为乙二醇二甲醚和乙腈体积比为2:1的混合溶剂。采用该溶剂相对于其他溶剂,可以实现目标产物更高的收率。
在一些实施方式中,所述催化剂和式V所示的化合物的摩尔比为0.01-0.2:1。
优选地,所述催化剂和式V所示的化合物的摩尔比为0.1:1。
在一些实施方式中,所述配体和式V所示的化合物的摩尔比为0.1-0.5:1。
优选地,所述配体和式V所示的化合物的摩尔比为0.2:1。
在一些实施方式中,所述叠氮基三甲基硅烷和式V所示的化合物的摩尔比为1:1.0-3.0。
在一些实施方式中,所述氧化剂为氧气,所述反应在氧气环境中进行。
在一些实施方式中,所述反应的温度为50-100℃。
在一些实施方式中,所述反应的时间为3-12h。
在一些实施方式中,所述合成方法还包括使式III所示的化合物
与式IV所示的化合物/>在碱性条件下,在有机溶剂中进行酰胺化反应,生成所述式V所示的化合物的步骤。
在一些实施方式中,所述碱性条件通过加入选自三乙胺和碳酸钾中的一种或两种碱形成。
优选地,所述碱性条件通过加入碳酸钾形成。
在一些实施方式中,所述式III所示的化合物与式IV所示的化合物的摩尔比为1:1.0-1.5:
在一些实施方式中,所述有机溶剂选自二氯甲烷、N,N-二甲基甲酰胺和四氢呋喃中的一种或多种的组合。
优选地,所述有机溶剂选自二氯甲烷。
在一些实施方式中,所述酰胺化反应的温度为20-35℃。
在一些实施方式中,所述酰胺化反应的时间为2-5h。
在一些实施方式中,所述合成方法还包括使式I所示的化合物与式II所示的化合物/>在钯催化剂的存在下,进行偶联反应,生成所述式III所示的化合物的步骤,其中,在式I中,X为溴Br或碘I。
式I所示的化合物中,X原子位于氨基的间位,偶联反应容易在X位置进行,且反应不涉及间位的氨基,该步骤反应收率高,目标产物III的选择性高。因此,采用本发明的反应路线,无需使用硝基后续再还原为氨基,而可以直接使用含有氨基的示I所示的化合物作为原料。
在一些实施方式中,所述钯催化剂选自醋酸钯、氯化钯、四三苯基膦钯、(1,1'-双(二苯基膦基)二茂铁)二氯化钯Pd(dppf)Cl2和二(三苯基膦)二氯化钯Pd(PPh3)2Cl2中的一种或多种的组合。
优选地,所述钯催化剂为四三苯基膦钯。
在一些实施方式中,所述偶联反应在碱性条件下进行,所述碱性条件通过加入选自碳酸铯、碳酸钾、碳酸钠,碳酸氢钾和碳酸氢钠中的一种或两种碱形成。
优选地,所述碱性条件通过加入碳酸钾形成。
在一些实施方式中,所述偶联反应在选自甲苯、乙醇、1,4-二氧六环、N,N-二甲基甲酰胺、二甲基亚砜、乙腈、甲醇和水中的一种或多种的组合的溶剂中进行。
优选地,所述偶联反应在甲苯、乙醇、水体积比为3:1:1的混合溶剂中进行。
在一些实施方式中,所述式I所示的化合物与所述式II所示的化合物的摩尔比为1:1.0-1.5。
在一些实施方式中,所述钯催化剂和式I所示的化合物的摩尔比为0.01-0.2:1,优选0.025:1。
在一些实施方式中,所述偶联反应的温度为90-130℃。
在一些实施方式中,所述偶联反应的时间为10-14h。
本发明还请求保护一种适用于制备2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺的化合物,所述化合物具有下式III或式V所示的结构:
与现有技术相比,本发明具有如下优势:
本发明合成2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺(维莫德吉)时,不采用传统吡啶基团的引入方式,而是在含有环戊烯基的式V所示的化合物中插入N原子,再经过重排反应生成吡啶基团,是合成维莫德吉目标产物的一种全新的反应路线。该反应路线的反应条件温和,采用的催化剂成本较低,且反应收率较高。
本发明在式V所示的化合物制备目标产物的步骤中,通过添加铵盐,可以进一步提高目标产物的收率。通过选择特定种类的配体,可以使得目标产物的收率高。
本发明从起始原料式I所示的化合物到最终目标产物,只需要三步反应,反应路线简单,而现有技术中通常至少需要四步反应,且本发明的反应过程中不涉及对水对氧气敏感的原料或者中间体,反应条件温和,也不涉及三氯氧磷,反应路线环保。
本发明采用的起始原料式I所示的化合物在X位置上偶联反应选择性高,第一步反应收率很高,能够达到94%,且第二步反应收率也能达到92%,第三步反应收率也较高,能够达到68%,因此目标产物的总体收率高。
