CN1478778A - 抗真菌剂及其制备方法和中间体 - Google Patents
抗真菌剂及其制备方法和中间体 Download PDFInfo
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- CN1478778A CN1478778A CNA031451500A CN03145150A CN1478778A CN 1478778 A CN1478778 A CN 1478778A CN A031451500 A CNA031451500 A CN A031451500A CN 03145150 A CN03145150 A CN 03145150A CN 1478778 A CN1478778 A CN 1478778A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 131
- 239000003429 antifungal agent Substances 0.000 title abstract description 18
- 229940121375 antifungal agent Drugs 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 548
- 238000000034 method Methods 0.000 claims abstract description 179
- 150000003839 salts Chemical class 0.000 claims abstract description 134
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 90
- 125000005843 halogen group Chemical group 0.000 claims abstract description 76
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 60
- -1 diethyl methylene Chemical group 0.000 claims description 116
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 91
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 72
- 239000002585 base Substances 0.000 claims description 69
- 239000002253 acid Substances 0.000 claims description 63
- 239000000460 chlorine Substances 0.000 claims description 45
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 42
- 125000000623 heterocyclic group Chemical group 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 125000005842 heteroatom Chemical group 0.000 claims description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 229920006395 saturated elastomer Polymers 0.000 claims description 28
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 18
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 18
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 17
- 230000001476 alcoholic effect Effects 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 239000012312 sodium hydride Substances 0.000 claims description 16
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 150000004965 peroxy acids Chemical class 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- 150000002460 imidazoles Chemical class 0.000 claims description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- 229910052740 iodine Chemical group 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- 150000001350 alkyl halides Chemical class 0.000 claims description 7
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 claims description 7
- GNLJBJNONOOOQC-UHFFFAOYSA-N $l^{3}-carbane;magnesium Chemical compound [Mg]C GNLJBJNONOOOQC-UHFFFAOYSA-N 0.000 claims description 6
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical group FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 claims description 6
- JNRLEMMIVRBKJE-UHFFFAOYSA-N 4,4'-Methylenebis(N,N-dimethylaniline) Chemical class C1=CC(N(C)C)=CC=C1CC1=CC=C(N(C)C)C=C1 JNRLEMMIVRBKJE-UHFFFAOYSA-N 0.000 claims description 6
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 238000006277 sulfonation reaction Methods 0.000 claims description 6
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 claims description 5
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 5
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 5
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 5
- LPSWFOCTMJQJIS-UHFFFAOYSA-N sulfanium;hydroxide Chemical compound [OH-].[SH3+] LPSWFOCTMJQJIS-UHFFFAOYSA-N 0.000 claims description 5
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 claims description 5
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 5
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims description 5
- VQFAIAKCILWQPZ-UHFFFAOYSA-N bromoacetone Chemical compound CC(=O)CBr VQFAIAKCILWQPZ-UHFFFAOYSA-N 0.000 claims description 4
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 claims description 4
- 150000002443 hydroxylamines Chemical class 0.000 claims description 4
- VQEVKEKJZVEGPH-UHFFFAOYSA-N lithium;chloromethane Chemical compound [Li+].Cl[CH2-] VQEVKEKJZVEGPH-UHFFFAOYSA-N 0.000 claims description 4
- FXFXBGVSPSAHDI-UHFFFAOYSA-M magnesium;methanidyl(trimethyl)silane;bromide Chemical compound [Mg+2].[Br-].C[Si](C)(C)[CH2-] FXFXBGVSPSAHDI-UHFFFAOYSA-M 0.000 claims description 4
- BXBLTKZWYAHPKM-UHFFFAOYSA-M magnesium;methanidyl(trimethyl)silane;chloride Chemical compound [Mg+2].[Cl-].C[Si](C)(C)[CH2-] BXBLTKZWYAHPKM-UHFFFAOYSA-M 0.000 claims description 4
- QRPRIOOKPZSVFN-UHFFFAOYSA-M methyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 QRPRIOOKPZSVFN-UHFFFAOYSA-M 0.000 claims description 4
- JNMIXMFEVJHFNY-UHFFFAOYSA-M methyl(triphenyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 JNMIXMFEVJHFNY-UHFFFAOYSA-M 0.000 claims description 4
- HIQXJRBKNONWAH-UHFFFAOYSA-N methylidenephosphane Chemical compound P=C HIQXJRBKNONWAH-UHFFFAOYSA-N 0.000 claims description 4
- REPWBKQJAMXHFL-UHFFFAOYSA-N phenylphosphane;hydrobromide Chemical class [Br-].[PH3+]C1=CC=CC=C1 REPWBKQJAMXHFL-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Chemical class 0.000 claims description 3
- 230000026030 halogenation Effects 0.000 claims description 3
- 238000005658 halogenation reaction Methods 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- JJNUJWMGIWJSLT-UHFFFAOYSA-N lithium trimethylsilanide Chemical compound [Li+].C[Si-](C)C JJNUJWMGIWJSLT-UHFFFAOYSA-N 0.000 claims description 3
- 229940107700 pyruvic acid Drugs 0.000 claims description 3
- 150000003536 tetrazoles Chemical group 0.000 claims description 3
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 125000005059 halophenyl group Chemical group 0.000 claims 1
- 150000002391 heterocyclic compounds Chemical class 0.000 claims 1
- 150000003557 thiazoles Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 133
- 230000008569 process Effects 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 211
- 239000000243 solution Substances 0.000 description 172
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 140
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 122
- 239000002904 solvent Substances 0.000 description 117
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 112
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 104
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- 238000005481 NMR spectroscopy Methods 0.000 description 76
- 239000011541 reaction mixture Substances 0.000 description 75
- 230000000704 physical effect Effects 0.000 description 66
- 239000007788 liquid Substances 0.000 description 65
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- 235000019439 ethyl acetate Nutrition 0.000 description 62
- 239000012044 organic layer Substances 0.000 description 57
- 238000005406 washing Methods 0.000 description 55
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 52
- 239000007787 solid Substances 0.000 description 51
- 238000003756 stirring Methods 0.000 description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
- 238000013459 approach Methods 0.000 description 37
- 239000007864 aqueous solution Substances 0.000 description 36
- 239000000741 silica gel Substances 0.000 description 36
- 229910002027 silica gel Inorganic materials 0.000 description 36
- 229960001866 silicon dioxide Drugs 0.000 description 36
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 35
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- 238000000605 extraction Methods 0.000 description 33
- 238000001035 drying Methods 0.000 description 32
- 235000019441 ethanol Nutrition 0.000 description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 31
- 239000000047 product Substances 0.000 description 30
- 238000010438 heat treatment Methods 0.000 description 29
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 26
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- 239000000284 extract Substances 0.000 description 23
- 238000010025 steaming Methods 0.000 description 22
- 239000000725 suspension Substances 0.000 description 21
- 238000003810 ethyl acetate extraction Methods 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 19
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 17
- 229910052760 oxygen Inorganic materials 0.000 description 17
- 239000002994 raw material Substances 0.000 description 17
- 229910004298 SiO 2 Inorganic materials 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- 235000019270 ammonium chloride Nutrition 0.000 description 13
- JVCOJGPZLXNDBU-UHFFFAOYSA-N 6-chloro-2-ethyl-1,3-benzothiazole Chemical compound C1=C(Cl)C=C2SC(CC)=NC2=C1 JVCOJGPZLXNDBU-UHFFFAOYSA-N 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 11
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- LJANCPRIUMHGJE-UHFFFAOYSA-N 4-(2-bromoacetyl)benzonitrile Chemical compound BrCC(=O)C1=CC=C(C#N)C=C1 LJANCPRIUMHGJE-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 230000004083 survival effect Effects 0.000 description 9
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 239000000654 additive Substances 0.000 description 7
- 230000000996 additive effect Effects 0.000 description 7
- 230000001857 anti-mycotic effect Effects 0.000 description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
- 239000011777 magnesium Substances 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 150000008064 anhydrides Chemical class 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 6
- 229910001873 dinitrogen Inorganic materials 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
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- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004802 cyanophenyl group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- IRDLUHRVLVEUHA-UHFFFAOYSA-N diethyl dithiophosphate Chemical compound CCOP(S)(=S)OCC IRDLUHRVLVEUHA-UHFFFAOYSA-N 0.000 description 1
- LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 description 1
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 description 1
- NKRNGKIEDAVMHL-UHFFFAOYSA-L dihydroxy(dioxo)chromium;pyridine Chemical compound O[Cr](O)(=O)=O.C1=CC=NC=C1 NKRNGKIEDAVMHL-UHFFFAOYSA-L 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- HXBZCHYDLURWIZ-UHFFFAOYSA-N diphenyl hydrogen phosphate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 HXBZCHYDLURWIZ-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- FDLDWKIEWAWOSL-UHFFFAOYSA-N ethyl acetate;2-methylpentane Chemical compound CCCC(C)C.CCOC(C)=O FDLDWKIEWAWOSL-UHFFFAOYSA-N 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- BNSOYWDFFBDEFB-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O BNSOYWDFFBDEFB-UHFFFAOYSA-L 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- AZFQCTBZOPUVOW-UHFFFAOYSA-N methyl(triphenyl)phosphanium Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 AZFQCTBZOPUVOW-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Substances [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 1
- CKLHRQNQYIJFFX-UHFFFAOYSA-K ytterbium(III) chloride Chemical class [Cl-].[Cl-].[Cl-].[Yb+3] CKLHRQNQYIJFFX-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/17—Unsaturated ethers containing halogen
- C07C43/174—Unsaturated ethers containing halogen containing six-membered aromatic rings
- C07C43/176—Unsaturated ethers containing halogen containing six-membered aromatic rings having unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
- C07C43/1786—Unsaturated ethers containing hydroxy or O-metal groups containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
右通式所示的化合物或其盐,其中间体或中间体的盐,以及其制备方法和适于作为抗真菌剂的药物组合物:其中R1和R2表示卤原子或氢原子;R3表示氢原子或低级烷基;l、r和m为0或1;A为N或CH;W、X、Y和Z如权利要求书中所定义。
Description
本申请是申请号为CN00130440.2母案的分案申请。该母案的申请日为1995年2月6日;发明名称为“抗真菌剂及其制备方法和中间体”。
技术领域
本发明涉及一种抗真菌剂,尤其是,本发明涉及用于治疗皮肤真菌病、内脏真菌病等的抗真菌剂。具体来说,本发明涉及含有5元杂环或其稠环的衍生物及其酸加成盐,它们用作抗真菌剂。而且,本发明涉及制备此衍生物和酸加成盐的方法,和含有该衍生物及其可药用盐的药物组合物。
更进一步,本发明涉及用作抗真菌剂的唑类化合物的合成中间体及其制备方法。特别是,本发明涉及用于制备对治疗皮肤真菌病、内脏微细感染(Visceral micotic infection)等有效的抗真菌剂的合成中间体,及其制备方法。
背景技术
在抗真菌剂领域中,在此之前已将两性霉素B(amphoterin B)或其类似物用于如治疗深度真菌。然而,唑类合成的抗真菌剂最近得到了发展。但即使在这些唑类的抗真菌剂中,也渴求从其抑制病人免疫功能作用的观点出发来发展一种极好的真菌剂。
例如,日本专利申请公开(KOKAI)号70885/1982公开了作为唑类合成抗真菌剂的三唑(tirazole)化合物。此外,日本专利申请公开(KOKAI)号224689/1985公开了(1,2,4-三唑-1-基)-甲基-甲醇衍生物。
发明内容
本发明打算提供一种比常规抗真菌剂更有效的抗真菌剂及其中间体。
本发明人已进行了广泛的研究。结果,完成了下列发明。
I.由下列通式代表的化合物或其盐:其中R1和R2彼此相同或不同,且各自表示卤原子或氢原子;R3为氢原子或低级烷基;l、r和m可相同或不同,且各自表示0或1;A为N或CH;W表示可具有一个或多个杂原子和可具有一个或多个取代基的芳香环或其稠环,或者W表示芳香环或其稠环,其中可具有一个或多个杂原子或可具有一个或多个取代基的芳香环或其稠环的部分或全部是饱和的,X表示可具有一个或多个取代基和可包含一个或多个选自N、S和O的杂原子的芳香环,可具有一个或多个取代基的链烷二基,可具有一个或多个取代基的链烯二基,或可具有一个或多个取代基的链炔二基;Y为由-S-、>SO、>SO2、>C=S、>C=O、-O-、>N-R6、>C=N-OR6或-(CH2)j-表示的基团,其中R6为氢原子或低级烷基,且j为1-4的整数,并且Z代表氢原子、卤原子、低级烷基、卤代低级烷基、低级烷氧基、卤代低级烷氧基、羟基、硫羟基、硝基、氰基、低级链烷酰基、可具有一个或多个取代基的苯基、可具有一个或多个取代基的苯氧基、可具有一个或多个取代基的咪唑基、可具有一个或多个取代基的三唑基、可具有一个或多个取代基的四唑基或可具有一个或多个取代基的氨基,除非当1=1且r=m=0时,W为噻唑环,R3为甲基且Z为氢原子。
II.制备旋光活性(2S,3R)-3-(2,4-二氟苯基)-3-羟基-2-甲基-4-(1H-1,2,4-三唑-1-基)丁腈的方法,包括将旋光活性(2R,3S)-2-(2,4-二氟苯基)-3-甲基-2-(1H-1,2,4-三唑-1-基)甲基环氧乙烷与二乙基氰化铝反应。
III.制备旋光活性(2S,3R)-3-(2,4-二氟苯基)-3-羟基-2-甲基-4-(1H-1,2,4-三唑-1-基)丁腈的方法,包括将旋光活性(2R,3S)-2-(2,4-二氟苯基)-3-甲基-2-(1H-1,2,4-三唑-1-基)甲基环氧乙烷与氰化镱反应。
IV.立体选择性地制备旋光活性(2S,3R)-3-(2,4-二氟苯基)-3-羟基-2-甲基-4-(1H-1,2,4-三唑-1-基)丁腈的方法,包括将旋光活性(2R,3S)-2-(2,4-二氟苯基)-3-甲基-2-(1H-1,2,4-三唑-1-基)甲基环氧乙烷与丙酮合氰化氢反应。
V.制备下式所示化合物或其酸加成盐的方法:其中W指取代的噻唑环,且A、R1、R2、R3、X、Y、Z、r和m定义同上,该方法包括将下式所示化合物:其中A、R1、R2和R3定义同上,与下式所示化合物进行反应:其中Hal为Br或Cl,且X,Y,Z,r和m定义同上。