本发明的三步反应的反应速率均较快,反应时间短。
附图说明
图1为实施例1制备得到的式III所示的化合物的核磁氢谱图;
图2为实施例1制备得到的式III所示的化合物的核磁碳谱图;
图3为实施例1制备得到的式V所示的化合物的核磁氢谱图;
图4为实施例1制备得到的式V所示的化合物的核磁碳谱图;
图5为实施例1制备得到的式VI所示的化合物的核磁氢谱图;
图6为实施例1制备得到的式VI所示的化合物的核磁碳谱图。
具体实施方式
下面结合实施例对本发明作进一步描述。但本发明并不限于以下实施例。实施例中采用的实施条件可以根据具体使用的不同要求做进一步调整,未注明的实施条件为本行业中的常规条件。本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
实施例1
本实施例提供一种2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺(式VI所示的化合物)的制备方法,具体如下:
步骤一:4-氯-3-(环戊-1-烯-1-基)苯胺(式III所示的化合物)的制备
向100ml的三口烧瓶中分别加入10mmol 3-溴-4-氯苯胺(式I),12mmol1-环戊烯基硼酸(式II),0.25mmol四三苯基膦钯Pd(PPh3)4,30mmol碳酸钾,加入20ml溶剂(甲苯:乙醇:水=3:1:1,体积比),N2置换三次,N2保护下110℃反应12小时,反应完成后乙酸乙酯萃取3次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂,柱纯化(石油醚:乙酸乙酯=5:1,体积比),得产物4-氯-3-(环戊-1-烯-1-基)苯胺(式III),收率94%。
式III化合物的核磁氢谱图如图1所示,核磁氢谱数据为:1H NMR(400MHz,CDCl3)δ7.12(d,J=8.4Hz,1H),6.60(d,J=2.8Hz,1H),6.49(dd,J=8.5,2.8Hz,1H),6.08(s,1H),3.50(s,2H),2.74–2.69(m,2H),2.55–2.50(m,2H),2.03–1.96(m,2H).式III化合物的核磁碳谱图如图2所示,核磁碳谱数据为:13C NMR(101MHz,CDCl3)δ144.8,141.4,137.7,131.3,130.6,121.6,116.2,114.7,35.9,33.5,23.7。
步骤二:2-氯-N-(4-氯-3-(环戊-1-烯-1-基)苯基)-4-(甲基磺酰基)苯甲酰胺(式V所示的化合物)的制备
在50ml茄形瓶中,将5mmol 4-氯-3-(环戊-1-烯-1-基)苯胺)(式III)溶于30ml干燥的二氯甲烷中,加入10mmol碳酸钾,混合物用冰水浴降温至0℃,缓慢加入5.5mmol 2-氯-4-(甲基磺酰基)苯甲酰氯,反应移至室温后继续反应3小时,反应结束后,加水20ml,二氯甲烷萃取三次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂后用二氯甲烷和石油醚打浆,得白色固体产物2-氯-N-(4-氯-3-(环戊-1-烯-1-基)苯基)-4-(甲基磺酰基)苯甲酰胺(式V),收率92%。
式V化合物的核磁氢谱图如图3所示,核磁氢谱数据为:1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.13(d,J=1.7Hz,1H),8.01(dd,J=8.0,1.7Hz,1H),7.89(d,J=7.9Hz,1H),7.76(d,J=2.6Hz,1H),7.59(dd,J=8.7,2.6Hz,1H),7.44(d,J=8.7Hz,1H),6.24–6.04(m,1H),3.35(s,3H),2.72–2.67(m,2H),2.55–2.50(m,2H),2.00–1.94(m,2H).式V化合物的核磁碳谱图如图4所示,核磁碳谱数据为:13C NMR(101MHz,DMSO-d6)δ164.2,143.6,141.4,140.9,137.9,137.1,132.1,131.4,130.8,130.4,128.6,126.5,126.4,121.0,119.9,43.6,36.0,33.6,23.6.
步骤三:维莫德吉(式VI所示的化合物)的制备
在100ml茄形瓶中,依次加入3mmol 2-氯-N-(4-氯-3-(环戊-1-烯-1-基)苯基)-4-(甲基磺酰基)苯甲酰胺(式V),7.5mmol叠氮基三甲基硅烷(TMSN3),0.3mmol MnCl2,0.6mmol2,9-二甲基-4,7-二苯基-1,10-菲啰啉(配体L4),3mmol醋酸铵,加入20ml溶剂(乙二醇二甲醚:乙腈=2:1,体积比),置换氧气三次,然后80℃反应3小时,反应完成后柱纯化(石油醚:乙酸乙酯=2:1,体积比),得白色固体维莫德吉,收率68%。
式VI化合物的核磁氢谱图如图5所示,核磁氢谱数据为:1H NMR(400MHz,CDCl3)δ9.98(s,1H),8.35(dd,J=5.0,0.8Hz,1H),7.99(dd,J=8.7,2.6Hz,1H),7.81(d,J=1.7Hz,1H),7.72(td,J=7.7,1.8Hz,1H),7.69–7.63(m,3H),7.50(d,J=7.9Hz,1H),7.45(d,J=8.8Hz,1H),7.20–7.16(m,1H),2.97(s,3H).式VI化合物的核磁碳谱图如图6所示,核磁碳谱数据为:13C NMR(101MHz,CDCl3)δ163.9,155.7,148.7,142.5,140.7,138.4,137.1,136.5,132.3,131.0,129.9,128.8,127.3,125.7,125.5,122.9,122.8,121.8,44.3.
实施例2
基本同实施例1,区别仅在于:将步骤三中的MnCl2替换为Mn(acac)2,结果步骤三的收率为34%。
实施例3
基本同实施例1,区别仅在于:将步骤三中的MnCl2替换为Mn(OAc)2,结果步骤三的收率为39%。
实施例4
基本同实施例1,区别仅在于:将步骤三中的MnCl2替换为MnBr2,反应时间由3h替换为24h,结果步骤三的收率为65%。
实施例5
基本同实施例1,区别仅在于:将步骤三中的MnCl2替换为乙酰丙酮钴Co(acac)2,反应时间由3h替换为24h,结果步骤三的收率为66%。可见,采用锰催化剂时,步骤三的反应速率更快。
实施例6
基本同实施例1,区别仅在于:将步骤三中的配体L4替换为配体L2结果步骤三的收率为53%。
实施例7
基本同实施例1,区别仅在于:将步骤三中的配体L4替换为配体L3结果步骤三的收率为25%。
实施例8
基本同实施例1,区别仅在于:将步骤三中的配体L4替换为配体L6结果步骤三的收率为22%。
实施例9
基本同实施例1,区别仅在于:将步骤三中的配体L4替换为配体L7结果步骤三的收率为38%。
实施例10
基本同实施例1,区别仅在于:将步骤三中的配体L4替换为配体L8
结果步骤三的收率为25%。
实施例11
基本同实施例1,区别仅在于:步骤三中不加入醋酸铵,结果步骤三的收率为59%。
实施例12
基本同实施例1,区别仅在于:步骤一中采用替换/>作为初始原料,结果步骤一的收率为96%。
对比例1
基本同实施例1,区别仅在于:将步骤三中的配体L4替换为以下结构式的配体结果步骤三的收率为7%。
对比例2
基本同实施例1,区别仅在于:将步骤三中的MnCl2替换为FeCl2,结果步骤三无法得到目标产物式VI化合物。
对比例3
基本同实施例1,区别仅在于:将步骤三中的MnCl2替换为乙酰丙酮镍Ni(acac)2,结果步骤三无法得到目标产物式VI化合物。
对比例4
基本同实施例1,区别仅在于:将步骤三中的MnCl2替换为醋酸钯Pd(OAc)2,结果步骤三无法得到目标产物式VI化合物。
可见,本发明通过在步骤三选择特定种类的催化剂和配体,可以以较高收率来合成目标产物。
上述实施例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
Claims (10)