VI.制备下式所示化合物或其酸加成盐的方法:其中A、R1、R2、R3、X、Y、Z、r和m定义同上,且W表示取代或未取代的、含氮5元杂环或其稠环,该方法包括将下式所示化合物:其中A、R1和R2定义同上,与下式所示化合物进行反应:其中D为取代或未取代的、含氮5元杂环或其稠环,且Z为H或CH3。
VII.制备下式所示化合物或其酸加成盐的方法:其中W意指取代的或未取代的5元杂环或其稠环,且A、R1、R2、R3、X、Y、Z、r和m定义同上,该方法包括将下式所示化合物:与下式所示化合物进行反应:其中R3、X、Y、Z、r和m定义同上。
VIII.制备下式所示化合物或其酸加成盐的方法:其中A、R1、R2、R3、W、X、Y、Z、r和m定义同上,该方法包括将下式所示化合物:其中A、R1、R2、R3、W、X、Y、Z、r和m定义同上,与间氯过苯甲酸反应,然后再与1,2,4-三唑钠或1,3-咪唑钠进行反应。
其中R1和R2相同或不同,且各自表示卤原子或氢原子,R3意指氢原子或低级烷基;r和m可以相同或不同,且分别表示0或1;A为N或CH;W表示可具有一个或多个取代基且可含有一个或多个选自N、S和O的杂原子的芳香环或其稠环;X意指可具有一个或多个取代基且可含有一个或多个选自N、S和O的杂原子的芳香环,可具有一个或多个取代基的链烷二基,可具有一个或多个取代基的链烯二基,或可具有一个或多个取代基的链炔二基;Y为-S-、>SO、>SO2、>C=S、>C=O、-O-、>N-R6、>C=N-OR6或-(CH2)j-所示基团,其中R6指氢原子或低级烷基,且j为1-4的整数;并且Z表示氢原子、卤原子、低级烷基、卤代低级烷基、低级烷氧基、卤代低级烷氧基、羟基、硫羟基、硝基、氰基、低级链烷酰基、可具有一个或多个取代基的苯基、可具有一个或多个取代基的苯氧基、可具有一个或多个取代基的咪唑基、可具有一个或多个取代基的三唑基、可具有一个或多个取代基的四唑基,或可具有一个或多个取代基的氨基,除非当r=m=O时,W为噻唑环、R3为甲基,且Z为氢原子。
L和M相同或不同,且各自表示氢原子或卤原子,且
R1意指5元杂环,它可含有一个或多个除硫原子外的其它杂原子且具有一个取代基;或5元杂环的稠环,它可含有一个或多个除硫原子外的其它杂原子且具有一个取代基;并具有可含一个或多个杂原子和可具有一个取代基的芳香环;或其部分或全部被饱和的稠环,该方法包括,在制备衍生物或其酸加成盐的时候,在正烷基锂存在下,将下列通式所示的2-卤代-苯乙酮加到含有5元杂环或其稠环或其部分或全部被饱和的稠环的化合物中进行反应,然后再将1,2,4-三唑和氢化钠加到所得的反应产物中进行反应:
其中U表示卤原子,且L和M定义同上。
L和M彼此相同或不同,且各自表示氢原子或卤原子,和
R1意指5元杂环,它可含有一个或多个除硫原子外的其它杂原子并具有一个取代基;或5元杂环的稠环,它可含有一个或多个除硫原子外的其杂原子且具有一个取代基,并具有可含一个或多个杂原子和一个取代基的芳香环;或其部分或全部被饱和的稠环,该方法包括:制备衍生物或其酸加成盐时,将其相应的含有氰基苯基取代的5元杂环与叠氮化钠和盐酸三乙胺进行反应。
XII.制备下列通式所示衍生物或其酸加成盐的方法:其中A为=CH=或=N-,
L和M彼此相同或不同,且各自表示氢原子或卤原子,和
R1意指5元杂环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基;或5元杂环的稠环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基,并具有可含一个或多个杂原子并可具有一个取代基的芳香环;或其部分或全部被饱和的稠环,所述衍生物在四唑环的3-或4-位上被烷基取代,该方法包括:在制备衍生物或其酸加成盐时,将其相应的含有四唑苯基取代的5元杂环的衍生物与烷基卤化物进行反应。
L和M彼此相同或不同,且各自表示氢原子或卤原子,和
R1意指5元杂环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基;或5元杂环的稠环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基;并具有可含一个或多个杂原子并可具有一个取代基的芳香环;或其部分或全部被饱和的稠环,该方法包括:在制备衍生物或其酸加成盐时,将其相应的含有卤代苯基取代的5元杂环与1,2,4-三唑和氢化钠进行反应。
XIV.制备下列通式所示衍生物或其酸加成盐的方法:其中A为=CH-或=N-,
L和M彼此相同或不同,且各自表示氢原子或卤原子,和
R1意指5元杂环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基;或5元杂环的稠环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基;并具有可含一个或多个杂原子并可具有一个取代基的芳香环;或其部分或全部被饱和的稠环,该方法包括:在制备衍生物或其酸加成盐时,将其相应的含有(1,2,4-三唑-1-基)乙醇的衍生物进行反应。
XV.制备下列通式所示化合物或其盐的方法:其中R意指低级烷基,Pr表示羟基保护基,且L为离去基团,该方法包括用保护基保护下列通式所示化合物的羟基:其中R定义同上,且R1表示氢原子或羟基的保护基,形成如下通式所示化合物:其中R、R1和Pr定义均同上,然后使式(2)所示化合物的羧基的保护基脱保护,形成如下通式所示的化合物:其中R和Pr定义同上,再进一步将式(3)所示化合物与式LH所示化合物进行反应,其中L定义如上。
XVI.制备下列通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同,且各自表示氢或卤原子,且Pr为羟基保护基,该方法包括将如下通式所示的化合物:其中R和Pr定义同上,且L表示离去基团,与如下通式所示化合物或其活性衍生物进行反应:其中两个X定义同上,且Y指氯、溴或碘原子。
XVII.制备如下通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同,且各自表示氢或卤原子,并且Pr为羟基保护基,该方法包括将如下通式所示的化合物与由甲基三苯基氯化鏻、甲基三苯基溴化鏻或甲基三苯基碘化鏻衍生的三苯基·亚甲基鏻(triphenyl-phosphonium methylide)反应,或者与三甲基甲硅烷基甲基氯化镁、三甲基甲硅烷基甲基溴化镁或三甲基甲硅基甲基锂进行反应,其中R、两个X和Pr定义同上。
XVIII.制备如下式通所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同,且各自表示氢或卤原子,并且Pr为羟基保护基,该方法包括将如下通式所示的化合物与过氧酸进行反应,其中R、两个X和Pr定义同上。
XIX.制备如下通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同,且各自表示氢或卤原子,并且Pr为羟基保护基,该方法包括将如下通式所示的化合物与由氯碘甲烷或溴氯甲烷形成的氯甲基锂进行反应,或与二甲基-氧化锍甲基化物、二甲基锍甲基化物、二乙基-氧化锍甲基化物或二乙基锍甲基化物进行反应:其中R、两个X和Pr定义同上。
XX.制备如下通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同,且各自表示氢或卤原子,且Pr为羟基保护基,该方法包括将如下通式所示的化合物与氧化剂进行反应:其中R、两个X和Pr定义同上。
XXI.制备如下通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,Pr为羟基保护基,R2指低级烷基,且R3表示甲基或低级烷氧基,该方法包括将如下通式所示的化合物与烷氧基二甲基甲硅烷基甲基镁卤化物或二烷氧基甲基甲硅烷基甲基镁卤化物进行反应:其中R、两个X和Pr定义同上。
XXII.制备如下通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且各自表示氢原子或卤原子,且Pr为羟基保护基,该方法包括将如下通式所示化合物在碱存在下与过氧酸进行反应:其中R、两个X和Pr定义同上,R2为低级烷基,且R3表示甲基或低级烷氧基。
XXIII.制备如下式通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,Pr为羟基保护基,且A指CH或氮原子,该方法包括将如下通式所示化合物与1,2,4-三唑或咪唑,或其盐进行反应:其中R、两个X和Pr定义同上。
XXIV.制备如下通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,Pr为羟基保护基,且L指离去基团,它包括将如下通式所示化合物卤化、烷基磺化或芳基磺化:其中R、两个X和Pr定义同上。
XXV.制备如下通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不相同且各自表示氢或卤原子,Pr为羟基保护基,且A为CH或氮原子,它包括将如下通式所示的化合物与1,2,4-三唑或咪唑、或其盐进行反应:其中R、两个X和Pr定义同上,且L表示离去基团。
XXVI.制备如下通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,且A指CH或氮原子,它包括解封如下通式所示化合物中的Pr(羟基保护基):其中R、两个X和A定义同上,且Pr为羟基保护基。
XXVIII.制备如下通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,并且A为CH或氮原子,它包括将如下通式所示化合物与羟胺衍生物进行反应:其中R、两个X和A定义同上。
XXIX.含有下列通式所示化合物或其盐和可药用盐的药物组合物:其中R1和R2彼此相同或不同,且各自表示卤原子或氢原子;R3意指氢原子或低级烷基;l、r和m可相同或不同,且各自表示0或1;A为N或CH;W表示可具有一个或多个杂原子且可用一个或多个取代基的芳香环或其稠环,或者W表示芳香环或其稠环,其中可具有一个或多个杂原子且可具有一个或多个取代基的芳香环或其稠环的一部分或全部是饱和的;X表示可具有一个或多个取代基且可包含一个或多个选自N、S和O的杂原子的芳香环,可具有一个或多个取代基的链烷二基,可具有一个或多个取代基的链烯二基,或可具有一个或多个取代基的链炔二基;Y为-S-、>SO、>SO2、>C=S、>C=O、-O-、>N-R6、>C=N-OR6或-(CH2)j-表示的基团,其中R6为氢原子或低级烷基,且j为1-4的整数,并且Z代表氢原子、卤原子、低级烷基、卤代纸级烷基、低级烷氧基、卤代低级烷氧基、羟基、硫羟基、硝基、氰基、低级链烷酰基、可具有一个或多个取代基的苯基、可具有一个或多个取代基的苯氧基、可具有一个或多个取代基的咪唑基、可具有一个或多个取代基的三唑基、可具有一个或多个取代基的四唑基或可具有一个或多个取代基的氨基,除非l=1且r=m=0时,W为噻唑环,R3为甲基,且Z为氢原子。
本发明提供一种具有极好抗真菌特性的通式(I)所示化合物或其酸加成盐:其中A为=CH-或=N-,
L和M彼此相同或不同且各自表示氢原子或卤原子,和
R1意指5元杂环,它可含有一个或多个除硫原子之外的其它杂原子,且具有一个取代基;或具有可含一个或多个杂原子并可具有一个取代基的芳香环的5元杂环的稠环,它可含有一个或多个除硫原子外的其它杂原子,并具有一个取代基;或其部分或全部被饱和的稠环。
本发明的衍生物可通过各种合成途径来制备。将其中某些方法例举如下:方法A:
在正丁锂存在下,将2-氯-2’,4’-二氟苯乙酮加到4-(2,4-二氟苯基)噻唑中,将反应产物进行后处理后,加入1,2,4-三唑和氢化钠,获得1-(2,4-二氟苯基)-1-(4-(2,4-二氟苯基)噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)-乙醇。方法B:
(1)在正丁基锂存在下,将2-氯-2’,4’-二氟苯乙酮加到6-氰基苯并噻唑中,形成1-(2,4-二氟苯基)-1-(6-氰基苯并噻唑-2-基)-2-氯乙醇。
(2)将1,2,4-三唑加到在二甲基甲酰胺中的氢化钠悬浮液中,将步骤(1)中形成的1-(2,4-二氟苯基)-1-(6-氰基苯并噻唑-2-基)-2-氯乙醇加到该悬浮液中进行反应,由此获得1-(2,4-二氟苯基)-1-(6-氰苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇。方法C:
将1-(2,4-二氟苯基)-1-(4-(4-氰基苯基)噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)-乙醇与叠氮化钠和盐酸三乙胺进行反应,获得1-(2,4-二氟苯基)-1-{4-[(4-(5-四唑)苯基)噻唑]-2-基}-2-(1H-1,2,4-三唑-1-基)-乙醇。方法D:
将甲基碘化物与上述方法C中获得的1-(2,4-二氟苯基)-1-{4-[(4-(5-四唑)-苯基)-噻唑]-2-基}-2-(1H-1,2,4-三唑-1-基)乙醇进行反应,获得两个异构体,在该异构体四唑环的3-或4-位被甲基取代。方法E:
将1-(2,4-二氟苯基)-1-(2-(4-氟苯基)噻唑-5-基)-2-(1H-1,2,4-三唑-1-基)乙醇与1,2,4-三唑和氢化钠反应,获得1-(2,4-二氟苯基)-1-{2[(4-(1-1H-1,2,4-三唑)苯基)-噻唑]-5-基}-2-(1H-1,2,4-三唑-1-基)乙醇。方法F:
将1-(2,4-二氟苯基)-1-(6-氨基硫羰基-苯并噻唑-2-基)-2-(1H-1,2,4-三唑-基)乙醇与碳酸氢钠和溴丙酮进行反应,获得1-(2,4-二氟苯基)-1-(6-(3-甲基噻唑-1-基)-苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇。方法G:
将1-(2,4-二氟苯基)-1-(6-氰基苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇和三乙胺溶于二甲基甲酰胺中。在所得溶液中通放硫化氢气体进行反应,由此获得1-(2,4-二氟苯基)-1-(6-氨基硫羰基-苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇。方法H:
将1-(2,4-二氟苯基)-1-(6-氨基硫羰基-苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇与溴代乙醛缩二甲醇进行反应来获得1-(2,4-二氟苯基)-1-(6-噻唑-1-基)-苯并噻唑-2-基-2-(1H-1,2,4-三唑-1-基)乙醇。方法I:
(1)将1-(2,4-二氟苯基)-1-(4-氨基硫羰基-苯硫-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇与-2-溴代乙基丙酮酸反应,形成1-(2,4-二氟苯基-1-(4-(4-乙氧羰基噻唑-2-基)-苯硫-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇(A)。
(2)将由此获得的化合物(A)溶于氨饱和的甲醇溶液中,并将所得溶液静置,因此化合物与氨反应而获得1-(2,4-二氟苯基)-1-(4-(4-氨基甲酰基噻唑-2-基)-苯硫-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇(B)。
方法J:
将上述方法I步骤(2)中获得的化合物(B)溶于吡啶中并与磷酰氯反应,获得1-(2,4-二氟苯基)-1-(4-(4-氰基噻唑-2-基)-苯硫-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇。
作为本发明可使用的溶剂的例子,可提到的有低级醇如甲醇、乙醇、丙醇和丁醇;多元醇如1,2-乙二醇;酮如丙酮、甲基乙基酮、二乙基酮和环己酮;醚如乙醚、异丙醚、四氢呋喃、二噁烷、2-甲氧基乙醇和1,2-二甲氧基乙烷;腈如乙腈和丙腈;酯如乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯和邻苯二甲酸二乙酯;卤代烃如二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、三氯乙烯和四氯乙烯;芳香族的如苯、甲苯、二甲苯、单氯苯、硝基苯、茚、吡啶、喹啉、可力丁和苯酚;烃如戊烷、环己烷、己烷、庚烷、辛烷、异辛烷和石油醚;胺如乙醇胺、二乙胺、三乙胺、吡咯烷、哌啶、哌嗪、吗啉、苯胺、二甲基苯胺、苯甲胺和甲苯胺;酰胺如甲酰胺、N-甲基吡咯烷酮、N,N-二甲基咪唑啉酮、N,N-二甲基乙酰胺和N,N-二甲基甲酰胺;磷酰胺如六甲基磷酰三胺和六甲基亚磷酰三胺;有机酸如甲酸、乙酸、二氟乙酸、三氟乙酸和氯乙酸;亚砜如二甲基亚砜;碳的硫化物如二硫化碳;水;和其它通用的溶剂。这些溶剂可以是单一的或其两种或多种混合的溶剂。对混合剂的混合比例上没有强制地特别限定。
可提及的本发明衍生物或其酸加成盐的可药用盐如下。
即,可提及的无机盐的例子有碱金属盐如钠盐和钾盐;铵盐;四乙基铵盐;季铵盐如内铵盐;碱土金属盐如钙盐和镁盐;和无机酸盐如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、碳酸盐和碳酸氢盐。
除此之外,可提及有机盐的例子是有机羧酸盐如乙酸盐、马来酸盐、乳酸盐和酒石酸盐;有机磺酸盐如甲磺酸盐、羟基甲磺酸盐、羟基乙磺酸盐、牛磺酸盐、苯磺酸盐和甲苯磺酸盐;氨基酸盐如精氨酸盐、赖氨酸盐、丝氨酸盐、天冬氨酸盐、谷氨酸盐和甘氨酸盐;胺盐如三甲胺盐、三乙胺盐、吡啶盐、普鲁卡因盐、甲基吡啶盐、二环己基胺盐、N,N-二苄基乙二胺盐、N-甲基葡糖胺盐、二乙醇胺盐、三乙醇胺盐、三(羟甲基氨基)甲烷盐和乙氧苯基苄基胺盐。
而且,本发明提供一种具有极好抗真菌特性的通式(I)所示的化合物或其酸加成盐:其中R1和R2彼此相同或不同且各自表示卤原子或氢原子;R3意指氢原子或低级烷基;r和m可彼此相同或不同且各自为0或1;A为N或CH;W表示芳香环(它可具有一个或多个取代基且可含有一个或多个选自N、S和O的杂原子)或其稠环;X意指可具有一个或多个取代基且可含有一个或多个选自N、S和O的杂原子的芳香环,可具有一个或多个取代基的链烷二基,可具有一个或多个取代基的链烯二基,或可具有一个或多个取代基的链炔二基;Y为-S-、>SO、>SO2、>C=S、>C=O、-O-、>N-R6、>C=N-OR6或-(CH2)j-所示的基团,其中R6为氢原子或低级烷基,且j为1-4的整数;和Z表示氢原子、卤原子、低级烷基、卤代低级烷基,低级烷氧基,卤代低级烷氧基、羟基、硫羟基、硝基、氰基、低级链烷酰基、可具有一个或多个取代基的苯基、可具有一个或多个取代基的苯氧基、可具有一个或多个取代基的咪唑基、可具有一个或多个取代基的三唑基、可具有一个或多个取代基的四唑基、或可具有一个或多个取代基的氨基,除非当r=m=0时,W为噻唑环,R3为甲基,且Z为氢原子。
本发明的化合物可通过各种合成途径来制备,其中某些途径例举如下:途径I:将下式化合物:其中A、R1、R2和R3定义同上,与下式化合物进行反应:其中Hal为Br或Cl,且X、Y、Z、r和m定义同上,获得下式所示化合物:其中W为由取代的唑类组成的基团,且A、R1、R2、R3、X、Y、Z、r和m定义同上。途径II.将下式化合物:其中A、R1和R2定义同上,与下式化合物进行反应:其中D为由取代的或未取代的、含氮5元杂环或其稠环组成的基团,且Z为H或CH3;由此获得下式所示的化合物:其中W为取代的或未取代的、含氮5元杂环或稠环,且A、R1、R2、R3、X、Y、Z、r和m定义同上。途径III:
将下式化合物:其中A、R1和R2定义同上,与下式化合物进行反应:其中R3、X、Y、Z、r和m定义同上,由此获得下式所示的化合物:其中W为由取代的或未取代的5元杂环或稠环组成的基团,且A、R1、R2、R3、X、Y、Z、r和m定义同上。途径IV:
将下式化合物:其中R1、R2、R3、X、Y、Z、r和m定义同上,与间氯过苯甲酸反应,然后再与1,2,4-三唑钠或1,3-咪唑钠反应,由此获得下式所示化合物:其中A、R1、R2、R3、W、X、Y、Z、r和m定义同上。
作为形成本发明化合物的酸加成盐的酸,可使用常规的无机酸如盐酸和硫酸,以及有机酸如乙酸和柠檬酸。优选的酸为盐酸和乙酸。
作为本发明的可使用的溶剂的例子,可提出的有低级醇如甲醇、乙醇、丙醇和丁醇;多元醇如1,2-乙二醇;酮如丙酮、甲乙酮、二乙基酮、和环己酮;醚如乙醚、异丙醚、四氢呋喃、二噁烷、2-甲氧基乙醇和1,2-二甲氧基乙烷;腈如乙腈和丙腈;酯如乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯和邻苯二甲酸二乙酯;卤代烃如二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、三氯乙烯和四氯乙烯;芳香族的如苯、甲苯、二甲苯、一氯苯、硝基苯、茚、吡啶、喹啉、可力丁和苯酚;烃如戊烷、环己烷、己烷、庚烷、辛烷、异辛烷和石油醚;胺如乙醇胺、二乙胺、三乙胺、吡咯烷、哌啶。哌嗪、吗啉、苯胺、二甲基苯胺、苯甲胺和甲苯胺;酰胺如甲酰胺、N-甲基吡咯烷酮、N,N-二甲基咪唑啉酮、N,N-二甲基乙酰胺和N,N-二甲基甲酰胺;磷酰胺如六甲基磷酰三胺和六甲亚磷酰三胺;有机酸如甲酸、乙酸、二氟乙酸、三氟乙酸和氯乙酸;亚砜如二甲基亚砜;碳的硫化物和二硫化碳;水;和其它常用溶剂。这些溶剂可以是单一溶剂或其两种或多种溶剂的混合溶剂。对混合溶剂的混合比例没有强制地特别限定。
作为本发明化合物或其酸加成盐的可药用的盐,可例举如下。
即,作为无机盐的例子,可提及碱金属盐如钠盐和钾盐;铵盐;四乙基铵盐;季铵盐如内铵盐;碱土金属盐如钙盐和镁盐;和无机酸盐如盐酸盐;氢溴酸盐,氢碘酸盐,硫酸盐,碳酸盐和碳酸氢盐。
除此之外,作为有机盐的例子,可提及的是有机羧酸盐如乙酸盐、马来酸盐、乳酸盐和琥珀酸盐;有机磺酸盐如甲磺酸盐、羟基甲磺酸盐、羟基乙磺酸盐、牛磺酸盐、苯磺酸盐和甲苯磺酸盐、羟基甲磺酸盐、羟基乙磺酸盐、牛磺酸盐、苯磺酸盐和甲苯磺酸盐;氨基酸盐如精氨酸盐、赖氨酸盐、丝氨酸盐、天冬氨酸盐、谷氨酸盐和甘氨酸盐;和胺盐如三甲胺盐、三乙胺盐、吡啶盐、普鲁卡因盐、甲基吡啶盐、二环己基胺盐、N,N-二苄基乙二胺盐、N-甲基葡萄糖胺盐、二乙醇胺盐、三乙醇胺盐、三(羟甲基氨基)甲烷盐和乙氧苯基苄基胺盐。
而且,本发明提供一种下列通式所示化合物或其盐的制备方法:其中R意指低级烷基,Pr表示羟基保护基且L为离去基团,它包括用保护基保护下列通式所示化合物的羟基:其中R定义同上,且R1表示氢原子或羧基保护基,以形成下列通式所示化合物:其中R、R1和Pr定义同上,使式(2)的羧基保护基脱保护,形成下式所示化合物:其中R和Pr定义同上,再将式(3)化合物与式LH(其中L表示离去基团)所示化合物的反应;
一种制备以下通式所示化合物或其盐的方法:其中R意指低级烷基、两个X彼此相同或不同且各自表示氢原子或卤原子,且Pr为羟基保护基,它包括将下列通式所示化合物:其中R和Pr定义同上,且L表示离去基团,与下列通式所示化合物或其活性衍生物进行反应:其中两个X定义同上,且Y代表氯原子、溴原子或碘原子;
一种制备下列通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,且Pr为羟基保护基,它包括将下列通式所示化合物:其中R、X和Pr定义同上,与由甲基三苯基氯化鏻、甲基三苯基溴化鏻或甲基三苯基碘化鏻衍生的三苯基·亚甲基鏻反应,或者与三甲基甲硅烷基甲基氯化镁、三甲基甲硅烷基甲基溴化镁或三甲基甲硅烷基甲基锂进行反应:
一种制备下列通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,且Pr为羟基保护基,它包括将一列通式所示化合物:其中R、X和Pr定义同上,与过氧酸进行反应;
一种制备下列通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,且Pr表示羟基保护基,它包括将下列通式所示化合物:其中R、X和Pr定义同上,与由氯碘甲烷或溴碘甲烷形成的氯甲基锂进行反应,或者与二甲基·亚甲基氧锍或二甲基·亚甲基锍进行反应;
一种制备下列通式所示化合物及其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,Pr为羟基保护基,R2表示低级烷基且R3表示甲基或低级烷氧基,它包括将下列通式所示化合物与烷氧基二甲基甲硅烷基甲基镁卤化物或二烷氧基甲基甲硅烷基甲基镁卤化物进行反应:其中R、X和Pr定义同上;
一种制备下列通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,Pr表示羟基保护基,它包括将下列通式所示化合物与过氧酸在碱存在下进行反应:其中R、X和Pr定义同上,R2代表低级烷基,且R3代表甲基或低级烷氧基;
一种制备下式所示化合物及其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,Pr指羟基保护基且A为CH或氮原子,它包括将下列通式所示化合物与1,2,4-三唑或咪唑或其盐进行反应:其中R、X和Pr定义同上;
一种制备下列通式化合物及其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,Pr羟基保护基,且L为离去基团,它包括卤化、烷基磺化经或芳基磺化下列通式所示化合物:其中R、X和Pr定义同上;
一种制备下列通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,Pr为羟基保护基,且A为CH或氮原子,它包括将下式所示化合物与1,2,4-三唑或咪唑或其盐进行反应:其中R、X和Pr定义同上且L为离去基团;
一种制备下列通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,Pr为羟基保护基,且A为CH或氮原子,它包括将下式所示化合物或其盐的羟基保护基Pr脱保护:其中R、X、Pr和A定义同上;一种制备下列通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,且A为CH或氮原子,它包括下列通式所示化合物与氧化剂进行反应:其中R、X和A定义同上;和
这些方法涉及制备用于制备抗真菌剂的合成中间体的方法。
本发明的进一步涉及用作合成中间体的下列化合物或其盐。即,本发明涉及下列通式所示化合物或其盐;其中R意指低级烷基,Pr表示羟基保护基,且L表示离去基团;
下列通式所示化合物或其盐;其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,且Pr为羟基保护基;
下列通式所示化合物或其盐:其中R意指低级烷基,两个X彼此相同或不同且表示氢原子或卤原子,且Pr为羟基保护基,M表示羟基或离去基团;和
下面详述本发明和文中所用的术语。R意指低级烷基。该低级烷基指含有1-6个碳原子的直链或支链烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、叔戊基、新戊基、1-甲基丁基、2-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、正己基、异己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基等等。优选的基团包括甲基、乙基、丙基等。
R1表示氢原子或羧基保护基。
本文所使用的羧基保护基可为通常在有机合成领域中作为羧基保护基的任何已知基团,并且不作特别的限定。可例举的羧基保护基包括例如,含有1-6个碳原子的直链或支链低级烷基,如甲基、乙基、异丙基和叔丁基;卤代低级烷基,如2-碘代乙基和2,2,2-三氯乙基;低级烷氧基烷基;如甲氧基甲基,乙氧基甲基和异丁氧基甲基;低级脂族酸基烷基如乙酸基甲基、丙酸基甲基、丁酸基甲基和新戊酸基甲基;低级烷氧基羰基氧烷基,如甲氧基羰基氧甲基、1-甲氧基羰基氧乙基、乙氧基羰基氧甲基、1-乙氧基羰基氧乙基和2-甲氧基羰基氧乙基;芳烷基,如苄基、对-甲氧基苄基、邻硝基苄基和对硝基苄基;二苯甲基和2-苯并[c]呋喃酮基;(5-甲基-2-氧代-1,3-二氧杂戊环-4-基)-甲基等等。
这些羰基保护基的脱保护可通过常规方法来完成,如水解,还原等,这取决于所使用保护基的类型。
Pr表示羟基保护基。
本文所使用的羟基保护基团可以是有机合成领域中用作羟基保护基的任何已知基团,并且不受到特别的限制。羟基保护基的例子包括,例如,低级烷基甲硅烷基,如三甲基甲硅烷基、叔丁基二甲基甲硅烷基等;低级烷基芳基甲硅烷基,如叔丁基二苯基甲硅烷基等;低级烷氧基甲基,如甲氧基甲基,2-甲氧基乙氧基甲基等,例如,四氢吡喃基;芳烷基,如苄基,对甲氧基苄基、2,4-二甲氧基苄基、邻硝基苄基、对硝基苄基、三苯甲基、甲氧基三苯甲基、二甲氧基三苯甲基等;酰基,如甲酰基、乙酰基等;低级烷氧基羰基,如叔-丁氧基羰基、2-碘代乙氧基羰基、2,2,2-三氯乙氧基羰基等;链烯基氧羰基,如2-丙烯基氧羰基、2-氯-2-丙烯基氧羰基、3-甲氧基羰基-2-丙烯基氧羰基、2-甲基-2-丙烯基氧羰基、2-丁烯基氧羰基、肉桂基氧羰基等;芳烷基氧羰基,如苄基氧羰基、对甲氧基苄基氧羰基、邻硝基苄基氧羰基、对硝基苄基氧羰基等。
这些羟基保护基脱保护可通过常规方法来完成,如水解、还原等,它取决于所使用保护基的类型。
L为离去基团。
本文所使用的离去基团可以是有机合成领域中作为离去基团的任何已知基团,并且不受特别的限定。离去基团的例子包括,例如,卤原子,如氯原子、溴原子、碘原子等;烷硫基,如甲硫基、乙硫基、丙硫基等;芳硫基,如苯硫基、甲苯硫基、2-吡啶硫基等;烷基磺酰氧基,如甲磺酰氧基,三氟甲磺酰氧基、乙磺酰氧基、丙磺酰氧基等;芳基磺酰氧基,如,苯磺酰氧基、甲苯磺酰氧基等;链烷酰氧基,如乙酰氧基、三氟乙酰氧基等;烷氧基,如甲氧基、乙氧基、丙氧基等;烷氨基,如甲氨基、乙氨基、丙氨基、丁氨基等;二烷氨基,如二甲氨基、二乙氨基、二丙氨基、甲基乙基氨基、乙基丙基氨基、甲基丙基氨基等;和取代的磷酰氧基,如二苯氧基磷酰氧基等。因此,在本发明反应中所使用的活化剂包括,例如,酸酐,如三氟乙酰酐、甲磺酸酐、三氟甲磺酸酐、对甲苯磺酸酐等;酰氯,如甲磺酰氯、对甲苯磺酰氯、氯代磷酸二苯酯,也包括2-巯基吡啶、草酰氯、亚硫酰氯、亚硫酰溴等。
两个X彼此相同或不同且表示氢原子或卤原子。卤原子的例子包括氟原子、氯原子、溴原子、碘原子等。
其中两个X彼此相同或不同且表示氢原子或卤原子,且Y代表氯原子、溴原子或碘原子。