1.一种2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺的合成方法,其特征在于:所述合成方法包括使式V所示的化合物叠氮基三甲基硅烷与氧化剂,在催化剂和配体的存在下,在溶剂中进行反应,制备得到所述2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺
的步骤,所述催化剂选自MnCl2、乙酰丙酮锰Mn(acac)2、醋酸锰Mn(OAc)2、MnBr2、MnCO3、MnF2、Mn2(CO)10、CoCl2和乙酰丙酮钴Co(acac)2中的一种或多种的组合。
2.根据权利要求1所述的合成方法,其特征在于:所述反应在铵盐的存在下进行,所述铵盐选自醋酸铵、碳酸铵、氯化铵、四丁基碘化铵、四丁基溴化铵和四丁基氯化铵中的一种或多种的组合。
3.根据权利要求1所述的合成方法,其特征在于:所述配体为选自如下结构所示化合物:
其中,Ph为苯环;和/或,所述氧化剂选自氧气、碘单质、醋酸碘苯、[双(三氟乙酰氧基)碘]苯、二叔丁基过氧化物、过硫酸钾、醋酸铜和2-碘酰基苯甲酸中的一种或多种的组合;和/或,所述溶剂选自甲苯、1,4-二氧六环、二氯甲烷、乙二醇二甲醚、N,N-二甲基甲酰胺、四氢呋喃、乙腈、甲基叔丁基醚和水中的一种或多种的组合。
4.根据权利要求1所述的合成方法,其特征在于:所述催化剂和式V所示的化合物的摩尔比为0.01-0.2:1;和/或,所述配体和式V所示的化合物的摩尔比为0.1-0.5:1;
和/或,所述叠氮基三甲基硅烷和式V所示的化合物的摩尔比为1.0-3.0:1。
5.根据权利要求1所述的合成方法,其特征在于:所述氧化剂为氧气,所述反应在氧气环境中进行;和/或,所述反应的温度为50-100℃;和/或,所述反应的时间为3-12h。
6.根据权利要求1所述的合成方法,其特征在于:所述合成方法还包括使式III所示的化合物与式IV所示的化合物/>在碱性条件下,在有机溶剂中进行酰胺化反应,生成所述式V所示的化合物的步骤。
7.根据权利要求6所述的合成方法,其特征在于:所述碱性条件通过加入选自三乙胺和碳酸钾中的一种或两种碱形成;和/或,所述式III所示的化合物与式IV所示的化合物的摩尔比为1:1.0-1.5;和/或,所述有机溶剂选自二氯甲烷、N,N-二甲基甲酰胺和四氢呋喃中的一种或多种的组合;和/或,所述酰胺化反应的温度为20-35℃;和/或,所述酰胺化反应的时间为2-5h。
8.根据权利要求6所述的合成方法,其特征在于:所述合成方法还包括使式I所示的化合物与式II所示的化合物/>在钯催化剂的存在下,进行偶联反应,生成所述式III所示的化合物的步骤,其中,在式I中,X为溴Br或碘I。
9.根据权利要求8所述的合成方法,其特征在于:所述钯催化剂选自醋酸钯、氯化钯、四三苯基膦钯、(1,1'-双(二苯基膦基)二茂铁)二氯化钯Pd(dppf)Cl2和二(三苯基膦)二氯化钯Pd(PPh3)2Cl2中的一种或多种的组合;和/或,所述偶联反应在碱性条件下进行,所述碱性条件通过加入选自碳酸铯、碳酸钾、碳酸钠,碳酸氢钾和碳酸氢钠中的一种或两种碱形成;和/或,所述偶联反应在选自甲苯、乙醇、1,4-二氧六环、N,N-二甲基甲酰胺、二甲基亚砜、乙腈、甲醇和水中的一种或多种的组合的溶剂中进行;和/或,所述式I所示的化合物与所述式II所示的化合物的摩尔比为1:1.0-1.5;和/或,所述偶联反应的温度为90-130℃;和/或,所述偶联反应的时间为10-14h。
10.一种适用于制备2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)苯甲酰胺的化合物,其特征在于:所述化合物具有下式III或式V所示的结构:
。
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