本文所使用的过氧酸可以是有机合成中常用的任何过氧酸,并且不受特别的限制。过氧酸的例子包括,例如有机过氧酸,如间氯过苯甲酸(metha chloroperbenzoic acid)(m CPBA)、过乙酸等,以及过氧化氢水溶液。间氯过苯甲酸是优选的。
本文所使用的氧化剂可以是任何有机合成中常用作氧化剂的那些,并且不受特别的限制。氧化剂的例子可以包括,例如,四氧化锇、高锰酸钾等。
烷氧基二甲基甲硅烷基甲基镁卤化物意指用与上述低级烷基相应的烷氧基取代的二甲基甲硅烷基甲基镁卤化物,并且具体包括甲氧基二甲基甲硅烷基甲基氯化镁,
甲氧基二甲基甲硅烷基甲基溴化镁,
乙氧基二甲基甲硅烷基甲基氯化镁,
乙氧基二甲基甲硅烷基甲基溴化镁,
丙氧基二甲基甲硅烷基甲基氯化镁,
异丙氧基二甲基甲硅烷基甲基氯化镁,
丙氧基二甲基甲硅烷基甲基溴化镁,
异丙氧基二甲基甲硅烷基甲基溴化镁等。
二烷氧基甲基甲硅烷基甲基镁卤化物意指用与上述低级烷基相应的烷氧基取代的甲基甲硅烷基甲基镁卤化物,具体包括:
二甲氧基甲基甲硅烷基甲基氯化镁,
二甲氧基甲基甲硅烷基甲基溴化镁,
二乙氧基甲基甲硅烷基甲基氯化镁,
二乙氧基甲基甲硅烷基甲基溴化镁,
二丙氧基甲基甲硅烷基甲基氯化镁,
二丙氧基甲基甲硅烷基甲基溴化镁,
二丁氧基甲基甲硅烷基甲基氯化镁,
二丁氧基甲基甲硅烷基甲基溴化镁等。
本文所使用的碱可以是有机合成领域常用作碱的任何已知碱,并且不受特别的限制。碱的例子包括,例如,碳酸钠、碳酸氢钠、碳酸钾、氢化钠、氢化钾、叔丁氧钾、吡啶、二甲基氨基吡啶基、三甲胺、三乙胺、N,N-二异丙基乙基胺、N-甲基吗啉、N-甲基吡咯烷、N-甲基哌啶、N,N-二甲基苯胺,1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、比啶、4-二甲基氨基吡啶、甲基吡啶、二甲基吡啶、喹啉、异喹啉、氢氧化钠、氢氧化钾、氢氧化锂、丁基锂等。
A为CH或氮原子。
R2表示低级烷基,该低级烷基定义同上。
R3表示甲基或低级烷氧基。低级烷氧基与上述低级基相应,具体为含1-6个碳原子的直链或支链烷氧基,并且包括,例如,甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基、仲戊氧基、叔戊氧基、新戊氧基、1-甲基丁氧基、2-甲基丁氧基。1,1-二甲基丙氧基、1,2-二甲基丙氧基、正己氧基、异己氧基、1-甲基戊氧基、2-甲基戊氧基、3-甲基戊氧基、1,1-二甲基丁氧基、1,2-二甲基丁氧基、2,2-二甲基丁氧基、1,3-二甲基丁氧基、2,3-二甲基丁氧基、3,3-二甲基丁氧基、1-乙基丁氧基、2-乙基丁氧基、1,1,2-三甲基丙氧基、1,2,2-三甲基丙氧基、1-乙基-1-甲基丙氧基、1-乙基-2-甲基丙氧基等。
Q表示氧原子或CH2。
M表示羟基或离去基团。该离去基团定义同上。
所使用的盐不受其类型的限制,并且包括,例如,无机酸的加成盐,如氢氟酸盐、盐酸盐、硫酸盐、硝酸盐、高氢酸盐、磷酸盐、碳酸盐、碳酸氢盐、氢溴酸盐、氢碘酸盐等;有机羧酸的加成盐,如乙酸盐、马来酸盐、富马酸盐、草酸盐、乳酸盐、柠檬酸盐、三氟乙酸盐等;有机磺酸的加成盐,如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐、羟基甲磺酸盐、羟基乙磺酸盐、苯磺酸盐、甲苯磺酸盐、牛磺酸盐等;胺的加成盐,如三甲胺盐、三乙胺盐、吡啶盐、普鲁卡因盐、甲基吡啶盐、二环己基胺盐、N,N-’-二苯甲基乙二胺盐、N-甲基葡糖胺盐、二乙醇胺盐、三乙醇胺盐、三(羟甲基氨基)甲烷基、乙氧苯基苄基胺盐等;碱金属的加成盐,如钠盐、钾盐等;碱土金属的加成盐、如镁盐、钙盐等;氨基酸的加成盐,如精氨酸盐、赖氨酸盐、丝氨酸盐、甘氨酸盐、天冬氨酸盐、谷氨酸盐等。
可药用的盐意指制备药物常用的常规盐。
本文使用的羟胺衍生物可以是在有机合成中通常可从甲酰基衍生氰基的任何化合物,并且不受特别的限定,它包括,例如,羟胺-O-磺酸等。
途径A-1为保护式(101)所示化合物羟基的途径[其中R和R1定义同上。下同]。根据现有技术已知的方法保护羟基,可制备式(102)所示化合物[其中Pr定义同上。下同],其羟基已按这种方式保护。按照,例如Green的“Protective Groups in Organic Synthesis(A Wiley-Interscience Publication CO.,)”所述方法可制备用各种保护基保护的羟基。
途径A-2为解封式(102)所示化合物的羧基保护基的途径。类似于途径A-1,在该途径中,按照常规方法,例如,用酸或碱水解或催化还原,解封羧酸的保护基,可制备式(103)所示化合物。更具体地,通过在不抑制反应的溶剂中,将式(102)化合物与盐酸、三氟乙酸、乙酸、氢溴酸、甲酸、tosic acid、过氧化氢、三甲基甲硅烷基氯化物、叔丁醇钾、氢氧化锂、氢氧化钠、氢氧化钾、肼、碳酸钾、碳酸钠、三氟化硼、三溴化硼、卤化铝、四丁基氟化铵或类似物进行反应可完成解封。
途径A-3为将离去基团(L)加到式(103)所示化合物上的过程。通过将式(103)所示化合物与活化剂,例如,酸酐如三氟乙酸酐、甲磺酰酐、三氟甲磺酸酐或对甲苯磺酸酐;酰氯,例如,甲磺酰氯、对甲苯磺酰氯、氯磷酸二酯、草酰氯或亚硫酰氯;或2-硫基吡啶进行反应,可获得式(104)化合物。如果需要,根据所使用试剂的活性可使用缩合剂如二环己基碳化二亚胺(DCC)。
在途径B-1中,通过将式(104)所示化合物与下式所示化合物:[其中X和Y定义同上,下同]、或其活性衍生物(例如,其中Y为由金属镁活化的-MgCl、-MgBr或-MgI的格利雅试剂)进行反应,可制备式(104)中离去基团L被二取代的苯基置换的式(105)化合物。
在途径C-1中,通过将式(105)所示化合物与三苯基·亚甲基鏻(它是通过用碱如丁基锂处理甲基三苯基氯化鏻,甲基三苯基溴化鏻或甲基三苯基碘化鏻而产生)反应(称为维悌希反应),或通过与三甲基甲硅烷基甲基氯化镁、三甲基甲硅烷基甲基溴化镁或三甲基甲硅烷基甲基锂反应而形成甲硅烷基醇中间体,再用三氟化硼醚复合物或类似物将甲硅烷基醇中间体脱甲硅烷醇化,可制备式(106)所示的烯烃化合物。
途径D-1为环氧化式(106)所示烯烃化合物的途径。所用的环氧化剂不受特别的限制,只要它是能环氧化双键的试剂。然而,作为其例子,可提及有机过氧酸如间氯过苯甲酸(mCPBA)和过乙酸,和过氧化氢水溶液。优选地,可通过与间氯过苯甲酸反应来制备式(107)所示的环氧化物。
也可通过下列途径E-1来获得式(107)所示的环氧化物。即,将式(105)化合物与氯甲基锂(由氯碘甲烷或溴碘甲烷加碱如丁基锂形成的)反应,或者与二甲基·亚甲基锍氧、二甲基·亚甲基锍、二乙基·亚甲基锍氧或二乙基·亚甲基锍反应可制备环氧化物。
途径F-1为式(107)所示环氧化物直接开环与咪唑环或1,2,4-三唑环结合的反应。可通过式(107)所示环氧化物与咪唑或1,2,4-三唑的碱金属盐(它是通过碱金属氢化物如氢化钠、氢化锂或氢化钾与咪唑或1,2,4-三唑在溶剂中混合而获得的)反应获得式(108)所示的化合物[其中A为氮原子或CH。下同]。
途径G-1为解封羟基保护基的途径。该羟基保护基可通过现有技术中已知的方法来解封。例如,它可通过以上给出的Green的文献所述的方法来进行。
途径H-1为用氧化剂将烯烃化合物氧化为1,2-乙二醇的途径。用氧化剂如四氧化锇或高锰酸钾处理式(106)所示化合物可制备式(110)所示化合物。
途径I-1为式(105)所示化合物转化为(110)所示化合物的途径。在该途径中,式(110)所示化合物可通过式(105)所示化合物与烷氧基二甲基甲硅烷基甲基镁卤化物或二烷氧基甲基甲硅烷基甲基镁卤化物反应形成下列通式所示化合物:
[其中R2为低级烷基,且R3表示甲基或低级烷氧基,下同],然后再将由此获得的化合物与过氧酸在碱存在下反应来制备。
途径J-1为式(110)所示化合物的伯羟基被离去基团L取代的途径。该方法可按途径A-3来进行。式(111)所示化合物可通过式(110)化合物与(优选地)酰氯如甲磺酰氯、对甲苯磺酰氯、氯磷酸二苯酯、草酰氯或亚硫酰氯反应来制备。
在途径J-2中,通过按途径F-1进行反应,可用咪唑基或1,2,4-三唑基置换式(111)所示化合物的离去基团L。
途径k-1为将式(109)所示化合物的伯羟基氧化为甲酰基的途径。该伯羟基的氧化可按现有技术已知的方法进行。通过使用,例如,金属如铬、锰或银的盐或氧化物,或二甲基亚砜(DMSO)类型的有机氧化剂来进行该反应是容易的。作为试剂,可使用,例如,铬酸·吡啶复合物、氯铬酸吡啶或重铬酸吡啶。另外,使用草酸氯的DMSO氧化法是常用的。
途径L-1为式(112)所示化合物的甲酰基被氰基置换的途径。式(113)所示化合物可通过式(112)所示化合物与羟胺衍生物如羟胺磺酸反应来制备。
途径M-1和N-1为制备抗真菌剂的过程,该抗真菌剂是式(115)所示的最终化合物。在这些途径中,显示极好抗真菌活性的由式(115)所示的化合物可通过将硫化氢加到式(113)所示的化合物中而形成式(114)所示化合物、然后再将所获得的化合物与2-溴-4’-甲基硫代苯乙酮反应来制备。
本发明中可使用的溶剂不受特别的限制,只要他们不妨碍反应且常用在有机合成中。然而,作为其例子,可提及低级醇如甲醇、乙醇、丙醇和丁醇;多元醇如1,2-乙二醇和甘油;酮如丙酮、甲基乙基酮、二乙基酮和环己酮;醚如乙醚、异丙醚、四氢呋喃、二噁烷、2-甲氧基乙醇和1,2-二甲氧基乙烷;腈如乙腈和丙腈;酯如乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯和邻苯二甲酸二乙酯;卤代烃如二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、三氯乙烯和四氯乙烯;芳香族的如苯、甲苯、二甲苯、一氯苯、硝基苯、茚、吡啶、喹啉、可力丁和苯酚;烃如戊烷、环己烷、己烷、庚烷、辛烷、异辛烷和石油醚;胺如乙醇胺、二乙胺、三乙胺、吡咯烷、哌啶、哌嗪、吗啉、苯胺、二甲基苯胺、苯甲胺和甲苯胺;酰胺如甲酰胺、N-甲基吡啶烷酮、N,N-二甲基咪唑啉酮、N,N-二甲基乙酰胺和N,N-二甲基甲酰胺;磷酰胺如六甲基磷酰三胺和六甲基亚磷酰三胺;有机酸如甲酸、乙酸、二氟乙酸、三氟乙酸和氯乙酸;亚砜如二甲基亚砜;碳的硫化物如二硫化碳;水;和其它常用溶剂。这些溶剂可以是单一溶剂或其两种或多种溶剂的混合溶剂。混合溶剂的混合比例不受特别的限制。
在以上途径中,如果需要,所形成的产物可按现有技术中已知的方法如硅胶或类似物的柱色谱进行纯化,而且如果需要,可进行解封其保护基的反应。保护基的解封可通过将产物还原(如催化还原)或溶剂分解来进行。
[其中式(116)到(120)中,R、Pr、L、X、Q、M和A定义均同上]在本申请制备方法中和在具有极好抗真菌活性化合物的合成中是有用的。
这里,在本发明的化合物及制备方法中,在其分子中有手性碳原子的立体异构体以S构型或R构型存在。除此之外,由于具有双键,存在E或Z型几何异构体。为方便起见,在本说明书中描述一种构型。然而,其两种化合物及其混合物均包含在本发明中。为了方便起见,本发明的化合物不受所述化学式所示化合物的限制。光学异构体可通过常规光学拆分技术分离,同时,非对映体可采用常用的分离方法如色谱进行分离。
当打算制备单一异构体时,按照本申请的相应制备方法,可立体选择性地或对映选择性地进行制备。
鉴于抗真菌活性的观点,空间上优选地使用以旋光活性羟基-2-甲基丙酸(S)甲酯作为通式(101)化合物或原料的制备方法来完成以上制备过程,以便在保持其立体结构的同时形成通式(113)的化合物,由此获得旋光活性(2S,3R)-3-(2,4-二氟苯基)-3-羟基-2-甲基-4-(1H-1,2,4-三唑-1-基)丁腈作为通式(113)的化合物,和获得用于具有此立体结构合成的中间体。
根据本申请,例如,可制备下列通式所示的新的化合物或其盐:其中两个X彼此相同或不同且各自为卤原子或氢原子;R4表示氢原子或低级烷基,r和m彼此相同或不同且各自为0或1;A为N或CH;W表示可具有一个或多个取代基并可含一个或多个选自N、S和氧的杂原子的芳香环,或其稠环;E为可具有一个或多个取代基且可含有一个或多个选自N、S和O的杂原子的芳香环、可具有一个或多个取代基的链烷二基、可具有一个或多个取代基的链烯二基,可具有一个或多个取代基的链炔二基;G为式-S-、>SO、>SO2、>C=S、>C-O、-O-、>N-R5、>C=N-OR5或-(CH2)j-所示的基团,其中R5为氢原子或低级烷基、且j为1-4的整数;并且Z表示氢原子、卤原子、低级烷基、卤代低级烷基、低级烷氧基、卤代低级烷氧基、羟基、硫羟基、硝基、氰基、低级链烷酰基、可具有一个或多个取代基的苯氧基、可具有一个或多个取代基的咪唑基、可具有一个或多个取代基的三唑基、可具有一个或多个取代在的四唑基、或具有一个或多个取代基的氨基。
下文将更详细地描述本发明的某些实施例。然而,本发明不受这些实施例的限制。在下列实施例中,1H NMR谱是用Varian Company制造的FT NMR(400MHz)测量的。
另外,下文中的Tr、Ms、MOM、TBDPS和Bn分别表示三苯甲基、甲磺酰基、甲氧基甲基、叔丁基二苯基甲硅烷基和苄基。
具体实施方式实施例
下文将通过实施例、实验实施例和制备实施例更具体地描述本发明。但本发明不只限制于这些实施例、实验实施例和制备实施例。实施例1
1-(2,4-二氟苯基)-1-(4-(2,4-二氟苯基)噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇的合成。
将4-(2,4-二氟苯基)噻唑(330mg)溶于乙醚(3ml)后,将该溶液在氮气氛下冷却至-78℃,加入1.6M正丁基锂的己烷溶液(1.06ml),并且将所得到的混合物搅拌约10分钟。滴加2-氯-2’,4’-二氟苯乙酮(306mg)的四氢呋喃溶液到该混合物中后,将该液体反应混合物加热至-20℃,加入氯化铵水溶液。用乙酸乙酯萃取该反应混合物。以硫酸镁干燥有机层后,减压蒸除溶剂。该残余物溶于二甲基甲酰胺(3ml)中生成溶液(A)。另一方面,制备含有1,2,4-三唑(350ml)和60%氢化钠(135mg)的二甲基甲酰胺溶液(3ml)(B)。然后将溶液(B)加至溶液(A)中,并将该混合物于60℃加热6小时。将乙酸乙酯和水加到该液体反应混合物中,并用水洗涤有机层数次,蒸除该溶剂。随后将该残余物于硅胶柱上进行色谱,用乙醚重结晶含有目的化合物的馏分,由此得到标题化合物(390mg)。随后所述的表1显示了其物理性质。实施例2
将6-氰基苯并噻唑(1.60g)溶于四氢呋喃(80ml)后,使该溶液在氮气氛下冷却至-98℃,用10分钟将1.6M正丁基锂的已烷溶液(5.9ml)滴加到该溶液中,并将所得的混合搅拌5分钟。滴加2-氯-2’,4’-二氟苯乙酮(2.85g)的四氢呋喃(20ml)溶液到该混合物中。将该液体反应混合物加热至-10℃后,往其中加入氯化铵溶液。将该混合物加热至室温后,取出有机层并减压蒸除溶剂。用乙酸乙酯萃取水层,该萃取液与有机层的残余物合并。该有机层用水洗涤,再用饱和盐水洗涤,用硫酸镁干燥,并减压蒸馏。随后将该残余物在硅胶柱上进行色谱(溶剂:己烷/乙酸乙酯=20/l,然后,己烷/乙酸乙酯=5/1),由此得到目的化合物(1.49g)。
将氢化钠(440mg)悬浮于二甲基甲酰胺(10ml)中,并将1,2,4-三唑(948mg)加至该悬浮液中,再往其中加入1-(2,4-二氟苯基)-1-(6-氰基苯并噻唑-2-基)-2-氯乙醇(1.49g)的二甲基甲酰胺(10ml)溶液。将该混合物于60℃加热4小时。该液体反应混合物冷却至室温后,将乙酸乙酯和水加入其中。将分离的有机层用水洗涤3次,再用硫酸镁干燥,之后再蒸除溶剂。该残余物在二氯甲烷-二异丙基醚中重结晶,得到目的化合物(1.17g)熔点:170-172℃。实施例3
将1-(2,4-二氟苯基)-1-(4-(4-氰基苯基)-噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇(熔点:195-198℃)(400mg)溶于二甲基甲酰胺(1.2ml)。往该溶液中加入叠氮化钠(191mg)和盐酸三乙胺(404mg)。所得混合物于100℃加热过夜(12小时)。过滤除去不溶物后,蒸除溶剂,该残余物溶于少量(各约2ml)的丙酮和乙酸乙酯中。将水加到该溶液中,用浓盐酸调节该溶液的pH至约4。过滤收集该生成的沉淀,用水洗,然后干燥,由此得到标题化合物(380mg)。熔点:252-254℃。随后所述表2显示了其物理特性。实施例4
1-(2,4-二氟苯基)-1-{4-[4-(5-(3-甲基)四唑)-苯基)噻唑]-2-基}-2-(1H-1,2,4-三唑-1-基)乙醇[结构式A]和1-(2,4-二氟苯基)-1-{4-[4-(5-(4-甲基)四唑)-苯基)噻唑]-2-基}-2-(1H-1,2,4-三唑-1-基)乙醇[结构式B]的合成结构式A:结构式B:
将实施例3得到的1-(2,4-二氟苯基)-1-{4-[(4-(5-四唑)-苯基)-噻唑]-2-基}-2-(1H-1,2,4-三唑-1-基)乙醇(320mg)溶于二甲基甲酰胺(3ml)中。往该溶液中加入碳酸铯(231mg)并将该混合物于60℃搅拌30分钟,然后冷却至室温。加入甲基碘(0.048ml),再将所得混合物于室温下的搅拌过夜。在该混合物中加入水并用乙酸乙酯萃取。该萃取液在减压下蒸除溶剂后,将残余物上硅胶柱进行色谱,,由此通过用1%甲醇·氯仿洗脱得到结构式A的化合物[熔点:188-191℃],然后用2%甲醇·氯仿洗脱得到结构式B的化合物[双熔点:110-115℃和185-187℃](60mg)。随后所述表2显示了它们的物理特性。实施例5
将1-(2,4-二氟苯基)-1-(2-(4-氟苯基)-噻唑-5-基)-2-(1H-1,2,4-三唑-1-基)乙醇的二甲基甲酰胺(3ml)溶液滴加到由1H-1,2,4-三唑(168mg)和60%氢化钠(81mg)制备的二甲基甲酰胺(3ml)溶液中。将所得混合物于100℃加热30小时。该液体反应混合物冷却至室温后,加入水并用乙酸乙酯萃取。蒸除该萃取液的溶剂,然后将所得残余物上硅胶柱进行色谱(用3%甲醇·乙酸乙酯洗脱),由此得到该标题化合物(60mg)。随后所述的表2显示了其物理特性。实施例6
将1-(2,4-二氟苯基)-1-(6-氰基苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇(418mg)和三乙胺(500ml)溶于二甲基甲酰胺(4ml)中。在用冰水冷却的同时,往所得溶液中通入硫化氢气体5分钟。于室温放置6小时后,往该溶液中加入水和乙酸乙酯使其分层。有机层用水洗涤两次,再用盐水洗涤并用硫酸镁干燥。蒸除溶剂,得到目的化合物(437mg)。随后所述表2中显示了其物理特性。实施例7
1-(2,4-二氟苯基)-1-(6-(3-甲基-噻唑-1-基)-苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇的合成
将1-(2,4-二氟苯基)-1-(6-硫代氨基甲酰基-苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇(219mg)溶于乙醇(2ml)中,并将碳酸氢钠(42mg)和溴代丙酮(46μl)加到该溶液中。将得到的混合物于60℃加热3小时。往该液体反应混合物中加入水和乙酸乙酯使其分层。有机层用盐水洗并干燥,然后蒸除溶剂。随后将该残余物上硅胶柱进行色谱(洗脱溶剂:氯仿∶甲醇=100∶1),由此得到目的化合物(114mg)。熔点:213-215℃。实施例8
将1-(2,4-二氟苯基)-1-(6-硫代氨基甲酰基苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-)乙醇(181mg)和溴代乙醛缩二甲醇(256μl)溶于乙醇(2ml)中。往该溶液中加入3滴浓硫酸并使其回流2.5小时。冷却该液体反应混合物后,往其中加入水和饱和的碳酸氢钠水溶液,所得混合物再用乙酸乙酯萃取。有机层用水洗涤,再用盐水洗涤,并用硫酸镁干燥。蒸除溶剂。将己烷加到该残余物中以固化反应产物,然后过滤收集反应产物并用己烷洗涤,由此得到目的化合物(168mg)。溶点162-166℃。
实施例9
(1)1-(2,4-二氟苯基)-1-(4-(4-乙氧羰基噻唑-2-基)-噻吩-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇的合成
将1-(2,4-二氟苯基)-1-(4-硫代氨基甲酰基噻吩-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇(1.6g)溶于二甲基甲酰胺(10ml)中,并往其中加入α-溴乙基丙酮酸(0.67ml)。所得到的混合物于60℃搅拌4小时。反应后,加入水并用乙酸乙酯萃取该反应混合物。有机层用饱和盐水洗涤。随后将残余物上硅胶柱进行色谱(氯仿∶甲醇=80∶1),由此得到油状物质(1.78g)。
将步骤(1)得到的1-(2,4-二氟苯基)-1-(4-(4-乙氧羰基噻唑-2-基)-噻吩-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇(1.7g)溶于饱和的氨的甲醇溶液(35ml)中,并且将所得溶液于室温放置23小时。减压蒸除溶剂后,从二氯甲烷-乙醚中得到结晶(1.2g)。熔点112-115℃。实施例10:
1-(2,4-二氟苯基)-1-(4-(4-氰基噻唑-2-基)-噻吩-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇的合成
将1-(2,4-2氟苯基)-1-(4-(4-氨基甲酰基噻唑-2-基)-噻吩-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇(1.2g)溶于吡啶(7.1ml)中。在冰浴中冷却该溶液,并往其中加入磷酰氯(0.29ml)。将得到的混合物搅拌30分钟。反应后,向该反应混合物中加入盐水并用乙酸乙酯萃取。有机层用6N盐酸(20ml)洗一次。再用水、饱和碳酸氢钠水溶液和饱和盐水各洗涤一次。如此洗涤过的有机层用硫酸镁干燥后蒸除溶剂。残余物在硅胶上经色谱进行纯化。从二氯甲烷的乙醚溶液中重结晶,得到固体(800mg)。熔点:172-173℃。
实施例11-17
表1
实施例18-87
实施例 | A M L | 物理特性 | |
111121314151617 | N F FCH F FN F HCH F HN Cl ClCH Cl ClN Cl HCH Cl H | mp:148~150℃1HN.M.R.(CDCl3)δ5.23(1H,d,J=14.1Hz),5.28(1H,d,J=14.1Hz),5.97(1H,s),6.8~7.0(4H,m),7.66(1H,d,J=2.2Hz),7.69(1H,td,J=9.5,6.4Hz),7.86(1H,s),8.10(1H,s),8.14(1H,td,J=9.5,6.6Hz)mp:191~192℃1HN.M.R.(DMS0-d6)δ4.98(2H,brs),6.67(1H,brs),6.81(1H,brs),7.0~7.08(1H,m),7.18~7.26(2H,m),7.30(1H,brs),7.35~7.42(1H,m)7.39(1H,s),7.55~7.62(1H,m),7.91(1H,d,J=2.5Hz),8.12~8.2(1H,m)mp:158~160℃1HN.M.R.(DMSO-d6)δ5.08(2H,brs),7.1~7.18(2H,m),7.22~7.28(1H,m),7.35~7.42(1H,m),7.37(1H,s),7.6~7.66(2H,m),7.75(1H,s),7.86(1H,d,J=2.8Hz),8.22(1H,s),8.24~8.3(1H,m)mp:184~186℃1HN.M.R.(DMSO-d6)δ4.79(1H,d,J=14.5Hz),4.87(1H,d,J=14.5Hz),6.66(1H,brs),6.81(1H,brs),7.1~7.18(2H,m),7.22~7.28(1H,m),7.30(1H,brs),7.32(1H,s),7.35~7.42(1H,m),7.86(1H,d,J=2.5Hz),8.25~8.32(1H,m)mp:188~189℃1HN.M.R.(DMSO-d6)δ5.35(1H,d,J=14.4Hz),5.50(1H,d,J=14.4Hz),7.2~7.26(1H,m),7.35~7.44(3H,m),7.54~7.58(2H,m),7.68(1H,s),8.00(1H,d,J=2.5Hz),8.15~8.22(1H,m),8.31(1H,s)mp:238~239℃1HN.M.R.(DMSO-d6)δ5.05(1H,d,J=14.4Hz),5.26(1H,d,J=14.4Hz),6.67(1H,brs),6.73(1H,brs),7.2~7.25(1H,m),7.23(1H,s),7.37(1H,s),7.37~7.42(2H,m),7.57(1H,d,J=2.5Hz),7.64(1H,d,J=8.8Hz),7.98(1H,d,J=2.5Hz),8.14~8.2(1H,m)mp:167~168℃1HN.M.R.(DMSO-d6)δ5.09(2H,brs),7.22~7.28(1H,m),7.35~7.40(2H,m),7.42(1H,s),7.6~7.64(2H,m),7.76(1H,s),7.87(1H,d,J=2.8Hz),8.24(1H,s),8.24~8.3(1H,m)mp:201~203℃1HN.M.R.(DMSO-d6)δ4.81(1H,d,J=14.5Hz),4.86(1H,d,J=14.5Hz),6.67(1H,s),6.83(1H,s),7.22~7.29(1H,m),7.31(1H,s),7.35~7.42(4H,m)7.62~7.66(2H,m),7.87(1H,d,J=2.5Hz),8.25~8.32(1H,m) |
表2汇总了采用与实施例1-10相同的方法制备的目的化合物。
表2实施例 目的化合物 物理特性18
mp:177~179℃1HN.M.R.(CDCl3)δ5.26(2H,s),5.93(1H,s),6.78~6.90(2H,m),7.11(2H,brt,J=8.7Hz),7.38(1H,s),7.65~7.72(1H,m),7.80~7.86(2H,m),7.87(1H,s),8.10(1H,s).19
mp:124~126℃1HN.M.R.(CDCl3)δ2.39(3H,s),5.26(2H,s),5.86(1H,s),6.77~6.87(2H,m),7.23(2H,brd,J=8.0Hz),7.38(1H,s),7.62~7.70(1H,m),7.75(2H,brd,J=8.0Hz),7.85(1H,s),8.10(1H,s)20
mp:168~169℃1HN.M.R.(CDCl3)δ5.26(2H,s),5.95(1H,s),6.77~6.88(2H,m),7.39(2H,brd,J=8.8Hz),7.43(1H,s),7.65~7.71(1H,m),7.79(2H,brd,J=8.8Hz),7.86(1H,s),8.09(1H,s)21
mp:195~198℃1HN.M.R.(CDCl3)δ5.24(1H,d,J=14.5Hz),5.28(1H,d,J=14.5Hz),6.05(1H,s),6.78~6.90(2H,m),7.60(1H,s),7.68~7.74(1H,m),7.71(2H,brd,J=8.5Hz),7.89(1H,s),7.97(2H,brd,J=8.5Hz),8.11(1H,s)3
mp:252~254℃1HN.M.R.(DMSO-d6)δ5.27(2H,s),7.0~7.05(1H,m),7.18~7.25(1H,m),7.43(1H,s),7.50~7.57(1H,m)7.72(1H,s),8.12(2H,brd,J=8.5Hz),8.20(2H,brd,J=8.5Hz),8.28(1H,s),8.33(1H,s)
表2(续)实施例 目的化合物 物理特性
结构式A4
mp:188~191℃1HN.M.R.(CDCl3)δ4.42(3H,s),5.27(1H,d,J=14.4Hz),5.32(1H,d,J=14.4Hz),5.94(1H,s),6.79~6.89(2H,m),7.55(1H,s),7.65~7.72(1H,m),7.88(1H,s),7.99(2H,brd,J=8.6Hz),8.13(1H,s),8.20(2H,brd,J=8.6Hz)
结构B
(结构式A的异构体)4
mp:185~187℃1HN.M.R.(CDCl3)δ4.22(3H,s),5.28(2H,brs),6.02(1H,s),6.79~6.91(2H,m),7.61(1H,s),7.69~7.76(1H,m),7.82(2H,brd,J=8.2Hz),7.89(1H,s),8.06(2H,brd,J=8.2Hz),8.14(1H,s)22
mp:142~143℃1HN.M.R.(CDCl3)δ2.41(3H,d,J=0.9Hz),5.19(2H,s),5.75(1H,s),6.75~6.9(2H,m),6.85(1H,brs),7.55~7.65(1H,m),7.83(1H,s),8.07(1H,s)23
mp:217~220℃1HN.M.R.(CDCl3)δ5.25(2H,s),5.94(1H,s),6.77~6.9(2H,m),7.65~7.72(1H,m),7.79(1H,s),7.80(1H,d,J=2.2Hz),7.86(1H,s),8.11(1H,s),8.82(1H,d,J=2.2Hz)24
mp:147~149℃1HN.M.R.(CDCl3)δ2.32(3H,d,J=2.1Hz),5.14(1H,d,J=14.1Hz),5.24(1H,d,J=14.1Hz),5.83(1H,s),6.78~7.00(4H,m),7.38~7.44(1H,m),7.61~7.68(1H,m),7.87(1H,s),8.10(1H,s)
表2(续)实施例 目的化合物 物理特性25
Oily or waxy matter1HN.M.R.(CDCl3)δ0.90(3H,t,J=7.0Hz),1.25~1.40(4H,m),1.60~1.75(2H,m),2.71(2H,t,J=7.9Hz),5.15(1H,d,J=14.1Hz),5.21(1H,d,J=14.1Hz),5.75(1H,s),6.76~6.86(3H,m),7.56~7.62(1H,m),7.83(1H,s),8.06(1H,s)26
Oily matter1HN.M.R.(CDCl3)δ5.19(2H,s),6.34(1H,s),6.78~6.9(2H,m),7.65~7.7(1H,m),7.90(1H,s),7.96(1H,s),8.12(1H,s)27
Solld,amorphous1HN.M.R.(CDCl3)δ4.89(1H,d,J=14.2Hz),5.22(1H,d,J=14.2Hz),5.84(1H,s),6.73~6.90(2H,m),7.11(2H,brt,J=9.0Hz),7.61(1H,d,J=1.6Hz),7.69~7.75(1H,m),7.84~7.89(2H,m),7.88(1H,s),8.05(1H,s)28
1HN.M.R.(CDCl3)δ4.91(1H,d,J=14.1Hz),5.23(1H,d,J=14.1Hz),5.86(1H,s),6.78~7.02(4H,m),7.68~7.76(2H,m),7.87(1H,s),8.05(1H,s),8.18~8.25(1H,m)29
Solid,amorphcus1HN.M.R.(CDCl3)δ4.90(1H,d,J=14.1Hz),5.22(1H,d,J=14.1Hz),5.96(1h,s),6.79~6.91(2H,m),7.7~7.77(4H,m),7.89(1H,s),7.99(2H,brd,J=8.5Hz),8.06(1H,s)
表2(续)实施例 目的化合物 物理特性30
mp:129~131℃1HN.M.R.(DMSO-d6)δ5.08(1H,d,J=14.3Hz),5.18(1H,d,J=14.3Hz),6.98~7.05(1H,m),7.18~7.25(1H,m),7.25(1H,s),7.45~7.52(1H,m),7.73(1H,s),8.02(1H,d,J=0.7Hz),8.11(4H,brs),8.34(1H,s)结构式A31
mp:147~149℃1HN.M.R.(CDCl3)δ4.42(3H,s),4.92(1H,d,J=14.1Hz),5.24(1H,d,J=14.1Hz),5.89(1H,s),6.79~6.91(2H,m),7.68(1H,d,J=1.5Hz),7.70~7.77(1H,m),7.88(1H,s),8.01(2H,brd,J=8.2Hz),8.07(1H,s),8.20(2H,brd,J=8.2Hz)
结构B
(结构式A的异构体)31
mp:113~115℃1HN.M.R.(CDCl3)δ4.22(3H,s),4.93(1H,d,J=14.1Hz),5.24(1H,d,J=14.1Hz),5.99(1H,s),6.80~6.92(2H,m),7.72(1H,d,J=1.6Hz),7.72~7.78(1H,m),7.83(2H,brd,J=8.6Hz),7.89(1H,s),8.08(1H,s),8.08(2H,brd,J=8.6Hz)32
Oily matter1HN.M.R.(CDCl3)δ1.27(6H,d,J=6.2Hz),2.48(2H,dd,J=12.1,10.6Hz),3.55(2H,dd,J=12.1,3.1Hz),3.75~3.83(2H,m),4.88(1H,d,J=14.1Hz),5.21(1H,d,J=14.1Hz),5.72(1H,s),6.79~6.9(2H,m),6.88(2H,brd,J=9.2Hz),7.51(1H,d,J=1.6Hz),7.67~7.73(1H,m),7.76(2H,brd,J=9.2Hz),7.86(1H,s),8.04(1H,s)
表2(续)实施例 目的化合物 物理特性33
1HN.M.R.(CDCl3)δ4.93(1H,d,J=14.1Hz),5.19(1H,d,J=14.1Hz),6.67(1H,brs),6.78~6.90(2H,m),7.14(1H,s),7.28(1H,s),7.37(2H,d,J=8.2Hz),7.65(1H,s),7.70~7.75(1H,m),7.74(1H,s),7.81(1H,s),7.92(2H,d,J=8.2Hz),8.11(1H,s)34
mp:170~171℃1HN.M.R.(CDCl3)δ4.92(1H,d,J=14.1Hz),5.24(1H,d,J=14.1Hz),5.87(1H,s),6.80~6.95(2H,m),7.67(1H,d,J=1.5Hz),7.71~7.77(1H,m),7.85(2H,s),7.89(1H,s),7.99~8.03(2H,m),8.07(1H,s),8.14~8.18(2H,m)35
1HN.M.R.(CDCl3)δ4.87(1H,d,J=14.1Hz),5.18(1H,d,J=14.1Hz),6.23(1H,s),6.79~6.90(2H,m),7.13(1H,dd,J=1.5,0.9Hz),7.38(1H,d,J=1.6Hz),7.41(1H,t,J=1.5Hz),7.67~7.73(1H,m),7.86(1H,s),8.06(1H,s),8.07(1H,t,J=0.9Hz)36
mp:240~242℃1HN.M.R.(DMSO-d6)δ3.45~3.57(8H,m),5.04~5.08(1H,m),5.20~5.24(1H,m),6.98~7.16(5H,m),7.38~7.45(1H,m),7.58~7.62(2H,m),8.17(1H,s),8.88(1H,s)
表2(续)实施例 目的化合物 物理特性37
mp:152~153℃1HN.M.R.(CDCl3)δ4.72(1H,d,J=14.1Hz),5.11(1H,d,J=14.1Hz),5.75(1H,s),6.74~6.84(2H,m),7.10~7.15(2H,m),7.40(1H,d,J=1.8Hz),7.58~7.65(3H,m),7.82(1H,s),7.98(1H,s)28
1HN.M.R.(DMSO-d6)δ5.08(1H,d,J=14.3Hz),5.19(1H,d,J=14.3Hz),6.9~7.05(1H,m),7.18~7.28(1H,m),7.24(1H,s),7.44~7.52(1H,m),7.72(1H,s),7.95~8.12(4H,m),7.99(1H,s),8.31(1H,d,J=2.0Hz),8.34(1H,s),9.23(1H,d,J=2.0Hz),9.46(1H,s)39(5) 1HN.M.R.(DMSO-d6)δ5.07(1H,d,J=14.4Hz),5.18(1H,d,J=14.4Hz),6.97~7.03(1H,m),7.18~7.25(1H,m),7.23(1H,s),7.44~7.5(1H,m),7.72(1H,s),7.97(2H,brd,J=8.8Hz),8.06(2H,brd,J=8.8Hz),8.27(1H,s),8.33(1H,s),9.38(1H,s)40
mp:142~144℃1HN.M.R.(DMSO-dG)δ2.50(3H,s),5.04(1H,d,J=14.3Hz),5.16(1H,d,J=14.3Hz),6.96~7.02(1H,m),7.15~7.25(1H,m),7.18(1H,s),7.31(2H,brd,J=8.2Hz),7.42~7.5(1H,m),7.71(1H,s),7.79(2H,brd,J=8.2Hz),7.89(1H,s),8.32(1H,s)
表2(续)实施例 目的化合物 物理特性41
mp:162~163℃1HN.M.R.(CDCl3)δ5.27(2H,s),5.88(1H,s),6.8~6.9(2H,m),7.25~7.35(8H,m),7.45~7.5(2H,m),7.7~7.78(1H,m),7.89(1H,s),8.15(1H,s)42
mp:126~127℃Elemental Calculated C;54.20,H;3.04 N;16.86analysis Found C;53.92,H;3.10 N;16.681HN.M.R.(CDCl3)δ4.84(1H,d,J=14.1Hz),5.18(1H,d,J=14.1Hz),6.19(1H,bs,),6.78~6.89(m,2H),7.02(1H,dd,J=4.0,1.8Hz),7.47(1H,d,J=4.0Hz),7.71(1H,dt,J=6.4,9.2Hz),7.81(1H,s),8.05(1H,s)43
Mass MH+ 376 Oily matter1HN.M.R.(DMSO-d6)δ5.02(1H,d,J=14.3Hz),5.14(1H,d,J=14.3Hz),6.93~6.99(1H,m),7.13(1H,d,J=2.7Hz).7.13~7.29(1H,m),7.43(1H,d,J=2.7Hz),7.44~7.50(1H,m),7.69(1H,s),7.93(1H,s),8.31(1H,s)结构式A44
mp:135~137℃1HN.M.R.(CDCl3)δ4.36(3H,s),4.90(1H,d,J=14.1Hz),5.23(1H,d,J=14.1Hz),5.80(1H,s),6.77~6.87(2H,m),6.99~7.00(1H,m),7.27(1H,s),7.61(1H,d,J=3.9Hz),7.72(1H,dt,J=9.2,6.4Hz),7.84(1H,s),8.06(1H,s)
表2(续)实施例 目的化合物 物理特性44 结构式B
(结构式A的异构体)mp:179~182℃1HN.M.R.(CDCl3)δ4.20(3H,s),5.07(1H,d,J=14.3Hz),5.18(1H,d,J=14.3Hz),6.98~7.02(1H,m),7.18~7.23(1H,m),7.24(1H,s),7.45(1H,dd,J=1.3,3.5Hz),7.48~7.52(1H,m),7.72(1H,s),7.73(1H,d,J=3.5Hz),8.33(1H,s)45
mp:142~145℃1HN.M.R.(CDCl3)δ5.19(1H,d,J=14.1Hz),5.30(1H,d,J=14.1Hz),6.41~6.43(1H,m),6.79~6.84(1H,m),6.86~6.92(1H,m),7.18(1H,d,J=5.3Hz),7.29(1H,d,J=5.3Hz),7.65(1H,dt,J=6.4,9.0Hz),7.84(1H,s),8.13(1H,s)Elemental Calculated C;54.20,H;3.04 N;16.86analysis Found C;54.00,H;2.88 N;16.7746
Solid,HNO3 salt 205~210℃1HN.M.R.(DMSO-d6)δ5.18(1H,d,J=13.9Hz),5.70(1H,d,J=13.9Hz),6.82~6.87(1H,m),7.00~7.06(1H,m),7.31~7.37(1H,m),7.33(1H,d,J=5.3Hz),7.64(1H,d,J=5.3Hz),7.69(1H,s),8.25(1H,s)Mass MH+ 376
结构式A47
0ily matter1HN.M.R.(CDCl3)δ4.32(3H,s),5.19(1H,brd,J=12.0Hz),5.25(1H,brd,J=12.0Hz),5.90~6.67(2H,m),7.33~7.39(1H,m),7.36(1H,d,J=5.3Hz),7.44(1H,d,J=1.1Hz),7.53(1H,d,J=5.3Hz),7.69(1H,s),8.23(1H,s)
表2(续)实施例 目的化合物 物理特性
结构式B
(结构式A的异构体)47Oily matter1HN.M.R.(CDCl3)δ3.75(3H,s),5.17(1H,d,J=13.6Hz),5.20(1H,d,J=13.6Hz),6.52(1H,d,J=1.1Hz),6.58~6.64(2H,m),7.09(1H,d,J=5.3Hz),7.15(1H,dt,J=6.41,9.0Hz),7.50(1H,d,J=5.3Hz),7.71(1H,s),8.23(1H,s)43
mp:244~245℃MS:MH-4131HN.M.R.(CDCl3)δ5.13(1H,d,J=14.1Hz),5.29(1H,d,J=14.1Hz),7.10~7.17(1H,m),7.22~7.28(1H,m).7.49(1H,s),7.70(1H,dt,J=6.4,9.0Hz),7.74(1H,s),7.90(1H,s),8.30(1H,s)Calculated C;43.75,H;2.21 N;13.61Fcund C;43.44,H;2.03 N;13.5149
mp:203~208℃1HN.M.R.(DMSO-d6)δ5.15(1H,d,J=13.9Hz),5.29(1H,d,J=13.9Hz),7.01~7.07(1H,m),7.12(1H,brs),7.16~7.22(1H,m),7.20(1H,s),7.56(1H,dt,J=6.8,9.0Hz),7.70(1H,s),8.30(1H,s)50 结构式Amp:191~194℃MS:MH+ 470,4891HN.M.R.(CDCl3)δ4.13(3H,s),5.21(1H,dd,J=3.30,14.4Hz),5.48(1H,dd,J=5.0,14.4Hz),5.94~6.01(1H,m),6.81~6.87(2H,m),7.39~7.46(1H,m),7.59~7.60(1H,m),7.86(1H,brd,J=14.5Hz),8.03(1H,d,J=3.7Hz)Calculated C;41.03,H;2.59 N;20.94Found C;40.93,H;2.37 N;20.81
表2(续)实施例 目的化合物 物理特性
结构式B
(结构式A的异构体)50
Solidmp:83~92℃1HN.M.R.(CDCl3)δ4.09(3H,s),5.24(1H,d,J=14.1Hz),5.43(1H,d,J=14.1Hz),6.13~6.20(1H,m),6.82~6.91(2H,m),5.41~7.47(1H,m),7.48(1H,s),7.87~7.90(1H,m),8.07(m,s)51
mp:54~58℃(Solid)IR 2231cm-11HN.M.R.(CDCl3)δ4.81(1H,d,J=13.9Hz),5.19(1H,d,J=13.9Hz),6.00(1H,s),6.80~6.89(2H,m),7.15(1Hbrs),7.67~7.73(1H,m),7.86(1H,brs),7.88(1H,s),8.05(1H,s)Colculaced C;54.20,H;3.04 N;16.86Found C;54.04,H;3.23 N;16.7452
HCl saltmp:213~221℃Oily matter1HN.M.R.(CDCl3)δ5.01(1H,d,J=14.3Hz),5.22(1H,d,J=14.3Hz),6.73~6.87(2H,m),7.67~7.73(1H,m),7.75(1H,brs),8.04(1H,s),8.17(1H,brs),8.21(1H,s)53 结构式Amp:118~120℃1HN.M.R.(CDCl3)δ4.36(3H,s),4.90(1H,d,J=14.3Hz),5.25(1H,d,J=14.3Hz),5.73(1H,s),6.77~6.89(2H,m),7.52(1H,brs),7.72(1H,dt,J=6.4,9.3Hz),7.86(1H,s),7.97(1H,brs),8.05(1H,s)
表2(续)实施例 目的化合物 物理特性43 结构B
(结构式A的异构体)mp:117~120℃1HN.M.R.(CDCl3)δ4.19(3H,s),4.99(1H,d,J=14.3Hz),5.25(1H,d,J=14.3Hz),5.95(1H,s),6.81~6.87(2H,m),7.50(1H,brs),7.73(1H,dt,J=6.4,9.2Hz),7.77(1H,brs),7.88(1H,s),8.07(1H,s)54
Yellow solid1HN.M.R.(CDCl3)δ4.85(1H,d,J=14.5Hz),5.21(1H,d,J=14.5Hz),5.83(1H,s),6.77~6.87(2H,m),7.14(1Hbrs),7.43(1H,brs),7.50(1H,brs),7.68(1H,dt,J=6.4,9.2Hz),7.83(1H,s),7.84(1H,s),8.04(1H,s)55
mp:112~115℃1HN.M.R.(CDCl3)δ4.88(1H,d,J=14.4Hz),5.27(1H,d,J=14.4Hz),5.65(1H,brs),5.80(1H,s),6.79~6.89(2H,m),7.19(1H,brs),7.42(1H,brs),7.70~7.76(1H,m),7.77(1H,brs),7.87(1H,s),8.06(1H,s),8.06(1H,s)56
mp:172~173℃1HN.M.R.(CDCl3)δ4.89(1H,d,J=14.0Hz),5.26(1H,d,J=14.0Hz),5.87(1H,s),6.80~6.89(2H,m),7.47(1H,s),7.72(1H,dt,J=6.4,9.3Hz),7.83(1H,s),7.87(1H,s),7.90(1H,s),8.07(1H, s)Calculated C;52.03,H;2.67 N;16.86Found C;51.93,H;2.75 N;16.79
表2(续)实施例 目的化合物 物理特性57
mp:162~165℃1HN.M.R.(DMSO-d6)δ5.11(1H,d,J=14.1Hz),5.19(1H,d,J=14.1Hz),6.98~7.03(1H,m),7.21~7.26(1H,m),7.50(1H,dt,J=7.0,9.2Hz),7.67(1H,s),7.79(1H,s),8.22(1H,s),8.47(1H,s),8.49(1H,s)58 结构式Amp:91~94℃(Solid)MS:MH+ 4731HN.M.R.(CDCl3)δ4.49(3H,s),4.90(1H,d,J=14.5Hz),5.27(1H,d,J=14.5Hz),5.85(1H,s),6.79~6.90(2H,m),7.45(1H,t,J=1.5Hz),7.73(1H,dt,J=8.4,9.2Hz),7.84(1H,d,1.5Hz),7.88(1H,s),8.07(1H,s),8.23(1H,s)58 结构式B(结构式A的异构体)mp:178~130℃1H.M.R.(CDCl3)δ4.44(3H,s),4.88(1H,d,J=13.6Hz),5.29(1H,d,J=13.6Hz),5.71(1H,s),6.77~6.87(2H,m),7.57(1H,t,J=1.5Hz),7.77(1H,dt,J=6.4,9.2Hz),7.87(1H,s),7.88(1H,d,J=1.5Hz),8.03(1H,s),8.06(1H,s)59
mp:189~191℃1HN.M.R.(CDCl3)δ4.89(1H,d,J=14.7Hz),5.21(1H,d,J=14.7Hz),5.84(1H,s),6.77~6.89(2H,m),6.98(1H,dd,J=1.7,4.0Hz),7.41(1H,d,J=4.0Hz),7.74(1H,dt,J=6.4,9.0Hz),7.87(1H,s),7.88(1H,s),8.06(1H,s)
表2(续)实施例 目的化合物 物理特性60
mp:140~147℃1HN.M.R.(DMSO~d6)δ5.06(1H,d,J=14.7Hz),5.15(1H,d,J=14.7Hz),6.98~7.02(1H,7.14(1H,s),7.17~7.23(1H,m),7.22(1H,d,J=4.0),7.49(1H,J=6.8,9.0Hz),7.64~7.66(1H,m),7.71(1H,s),8.22~8.27(1H,m),8.32(1H,s)61
(Solid)Minor component1HN.M.R.(CDCl3)δ4.44(3H,s),4.90(1H,d,J=14.2Hz),5.22(1H,d,J=14.2Hz),6.70(1H,s),6.78~6.90(2H,m),6.98~6.99(1H,m),7.46(1H,d,J=4.0Hz),7.71~7.79(1H,m),7.88(1H,s),8.02(1H,s),8.06(1H,s)Maor component1HN.M.R.(CDCl3)δ4.50(3H,s),4.90(1H,d,J=14.2Hz),5.24(1H,d,J=14.2Hz),5.90(1H,s),6.73~6.90(2H,m),6.98(1H,dd,J=1.8,4.0Hz),7.42(1H,d,J=4.0Hz),7.71~7.79(1H,m),7.89(1H,s),8.07(1H,s),8.23(1H,s)62
mp:166~166.5℃1HN.M.R.(CDCl3)δ5.27(1H,d=14.1Hz),5.37(1H,d,J=14.1Hz),6.26(1H,s),6.77~6.83(1H,m),6.86~6.91(1H,m),7.61(1H,dd,J=1.7,8.4Hz),7.74(1H,dt,J=6.4,9.0Hz),7.88(1H,s),7.95(1H,d,J=8.4Hz),8.17(1H,s),8.23(1H,s)Calculated C;50.71,H;2.60 N;13.14Fcund C;50.57,H;2.58 N;12.89
表2(续)实施例 目的化合物 物理特性63
mp:130~131℃1HN.M.R.(CDCl3)δ5.32(2H,q,J=14.3Hz),6.05(1H,s),6.77~6.89(2H,m),7.26~7.40(1H,m),7.46~7.50(1H,m),7.70(1H,dt,J=6.4,8.9Hz),7.83~7.85(1H,m),7.86(1H,s),7.99~8.02(1H,m),8.15(1H,s)Celculated C;55.31,H;3.80 N;15.18Found C;55.21,H;3.36 N;15.0364
mp:170~172℃1HN.M.R.(CDCl3)δ5.26(1H,d,J=14.0Hz)5.35(1H,d,J=14.0Hz),6.33(1H,s),6.78~6.83(1H,m),6.87~6.92(1H,m),7.72(1H,dd,J=1.4Hz,8.3Hz),7.89(1H,s),8.07(1H,dd,J=8.3Hz,0.4Hz),8.16(1H,s),8.18(1H,dd,J=0.4Hz,1.4Hz)MS:MH+=38465
mp:182~186℃1HN.M.R.(CDCl3)δ4.42(3H,s),5.30(1H,d,J=14.0Hz),5.36(1H,d,J=14.0Hz),6.18(1H,s),6.78~6.88(2H,m),7.43~7.55(1H,m),7.72(1H,s),7.73(1H,s),8.19(1H,dd,J=0.4Hz,8.8Hz),8.31(1H,dd,J=1.6Hz,8.8Hz),8.66(1H,d,J=0.4Hz)MS:MH+=441
表2(续)实施例 目的化合物 物理特性66
Solid1HN.M.R.(CDCl3)δ5.26(1H,d,J=14.1Hz),5.34(1H,d,J=14.1Hz),6.20(1H,s),6.77~6.83(1H,m),6.86~6.90(1H,m),7.25(1H,brs),7.66(1H,brs),7.69~7.74(1H,m),7.80(1H,s),7.90(1H,dd,J=2.0Hz,8.8Hz),7.98(1H,dd,J=0.4Hz,8.8Hz),8.14(1H,s),8.46(1H,dd,J=0.4Hz,2.0Hz)67
mp:162~166℃MS:MH+=4421HN.M.R.(CDCl3)δ5.29(1H,d,J=14.2Hz),5.35(1H,d,J=14.2Hz),6.12(1H,s),6.78~6.83(1H,m),6.85~6.91(1H,m),7.37(1H,d,J=3.4Hz),7.70~7.76(1H,m),7.88(1H,s),7.88(1H,d,J=3.4Hz),8.03(1H,dd,J=0.8Hz,8.4Hz),8.06(1H,dd,J=1.6Hz,8.4Hz),8.16(1H,s),8.48(1H,dd,J=0.8Hz,1.6Hz)68
mp:213~215℃MS:MH+=4561HN.M.R.(CDCl3)δ2.51(3H,s),5.30(1H,d,J=14.4Hz),5.33(1H,d,J=14.4Hz),6.10(1H,s),6.78~6.90(2H,m),6.91(1H,s),7.69~7.76(1H,m),7.87(1H,s),8.01(1H,s),8.02(1H,s),8.16(1H,s),8.45(1H,s)
表2(续)实施例 目的化合物 物理特性69
mp:232~233℃MS:MH+=5521HN.M.R.(CDCl3)δ5.30(1H,d,J=14.0H2),5.35(1H,d,J=14.0Hz),6.13(1H,s),6.79~6.82(1H,m),6.87~6.91(1H,m),7.42(2H,d,J=8.8H2),7.49(1H,s),7.71~7.77(1H,m),7.88(1H,s),7.94(2H,d,J=8.8Hz),8.05(1H,dd,J=0.4Hz,8.4Hz),3.12(1H,dd,J=1.8Hz,8.4Hz),3.17(1H,s),8.55(1H,dd,J=0.4Hz,1.8Hz)70
mp:158~160℃1HN.M.R.(CDCl3)δ2.46(3H,s),5.26(1H,d,J=14.1Hz),5.32(1H,d,J=14.1Hz),5.99(1H,s),6.72~6.88(2H,m),7.28(1H,dd,J=8.5,1.6Hz),7.61(1H,d,J=1.6Hz),7.63~7.71(1H,m),7.84(1H,3),7.87(1H,d,J=8.5Hz),8.13(1H,s)71
mp:141~142℃1HN.M.R.(CDCl3)δ6.26(1H,d,J=14.1Hz),5.33(1H,d,J=14.1Hz),6.13(1H,s),6.77~6.83(1H,m),6.85~6.80(1H,m),7.44(1H,dd,J=3.8,1.6Hz),7.68~7.74(1H,m),7.81(1H,d,J=1.6Hz),7.87(1H,s),7.90(1H,d,J=8.8Hz),8.14(1H,s)72
mp:139~140℃1HN.M.R.(CDCl3)δ5.28(1H,d,J=14.1Hz),5.32(1H,d,J=14.1Hz),6.16(brs),6.72~6.82(1H,m),6.83~6.90(1H,m),7.20(1H,ddd,J=9.0,9.0,2.8Hz),7.50(1H,dd,J=8.4,2.8Hz),7.64~7.74(1H,m),7.84(1H,s),7.93(1H,dd,J=9.0,5.2Hz),8.13(1H,s)
表2(续)实施例 目的化合物 物理特性73
1HN.M.R.(CDCl3)δ1.75~2.20(1H,brs),5.28(1H,d,J=14.1Hz),5.36(1H,d,J=14.1Hz),6.74~6.84(1H,m),6.84~6.90(1H,m),7.16(1H,d,J=0.8Hz),7.25~7.28(1H,m),7.47(1H,dd,J=8.8,2.2Hz),7.68~7.76(1H,m),7.77~7.81(1H,m),7.80(1H,d,J=2.2Hz),7.82(1H,s),8.07(1H,d,J=8.8Hz),8.16(1H,s)74
mp:175~177℃1HN.M.R.(CDCl3)δ3.16~3.20(4H,m),3.86~3.90(4H,m),5.24(1H,d,J=14.3Hz),5.32(1H,d,J=14.3Hz),5.95(1H,s),6.74~6.89(2H,m),7.12(1H,dd,J=9.2,2.5Hz),7.23(1H,d,J=2.5Hz),7.63~7.70(1H,m),7.85(1H,s),7.86(1H,d,J=9.2Hz),8.13(1H,s)75
mp:148~149℃1HN.M.R.(CDCl3)δ5.29(1H,d,J=14.2Hz),5.34(1H,d,J=14.2Hz),6.24(1H,brs),6.76~6.83(1H,m),6.84~6.90(1H,m),7.68~7.75(1H,m),7.83(2H,brs),7.85(1H,s),8.07(1H,d,J=8.8Hz),8.16(1H,brs),8.24(1H,dd,J=8.8,2.0Hz),8.54(1H,d,J=2.0Hz)76
mp:207~209℃1HN.M.R.(CDCl3)δ5.28(1H,d,J=14.1Hz),5.36(1H,d,J=14.1Hz),6.42(1H,brs),6.76~6.84(1H,m),6.84~6.91(1H,m),7.69~7.77(1H,m),7.80(1H,dd,J=8.8,2.0Hz),7.84(1H,s),7.85(1H,d,J=1.6Hz),8.03(1H,d,J=1.6Hz),8.10(1H,d,J=8.8Hz),8.18(1H,s),8.23(1H,d,J=2.0Hz)
表2(续)实施例 目的化合物 物理特性77
Oily matter1HN.M.R.(CD3OD)δ5.37(1H,d,J=14.5Hz),5.44(1H,d,J=14.5Hz),6.93~7.02(2H,m),7.63~7.70(1H,m),7.73(1H,s),8.42(1H,s),8.63(1H,d,J=2.8Hz),8.74(1H,d,J=2.8Hz)78
Oily matter1NH.M.R.(CDCl3)δ5.26(1H,d,J=14.1Hz),5.36(1H,d,J=14.1Hz),6.23(1H,s),6.77~6.92(2H,m),7.43(1H,dd,J=8.2,4.5Hz),7.73~7.80(1H,m),7.68(1H,s),8.16(1H,s),8.23(1H,dd,J=8.2,1.6Hz),8.57(1H,dd,J=4.5,1.6Hz)79
mp:199~201℃1HN.M.R.(CDCl3)δ5.23(1H,d,J=14.4Hz),5.32(1H,d,J=14.4Hz),6.30(1H,s)6.76~6.82(1H,m),6.87~6.91(1H,m),7.42(1H,d,J=8.4Hz),7.73~7.79(1H,m),7.83(1H,s),8.15(1H,s),8.15(1H,d,J=8.4Hz)80
Amorphous1HN.M.R.(CDCl3)δ5.25(1H,d,J=14.4Hz),5.36(1H,d,J=14.4Hz),6.33(1H,s),6.89~6.94(1H,m).7.22(1H,s,(br)),7.49(1H,d,J=8.8Hz),7.67(1H,brs),7.76~7.82(1H,m),7.90(1H,s),8.18(1H,s),8.32(1H,d,J=8.8Hz),8.36(1H,brs),MS:MH+=427
表2(续)实施例 目的化合物 物理特性81
mp:144~146℃1HN.M.R.(CDCl3)δ3.97(3H,s),5.23(1H,d,J=14.2Hz),5.31(1H,d,J=14.2Hz),6.04(1H,s),6.77~6.90(2H,m),6.84(1H,d,J=8.8Hz),7.68~7.74(1H,m),7.87(1H,s),8.06(1H,d,J=8.8Hz),8.14(1H,s)82
mp:112~115℃1HN.M.R.(CDCl3)δ4.95(1H,d,J=14.4Hz),5.28(1H,d,J=14.4Hz),5.69(1H,s),6.78~6.88(2H,m),7.15(1H,d,J=1.1Hz),7.29~7.36(2H,m),7.88~7.79(3H,m),7.85(1H,s),8.06(1H,s)83
mp:186~189℃1R 2227cm-1HN.M.R.(CDCl3)δ4.95(1H,d,J=14.2Hz),5.27(1H,d,J=14.2Hz),5.97(1H,s),6.58~6.90(2H,m),7.24(1H,brs),7.26(1H,s),7.51~7.54(1H,m),7.76(1H,dt,J=6.4,9.2Hz),7.87(1H,s),7.87(1H,d,J=8.4Hz),8.01(1H,s),8.07(1H,s)MS:MH+=33384
mp:122~127℃1HN.M.R.(DMSO-d6)δ5.17(1H,d,J=14.3Hz),5.29(1H,d,J=14.3Hz),6.97~7.03(1H,m),7.16~7.21(1H,m),7.51(1H,dt,J=8.8,9.3Hz),7.69(1H,s),7.81(1H,s),7.98(1H,brd,J=8.4Hz),8.12(1H,d,J=8.4Hz),8.50(1H,s),8.53(1H,s)MS:MH+=426
表2(续)实施例 目的化合物 物理特性85 结构式Amp:162~166℃1HN.M.R.(CDCl3)δ4.42(3H,s),4.98(1H,d,J=14.1Hz),5.31(1H,d,J=14.1Hz),5.80(1H,s),6.79~6.85(2H,m),7.25(1H,brs),7.75(1H,dt,J=6.4,9.2Hz),7.87(1H,s),7.88(1H,d,J=8.4Hz),8.03(1H,dd,J=1.7,8.4Hz),8.08(1H,s),8.49(1H,d,J=1.7Hz)MS:MH+=44085 结构式B
(结构式A的异构体)mp:105~110℃1HN.M.R.(CDCl3)δ4.19(3H,s),4.49(1h,d,J=14.3Hz),5.29(1H,d,J=14.3Hz),5.97(1H,s),6.79~6.91(2H,m),7.28(1H,brs),7.64(1H,dd,J=1.7,8.4Hz),7.77(1H,1H,dt,J=6.4,9.2Hz),7.88(1H,s),7.96(1H,d,J=8.4Hz),8.05(1H,d,J=1.7Hz),8.10(1H,s)MS:MH+=44086
1HN.M.R.(CDCl3)δ5.27(1H,d,J=14.0Hz),5.37(1H,d,J=14.0Hz),6.35(1H,s),6.79~6.85(1H,m),6.89~6.94(1H,m),7.76~7.82(1H,m),7.85(1H,d,J=1.2Hz),7.90(1H,s),8.19(1H,s),8.37(1H,d,J=8.3Hz),8.41(1H,d,J=8.8Hz),3.61(1H,d,J=1.7Hz)MH+=42787
1HN.M.R.(CDCl3)δ5.28(1H,d,J=10Hz),5.34(1H,d,J=10Hz),6.29(1H,s),6.78~6.84(1H,m),6.88~6.94(1H,m),7.75~7.82(1H,m),7.89(1H,s),7.93(2H,s),8.13(1H,s),8.26(1H,d,J=9.0Hz),8.39(1H,d,J=9.0Hz)MH+=427[0070]实验实施例1
每组五只的ICR小鼠通过其尾静脉注入白色假丝酵母MCY 8622菌株(2×106cfu/鼠)而被感染。1小时后,给各组的鼠口服施用表3所示[通示(III)表示的化合物]化合物,剂量为每Kg小鼠2.5mg或10mg。观察7天来计算每组的平均存活天数。将该平均数作为一表示体内抗真菌活性的指数。附带说明,通式(III)化合物如下所示:
表3
平均存活天数(天)
表3(续)
平均存活天数(天)
在氮气氛下,向溶于40ml甲苯中的5g(20.0ml)光学活性的(2R,3S)-2-(2,4-二氟苯基)-3-甲基-2-(1H-1,2,4-三唑-1-基)甲基环氧乙烷溶液中加入80ml二乙基氰化铝(1.0M甲苯溶液)。于50℃加热该混合物12小时,并逐次往其中滴加10ml水和120ml 1N HCl。将得到的混合物于室温搅拌2小时,经硅酸镁载体滤板过滤,然后再用乙酸乙酯进行萃取。所得到的有机层用1∶1比率混合的水和饱和盐水的液体洗涤4次,最后再用饱和盐水洗涤。减压蒸除溶剂后,该残余物用二异丙基醚洗涤,由此得到3.15g(56.6%)光学活性的(2S,3R)-3-(2,4-二氟苯基)-3-羟基-2-甲基-4-(1H-1,2,4-三唑-1-基)丁腈。该产物的物理特性如下所述。mp.181-182℃NMR:δ溶剂(CDCl3)
1.17(3H,d,J=7.2Hz),3.29(1H,q,J=7.2Hz),
4.82(1H,d,J=14.0Hz),4.97(1H,d,J=14.0Hz),
5.44(1H,d,J=0.8Hz),6.74-6.82(2H,m),7.39-7.46(1H,m),
7.83(1H,s),7.84(1H,s)MS:MH+=279.制备实施例2:
通过另一种方法制备原料1:
将388mg(1mmol)量的六水合氯化镱于120℃,减压下放置6个多小时。将该化合物于氮气氛下悬浮于10ml四氢呋喃中,并使该悬浮液冷却至-78℃。往该悬浮液中滴加1.9ml正丁基锂(1.63M己烷溶液),将该所得混合物于室温下搅拌5分钟,然后冷却至-78℃。将0.8ml三甲基甲硅烷基氰慢慢滴加到该混合物中。将所得到的混合物于-78℃搅拌10分钟,然后再于室温搅拌5分钟,之后再冷却至-78℃。将溶于1ml四氢呋喃的128mg(0.5mmol)光学活性的(2R,3S)-2-(2,4-二氟苯基)-3-甲基-2-(1H-1,2,4-三唑-1-基)甲基环氧乙烷滴加到该混合物中,并且同时使所得到的混合物的温度升至室温。将饱和氯化铵水溶液加到该混合物中,然后用乙酸乙酯萃取。所得到的有机层用水和饱和盐水洗涤。减压蒸除该溶剂后,该残余物用乙醚重结晶,由此得到81mg(58.2%)光学活性的(2S,3R)-3-(2,4-二氟苯基)-3-羟基-2-甲基-4-(1H-1,2,4-三唑-1-基)丁腈。制备实施例3:
通过另一种方法制备原料1:
将478mg(60.0mmol)量的氢化锂加到冰冷却的四氢呋喃溶液(50ml)中使其完全悬浮。10分钟后,将5.4g(63.5mmol)丙酮合氰化氢[(CH3)2C(OH)CN]滴加到悬浮液中,之后继续于室温再搅拌1.5小时。往该混合物中加入5g(20.0mmol)光学活性的(2R,3S)-2-(2,4-二氟苯基)-3-甲基-2-(1H-1,2,4-三唑-1-基)甲基环氧乙烷。将全部反应物回流7小时。往所得的反应混合物中加入100ml乙酸乙酯,然后逐次用100ml水和50ml氯化钠溶液洗涤。然后,将它以硫酸镁干燥。而后再过滤所得溶液。减压浓缩滤液。往该浓缩液中加入50ml二异丙基醚。接着过滤所得溶液,得到4.2g(76.0%)光学活性的(2S,3R)-3-(2,4-二氟苯基)-3-羟基-2-甲基-4-(1H-1,2,4-三唑-1-基)丁基。制备实施例4制备原料2:
制备2-(2,4-二氟苯基)-3-硫代酰胺-1-(1H-1,2,4-三唑-1-基)-2-丁醇结构式:
往制备实施例1或2得到的原料1的外消旋体,即3-(2,4-二氟苯基)-3-羟基-2-甲基-4-(1H-1,2,4-三唑-1-基)丁腈(14g)中加入14ml H2O和O,O-二硫代磷酸二乙酯(73ml),将所得混合物加热回流30分钟。该液体反应混合物冷却至室温,加入水,然后用AcOEt萃取。所得AcOEt层用H2O和饱和NaCl水溶液洗涤,并用MgSO4干燥。此后,蒸除溶剂。所得残余物经硅胶色谱纯化(SiO2:300g,用CH2Cl2洗脱,然后逐次用1%、2%和3%MeOH的CH2Cl2溶液洗脱),然后用CH2Cl2-IPE重结晶,由此得到目的化合物(8.1g)。附带说明的是,当用原料1的光学活性物质替代原料1的外消旋体时,可类似地得到光学活性的原料2。
该产品的物理特性如下所述。mp:164-167℃NMR:δ溶剂(CDCl3)
1.11(3H,d,J=7.1Hz),3.69-3.72(1H,m),
4.55(1H,d,J=14.3Hz),5.08(1H,d,J=14.3Hz),
6.71-6.08(2H,m),7,42-7.48(1H,m),
7.80(1H,brs),7.94(1H,s),8.41(1H,brs).MS:MH+=313.制备实施例5:
制备原料3:
制备2-溴-4’-氰基苯乙酮结构式:
将4’-氰基苯乙酮(10g)溶于100ml CHCl3,并往所得溶液中加入1m 148%HBr。于室温下,往该混合物中滴加Br2(3.7ml)的CHCl3(10ml)溶液。于室温搅拌2小时后,将饱和NaHCO3水溶液加到该液体反应混合物中使其中和。该CHCl3层用水洗涤,然后用饱和NaCl溶液洗涤,再用MgSO4干燥。之后,蒸除氯仿。将所得固体物质在AcOEt-nHex中重结晶,由此得到目的化合物(3.49g)。该产品的物理特性如下所述。mp.82-84℃NMR:δ溶剂(CDCl3)
4.44(2H,s),7.81-7.84(2H,m),8.09(1H,d,J=8Hz),
8.23(1H,d,J=8Hz)制备实施例6:
制备原料4:
制备2-乙基-6-氯苯并噻唑结构式:
将2-氨基-5-硫代苯酚(2.618g)溶于N-甲基吡咯烷酮(6ml),并往该溶液中加入丙酰氯(1.57ml),之后于130℃加热1.5小时。往该液体反应混合物中加入乙酸乙酯和碳酸氢钠水溶液以使该混合物分层。所得有机层用水洗涤,干燥并浓缩。该残余物经硅胶柱(己烷∶乙酸乙酯=20∶1)纯化,得到2-乙基-6-氯苯并噻唑(2.3 g)。该产品物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)
1.47(3H,t,J=7.4Hz),3.14(2H,q,J=7.4Hz),
7.40(1H,dd,J=2.0Hz,8.8Hz),7.81(1H,d,J=2.0Hz),
7.86(1H,d,J=8.8Hz).制备实施例7:
制备原料5:
制备2-乙基-6-(1,2,3-三唑-2-基)-苯并噻唑结构式:
将1H-1,2,3-三唑(10.0g)溶于二甲基甲酰胺(280ml)中,并将60%氢化钠(5.79g)在矿物油中的分散液在10分钟内一点一点地加到该溶液中。于室温下,往该混合物中滴加4-氟硝基苯(18.6g)的二甲基甲酰胺(40ml)溶液,然后将所得混合物于50℃加热搅拌9小时。将该反应混合物倾入400ml饱和氯化铵水溶液中,再往其中加入200ml水。然后将混合物用乙酸乙酯萃取(400ml×1,200ml×2),该乙酸乙酯层用水、然后用饱和盐水洗涤,再用无水硫酸镁干燥。有机层减压浓缩并经硅胶柱(己烷∶乙酸乙酯=2∶1→1∶1)纯化,得到4-(1,2,3-三唑-2-基)-硝基苯(11.5g)。
将4-(1,2,3-三唑-2-基)-硝基苯(5.75g)溶于300ml乙醇中,并往其中加入10%钯-碳(0.58g)和水合肼(15.0g)。然后加热回流5小时。该反应混合物冷却至室温并经硅藻土过滤。该滤液在减压下浓缩一次,加入500ml水,然后用乙酸乙酯(200ml,100ml×2)进行萃取。如此得到的有机层用水、然后饱和盐水洗涤,再用无水硫酸钠干燥,然后减压浓缩,得到4-(1,2,3-三唑-2-基)-苯胺(5.0g)。该产物无需纯化可用于下一步反应。
将上面反应得到的4-(1,2,3-三唑-2-基)-苯胺(5.0g)溶于55ml乙酸,并将硫氰酸铵(6.0g)加到该溶液中。在冰水冷却的同时,搅拌所得到的混合物。将溴(1.62ml)的20ml乙酸溶液用30分钟滴加到该混合物中。此后,将该混合物加热至室温并在该温度地下搅拌4小时。
将该反应混合物用冰水冷却并滴加入浓氨水,然后调至pH6。过滤回收生成的沉淀,该沉淀用水、然后用冷乙醇洗涤,并在减压下干燥,得到2-氨基-6-(1,2,3-三唑-2-基)苯并噻唑(5.6g)。
将2-氨基-6-(1,2,3-三唑-2-基)苯并噻唑(2.8g)溶于N,N-二甲基甲酰胺(60ml),再将硝酸异戊酯(8.66ml)加到该溶液中,然后于65℃搅拌20分钟。将该反应混合物倾入100ml水中,再用乙酸乙酯萃取(100ml×3)。所得有机层用水、然后用饱和盐水洗涤,用无水硫酸镁干燥,然后减压浓缩。所得油状物经硅胶柱色谱(二氯甲烷)纯化,得到6-(1,2,3-三唑-2-基)苯并噻唑(1.1g)。
将6-(1,2,3-三唑-2-基)苯并噻唑(1.1g)悬浮于乙醇(90ml)中,并将12ml一水合肼加到该悬浮液中。将所得混合物加热回流2小时。减压浓缩该反应混合物后,往其中加入20ml水,并用乙酸将其pH调至约7。将该中和好的混合物用惭酸乙酯萃取3次,所得有机层用饱和盐水洗涤,用无水硫酸镁干燥,然后减压浓缩,得到2-氨基-5-(1,2,3-三唑-2-基)硫代苯酚(2.3g)。该产物无需纯化可用下一步反应。
将2-氨基-5-(1,2,3-三唑-2-基)硫代苯酚(2.3g)溶于N-甲基吡咯烷酮(8ml),并将丙酰氯(0.472ml)加到该溶液中,然后于70℃加热搅拌5小时。将该反应混合物倾入饱和碳酸氢钠水溶液中,之后用二氯甲烷萃取。所得有机层用无水硫酸镁干燥,减压浓缩, 然后经硅胶柱(己烷乙酸乙酯=4∶1→1∶1)纯化,得到目的化合物,即2-乙基-6-(1,2,3-三唑-2-基)-苯并噻唑(940mg)。该产物的物理特性如下所述。状态:固体NMR:δ溶剂(CDCl3)
1.49(3H,t,J=7.7Hz),3.17(2H,q,J=7.7Hz)
7.83(2H,s),8.03(1H,d,J=8.8Hz),
8.20(1H,dd,J=8.8,3.2Hz),8.55(1H,d,J=8.8Hz)实施例88:
将2-(2,4-二氟苯基)-3-硫代酰胺-1-(1H,1,2,4-三唑-1-基)-2-丁醇(原料2)(156mg)溶于EtOH(2ml),并将2-溴-4’-氰基苯乙酮(原料3)(224mg)加到该溶液中,之后加热回流1小时。用饱和NaHCO3水溶液中和该液体反应混合物,然后用AcOEt萃取。该萃取液用H2O、然后用饱和NaCl水溶液洗后,用MgSO4干燥,蒸除AcOEt。所得残余物经硅胶色谱(SiO2:20g,用CH2Cl2、然后用1%MeOH的CH2Cl2溶液洗脱)纯化,再用IPE重结晶,得到目的化合物(109mg)。该化合物的物理特性如下所述。mp:196-197℃NR:δ溶剂(CDCl2)
1.23(3H,d,J=8.0Hz),4.09(1H,q,J=8.0Hz),
4.26(1H,d,J=14.3Hz),4.92(1H,d,J=14.3Hz)
5.74(1H,s),6.78-6.85(2H,m),7.48-7.54(1H,m),
7.64(1H,s),7.69(1H,s),7.75(1H,d,J=8.1Hz),
7.85(1H,s),8.03(1H,d,J=8.1Hz).MS:MH+=438.实施例89:
制备下列结构式表示的化合物:
除了用2-溴-4’-甲基硫代苯乙酮替代2-溴-4’-氰基苯乙酮外,按照实施例88所述相同方法,得到该目的化合物。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl2)
1.23(3H,d,J=7.2Hz),2.54(3H,s)4.05(1H,q,J=7.2Hz),
4.28(1H,d,J=14.4Hz),4.88(1H,d,J=14.4 Hz),6.13(1H,s),
6.75-6.85(2H,m),7.33(2H,br-d,J=8.4Hz),7.42(1H,s),
7.46-7.54(1H,m),7.66(1H,s),7.82(2H,br-d,J=8.4Hz),
7.92(1H,s)).MS:MH+=459.实施例90:
[0081]
除了用2-溴-2’,4’-二氟苯乙酮代替2-溴-4’-氰基苯乙酮外,按实施例88所述相同方法,和得到该目的化合物。该化合物的物理特性如下述。状态:固体。NMR:δ溶剂(CDCl2)
1.23(3H,d,J=7.1Hz),4.07(1H,q,J=7.1Hz),
4.26(1H,d,J=14.4Hz),4.89(1H,d,J=14.4Hz),5.93(1H,s),
6.92-6.98(1H,m),7.00-7.05(1H,m),7.47-7.54(1H,m),
7.67(1H,s),7.68(1H,s),7.88(1H,s),8.13-8.19(1H,m).MS:MH+=449.实施例91:
制备下列结构式表示的化合物:
除了用2-溴-4’-甲基苯乙酮替代2-溴-4’-氰基苯乙酮外,按照实施例88的相同方法,得到目的化合物。该化合物的物理特性如下述。状态:固体。NMR:δ溶剂(CDCl3)
1.23(3H,d,J=7.1Hz),2.41(3H,s),4.04(1H,q,J=7.1Hz),
4.28(1H,d,J=14.3Hz),4.88(1H,d,J=143Hz),6.24(1H,s),
6.76-6.84(1H,s),7.27(1H,d,J=8.3Hz),7.40(1H,s),
7.47-7.53(1H,m),7.65(1H,s),7.80(2H,d,J=8.3Hz),
7.94(1H,s).MS:MH+=427.实施例92:
除了用2-溴-4’-甲基苯乙酮替代2-溴-4’-氰基苯乙酮外,按照实施例88的相同方法,得到目的化合物。该化合物的物理特性如下述。状态:固体。NMR:δ溶剂(CDCl3)
1.23(3H,d,J=7.1Hz),3.88(3H,s),4.04(1H,q,J=7.1Hz),
4.28(1H,d,J=14.3Hz),4.87(1H,d,J=14.3Hz),6.24(1H,s),
6.76-6.84(2H,m),7.00(2H,d,J=8.2Hz),7.32(1H,s),
7.47-7.53(1H,m),7.65(1H,s),7.84(2H,d,J=8.2Hz),
7.94(1H,s).MS:MH+=443实施例93:
除了用2-溴-4’-硝基苯乙酮替代2-溴-4’-氰基苯乙酮外,按照实施例88的相同方法,得到目的化合物。该化合物的物理特性如下述。mp:180-182℃NMR:δ溶剂(CDCl3)
1.25(3H,d,J=7.1HZ),4.11(1H,d,J=7.1Hz),
4.27(1H,d,J=14.2Hz),4.94(1H,d,J=14.2Hz),5.70(1H,s),
6.79-6.85(2H,m),7.43-7.55(1H,m),7.70(1H,s),
7.71(1H,s),7.85(1H,s),8.08(2H,d,J=9.0Hz),
8.32(2H,d,J=9.0Hz).MS:MH+=458.实施例94:
向在30ml DMD中的1.570g 60%氢化钠的悬浮液中加入5g-4氟硫代苯酚,将所得混合物于室温搅拌5分钟。再往该混合物中加入4.9g 4’-氟苯乙酮,然后于80℃搅拌3.5小时。将水加到该反应混合物中,再用乙酸乙酯萃取。萃取液用水、然后用饱和盐水洗涤,减压蒸除溶剂,得到10.008g 4-氟-4’-乙酰苯硫醚。
然后除了用该化合物替代2-溴-4’-氰基苯乙酮外,按照实施例88所述的相同方法得到目的化合物。此化合物的物理特性如下述。状态:固体。NMR:δ溶剂(CDCl3)
1.22(3H,d,J=7.0Hz),4.05(1H,q,J=7.0Hz),
4.26(1H,d,J=14.6Hz),4.88(1H,d,J=14.6Hz),6.04(1H,s),
6.76-6.85(2H,m),7.07(2H,br-dd,J=8.4,8.4Hz),
7.32(2H,br-d,J=8.4Hz),7.44(1H,br-s),
7.44(2H,br-dd,J=8.4,8.4Hz),7.45-7.54(1H,m),
7.66(1H,s),7.82(2H,br-dd,J=8.4Hz),7.89(1H,s).MS:MH+=539.实施例95:
制备下列结构式表示的化合物:
将400mg实施例88制得的化合物溶于4mlN-甲基吡咯烷酮,并往该溶液中加入123mg NaN3和260mg Et3N·HCl。将所得混合物于外部温度为100℃的油浴中加热6.5小时,并再加入31mg NaN3和65mg Et3N·HCl,使其于90℃反应20小时。往该反应混合物中加入CH2Cl2,滤除生成的盐,然后将该液体反应混合物进行蒸发。该该残余物中加入EtOH、丙酮、H2O和1N Hcl,所得混合物放置,沉淀出固体物质。过滤收集该固体物质,得到390mg目的化合物。此化合物的物理特性如下所述。mp:166-169℃。NMR:δ溶剂(CDCl3)
1.14(3H,d,J=7.3Hz),4.11(1H,q,J=7.3Hz),
4.37(1H,d,J=14.6Hz),4.87(1H,d,J=14.6Hz),6.08(1H,s),
6.91-6.96(1H,m),7.18-7.25(1H,m),7.27-7.34(1H,m),
7.62(1H,s),8.11(2H,d,J=8.5Hz),8.20(2H,d,J=8.5Hz),
8.22(1H,s),8.29(1H,s).MS:MH+=481.实施例96:
将800mg实施例88得到的化合物悬浮于4ml水中,并往该悬浮液中加入2.6ml(16.479mmol)下式表示的化合物:然后加热回流30分钟。将H2O加入该液体反应混合物中,然后用AcOEt萃取该混合物。萃取液用H2O、再用饱和NaCl水溶液洗涤后,用MgSO4干燥,蒸除AcOEt。无需纯化即将所得残余物溶于10ml丙酮,向该溶液中加入0.45ml CH3I,然后于40℃搅拌40分钟。往所得液体反应混合物中加入水,然后用AcOEt萃取。萃取液用水、再用饱和NaCl水溶液洗涤,用MgSO4干燥后,蒸除AcOEt。无需纯化将所得残余物溶于10ml EtOH,并将220mg NH2NHCHO、0.26mlEt3N和1滴H2SO4加到该溶液中,之后加热回流1小时。在所得液体反应混合物中加入水,再用AcOEt萃取。所得萃取液用水、再用饱和NaCl水溶液洗涤,用MgSO4干燥后蒸除AcOEt。所得残余物经柱色谱(SiO2:50g,用CH2Cl2、再用1%MeOH的CH2Cl2溶液、2%MeOH的CH2Cl2溶液洗脱)纯化,由此得到369mg目的化合物。此化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)
1.24(3H,d,J=7.1Hz),4.08(1H,q,J=7.1Hz),
4.34(1H,d,J=14.4Hz),4.91(1H,d,J=14.4Hz),6.15(1H,s),
6.79-6.85(1H,s),7.52-7.56(2H,m),7.69(1Hs),
7.97-7.99(3H,m),8.14(2H,d,J=8.2Hz),8.25(1H,s).MS:MH+=480.实施例97:
制备下列结构式表示的化合物:
将250mg实施例95得到的化合物溶于3mlDMF中,并将174mgCsCO3加到该溶液中。将所得混合物于外部温度为60℃的油浴中加热30分钟并加入0.05mlCH3I,然后于室温搅拌30分钟。将水加到该液体反应混合物中并用AcOEt萃取。萃取液用H2O、再用饱和NaCl水溶液洗涤,并用MgSO4干燥后,蒸出AcOEt。所得残余物经柱色谱(SiO2:30g,用CH2Cl2、再用1%MeOH的CH2Cl2溶液和2%MeOH的CH2Cl2溶液洗脱)纯化,得到125mg目的化合物。此化合物的物理特性如下述。mp:191-193℃NMR:δ溶剂(CDCl3)
1.25(3H,d,J=7.0Hz),4.09(1H,q,J=7.0Hz),
4.29(1H,d,J=14Hz),4.33(3H,s),4.92(1H,d,J=14Hz),
6.01(1H,s),6.77-6.85(2H,m),7.49-7.55(1H,m),
7.58(1H,s),7.67(1H,s),7.91(1H,s),
8.04(2H,d,J=8.2,Hz),8.24(2H,d,J=8.2Hz).MS:MH+=495.实施例98:
制备下列结构式表示的化合物:
将200mg实施例96得到的化合物溶于5ml丙酮中,并将60.6mg K2CO3和0.03ml CH3I加入其中。将所得混合物于室温搅拌19小时。将水加入该液体反应混合物中并用AcOEt萃取。该萃取液用水、再用饱和NaCl水溶液洗涤并用MgSO4干燥后,蒸出AcOEt。所得残余物经柱色谱(SiO2:40g)用CH2Cl2、然后用0.5%MeOH的CH2Cl2溶液和1%MeOH的CH2Cl2溶液洗脱)纯化,得到142mg目的化合物。该化合物的物理特性如下述。状态:固体。NMR:δ溶剂(CDCl3)
1.13(1H,d,J=6.0Hz),1.25(2H,d,J=7.1Hz),
4.01-4.13(4H,m),4.27(2/3H,d,J=14Hz),
4.29(1/3H,d,J=14Hz),4.91(1H,d,J=14Hz),
5.45(1/3H,s),6.08(2/3H,s),6.70-6.84(2H,m),
7.50-7.55(2H,m),7.67-7.68(4/3H,m),7.79-7.81(2/3H,m).
7.93(1H,s),7.96(1H,s),7.98(1H,s),8.10(1H,s),
8.19(2H,d,H=8.4Hz).实施例99:
制备下列结构式表示的化合物:
将215mg间氯过苯甲酸加到溶于3ml氯仿中的138mg实施例89得到的化合物溶液中,然后于室温搅拌。当原料消失后,将水加到该液体反应化合物中,再用乙酸乙酯萃取。所得有机层用50%饱和NaHCO3水溶液洗涤,再用水和饱和盐水洗涤。减压蒸出溶剂后,残余物经硅胶柱色谱纯化并用二氟甲烷-二异丙基醚结晶,得到98.5mg目的化合物。该产物的物理特性如下所述。NMR:δ溶剂(CDCl3)
1.24(3H,d,J=7.2Hz),3.09(3H,s),4.09(1H,q,J=7.2Hz),
4.27(1H,d,J=14.4Hz),4.91(1H,d,J=14.4Hz),
5.78(1H,s),6.78-6.85(2H,m),7.47-7.55(1H,m),
7.67(1H,s),7.69(1H,s),7.87(1H,s),
8.02(2H,br-d,J=8.4Hz),8.10(2H,br-d,J=8.4Hz).MS:MH+=491.实施例100:
制备下列结构式表示的化合物:
按照实施例99的相同方法,由实施例7得到的化合物可得到该目的化合物。该产物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)
1.22(3H,d,J=7.2Hz),4.07(1H,q,J=7.2Hz),
4.23(1H,d,J=14.4Hz),4.90(1H,d,J=14.4Hz),5.73(1H,s),
6.77-6.84(2H,m),7.20(2H,br-dd,J=8.4,8.4Hz),
7.46-7.53(1H,m),7.63(1H,s),7.68(1H,s),7.83(1H,s),
7.97-8.07(6H,m).MS:MH+=571.实施例101:
除将原料3中的4-氰基苯基部分改变为化合物I、II和III中相应的彼此间连结位置不同的吡啶基外,按照实施例88的相同方法可得到该实施例的化合物I、II和III。这些化合物的物理特性如下所述。(I)mp:149-151℃NMR:δ溶剂(DMSO-d6)
1.13(3H,d,J=7.1Hz),4.07(1H,q,J=7.1Hz),
4.36(1H,d,J=14.3Hz),4.86(1H,d,J=14.3Hz),6.07(1H,s),
6.91-6.96(1H,m),7.18-7.24(1H,m),7.27-7.36(2H,m),
7.61(1H,s),7.88(1H,t,J=8 Hz),8.11(1H,d,J=8Hz),
8.22(1H,s),8.28(1H,s),8.60-8.62(1H,m).MS:MH+=414.(II)mp:148-149℃NMR:δ溶剂(DMSO-d6)
1.24(3H,d,J=7.1Hz),4.09(1H,q,J=7.1Hz),
4.27(1H,d,J=14.3Hz),4.92(1H,d,J=14.3Hz),
5.84(1H,brs),6.77-6.85(2H,m),
7.40(1H,ddd,J=7.8,4.8,0.92Hz),7.48-7.56(1H,m),
7.58(1H,s),7.68(1H,s),7.88(1H,s),
8.21(1H,ddd,J=7.8,2.2,1.6Hz),
8.61(1H,dd,J=4.8,1.6Hz),9.15(1H,dd,J=2.2,0.92Hz).MS:MH+=414.(III)状态:固体。NMR:δ溶剂(CDCl3)
1.24(3Hx4/5,d,J=7.1Hz),1.68(3Hx1/5,d,J=6.2Hz),
4.08-4.15(1H,m),4.25(4/5H,q,J=14.5Hz),
4.73(1/5H,d,J=13.9Hz),4.92(1/5H,d,J=13.9Hz),
4.95(4/5H,d,J=14.5Hz),5.77(4/5H,brs),5.88(1/5H,brs),
6.49-6.55(1/5H,m),6.66-6.72(1/5H,m),6.76-6.85(1H,m),
7.07-7.14(4/5H,m)7.26(1/5H,s),7.44(1/5H s),
7.47-7.55(4/5H,m),7.61-7.64(1/5H,m,)7.69(4/5H,s),
7.73(4/5H,s),7.78-7.81(4/5H,m),7.87(4/5H,s),
8.03(1/5H,s),8.64-8.66(4/5H,m),8.69-8.72(1/5H,m).MS:MH+=414.实施例102:
制备下列结构式表示的化合物:
将700mg实施例101得到的化合物(I)溶于7ml AcOEt和5ml THF中,并往其中加入500mg mCPBA,之后于室温搅拌1小时,然后再加入227mg(0.882mmol)mCPBA。将所得混合物搅拌1小时。往该液体反应混合物中加入亚硫酸钠水溶液,搅拌5分钟,然后用AcOEt萃取。该萃取液用亚硫酸钠水溶液、NaHCO3水溶液、水洗涤后,再用NaCl水溶液洗涤,并用MgSO4干燥后,蒸出溶剂。该残余物用CH2Cl2-IPE结晶,得到510mg N-氧化物中间体。将该化合物溶于5mlCH2Cl2,并于室温下往其中加入0.49ml TMS-CN。5分钟后,加入0.34ml Me2NCOCl,并将该混合物加热回流1.5小时。再加入0.25mlTMS-CN和0.17Me2NCOCl,再将所得混合物加热回流2.5小时。往该液体反应混合物中加入NaHCO3水溶液,再用AcOEt萃取。该萃取液用水和饱和NaCl水溶液洗涤并且用MgSO4干燥后,蒸除溶剂。所得残余物经硅胶色谱(SiO2:40g,用CH2Cl2、然后用1%MeOH的CH2Cl2溶液和2%MeOH的CH2Cl2溶液洗脱)纯化,得到198mg目的化合物。该化合物的物理特性如下所述。mp:197-200℃NMR:δ溶剂(DMSO-d6)
1.14(3H,d,J=7.0Hz),4.07-4.11(1H,m),
4.47(1H,q,H=14.3Hz),4.84(1H,d,J=14.3Hz),6.10(1H,s),
6.91-6.96(1H,m),7.17-7.22(1H,m),7.23-7.33(2H,m)),
7.61(1H,s),7.98(1H,d,J=7.7Hz),8.14(1H,t,J=7.7Hz),
8.21(1H,s),8.40(1H,d,J=7.7Hz),8.44(1H,s).MS:MH+=439.实施例103:
将1.6g 2-(2,4-二氟苯基)-3-硫酰胺-1-(1H,1,2,4-三唑-1-基)-2-丁醇(156mg)溶于16ml EtOH中,并往该溶液中加入0.71ml溴丙酮酸乙酯。将所得混合物加热回流5小时。使该液体反应混合物冷却至室温,用饱和NaHCO3水溶液中和,然后用AcOEt萃取。该萃取液用水、然后用饱和NaCL水溶液洗涤并用MgSO4干燥后,蒸除溶剂。该残余物经色谱(SiO2:150g,用CH2Cl2、再用1%MeOH的CH2Cl2溶液和2%MeOH的CH2Cl2溶液洗脱)纯化,得到435mg 2-(2,4-二氟苯基)-3-(4-乙氧羰基噻唑-2-基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇。将1.9g该化合物溶于20ml THF中,并-78℃将5.1ml 1M DIBAL的甲苯溶液慢慢加到该该溶液中。40分钟后,再于相同温度下加入2.3ml 1M DIBAL的甲苯溶液。1小时后,于-78℃,将NH4Cl水溶液加到该液体反应混合物中。将该反应混合物加热至室温,加入水,再用AcOEt萃取。该萃取液用H2O洗涤并用MgSO4干燥后,蒸出溶剂,得到989mg 2-(2,4-二氟苯基)-3-(4-甲酰基噻唑-2-基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇粗产物。
在冰水冷却的同时,将60%NaH(109mg)加到5ml THF中,并往该混合物中滴加(Et2O)2P(=O)CH2CN(0.44ml)的5ml THF溶液。将该混合物搅拌1小时后,将溶于10ml THF的989mg上述所得产物的溶液慢慢加到该混合物中。所得混合物于室温搅拌30分钟后,往该液体反应混合物中加入水,然后用AcOEt萃取。该萃取液用H2O洗涤,然后用饱和NaCl水溶液洗涤并用MgSO4干燥后,蒸除AcOEt。所得残余物经硅胶色谱(SiO2:60g,用CHCl3洗脱,然后用1%MOH的CHCl3溶液和2%MeOH的CHCl3溶液洗脱)纯化,得到作为第一洗脱物的115mg化合物I和作为第二洗脱物的220mg几何异构体化合物II。这些化合物的物理特性如下所述。(I)状态:固体mp:175-177℃NMR:δ溶剂(CDCl3)
1.19(3H,d,J=7.1Hz),4.02(1H,q,J=7.1Hz),
4.16(1H,d,J=14.3Hz),4.91(1H,d,J=14.3Hz),
5.47(1H,s),6.33(1H,d,J=16.0Hz),6.77-6.84(2H,m),
7.33(1H,d,J=16.0Hz),7.46(1H,s),7.47-7.51(1H,m,),
7.72(1H,s),7.82(1H,s).MS:MH+=388.(II)状态:固体。NMR:δ溶剂(CDCl3)
1.20(3H,d,J=7.0Hz),4.05(1H,q,J=7.0Hz),
4.45(1H,d,J=14.0Hz),4.89(1H,d,J=14.0Hz),
5.56(1H,d,J=11.9Hz),5.78(1H,s),6.75-6.82(2H,m),
7.17(1H,d,J=11.9Hz),7.50-7.59(1H,m),7.60(1H,s),
7.75(1H,s),8.10(1H,s).MS:MH+=388.实施例104:
制备下列结构式表示的化合物:
除了用2-(2,4-二氟苯基)-3-硫代酰胺-1-(1H-1,2,4-三唑-1-基)丙-2-醇代替2-(2,4-二氟苯基)-3-硫代酰胺-1-(1H-1,2,4-三唑-1-基)丁-2-醇之外,按照实施例88的相同方法可得到该目的化合物。此化合物的物理特性如下所述。mp:148-149℃NMR:δ溶剂(CDCl3)
3.38(1H,d,J=15.2Hz),3.87(1H,d,J=15.2Hz),
4.65(1H,d,J=14.0Hz),4.71(1H,d,J=14.0Hz,5.97(1H,s),
6.70-6.76(1H,m),6.77-6.83(1H,m),7.42(1H,m),
7.47-7.41(1H,m),7.69-7.72(2H,m),7.86(1H,s),
7.86-7.90(2H,m),8.18(1H,s),MS:MH+=424.实施例105:
除了用2-溴-4’-氟苯乙酮代替2-溴-4’-氰基苯乙酮之外,按照实施例104所述的相同方法,得到该目的化合物。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)
3.34(1H,d,J=15.4Hz),3.84(1H,d,J=15.4Hz),
4.62(1H,d,J=14.0Hz),4.71(1H,d,J=14.0Hz),6.25(1H,s),
6.82-6.69(2H,m),7.13-7.08(2H,m),7.17(1H,s),
7.47-7.40(1H,m),7.76-7.72(2H,m),7.85(1H,s),
8.12(1H,s).MS:MH+=417.实施例106:
于-65℃下将正丁基锂(1.6M己烷溶液;313ml)滴加到在15ml四氢呋喃中的二异丙胺(840μl)中后,将该混合物升至4℃,使其反应15分钟以制备二异丙基氨化锂溶液。将该溶液冷却至-63℃后,在不超过-60℃温度下,将实施例5制备的2-乙基-6-氯-苯并噻唑(988mg)的四氢呋喃溶液(10ml)和1-(1H-1,2,4-三唑-1-基)-2’,4’-二氟苯乙酮(1.227g)的四氢呋喃溶液(12ml)逐次加到该酰胺溶液中。待其反应15分钟后,将该反应混合物加热至0℃并加入氯化铵水溶液。然后用乙酸乙酯萃取得到的混合物。所得有机层用水洗涤,然后用盐水洗涤,再干燥并减压蒸干。该残余物经硅胶柱(二氯甲烷∶甲醇=100∶1)纯化。如此得到的非对映体混合物进一步通过硅胶柱(二氯甲烷∶乙酸乙酯=10∶1→5∶1),由此得到低极性馏份、即442mg化合物I和高极性馏份、即66mg化合物II,后者是化合物I的非对映体。这些化合物的物理特性如下述。Imp:187℃。NMR:δ溶剂(CDCl3)
1.25(3H,d,J=7.0Hz),4.09(1H,q,J=7.0Hz),
4.27(1H,d,J=14.4Hz),4.93(1H,d,J=14.4Hz),5.80(1H,s),
6.85-6.78(2H,m),7.48(1H,dd,J=8.8Hz,2.4Hz),
7.49-7.55(1H,m),7.67(1H,s),7.87(1H,s),
7.90(1H,d,J=2.4Hz)7.94(1H,d,J=8.8Hz).MS:MH+=421.IImp:127-130℃。NMR:δ溶剂(CDCl3)
1.68(3H,d,J=6.8Hz),4.13(1H,q,J=6.8Hz),
4.71(1H,d,J=14Hz),4.94(1H,d,J=14Hz),5.87(1H,s),
6.46-6.50(1H,m),6.43-6.69(1H,m),7.09-7.16(1H,m),
7.38(1H,dd,J=2.0Hz,8.8Hz),7.69(1H,s),
7.72(1H,d,J=2.0Hz),7.80(1H,d,J=8.8Hz),8.04(1H,s).MS:MH+=421.实施例107:
将2-乙基-6-氰基苯并噻唑(1.78g),叠氮化钠(1.22g)和盐酸三乙胺(2.59g)的混合物在300ml N-甲基吡咯烷酮中、于100℃加热3小时。将该混合物冷却至室温后,加入150ml水,用浓HCl调至pH3,再用乙酸乙酯萃取2次。所得有机层用饱和盐水洗涤并干燥。蒸除溶剂,并将残余溶剂进一步与甲苯通过共沸蒸馏除去,得到2-乙基-6-(四唑-5-基)苯并噻唑(1.86g)。将该化合物溶于二甲基甲酰胺(20ml)中,并往其中加入碳酸铯(3.06g),然后于80℃加热1.5小时。再在冰冷却下,将1.17ml碘甲烷加到该反应混合物中。使该混合物回升至室温并搅拌7小时。加入水和乙酸乙酯使该混合物分层,并将所得有机层用水洗并干燥。该残余物经硅胶柱(己烷∶乙酸乙酯=4∶1)纯化,得到2-乙基-6-(2-甲基-四唑-5-基)苯并噻唑(930mg)。用如此制得的该化合物,以实施例106的相同方法得到目的化合物。此化合物的物理特性如下所述。mp:184-185℃。NMR:δ溶剂(CDCl3)
1.28(3H,d,J=7.2Hz),4.13(1H,q,J=7.2Hz),
4.31(1H,d,J=14.2Hz),4.44(3H,s),4.96(1H,d,J=14.2Hz),
5.89(1H,s),6.78-6.86(2H,m),7.50-7.58(1H,m),
7.67(1H,s),7.89(1H,s),8.13(1H,dd,J=0.4Hz,8.8Hz),
8.30(1H,dd,J=1.6Hz,8.8Hz),8.74(1H,dd,J=0.4Hz,16Hz).实施例108:
除用2-乙基-6-氟-苯并噻唑代替2-乙基-6-氯-苯并噻唑以外,以实施例106的相同方法制得该目的化合物。该化合物的物理特性如下所述。mp:151-153℃。NMR:δ溶剂(CDCl3)
1.25(3H,d,J=7.1Hz),4.08(1H,q,J=7.1Hz),
4.28(1H,d,J=14.4Hz),4.93(1H,d,J=14.4Hz),5.83(1H,s),
6.77-6.85(2H,m),7.23-7.29(1H,m),7.49-7.56(1H,m),
7.58-7.62(1H,m),7.67(1H,s),7.87(1H,s),
7.96-8.00(1H,m).MS:MH+=405实施例109:
制备下列结构式表示的化合物:除用2-乙基-6-氰基-苯并噻唑代替2-乙基-6-氯-苯并噻唑以外,以实施例106相同的方式制备该目的化合物。该化合物的物理特性如下所述。mp:186-188℃。NMR:δ溶剂(CDCl3)
1.27(3H,d,J=7.2Hz),4.16(1H,q,J=7.2Hz),
4.24(1H,d,J=14.0Hz),4.96(1H,d,J=14.0Hz),5.67(1H,s),
6.79-6.86(2H,m),7.49-7.56(1H,m),7.69(1H,s),
7.77(1H,dd,J=1.6Hz,8.4Hz),7.83(1H,s),
8.11(1H,d,J=8.4Hz),8.27(1H,d,J=1.6Hz).MS:MH+=412.实施例110:
制备下列结构式表示的化合物:
将实施例109得到的化合物(506mg)悬浮于甲醇(10ml)中,并将0.37ml 1N氢氧化钠水溶液和30%过氧化氢水溶液(0.42ml),依次加到该悬浮液中。将所得混合物于室温搅拌2小时。再加入水和乙酸乙酯进行萃取。将所得有机层进行水洗、干燥,然后再进行蒸馏。该残余物经硅胶柱(二氯甲烷∶甲醇=50∶1→20∶1)纯化,得到该目的化合物(311mg)。该化合物的物理特性如下所述。mp:112-117℃。NMR:δ溶剂(CDCl3)
1.25(3H,d,J=7.0Hz),4.13(1H,q,J=7.0Hz),
4.29(1H,d,J=14.4Hz),4.94(1H,d,J=14.4Hz),5.82(1H,s),
5.60-6.25(2H,br),6.78-6.86(2H,m),7.50-7.56(1H,m),
7.67(1H,s),7.87(1H,s),7.09(1H,dd,J=1.6Hz,8.4Hz),
8.08(1H,dd,J=1.6Hz,8.4Hz),8.48(1H,dd,J=0.6Hz,1.6Hz).MS:MH+=430.实施例111:
将实施例109得到的化合物(507mg)和一滴三乙胺溶于二甲基甲酰胺(5ml)中,于室温下,用硫化氢气体使该溶液饱和并于室温放置6小时。将碳酸氢钠水溶液和乙酸乙酯加到该液体反应混合物中使其分层。所得有机层用水洗涤、干燥并浓缩。该残余物用硅胶柱(洗脱剂:二氯甲烷∶甲醇=50∶1)纯化,得到该目的化合物(538mg)。该化合物的物理特性如下所述。mp:157-160℃。NMR:δ溶剂(CDCl3)
1.23(3H,d,J=7.2Hz),4.13(1H,q,J=7.2Hz),
4.27(1H,d,J=14.0Hz),4.94(1H,d,J=14.0Hz),5.81(1H,s),
6.78-6.85(2H,m),7.24-7.30(1H,br-s),7.39-7.56(1H,m),
7.67(1H,s),7.66-7.72(1H,brs),7.86(1H,s),
7.95(1H,dd,J=2.0Hz,8.8Hz),8.02(1H,d,J=8.8Hz),
8.59(1H,d,J=2.0Hz).MS:MH+=446实施例112:
制备下列结构式表示的化合物(1∶1非对映体混合物):
将实施例111得到的化合物(2.67g)悬浮于130ml丙酮中,再往该悬浮液中加入1.12ml碘甲烷,并将所得混合物于40℃加热回流8小时。蒸除溶剂,得到下列结构式表示的中间体化合物:将该中间体化合物(584mg)溶于乙醇(5.8ml),并将氨基二乙基乙缩醛(174μl)加到该溶液中,将该所得混合物加热回流5小时。然后,加6N盐酸(5ml)到该混合物中,再加热回流1小时。将碳酸氢钠水溶液和乙酸乙酯加到该液体反应混合物中使其分层。所得有机层用水洗涤、干燥并蒸发至干。该残余物经硅胶柱(二氯甲烷∶甲醇=100∶1-10∶1)纯化,得到1∶1非对映体混合物形式的目的化合物。状态:固体。NMR:δ溶剂(CDCl3)
1.27(3H,d,J=7.2Hz),1.73(1H,d,J=7.2Hz),
4.10(1H,q,J=7.2Hz),4.15(1H,q,J=7.2Hz),
4.32(1H,d,J=14.0Hz),4.73(1H,d,J=14.0H),
4.94(1H,d,J=14.0Hz),4.95(1H,d,J=14.0Hz),5.92(1H,s),
5.98(1H,s),6.44-6.50(1H,m),6.63-6.70(1H,m),
6.77-6.84(2H,m),7.12-7.17(1H,m),7.17(1H,br-s),
7.22(1H,br-s),7.50-7.57(1H,m),7.66(1H,s),
7.69(1H,s),7.84(1H,dd,J=1.6Hz,8.4Hz,7.89(1H,s),
7.91(1H,d,J=8.4Hz),7.93(H,dd,J=1.6Hz,8.4Hz),
8.05(1H,d,J=8.4Hz),8.06(1H,s),8.27(1H,d,J=1.6Hz),
8.46(1H,d,J=1.6Hz).实施例113:
将实施例112中的中间体化合物(1.17g)溶于乙醇(12ml),并将甲酰肼(240mg)、三乙胺(250μl)和一滴浓硫酸依次加到该溶液中,使其在室温反应40分钟,然后再将该反应混合物加热回流1.5小时。待该反应混合物冷却后,加入乙酸乙酯和水进行萃取。将所得有机层用水洗涤、干燥并浓缩。该残余物经硅胶柱色谱(二氯甲烷∶甲醇=20∶1)纯化,得到目的化合物(742mg)。该化合物的物理特性如下所述。mp:138-140℃。NMR:δ溶剂(CDCl3)
1.27(3H,d,J=7.2Hz),4.13(1H,q,J=7.2Hz),
4.33(1H,d,J=14.2Hz),4.95(1H,d,J=14.2Hz),5.96(1H,s),
6.78-6.86(2H,m),7.51-7.57(1H,m),7.67(1H,s),
7.91(1H,s),8.10(1H,d,J=8.4Hz),8.25(1H,d,J=8.4Hz),
8.32(1H,s),8.69(1H,s).MS:MH+=472.实施例114:
制备下列结构式表示的化合物:
将实施例111得到的化合物(264mg)、溴代乙醛缩二甲醇(390μl)和1滴浓硫酸在乙醇(2.5ml)中加热回流1小时。加入溴代乙醛缩二甲醇(390μl)后,再将该混合物加热回流1小时,往该液体反应混合物中加入乙酸乙酯和水使其分层。所得有机层用水洗涤并干燥,蒸除溶剂。将己烷加到该残余物中,过滤收集生成的沉淀,得到目的化合物(180mg)。该化合物的物理特性如下所述。mp:153-158℃。NMR:δ溶剂(CDCl3)
1.28(3H,d,J=7.2Hz),4.12(1H,q,J=7.2Hz),
4.31(1H,d,J=14.2Hz),4.96(1H,d,J=14.2Hz),5.89(1H,s),
6.78-6.25(2H,m),7.40(1H,d,J=3.4Hz),7.66(1H,s),
7.89(1H,s),7.92(1H,d,J=3.4Hz),8.09(1H,d,J=0.4Hz),
8.10(1H,d,J=1.6Hz),8.75(1H,dd,J=0.4Hz,1.6Hz).MS:MH+=470.实施例115:
将实施例113中得到的化合物(453mg)溶于丙酮(4.5ml)中,并往其中加入碳酸钾粉末(138mg)和碘甲烷(62μl)。将所得混合物于室温搅拌过夜。然后将该混合物用乙酸乙酯-水萃取。所得有机层用水洗并干燥,蒸除溶剂。该残余物经硅胶柱(二氯甲烷∶甲醇=50∶1→30∶1)纯化,然后再经ODS柱(甲醇∶水=60∶40→65∶35)分离和纯化,得到结构式A的化合物(192mg)和结构式B的化合物(52mg)。这些化合物的物理特性如下所述。Amp:180-190℃。NMR:δ溶剂(CDCl3)
1.27(3H,d,J=7.0Hz),4.10(3H,s),4.11(1HJ,q,J=7.0Hz),
4.32(1H,d,J=14.0Hz),4.94(1H,d,J=14.0Hz),5.99(1H,s),
6.77-6.86(2H,m),7.50-7.57(1H,s),7.65(1H,s),
7.91(1H,s),8.08(1H,d,J=8.4Hz),8.10(1H,s),
8.27(1H,dd,J=8.4Hz,1.6Hz),8.67(1H,d,J=1.6Hz).MS:MH+=454.Bmp:196-197℃。NMR:δ溶剂(CDCl3)
1.29(3H,d,J=7.2Hz),4.07(1H,s),4.15(1H,q,J=7.2Hz),
4.30(1H,d,J=14.2Hz),4.97(1H,d,J=14.2Hz),5.82(1H,s),
6.79-6.86(2H,m),7.50-7.58(1H,m),7.68(1H,s),
7.82(1H,dd,J=1.8Hz,8.4Hz),7.87(1H,s),7.99(1H,s).
8.16(1H,d,J=8.4Hz),8.28(1H,d,J=1.8Hz).实施例116:
除了用2-乙基-6-(1,2,3-三唑-2-基)-苯并噻唑(529mg)(该化合物是制备实施例7制备的原料5)代替2-乙基-6-氯苯并噻唑外,按照实施例106所述相同方法得到该目的化合物。该化合物的物理特性所下所述。状态:油状。NMR:δ溶剂(CDCl3)
1.29(3H,d,J=71Hz),4.12(1H,q,J=7.1Hz),
4.32(1H,d,J=14.2Hz),4.97(1H,d,J=14.2Hz),
5.87(1H,brs),6.79-6.83(2H,m),7.50-7.58(1H,m),
7.67(1H,s),7.87(2H,s),7.89(1H,s),
8.12(1H,d,J=9.0Hz),8.30(1H,dd,J=8.8,2.2Hz),
8.65(1H,d,J=2.2Hz).实施例117:
制备下列结构式表示的化合物(1∶1非对映体混合物):
按照制备实施例7的相同方法制备2-乙基-6-甲氧羰基苯并噻唑。将该化合物溶于1ml乙醚中,并于0℃往该溶液中加入甲基碘化镁(2.0M乙醚溶液,1.2ml)。于室温搅拌该混合物后,加入饱和氯化铵水溶液,然后用乙酸乙酯萃取。将得取的有机层用水、然后用饱和盐水洗涤,并减压蒸除溶剂。如此得到的粗产物经硅胶柱色谱纯化得到(2-甲基-2-(2-乙基苯并噻唑-6-基)乙醇)(138mg)。除了用此产物代替2-乙基-6-氯苯并噻唑及正丁基锂的用量是实施例116的2倍以外,按实施例19所述相同方法得到目的化合物(1∶1非对映体混合物)。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)
1.25(1.5H,d,J=7.2Hz),1.60(3H,s),1.67(3H,s),
1.80(1.5H,d,J=8.4Hz),4.05-4.17(1H,m),
4.27(0.5H,d,J=14.4Hz),4.71(0.5H,d,J=14.0Hz),
4.90-4.95(1H,n),6.02(0.5H,s),6.13(0.5H,d,J=1.6Hz),
6.44-6.51(0.5H,m),6.63-6.70(0.5H,m),
6.63-6.70(0.5H,m),6.76-6.85(1H,m),7.10-7.17(0.5H,m)
7.50-7.56(1H,m),7.61-7.65(0.5H,m),7.64(0.5H,s),
7.66(0.5H,s),7.84(0.5H,d,J=8.8Hz),7.89(0.5H,s),
7.91(0.5H,d,J=1.6 Hz),8.00(0.5H,d,J=8.8Hz),
8.06(0.5H,s)8.10(0.5H,d,J=1.6Hz).MS:MH+=445实施例118:
制备下列结构式表示的化合物(1∶1非对映体混合物):
将实施例117中使用的相同的2-乙基-6-甲氧羰基苯并噻唑(699mg)溶于1∶1混合的水和甲醇溶剂(20ml)中并往该溶液中加入1NNaOH水溶液(8ml),然后加热并回流4.5小时。往该反应混合物中加入8ml1NHCl,然后加入食盐,再用乙酸乙酯进行萃取。该萃取液用饱和盐水洗涤后,在减压下蒸除溶剂,得到6-羧基-2-乙基苯并噻唑(642mg)。无需纯化将该产物(1.957g)溶于二甲苯(50ml)中,并将2-氨基-2-甲基-1-丙醇(6ml)加到该溶液中。然后将所得混合物通过迪安-斯达克榻分水器加热回流3天。减压从该液体反应混合物中蒸除溶剂,所得残余物经硅胶柱色谱纯化,得到下列结构式表示的中间体化合物:
使用该中间体化合物,按照如实施例106的相同方法得到目的化合物。该化合物的物理特性如下所述。mp:状态:固体。NMR:δ溶剂(CDCl3)
1.27(1.5H,d,J=6.8Hz),1.38(3H,s),1.42(3H,s),
1.70(1.5H,d,J=6.8Hz),4.08-4.18(1H,m),4.12(1H,s),
4.18(1H,s),4.29(0.5H,d,J=14.4Hz),
4.74(0.5H,d,J=14Hz),4.94(0.5H,d,J=14.4Hz),
4.95(0.5H,d,J=14Hz),5.90(0.5H,s),
5.94(0.5H,d,J=1.6Hz),6.43-6.49(0.5H,m)
6.62-6.69(0.5H,m),6.77-6.85(1H,m),7.07-7.14(0.5H,m),
7.49-7.57(0.5H,m),7.66(0.5H,s),7.68(0.5H,s),
7.89(0.5H,d,J=8.4Hz),7.89(0.5H,s),
8.00(0.5H,dd,J=1.6,8.4Hz),8.03(0.5H,d,J=8.4Hz),
8.05(0.5H,s),8.10(0.5H,dd,J=1.68,8.4Hz),
按照与制备实施例7所述相同方法制备2-乙基-6-甲基硫代苯并噻唑,因此除使用该产物外,按照与实施例106相同的方法可得到目的化合物的非对映体混合物。然后将该混合物进行硅胶色谱,分离出化合物(I)和化合物(II),二者各自为另一个的非对映体。状态:固体。NMR:δ溶剂(CDCl3)
1.24(3H,d,J=7.0Hz),2.57(3H,s),4.06(1H,q,J=7.0Hz),
4.27(1H,d,J=14.2Hz),4.92(1H,d,J=14.2Hz),5.93(1H,s),
6.76-6.84(2H,m),7.42(1H,dd,J=2.08,8.4Hz),
7.47-7.55(1H,m),7.65(1H,s),7.76(1H,d,J=2.0),
7.88(1H,s),7.92(1H,d,J=8.4Hz).MS:MH+=433状态:固体。NMR:δ溶剂(CDCl3)
1.24(3H,d,J=7.0Hz),2.57(3H,s),4.06(1H,q,J=7.0Hz),
4.27(1H,d,J=14.2Hz),4.92(1H,d,J=14.2Hz),5.93(1H,s),
6.76-6.84(2H,m),7.42(1H,dd,J=2.0,8.4Hz),
7.47-7.55(1H,m),7.65(1H,s),7.76(1H,d,J=2.0),
7.88(1H,s),7.92(1H,d,J=8.4Hz).MS:MH+=433.实施例120:
制备下列结构式表示的化合物(I):及其非对映体的另一个化合物(II):
分别由实施例119得到的化合物及其非映体,按照如实施例99所述相同的方法分别得到上述化合物(I)和其非对映体化合物(II)。这些化合物的物理特性如下所述。(I)状态:固体。NMR:δ溶剂(CDCl3)
1.29(3H,d,J=7.2Hz),3.13(3H,s),4.18(1H,q,J=7.2Hz),
4.24(1H,d,J=14.12Hz),4.98(1H,d,J=14.2Hz),5.68(1H,s),
6.79-6.86(2H,m),7.49-7.56(1H,m),7.70(1H,s),
7.84(1H,s),8.06(1H,dd,J=2.0,8.8Hz),
8.19(1H,d,J=8.8Hz),8.58(1H,d,J=2.0Hz).MS:MH+=465.(II)状态:固体。NMR:δ溶剂(CDCl3)
1.71(3H,d,J=6.8Hz),3.08(3H,s),4.22(1H,q,J=6.8Hz),
4.73(1H,d,J=14.0Hz),4.98(1H,d,J=14.0Hz),5.72(1H,s),
6.47-6.54(1H,m),6.64-6.71(1H,m),7.12-7.19(1H,m),
7.72(1H,s),7.96(1H,dd,J=1.7,8.8Hz),8.02(1H,s),
8.04(1H,d,J=8.8Hz),8.41(1H,brd,J=1.7Hz).MS:MH+=465.实施例121:
除了使用与制备实施例6所述相同的方法制备的2-乙基-6-(4-氟苯基硫)苯并噻唑来代替2-乙基-6-氯苯并噻唑外,按照实施例106所述相同方法制备该目的化合物。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)
1.24(3H,d,J=7.2Hz),4.07(1H,q,J=7.2Hz),
4.26(1H,d,J=14.4Hz),4.92(1H,d,J=14.4Hz),5.84(1H,s),
6.76-6.84(2H,m),7.06(2H,br-dd,J=8.6,8.6Hz),
7.39-7.44(3H,m),7.47-7.55(1H,m),7.66(1H,s),
7.77(1H,d,J=1.6Hz),7.86(1H,s),7.93(1H,d,J=8.8Hz).MS:MH+=513.实施例122:
由按实施例121制备的化合物,按照实施例99所述的相同方法制得上述化合物的混合物。然后将该混合物进行硅胶色谱,使二个化合物彼此分离,得到单一化合物。这些化合物的物理特性如下所述。(I)状态:固体。NMR:δ溶剂(CDCl3)
1.27(3H,d,J=7.2Hz),4.22(1H,d,J=14.4Hz),
4.63(1H,q,J=7.2Hz),5.11(1H,d,J=14.4Hz),6.56(1H,brs),
6.76-6.87(2H,m),7.23(2H,br-dd,J=8.4,8.4Hz),
7.46-7.54(1H,m),7.68(1H,s),7.92(1H,s),
7.99-8.04(2H,m),8.12(1H,dd,J=1.6,8.4Hz),
8.32(1H,d,J=8.4Hz),8.51(1H,br-d,J=1.6Hz).MS:MH+=561.(II)状态:固体。NMR:δ溶剂(CDCl3)
1.26(3H,d,J=7.2Hz),4.14(1H,q,J=7.2Hz),
4.19(1H,d,J=14.4Hz),4.94(1H,d,J=14.4Hz),
5.64(1H,s),6.78-6.85(2H,m),
7.20(2H,br-dd,J=8.6,8.6Hz),7.47-7.54(1H,m),
7.68(1H,s),7.81(1H,s),7.98-8.03(3H,m),
8.12(1H,d,J=8.8Hz),8.58(1H,d,J=2.0Hz).MS:MH+=545.实施例123:
制备下列结构式表示的化合物:
除了使用2-乙基-4-氯苯并噻唑代替2-乙基-6-氯-苯并噻唑以外,按照实施例106所述的相同方法得到该目的化合物。该化合物的物理特性如下所述。状态:油状。NMR:δ溶剂(CDCl3)
1.26(3H,d,J=8.0Hz),4.19(1H,q,J=8.0Hz),
4.34(1H,d,J=15.2Hz),4.96(1H,d,J=15.2Hz),
5.92(1H,brs),6.78-6.84(2H,m),7.34-7.40(1H,m),
7.50-7.58(2H,m),7.68(1H,s),7.78-7.58(2H,m),
7.68(1H,s),7.78-7.85(1H,m),7.92(1H,s).实施例124:
制备下列结构式表示的化合物:
除了使用2-乙基-4-氰基苯并噻唑来代替2-乙基-6-氰基苯并噻唑以外,按实施例109所述相同方法,得到该目的化合物。该化合物的物理特性如下述。NMR:δ溶剂(CDCl3)
1.26(3H,d,J=7.1Hz),4.15(1H,q,J=7.1Hz),
4.22(1H,d,J=14.2Hz),4.98(1H,d,J=14.2Hz),
5.63(1H,brs),6.78-6.86(2H,m),7.48-7.56(1H,m),
7.67(1H,dd,J=8.2,1.5Hz),7.70(1H,s),7.84(1H,s),
8.03(1H,d,J=8.2Hz),8.33(1H,d,J=1.5Hz).实施例125:
在90℃,将2-乙基-6-氯-7-氮杂苯并噻唑(3.16g)与硫代甲醇钠(1.67g)于N-甲基吡咯烷酮(9ml)中反应1小时。冷却该反应混合物后,往其中加入水和乙酸乙酯使其分层。将所得有机层用水洗涤并干燥,再蒸除溶剂。该残余物经硅胶柱(己烷∶乙酸乙酯=10∶1)纯化,得到中间体化合物,即2-乙基-6-硫代甲氧基-7-氮杂苯并噻唑(2.25g)。使用该中间体化合物,按照实施例106的同样方法,得到目的化合物。该化合物的物理物性如下所述。mp:185-186℃NMR:δ溶剂(CDCl3)
1.25(3H,d,J=7.2Hz),2.65(3H,s),4.03(1H,q,J=7.2Hz),
4.30(1H,d,J=14.2Hz),4.94(1H,d,J=14.2Hz),5.75(1H,s),
6.77-6.85(2H,m),7.31(1H,d,J=8.4Hz),7.48-7.55(1H,m),
7.68(1H,s),7.86(1H,s),8.02(1H,d,J=8.4).实施例126:
制备下列结构式表示的化合物:
将实施例125中得到的化合物(400mg)溶于二氯甲烷(4ml),并将间氯过苯甲酸(476mg)加到该溶液中,然后于室温搅拌1.5小时。该反应混合物依次用加有二氯甲烷的碳酸氢钠水溶液和水洗涤,并干燥。蒸出溶剂,得到目的化合物(425mg)。该化合物的物理物性如下所述。mp:211-214℃。NMR:δ溶剂(CDCl3)
1.30(3H,d,J = 7.0Hz),3.32(3H,s),4.14(1H,q,J=7.0Hz),
4.23(1H,d,J = 14.4Hz),5.01(1H,d,J=14.4Hz),5.59(1H,s),
6.80-6.86(2H,m),7.48-7.56(1H,m),7.72(1H,s),
7.82(1H,s),8.25(1H,d,J=8.4Hz),8.47(1H,d,J=8.4Hz).MS:MH+=466.实施例127:
制备下列结构式表示的化合物:
除了使用2-乙基-6-氯-7-氮杂苯并噻唑作为中间体化合物外,按实施例125所述相同方法得到该目的化合物。该化合物的物理特性如下所述。mp:177-178℃NMR:δ溶剂(CDCl3)
1.27(3H,d,J=7.2Hz),4.07(1H,q,J=7.2Hz),
4.27(1H,d,J=14.0Hz),4.96(1H,d,J=14.0Hz),
5.63(1H,s),6.78-6.85(2H,m),7.47(1H,d,J=8.4Hz),
7.48-7.55(1H,m),7.70(1H,s),7.83(1H,s),
8.19(1H,d,J=8.4Hz).实施例128:
将2-乙基-7-氮杂苯并噻唑(2.95g)溶于二氯甲烷(30ml)中,并于室温下将间氯过苯甲酸(4.7g)加到该溶液中。3.5小时后,再加入间氯过苯甲酸(2.3g)。待反应完成后,在冰水冷却下用亚硫酸钠水溶液处理该反应混合物。如此得到的反应混合物用二氯甲烷稀释,并将所得有机层按顺序用碳酸氢钠水溶液、水和盐水洗涤并干燥。蒸除溶剂得到2-乙基-7-氮杂苯并噻唑-7-氧化物(2.69g)。将该化合物加到二氯甲烷(27ml)中,依次加入二甲氨基氨基甲酰氯(4.16g),三甲基甲硅烷基氰化物(5.69ml)和三乙胺(6.3ml),并使之在在室温反应8小时。再加入三甲基基甲硅烷基氰化物(2.5ml)和二甲氨基氨基甲酰氯(2.5ml)。该反应于室温进行2天后,往该反应混合物中加入碳酸氢钠水溶液,然后搅拌1小时。而后将该反应混合物用乙酸乙酯萃取,所得有机层用水洗涤、干燥并蒸发。该残余物径硅胶柱(用二氯甲烷∶甲醇=200∶1洗脱)纯化后,用二氯甲烷-异丙醚重结晶,得到2-乙基-6-氰基-7-氮杂苯并噻唑(1.37g)。除使用上述化合物代替2-乙基-6-氯代苯并噻唑外,按实施例106相同方法得到该目的化合物。该化合物的物理特性如下所述。mp:170-173℃NMR:δ溶剂(CDCl3)
1.30(3H,d,J=7.0Hz),4.13(1H,qd,J=7.0Hz,0.8Hz),
4.25(1H,d,J=14.0Hz),4.98(1H,d,J=14.0Hz),
5.59(1H,d,J=0.8Hz),5.59(1H,d,J=0.8Hz),
6.79-6.86(2H,m),7.49-7.56(1H,m),7.72(1H,s),
7.81(1H,s),7.84(1H,d,J=8.4Hz),8.35(1H,d,J=8.4Hz).MS:MH+=413.实施例129:
制备下列结构式表示的化合物:
由实施例128制备的化合物,按照实施例111所述相同方法制备该目的化合物。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)
1.30(3H,d,J=7.2Hz),4.12(1H,q,J=7.2Hz),
4.28(1H,d,J=14.4Hz),5.00(1H,d,J=14.4Hz),5.65(1H,s),
6.80-6.87(2H,m),7.49-7.56(1H,m),7.70(1H,s),
7.70-7.76(1H,brs),7.80(1H,s),8.33(1H,d,J=8.8Hz),
8.91(1H,d,J=8.8 Hz),9.32-8.38(1H,br-s).实施例130:
除了使用1-(1H-1,2,4-三唑-1-基)-2’-氯苯乙酮代替1-(1H-1,2,4-三唑-1-基)-2’,4’-二氟苯乙酮外,按照实施例127所述相同方法得到目的化合物。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDC13)
1.22(3H,d,J=7.2Hz),4.22(1H,d,J=14.4Hz),
4.67(1H,q,J=7.2Hz),5.55(1H,s),5.60(1H,d,J=14.4Hz),
7.18-7.22(2H,m),7.34-7.38(1H,m),7.46(1H,d,J=8.8Hz),
7.68(1H,s),7.69-7.73(1H,2),7.81(1H,s),
8.20(1H,d,J=8.8Hz).实施例131:
制备下列结构式表示的化合物:
除了使用2-甲基-6-氯代苯并噻唑代替2-乙基-6-氯代苯并噻唑以外,按照实施例106所述相同方法制备该目的化合物。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)
3.43(1H,d,J=15.2Hz),3.88(1H,d,J=15.2Hz),
4.65(1H,d,J=14.2Hz),4.70(1H,d,J=14.2Hz),6.03(1H,s),
6.69-6.74(1H,m),6.76-6.81(1H,m),
7.40(1H,dd,J=8.8Hz,2.0Hz),7.42-7.50(1H,m),
7.75(1H,d,J=2.0Hz),7.82(1H,d,H=8.8H),7.85(1H,s)
8.18(1H,s).实施例132:
制备下列结构式表示的化合物:
除了使用2-甲基-6-氰基苯并噻唑代替2-甲基-6-氯代苯并噻唑以外,按照实施例131所述相同方法制备该目的化合物。该化合物的物理特性如下所述。mp:176-178℃。NMR:δ溶剂(CDCl3)
3.52(1H,d,J=15.4Hz),3.95(1H,d,J=15.4Hz),4.69(2H,s)
5.87(1H,s),6.71-6.82(1H,m),7.51-7.45(1H,m),
7.69(1H,dd,J=1.6Hz,8.6Hz),7.86(1H,s),
7.99(1H,dd,J=0.4Hz,8.6Hz),8.13(1H,dd,J=0.4Hz,1.6Hz),
8.15(1H,s).实施例133:制备下述结构式表示的化合物:
除了使用2-甲基-6-氯-7-氮杂苯并噻唑代替2-乙基-6-氯-7-氮杂苯并噻唑以外,按实施例127所述相同方法制备该目的化合物。该目的化合物的物理特性如下所述。
mp:145-147℃(MeOH)。
NMR:δ溶剂(CDCl3)
3.47(1H,d,J=15.2Hz),3.90(1H,d,J=15.2Hz),
4.69(2H,S),5.76(1H,S),6.70-6.83(2H,m),
7.39(1H,d,J=8.4Hz),7.42-749(1H,m),
7.86(1H,S),8.08(1H,d,J=8.4Hz),8.13(1H,S)。实施例134:
制备下列结构式表示的化合物:
将3-硝基-4-氯化吡啶盐酸盐(2038mg)溶于乙醇(42ml),再将亚硫酸氢钠(2148mg)加到该溶液中,然后于室温搅拌40分钟。往该反应混合物中加入亚硫酸氢钠(6.67g)水溶液,并将所得混合物于80℃加热搅拌12小时。过滤除去不溶物后,浓缩该溶液。将该浓缩物溶于甲醇-水中,并将该溶液与硅胶混合并减压干燥。此后,用5∶1氯仿-甲醇、然后用1∶1氯仿-甲醇洗脱,得到3-氨基-4-巯基吡啶(892mg)。将7ml乙酸乙酯和4分子筛加到该产物中,并将所得混合物于氮气氛下加热回流20分钟。该反应混合物于减压下干燥,将其溶于甲醇。使该溶液吸附于硅胶上。用50∶1氯仿-甲醇洗脱该溶液,得到590mg 2-甲基-5-氮杂苯并噻唑。除了使用上述2-甲基-5-氮杂苯并噻唑代替2-甲基-6-氯代苯并噻唑以外,按照实施例131所述相同方法得到目的化合物。该化合物的物理特性如所述。mp:137-148℃NMR:δ溶剂(CD3OD)
3.69(1H,d,J=14.8Hz),4.08(1H,d,J=14.8Hz),
4.77(1H,d,J=14.4Hz),4.87(1H,d,J=14.4Hz),
6.71-6.84(1H,m),6.92-7.04(1H,m),7.32-7.46(1H,m),
7.83(1H,s),7.97(1H,d,J=5.2Hz),8.37(1H,d,J=5.2Hz),
8.37(1H,s),9.06(1H,s).实施例135:
制备下列结构式表示的化合物:
将叠氮化钠(2301mg)溶于二甲基亚砜(60ml)中,往该溶液中加入2-溴-4’-硫甲基苯乙酮(3000mg),然后于室温搅拌20分钟。将该反应混合物倾入200ml冰水中,然后用乙酸乙酯(200ml×5)萃取。该萃取液用无水硫酸镁干燥,并减压浓缩,然后经硅胶柱色谱(己烷→己烷-乙酸乙酯=8∶1)纯化,得到2-叠氮基(azide)-4’-硫甲基苯乙酮(2155mg)。将由二异丙胺(1.75ml)和1.6M正丁基锂的己烷溶液(7.8ml)在47ml四氢呋喃中生成的二异丙胺锂溶液,在冰水冷却下,冷却至-78℃,用5分钟往其中滴加2-叠氮基(azide)-4’-硫甲基苯乙酮(2155mg)的四氢呋喃溶液(19ml),然后于-78℃搅拌1小时。然后再滴加丙酰氯(1.81ml),并使该所得混合物于-78℃放置10分钟,再加热至室温并于室温搅拌10分钟。将该反应混合物倾入冰水中,再用乙酸乙酯(300ml×3)萃取。萃取液用无水硫酸镁干燥,再减压浓缩。所得油状物质经硅胶柱色谱(己烷→己烷∶乙酸乙酯=10∶1)纯化,得到丙酸2-叠氮基(azide)-1-(4’-硫甲基苯基)乙烯酯(1.98g)。将该产物溶于环己烷(38ml)中,并往该溶液中加入磷酸酯。所得混合物于氮气氛下、在室温搅拌1小时,然后于90℃加热20小时。该反应混合物经硅胶柱色谱(己烷→己烷∶乙酸乙酯=30∶1)纯化,得到2-乙基-5-(4-硫甲基苯基)噁唑(630mg)。使用该化合物代替2-乙基-6-氯代苯并噻唑,按实施例106所述相同方法得到目的化合物。该化合物的物理特性如下所述。状态:油状。NMR:δ溶剂(CDCl3)
1.55(3H,d,J=8.0Hz),2.50(3H,s),3.88(1H,d,J=8.0Hz),
4.69(1H,d,J=13.3Hz),4.98(1H,d,J=13.3Hz),
5.56(1H,brs),6.60-6.72(2H,m),7.20-7.26(2H,m),
7.22-7.34(1H,m),7.27(2H,s),7.33-7.38(2H,m),
将实施例135的产物(77mg)溶于二氯甲烷(6.0ml)中,在冰水冷却下,往该溶液中加入间过苯甲酸(156mg)。加热该混合物至室温后,搅拌1小时。往该反应混合物中加入饱和硫代硫酸钠水溶液和饱和碳酸氢钠水溶液。再往所得混合物中加入10ml二氯甲烷使该混合物分层。然后将所得水层进一步用二氯甲烷(10ml×2)萃取。有机层合并,用饱和盐水洗涤,用无水硫酸镁干燥,然后减压浓缩。如此得到的油状物经硅胶柱色谱(己烷-乙酸乙酯=4∶1→二氯甲烷-甲醇=10∶1)纯化,得到目的化合物(54mg)。该化合物的物理特性如下所述。状态:油状。NMR:δ溶剂(CDCl3)
1.60(3H,d,J=7.2Hz),3.07(3H,s),3.91(1H,q,J=7.1Hz),
4.71(1H,d,J=14.1Hz),5.00(1H,d,J=14.1Hz),
5.40-5.50(1H,brs),6.62-6.72(2H,m),7.26-7.33(1H,m),
7.31(1H,s),7.6-7.64(2H,m),7.73(1H,s),
7.92-7.97(2H,m),8.05(1H,s).MS:m/e FAB 475(MH+)。实施例137:制备下列结构式表示的化合物:及其非对映体:
于-65℃,将2-乙基-4-氰基-5-三甲基甲硅烷基噻唑(1.58g)的10ml四氢呋喃溶液滴加到20ml二异丙基氨化锂(由1.40ml二异丙胺和3.2ml丁基锂(1.6M己烷溶液)制备)的四氢呋喃溶液中。然后于-65℃,再滴加10ml(1H-1,2,4-三唑-1-基)-2,4-二氟苯基苯乙酮的四氢呋喃溶液。将该混合物搅拌1.5小时后,往其中加入氯化铵水溶液,并加入乙酸乙酯和水分离所得混合物。所得有机层用水洗涤并干燥,蒸除溶剂。将该残余物溶于20ml四氢呋喃中,并往该溶液中加入1.0M四丁基氟化铵的四氢呋喃溶液(20ml),然后于室温搅拌1小时。将该反应混合物用乙酸乙酯和水分层后,所得有机层用水洗涤,干燥并浓缩至干。该残余物经硅胶柱色谱(二氯甲烷∶甲醇=200∶1)纯化,得到单一的非对映体化合物(I)(464mg)。用硼氢化钠的甲醇溶液处理含有另一个非对映体和(1H-1,2,4-三唑-1-基)-2,4-二氟苯乙酮的馏份,然后通过硅胶柱分离,得到(564mg)另一个非映体化合物(II)。这些化合物的物理特性如下所述。(I)mp:198-205℃NMR:δ溶剂(CDCl3)
1.20(3H,d,J=7.1Hz),4.06(1H,q,J=14.4Hz),
4.08(1H,q,J=7.1Hz),4.96(1H,d,J=14.4Hz),5.41(1H,s),
6.77-6.83(2H,m),7.42-7.49(1H,m),7.75(1H,s),
7.80(1H,s),8.05(1H,s).MS:MH+=362。(II)mp:191-194℃。NMR:δ溶剂(CDCl3)
1.61(3H,d,J=7.1Hz),4.08(1H,q,J=7.1Hz),
4.66(1H,d,J=14.0Hz),4.98(1H,d,J=14.0Hz),5.37(1H,s),
6.58-6.70(2H,m),7.12-7.1 8(1H,m),7.75(1H,s),
7.79(1H,s),7.97(1H,s).MS:MH+=362。实施例138:
在2mlN-甲基-吡咯烷酮中溶解150mg实施例137制备的化合物,并将54mg NaN3和115mg Et3N·HCl加到该溶液中,然后在外部温度为100℃的油浴中加热5小时。往该液体反应混合物中加入水,然后用AcOEt萃取3次。该萃取液用水洗涤,然后用饱和NaCl水溶液洗涤并用MgSO4干燥,蒸除ACOEt。往残余物中加入丙酮、4mlEtOH和10ml H2O。用1NHCl水溶液调节所得混合物至pH3,然后放置。结果,固体物质沉淀出来。过滤回收固体物质,得到82mg目的化合物。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(DMSO-d6)。
1.13(3H,d,J=7.0Hz),4.11-4.14(1H,m),
4.34(1H,d,J=14.2Hz),4.80(1H,d,J=14.2Hz),6.16(1H,s),
6.93-6.98(1H,m),7.18-7.24(1H,m),7.28-7.33(1H,m),
7.61(1H,s),8.22(1H,s),8.45(1H,br-s).MS:MH+=405。实施例139:
将80mg实施例138得到的化合物溶于1ml DMF中,并将65mgCSCO3加到该溶液中,然后于外部温度为60℃的油浴中加热30分钟。再将0.02ml CH3I加到该反应混合物中,之后于室温搅拌30分钟。将H2O加到该液体反应混合物中并用AcOEt萃取。该萃取液用H2O洗涤,然后用饱和NaCl水溶液洗涤后,用MgSO4干燥,蒸除AcOEt。所得残余物经柱色谱(SiO2:20g,用CH2Cl2洗脱,然后用1%MeOH的CH2Cl2溶液和2%MeOH的CH2Cl2溶液洗脱)纯化,得到58mg目的化合物。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)。
1.22(0.9H,d,J=7.1Hz),1.25(2.1H,d,J=7.1Hz),
4.08-4.21(2H,m),4.45(0.9H,s),4.49(2.1H,s),
4.95(0.7H,d,J=14.2Hz),5.00(0.3H,d,J=14.8Hz),
5.40(0.7H,s),5.53(0.3H,s),6.76-6.84(2H,m),
7.45-7.52(1H,m),7.72(0.3H,s),7.75(0.7H,s),
7.78(0.7H,s),7.81(0.3H,s),8.14(0.3H,s),8.35(0.7H,s).MS:MH+=419。实施例140:
除了使用2-乙基-4-(4’-氟苯基)-5-三甲基甲硅烷基-噻唑代替2-乙基-4-氰基-5-三甲基甲硅烷基-噻唑之外,按照与实施例137所述相同的方法得到相应的目的化合物。这些化合物的物理特性如下所述。(I)mp:122-124℃NR:δ溶剂(CDCl3)
1.67(3H,d,J=7.0Hz),4.09(1H,q,J=7.0Hz),
4.73(1H,d,J=13.8Hz),4.93(1H,d,J=13.8-,
6.14(1H,d,J=1.7Hz),6.48-6.54(1H,m),6.66-6.73(1H,m),
7.06-7.12(3H,m),7.67(1H,s),7.71-7.74(1H,m),
8.05(1H,s).(II)mp:87-89℃。NMR:δ溶剂(CDCl3)
1.23(3H,d,J=7.1Hz),4.06(1H,q,J=7.1Hz),
4.28(1H,d,J=14.4Hz),4.89(1H,d,J=14.4Hz),6.04(1H,s),
6.77-6.85(2H,m),7.13-7.17(1H,m),7.41(1H,s),
7.47-7.55(1H,m),7.67(1H,s),7.85-7.92(2H,m),
7.90(1H,s)实施例141:
制备下列结构式表示的化合物(I):及其非对映体化合物(II):
除了使用2-乙基-4-(4’-氯苯基)-5-三甲基甲硅烷基噻唑代替2-乙基-4-氰基-5-三甲基甲硅烷基噻唑之外,按照与实施例137所述相同的方法得到相应的目的化合物。这些化合物的物理特性如下所述。(I)mp:132-133℃NMR:δ溶剂(CDCl3)
1.67(3H,d,J=7.0Hz),4.10(1H,q,J=7.0Hz),
4.73(1H,d,J=13.9Hz),4.93(1H,d,J=13.9Hz),
6.09(1H,m),6.46-6.55(2H,m),7.65-6.73(1H,m),
7.05-7.13(1H,m),7.17(1H,s),7.35-7.40(2H,m),
7.65-7.70(2H,m),8.04(1H,s)(II)mp:162-164℃。NMR:δ溶剂(CDCl3)
1.23(3H,d,J=7.1Hz),4.06(1H,q,J=7.1Hz),
4.27(1H,d,J=14.4Hz),4.89(1H,d,J=14.4Hz),5.97(1H,s),
6.76-6.85(2H,m),7.40-7.55(4H,m),7.67(1H,s),
7.72-7.77(2H,s),7.89(1H,s).
实施例142:
除了使用2-甲基-4-氰基-5-三甲基甲硅烷基噻唑代替2-乙基-4-氰基-5-三甲基甲硅烷基噻唑以外,按照与实施例137所述相同的方法得到目的化合物。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)
3.44(3H,d,J=15.0Hz),3.81(1H,d,J=15.0Hz),
4.58(1H,d,J=14.2Hz),4.74(1H,d,J=14.2Hz),
5.48(1H,s),6.74-6.82(2H,m),7.40-7.46(1H,m),
7.85(1H,s),7.87(1H,s),8.07(1H,s).MS:MH+=348。实施例143:
除了使用2-甲基-4-(4’-氯苯基)-5-三甲基甲硅烷基噻唑代替2-乙基-4-氰基-5-三甲基甲硅烷噻唑以外,按照与实施例137所述相同的方法得到目的化合物。该化合物的物理特性如下所述。状态:固体。NMR:δ溶剂(CDCl3)
3.34(1H,d,J=15.3Hz),3.85(1H,d,J=15.3Hz),
4.62(1H,d,J=14.2Hz),4.71(1H,d,J=14.2Hz),
6.21(1H,s),6.69-6.83(2H,m),7.27(1H,s),
7.36-7.46(3H,m),7.68-7.73(2H,m),
7.85(1H,s),8.20(1H,s).实施例144:
将5.77g二氟苯加到AlCl3(5.88g)在CH2Cl2(50ml)中的悬浮液中,并将2-(4-氰基苯基)乙酰氯(5.28g)的CH2Cl2(30ml)溶液滴加到所得混合物中,将该混合物加热回流6小时后,往其中加入冰水。将用CHCl3萃取的产物进行柱色谱(SiO2),用CH2Cl2-己烷(1∶1)进行洗脱,得到4-(2-(2,4-二氟苯基)-2-氧代)乙基苄腈(2.45g)。
往该化合物的EtOH(12ml)溶液中,加入50%NaOH(0.67g),然后滴加MeI(0.46ml)。所得混合物于室温搅拌4小时。向该混合物中加入乙酸乙酯后,用水洗涤,通过蒸发该有机层得到的残余物经柱色谱(SiO2;己烷-CH2Cl2=3∶1→1∶1)纯化,得到0.5g化合物,即4-(2-(2,4-二氟苯基)-1-甲基-2-氧代)乙基苄腈。
将1.0M TMSCH2MgCl乙醚溶液3.9ml)冷却至-78℃,并往其中滴加上述化合物(0.5g)的乙醚溶液(5ml)。之后,将该混合物加热至0℃并搅拌10分钟。往该混合物中加入饱和氯化铵水溶液,然后用AcOEt萃取。将所得有机层蒸发至干,并于0℃加入CH2Cl2(10ml)和BF3-OEt2(0.24ml),然后于该温度下搅拌1.5小时。将AcOEt加到该混合物中后,用饱和NaHCO3水溶液、然后用饱和盐水洗涤,蒸除溶剂。所得残余物经柱色谱(SiO2;己烷-CH2Cl2=3∶1→1∶1)纯化,得到化合物,即4-(2-(2,4-二氟苯基)-1-甲基-2-丙烯基苄腈(0.2g)。
在冰水冷却下,将间氯过苯甲酸(490mg)加到该化合物(200mg)的氯仿(4ml)溶液中,并将该所得混合物放置过夜。该液体反应混合物用稀Na2CO3洗涤,然后用水洗涤,之后往通过蒸发所得有机层得到的残余物中加入5ml DMF。将如此得到的混合物加到1,2,4-三唑钠的DMF(3ml)溶液中,后者的溶液是由1,2,4-三唑(272mg)和60%NaOH(141mg)制得的。于90℃使该反应进行2小时后,往该反应混合物中加入乙酸乙酯,然后用水洗涤。蒸除溶剂,将所得到的残余物进行柱色谱(SiO2;己烷-乙酸乙酯=1∶1→1∶2),得到50 mg目的化合物。该化合物的物理特性如下所述。mp:208-209℃。NMR:δ溶剂(CDCl3)
1.13(3H,t,J=7.1Hz),3.38(1H,q,J=7.1Hz),
3.79(1H,d,J=14.5Hz),4.79(1H,d,J=14.5Hz),
4.98(1H,d,J=1.5Hz),6.74-6.81(2H,m),
7.44-7.51(1H,m),7.64(2H,d,J=8.4Hz),
7.67(2H,d,J=8.4Hz),7.72(1H,s),7.75(1H,s).实施例145:
制备下列结构式A表示的化合物:及下列结构式B表示的化合物:
i)将实施例144得到的化合物(625mg)溶于N,N-二甲基甲酰胺(2ml)中,并于100℃将该溶液与NaN3(345mg)和Et3N·Hcl(731mg)一起加热7小时。过滤除去不溶物后,减压蒸除溶剂,并将少量乙醇和水加到得到的残余物中。之后,用HCl将所得混合物调至pH2。过滤回收沉淀的固体物质,用水洗涤,然后干燥。收率:539mg。
ii)将上述固体物质(514mg)溶于N,N-二甲基甲酰胺(5ml)中,将Cs2CO3(422mg)和MeI(0.089ml)加到该溶液中,然后于室温搅拌4小时。加入乙酸乙酯,所得有机层用水洗涤3次。之后,蒸除溶剂,所得残余物经柱色谱(SiO2;CH2Cl2→CH2Cl2∶EtOAc=4∶1)纯化,得到结构式A的化合物(333mg)和结构式B的化合物(93mg)。该化合物的物理特性如下所述。Amp:216-218℃。NMR:δ溶剂(CDCl3)
1.17(3H,t,J=7.0Hz),3.39(1H,q,J=7.0Hz),
3.89(1H,d,J=14.3Hz),4.41(3H,s),4.83(1H,d,J=14.3Hz),
4.83(1H,d,J=1.5Hz),6.74-6.81(2H,m),7.44-7.54(1H,m),
7.64(2H,d,J=8.4Hz),7.71(1H,s),7.75(1H,s),
8.14(2H,d,J=8.4Hz)Bmp:169-171℃.NMR:δ溶剂(CDCl3)
1.17(3H,d,J=7.1Hz),3.42(1H,q,J=7.1Hz),
3.88(1H,d,J=14.1Hz),4.22(3H,s),4.83(1H,d,J=14.1Hz),
4.95(1H,d,J=1.5Hz),6.75-6.82(2H,m),7.44-7.55(1H,m),
7.70-7.78(6H,m).实施例146:
除了使用2-(4-(1,2,3-三唑-2-苯基)乙酰氯代替2-(4-氰基苯基)乙酰氯以外,按照实施例144的相同方法得到目的化合物。这些化合物的物理特性如下所述。Amp:198-199℃。NMR:δ溶剂(CDCl3)
1.16(3H,d,J=7.1Hz),3.39(1H,q,J=7.1Hz),
3.89(1H,d,J=14.1Hz),4.83(1H,d,J=14.1Hz),
4.85(1H,s),6.72-6.80(2H,m),7.44-7.55(1H,m),
7.64(2H,d,J=8.6Hz),7.72(1H,s),7.76(1H,s)
7.83(2H,s),8.08(2H,d,J=8.6Hz).B状态:固体。NMR:δ溶剂(CDCl3)
1.58(3H,d,J=7.0Hz),3.46(1H,q,J=7.0Hz),
4.67(1H,d,J=13.9Hz),4.85(1H,d,J=1.3Hz),
5.03(1H,d,J=13.9Hz),6.42-6.48(1H,m),6.61-6.67(1H,m),
6.93-6.99(1H,m),7.14((2H,brd,J=8.6Hz)7.75(2H,s),
7.76(1H,s),7.80(2H,brd,J=8.6Hz),7.86(1H,s).实验实施例2:
每组五只的ICR小鼠通过其尾静脉注入白色假丝酵母MCY 8622菌株(2×106cfu/鼠)而被感染。1小时后,给各组小鼠口服施用表4所示化合物,剂量为每kg小鼠2.5mg或10mg。观察7天来计算每组的平均存活天数。将该平均数作为表示体内抗真菌活性的指数。
表4
平均存活天数(天)
表4(续)
平均存活天数(天)
表4(续)
平均存活天数(天)
在33ml吡啶中溶解6.6ml(60mmol)(S)-羟基-2-甲基丙酸甲酯。往所得溶液中加入18.1g(1.5当量)三苯基氯甲烷,然后于80℃加热1小时。将该反应混合物冷却至室温,然后一点一点地加到350ml水中。过滤收集沉淀的结晶,用水洗涤并干燥。如此得到的产物用乙醇重结晶,得到18.3g(收率:85%)目的化合物(203)。C24H24O3 MH+=360
H C N计算值% 6.71 79.97 0实测值% 6.76 79.77 0.05结晶熔点: 84-85℃1H-NMR(δ,CDCl3):
1.15(3H,d;J=7.1Hz),2.69-2.77(1H,m),
3.17(1H,dd,J=5.6Hz,8.8Hz),3.29(1H,dd;J=5.6Hz,8.8Hz),
在108ml四氢呋喃和54ml甲醇的液体混合物中溶解10.8g(30.0mmol)化合物(203)。在冰水冷却的同时,用15分钟在搅拌下往该所得溶液中滴加2.52g(2当量)氢氧化锂一水合物的54ml水溶液。将所得混合物加热至室温并搅拌4小时,加入3.6ml冰乙酸并减压蒸除有机溶剂。该残余物用乙酸乙酯萃取后,萃取液用水洗涤,干燥并浓缩,得到10.4g目的化合物(204)。通过从二氯甲烷-己烷中重结晶,得到(定量)分析样品。C23H22O3 MH+=347
C H N计算值% 79.74 6.47 0实测值% 79.59 6.47 0.07结晶熔点: 99-102℃1H-NMR(δ,CDCl3):
1.18(3H,d;J=7.2Hz),2.69-2.78(1H,m),
3.25(1H,dd,J=5.6Hz,8.8Hz),3.32(1H,dd;J=5.6Hz,8.8Hz),
7.15-7.45(15H,m).
在50ml二氯甲烷中溶解10.3g(29.8mmol)该化合物(204)。在冰水冷却下,依次往所得溶液中加入3.64g(1.1当量)2-巯基吡啶、3.64g(0.1当量)4-二甲氨基吡啶和6.76g(1.1当量)二环己基碳化二亚胺。所得混合物在冰水冷却下搅拌3.5小时后,再于室温搅拌2小时,过滤分离生成的沉淀。滤液用乙酸乙酯稀释后,用水洗涤两次,再用饱和盐水洗涤并用硫酸镁干燥,减压蒸除溶剂。
该残余物经硅胶柱(用己烷∶乙酸乙酯=9∶1洗脱)纯化,得到11.9g(收率:91%)黄色油状目的化合物(205)。1H-NMR(δ,CDCl3):
1.21(3H,d;J=7.2Hz),2.99-3.09(1H,m),
3.21(1H,dd,J=5.6Hz,9.2Hz),3.44(1H,dd;J=7.6Hz,9.2Hz),
7.21-7.33(10H,m),7.43-7.47(6H,m),7.63(1H,d;J=8.0Hz),
在7.8ml四氢呋喃中悬浮780mg[相当于化合物(205)的1.2当量]通过在120℃氮气流下搅拌过夜而被活化的镁粉。将1滴2,4-二氟溴苯和一颗碘结晶加到该悬浮液中,搅拌,在内部温度保持在40-60℃下,再往其中滴加溶于17ml四氢呋喃中的3.67ml[相当于化合物(205)的1.2当量]2,4-二氟溴苯溶液。加入20ml四氢呋喃后,将该混合物的内部温度冷却至-30℃。在保持其内部温度于-25~-30℃时,将溶于90ml四氢呋喃中的11.9g(27.1mmol)化合物(205)的溶液滴加到该混合物中。所得混合物于-30℃搅拌15分钟后,再于室温搅拌2小时,再往该反应混合物中加入饮和氯化铵水溶液,然后搅拌15分钟。将乙酸乙酯和水加到该混合物中,回收有机层。该有机层用水洗涤两次并用饱和盐水洗涤一次,然后用无水硫酸镁干燥,并在减压下蒸除溶剂。所得残余物经硅胶柱(用己烷∶乙酸乙酯=9∶1洗脱)纯化,并进一步用甲醇重结晶,得到7.46g(收率62%)目的化合物(206)。C29H24F2O2 MH+=442
H C N计算值% 5.47 78.7 0实测值% 5.48 78.73 0结晶熔点: 94-97℃1H-NMR(δ,CDCl3):
1.21(3H,d,J=6.8Hz),3.21(1H,dd,J=5.2Hz,8.8Hz),
3.42(1H,dd,J=6.4Hz,8.8Hz),3.56(1H,m),6.80(1H,m),
在氮气流下,于64ml四氢呋喃中悬浮6.43g[相当于化合物(206)的1.2当量]甲基三苯溴化鏻。在冰水冷却下,往该悬浮液中滴加11.2ml[相当于化合物(206)的1.2当量]丁基锂(1.6mol己烷溶液)。将所得混合物加热至室温,然后搅拌2小时,滴加6.63g(15.0mmol)化合物(206)的30ml四氢呋喃溶液,然后搅拌30分钟。往该液体反应混合物中加入500ml己烷和300ml水,并过滤除去不溶物。
回收有机层并用水洗涤3次,用饱和盐水洗涤一次,用无水硫酸镁干燥并在减压下蒸除溶剂。该残余物经硅胶柱(用己烷∶乙酸乙酯=50∶1洗脱)纯化,得到5.4g(收率85%)油状产物(207)。1H-NMR(δ,CDCl3):
1.16(3H,d,J=7.0Hz),2.81-2.89(1H,m),
2.97-3.01(1H,dd,J=6.0Hz,9.2Hz),
3.04-3.08(1H,dd,J=6.0Hz,9.2Hz),5.11(1H,S),5.21(1H,s),
6.68-6.75(2H,m),7.00-7.06(1H,m),7.18-7.28(9H,m),
7.35-7.39(6H,m).实施例150:
在25ml二氯甲烷中溶解2.70g(6.14mmol)化合物(207)。在冰水冷却下,将1.46(1.1当量)间氯过苯甲酸(纯度:80%)加到该溶液中,之后于4℃搅拌12小时。将290mg(0.34当量)间氯过苯甲酸加到该反应混合物中,之后于室温再拌5小时。将10%的亚硫酸氢钠水溶液加到该混合物中,然后用乙酸乙酯萃取。所得有机层依次用水、饱和碳酸氢钠水溶液、水和饱和盐水洗涤,再用硫酸镁干燥,并在减压下蒸除溶剂,得到2.813g油状化合物(208)。质子NMR分析的结果发现该化合物是所需异构体(208a)和其非对映体(208b)的2∶1混合物。1H-NMR(δ,CDCl3):
0.93(3H,d;J=8.8Hz),<a>,0.98(3H,d;J=8.8Hz)<b>,
2.04-2.12(1H,m)<b>,2.20-2.28(1H,m)<a>,
2.76(1H,d;J=5.2Hz),<a>,2.76(1H,d;J=5.2Hz),<b>,
2.88(1H,dd;J=7.2Hz,9.2Hz)<a>,
2.96(1H,dd;J=7.2Hz,9.2Hz)<b>,3.00-3.06(1H,m)<a+b>,
3.02(1H,d;J=5.2Hz)<a>,3.11(1H,d;J=5.2Hz)<b>,
6.61-6.73(2H,m)<a+b>,7.12-7.50(16H,m)<a+b>.实施例151:<可供选择的万法>
在-70℃、通氮气条件下,将1.6M丁基锂的己烷溶液滴加到221mg化合物(206)和44μl(1.2当量)氯碘甲烷的四氢呋喃(2.2ml)溶液中。在该温度下将所得混合物搅拌5分钟,然后加热至其内部温度达室温,搅拌1小时。将氯化铵水溶液和乙酸乙酯依次加到该混合物中使其分层。将所得有机层用水和饱和盐水洗涤,并用硫酸镁干燥,减压蒸除溶剂。所得残余物经硅胶柱(用己烷∶乙酸乙酯=9∶1洗脱)纯化,得到219mg(收率:96%)化合物(208)。质子NMP分析的结果发现该化合物是含有1∶2.5的化合物(208a)和(208b)的非对映体混合物。实施例152:
在8.5ml二甲基甲酰胺中,悬浮370mg[相当于化合物(208)的1.5当量]氢化钠(60%矿物油分散液),并将851mg[相当于化合物(208)的2当量]1,2,4-三唑加到该悬浮液中。于室温搅拌15分钟后,往该悬浮液中加入溶于22ml二甲基甲酰胺中的2.813g(6.17mmol)化合物(208)(<a>∶<b>=2∶1的非对映体混合物)溶液,并将所得混合物于80℃搅拌7.5小时。该混合物冷却至室温后,往其中加入水和乙酸乙酯使其分层。所得有机层用盐水洗涤,然后硫酸镁干燥,减压蒸除溶剂。该残余物经硅胶柱(用二氯甲烷∶甲醇=200∶1洗脱)纯化,分别得到860mg目的化合物(209a),99mg其高极性非对映体(209b)和867mg这两种化合物的混合物,为白色固体。1H-NMR(δ,CDCl3):
0.87(3H,d;J=7.6Hz),2.37-2.45(1H,m),
3.40(1H,dd;J=3.2Hz,10.0Hz),
3.55(1H,dd;J=5.6Hz,10.0Hz),4.19(1H,d;J=14.4Hz),
4.65(1H,d;J=14.4Hz),4.88(1H,s),6.64-6.72(2H,m),
7.22-7.30(6H,m),7.32-7.37(6H,m),7.46-7.50(6H,m),
参见化合物(209a)的描述。固体。1H-NMR(δ,CDCl3):
1.48(3H,d;J=7.6Hz),2.47-2.56(1H,m),
2.92(1H,dd;J=3.2Hz,9.6Hz),3.19(1H,dd;J=3.2Hz,9.6Hz),
4.56(1H,d;J=14.0Hz),4.69(1H,d;J=14.0Hz),4.78(1H,s),
6.49-6.61(2H,m),7.01-7.09(1H,m),7.16-7.37(15H,m),
在7.4ml甲醇中溶解740mg(1.41mmol)化合物(209a),并往其中加入295mg(1.1当量)甲苯磺酸一水合物,然后于室温搅拌1小时。再往得到的混合物中,加入295mg(1.1当量)甲苯磺酸一水合物,随后于室温再搅拌3小时。将饱和碳酸氢钠水溶液和乙酸乙酯加到该混合物中使液体分层。将所得有机层用水洗涤,然后用饱和盐水洗涤并用硫酸镁干燥,减压蒸除溶剂。该残余物经硅胶柱(依次用二氯甲烷和甲醇的混合物(比例为100∶1,50∶1和25∶1)洗脱)纯化,得到246mg粗产物。该粗产物用二氯甲烷和异丙基醚的混合溶剂重结晶,得到190mg(收率:48%)目的化合物(210),为纯产物。C13H15F2N3O2 MH++284
H C N计算值% 5.34 55.12 14.83实测值% 5.33 55.09 14.93结晶熔点: 134-135℃1H-NMR(δ,CDCl3):
0.84(3H,d,J=7.2Hz),2.30-2.39(1H,m),
2.67-2.77(1H,br,s),3.83(1H,dd;J=5.4Hz,11,2Hz),
3.99(1H,dd;J=3.2 Hz,11.2 Hz),4.76(1H,d,J=14.0Hz),
4.97(1H,d,J=14.0Hz),5.28(1H,s),6.69-6.79(2H,m),
在5ml水和2.5ml丙酮的混合溶液中,溶解144mgN-甲基吗啉氧化物(50%水溶液),并将36μl四氧化锇(4%水溶液)和247mg化合物(207)的2.54ml丙酮溶液依次加到所得溶液中。于室温搅拌过夜后,将100μl四氧化锇(4%水溶液)加到该混合物中,然后再于室温搅拌24小时。再往该混合物中加入10%亚硫酸氢钠水溶液,然后用乙酸乙酯进行萃取。所得有机层用盐水洗涤并用硫酸镁干燥,然后在减压下蒸除溶剂。该残余物经硅胶柱(依次用10∶1的己烷∶乙酸乙酯和4∶1的己烷∶乙酸乙酯混合物洗脱)纯化,得到153mg固体形式的主产物(211a)和23g其高极性的非对映体(211b)。1H-NMR(δ,CDCl3):
0.75(3H,d,J=8.8Hz),1.80(1H,dd;J=5.2Hz,8.4Hz),
2.44-2.53(1H,m),2.77(1H,dd;J=5.6Hz,8.4Hz),
3.21(1H,dd;J=8.4Hz,14.0Hz),
3.32(1H,dd;J=2.8Hz,14.0Hz),
3.63(1H,dd;J=8.4Hz,11.2Hz),
3.96(1H,ddd;2.8Hz,5.6Hz,11.2Hz),4.39(1H,s),
6.69-6.76(1H,m),6.79-6.84(1H,m),7.22-7.30(3H,m),
7.32-7.37(6H,m),7.43-7.47(6H,m),7.52-7.58(1H,m).
参见化合物(211a)的描述。固体。1H-NMR(δ,CDCl3):
1.35(3H,d,J=7.2Hz),2.34-2.44(1H,m),
2.93(1H,dd;J=3.6Hz,9.6Hz),3.19(1H,dd;J=3.6Hz,9.6Hz),
3.82(1H,dd;J=6.8Hz,10.6Hz),
3.96(1H,dd;J=5.2Hz,10.6Hz),4.50(1H,s),
6.57-6.64(1H,m),6.70-6.75(1H,m),7.18-7.31(15H,m),
7.39-7.45(1H,m).实施例155:
在3.3ml二氯甲烷中溶解96μl(底物的2.2当量)草酰氯,并在氮气流中和-60℃将185μl(底物的4.8当量)二甲基亚砜的二氯甲烷(0.9ml)溶液滴加到所得溶液中。搅拌5分钟后,滴加142mg(0.500mmol)化合物(210a)的二氯甲烷(4.2ml)溶液。搅拌30分钟后,加入350μl三乙胺(底物的5当量)。将所得混合物加热至室温。将水加到该混合物中,然后用二氯甲烷萃取两次。所得有机层用水洗涤两次,用饱和盐水洗涤一次并用硫酸镁干燥,减压蒸除溶剂。所得残余物经硅胶柱(用二氯甲烷∶甲醇=50∶1洗脱)纯化,得到106mg(收率:75%)目的化合物(212)。C13H13F2N3O2 MH+=262
H C N计算值% 4.66 55.52 14.96实测值% 4.68 55.44 14.96结晶熔点: 140-144℃1H-NMR(δ,CDCl3):
1.01(3H,d;J=7.2Hz),2.96-3.03(1H,m),
4.62(1H,d;J=14.0Hz),4.90(1H,d,J=14.0Hz),5.16(1H,s),
6.73-6.81(2H,m),7.37-7.44(1H,m),7.79(1H,s),
7.86(1H,s),9.85(1H,d;J=3.2Hz)实施例156:
将36mg(0.128mmol)化合物(212)悬浮于0.36ml水中,并往该悬浮液中加入17mg(1.2当量)羟胺磺酸,然后于50℃加热1.5小时。再往所得混合物中加入21mg羟胺磺酸,之后再加热40分钟。往该液体反应混合物中加入乙酸乙酯和碳酸氢钠水溶液使液体分层。所得有机层用水和饱和盐水洗涤并用硫酸镁干燥,然后在减压下蒸除溶剂。该残余物经硅胶柱(用二氯甲烷∶甲醇=100∶1洗脱)纯化,得到12mg目的产物(202)。C13H12F2N4O1 MH+=279熔点:181-182℃。1H-NMR(δ,CDCl3):
1.17(3H,d;J=7.2Hz),3.29(1H,q;J=7.2Hz),
4.82(1H,d;J=14.0Hz),4.97(1H,d;J=14.0Hz),
5.44(1H,d;J=0.8Hz),6.74-6.82(2H,m),7.39-7.46(1H,m),
7.83(1H,s),7.84(1H,s).实施例157:
将110mg化合物(206)溶于1.1ml甲醇中,并往该溶液中加入53mg(1.1当量)对甲苯磺酸一水合物,,然后于40℃加热20分钟。将水和乙酸乙酯加到该混合物中进行萃取。所得有机层用饱和盐水洗涤,用硫酸镁干燥,然后在减压下蒸除溶剂。该残余物经硅胶柱纯化得到32mg(收率:58%)油状目的化合物。通过高效液相色谱,利用手性柱测定该化合物的光学纯度。该学光纯度为90.0%ee.。该分析条件如下所述。
柱:Chiral Cell OB(内径:4mm,长度:250mm)
流动相:己烷∶异丙醇=9∶1。
流速:0.5ml/min1H-NMR(δ,CDCl3):
1.18(3H,d;J=6.8Hz),2.50(1H,t;J = 6.0Hz),
3.45-3.54(1H,m),3.72-3.79(1H,m),3.84-3.94(1H,m),
将472mg(2.36mmol)化合物(213)溶于5ml二氯甲烷中,并往该溶液中加入448μl(2.5当量)氯甲基甲基醚,822μl(2当量)二乙基异丙基胺和催化量的4-二甲基氨基吡啶,然后于室温搅拌过夜。将二氯甲烷和水加到该混合物中进行萃取。所得有机层用水和饱和盐水洗涤,并用硫酸镁干燥,然后减压蒸除溶剂。该残余物经硅胶柱(用己烷∶酸乙酯=10∶1洗脱)纯化,得到485mg(收率:84%)油状目的化合物)214)。1H-NMR(δ,CDCl3):
1.22(3H,d;J=6.8Hz),3.29(1H,s),3.85-3.68(2H,m),
3.87-3.94(1H,m),4.56(1H,d;J=8.4Hz),
4.59(1H,d;J=8.4Hz),6.84-6.91(1H,m),6.94-6.99(1H,m),
7.85-7.92(1H,m).实施例159:
按照合成化合物(208)的可供选择的方法,得到油状的、1∶1非对映体混合物的目的化合物(215)。1H-NMR(δ,CDCl3):
0.99(3H,d;J=6.8Hz),<a>,1.20(3H,d;J=6.8Hz)<b>,
2.08-2.22(1H,m)<a+b>,2.78(1H,d;J=5.2Hz)<a+b>,
3.09(1H,d;J=5.2Hz),3.33(1H,s)<a>,3.36(1H,s),<b>,
3.19-3.38(1H,m),<a+b>,3.45-3.54(1H,m)<a+b>,
4.57(2H,s)<a>,4.61(1H,s)<b>,6.75-6.88(2H,m)<a+b>,
将500mg化合物(213)溶于2.5ml二甲基甲酰胺中,并依次往该溶液中加入715mg咪唑和715μl叔丁基二苯基氯甲硅烷,然后于室温搅拌2.5小时。往该反应混合物中加入乙酸乙酯和水使液体分层。所得有机层用水和饱和盐水洗涤并用硫酸镁干燥。该产物经硅胶柱(用己烷∶乙酸乙酯=9∶1洗脱)纯化,得到939mg固化形式的目的化合物(216)。1H-NMR(δ,CDCl3):
0.94(9H,s),1.19(3H,d;J=10.0Hz),3.58(1H,m),
3.75(1H,ddd;J=10.0Hz,5.2Hz,0.8Hz),
3.94(1H,ddd;J=10.0Hz,6.8Hz,1.6Hz),6.82-6.87(1H,m),
6.92-6.98(1H,m),7.29-7.44(6H,m),7.49-7.52(2H,m),
7.57-7.61(2H,m),7.79-7.85(1H,m).实施例161:
于室温和氮气流下,将438mg(1.00mmol)化合物(216)的4.4ml乙醚溶液滴加到3.0ml 1.0M三甲基氯化镁的乙醚溶液中,之后于室温搅拌2.5小时。将氯化铵水溶液加到所得混合物中后,用乙酸乙酯进行萃取。该萃取液用水和饱和盐水洗涤,然后用硫酸镁干燥。与甲苯共沸蒸馏得到524mg固体产物。
将262mg该产物溶于2.5ml二氯甲烷中,并在冰水冷却下往该溶液中滴加69μl三氟化硼-乙醚复合物。搅拌10分钟后,将碳酸氢钠水溶液加到该反应混合物中。然后用二氯甲烷萃取。该萃取液用水和饱和盐水洗涤,并用硫酸镁干燥,然后减压蒸除溶剂。该残余物经硅胶柱(用己烷∶乙酸乙酯=20∶1洗脱)纯化,得到1 74 mg油状目的化合物(217)。1H-NMR(δ,CDCl3):
1.02(9H,s),1.17(3H,d;J=6.8Hz),2.72-2.80(1H,m),
3.50(1H,dd;J=6.4Hz,10.0Hz),
3.64(1H,dd;J=5.2Hz,10.0Hz),5.13(1H,s),5.23(1H,s),
6.71-6.78(2H,m),7.04-7.11(1H,m),7.31-7.43(6H,m),
下面是合成化合物(208)的方法由质子NMP分析的结果发现油状产物(218)的非对映体比例是1∶2。1H-NMR(δ,CDCl3):
0.92(3H,d;J=8.8Hz)<a>,0.97(3H,d;J=8.8Hz)<b>,
1.03(9H,s)<b>,1.06(9H,s)<a>,1.96-2.05(1H,m)<b>,
2.14-2.22(1H,m)<a>,2.78(1H,d;J=5.2Hz),<b>,
2.79(1H,d;J=5.2Hz)<a>,3.08(1H,d;J=5.2Hz)<b>,
3.17(1H,d;J=5.2Hz)<a>,3.45-3.66(2H,m)<a+b>,
6.70-6.82(2H,m)<a+b>,7.30-7.45(6H,m)<a+b>,
在2ml四氢呋喃中溶解72mg(0.16mmol)化合物(216)和3.2μ1(0.18mmol)氯碘甲烷。使所得溶液于氮气流下冷却至-78℃。将0.12ml(0.17mmol)1.5M甲基锂·溴化锂复合物的乙醚溶液滴加到该溶液中。将该所得混合物加热至室温,同时搅拌1小时。往该反应混合物中加入饱和氯化铵水溶液,然后用乙酸乙酯进行萃取。所得有机层用饱和盐水洗涤并干燥,然后减压浓缩,得到86mg油状化合物(218)。由质子NMR分析的结果发现该产物的非对映体比例是1∶1。实施例164:
将化合物(213)(223mg;0.507mmol)溶于5.0ml甲苯中,并往该溶液中加入141mg(0.609mmol)氧化银和84μl(0.710mmol)苄基溴,然后于室温搅拌7天。该反应混合物经硅藻土过滤,所得滤液用乙醚洗涤。将该滤液浓缩,再经硅胶柱色谱(用己烷洗脱,然后用己烷∶乙酸乙酯=12∶1洗脱)纯化,得到66mg(收率:44%)无色油状产物:即化合物(219)。1H-NMR(δ,CDCl3):
1.21(3H,d;J=7.0Hz),3.54(1H,dd;J=8.8Hz,5.5Hz),
3.60-3.70(1H,m),3.82(1H,dd;J=8.8Hz,3.6Hz),
4.47(1H,d;J=11.9Hz),4.54(1H,d;J=11.9Hz),
在2ml无水四氢呋喃中溶解66mg(0.23mmol)化合物(219)和18μl(0.25mmol)氯碘甲烷。将所得溶液冷却至-78℃。往该溶液中滴加0.16ml(0.24mmol)1.5M甲基锂·溴化锂复合物的乙醚溶液。然后将所得混合物加热至室温并搅拌2.5小时。将饱和氯化铵水溶液加到该反应混合物中,然后用乙酸乙酯萃取。所得有机层用饱和盐水洗涤,用无水硫酸镁干燥,然后减压浓缩,得到60mg(收率:86%)油状产物:即化合物(220)。
顺带说一下,该化合物(220)是1∶1的非对映体混合物。1H-NMR(δ,CDCl3):
0.97(3H,d;J=7.2Hz)<a>,1.01(3H,d;J=7.5Hz)<b>,
2.14-2.18(1H,m)<a>,2.20-2.28(1H,m)<b>,
2.77-2.80(2H,m)<a+b>,3.07-3.10(2H,m),<a+b>,
3.24-3.32(2H,m)<a+b>,3.38-3.46(2H,m),<a+b>,
4.40-4.52(4H,m)<a+b>,6.75-6.84(2H,m),<a+b>,
7.26-7.40(12H,m)<a+b>.制备实施例:
将33mlH2O和172ml二硫代磷酸二乙基酯加到33g化合物(202)中,并将该混合物加热回流30分钟。将反应混合物冷却至室温,加入水,然后用乙酸乙酯萃取。所得乙酸乙酯层用水和饱和盐水洗涤并用硫酸镁干燥。蒸除溶剂。将70ml乙醚加到所得残余物中形成晶体。过滤收集如此生成的结晶,得到粗品目的化合物(35g)。将该粗产物(13.9g)溶于乙酸乙酯中,用5%碳酸钠水溶液洗涤该溶液,然后蒸除溶剂。该所得残余物用乙醚和二异丙醚重结晶,得到7.8g目的化合物(221)。MH+=313熔点:132-134℃1H-NMR(δ,CDCl3):
1.11(3H,d;J=7.1Hz),3.71(1H,q;J=7.1Hz),
4.55(1H,d;J=14.3Hz),5.08(1H,d;J=14.3Hz),
6.71-6.80(2H,m),7.42-7.48(1H,m),7.80(1H,brs),
将化合物(221)(15.02g)溶于乙醇(150ml)中,并加入2-溴-4’-甲基硫代苯乙酮(14.97mg),然后加热回流4小时。将该液体反应混合物冷却至0℃,然后用碳酸氢钠水溶液中和,再用乙酸乙酯进行萃取。该萃取液用水洗涤,然后用饱和盐水洗涤并用硫酸镁干燥,蒸除乙酸乙酯。该残余物经硅胶色谱(SiO2,用二氯甲烷洗脱,然后用1%甲醇的二氯甲烷溶液洗脱)纯化,得到目的化合物(222)(10.19g),为固体产物。MH+=4591H-NMR(δ,CDCl3):
1.23(3H,d;J=7.2 Hz),2.54(1H,s),4.05(1H,q;J=7.2Hz),
4.28(1H,d;J=14.4Hz),4.88(1H,d;J=14.4Hz,6.13(H,s),
6.75-6.85(2H,m),7.33(2H,br-d:J=8.4Hz),7.42(1H,s),
7.46-7.54(1H,m),7.66(1H,s),7.82(2H,br-d:J=8.4Hz),
7.92(1H,s).制备实施例10:
往溶于150ml氯仿的化合物(222)(10.19g)的溶液中,加入18.35g间氯过苯甲酸,然后于室温搅拌。待原料消失后,将水加到该液体反应混合物中,再用氯仿萃取。所得有机层用50%饱和碳酸氢钠水溶液洗涤,用水洗涤,然后再用饱和盐水洗涤,并用硫酸镁干燥。减压蒸除溶剂后,该残余物经硅胶柱色谱纯化,得到目的化合物(223)(8.2g),为固体产物。MH+=4911H-NMR(δ,CDCl3):
1.24(3H,d;J=7.2Hz),3.09(3H,s),4.09(1H,q;J=7.2Hz),
4.27(1H,d;J=14.4Hz),4.91(1H,d;J=14.4Hz),5.78(1H,s),
6.78-6.85(2H,m),7.47-7.55(1H,m),7.67(1H,s),
7.69(1H,s),7.87(1H,s),8.02(2H,br-d:J=8.4Hz),
8.10(2H,br-d:J=8.4Hz).实验实施例3:
每组五只的ICR小鼠通过往其尾静脉注射白色假丝酵母MCY8622菌株(2×106cfu/只)而感染。1小时后,给各组的小鼠口服施用本发明的化合物(223),施用剂量为2.5mg或10mg/kg鼠。观察7天来计算每组鼠的平均存活天数。该平均数作为表示体内抗真菌活性的指数。[结果]
下表5显示了该实验结果。
表5
平均存活天数(天)
由该结果明显看出,通过本发明的制备方法用合成中间体制备的化合物表现出显著的抗真菌活性,因此可用于预防和治疗各种真菌感染疾病。
Claims (31)
A为=CH-或=N-,
L和M彼此相同或不同,且各自表示氢原子或卤原子,和
R1意指5元杂环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基;或5元杂环的稠环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基,并且具有可含一个或多个杂原子并可具有一个取代基的芳香环;或其部分或全部被饱和的稠环,该方法包括,当制备该衍生物或其酸加成盐时,将下列通式所示的2-卤化苯乙酮在正烷基锂存在下加到含有5元杂环或稠环或其部分或全部饱和的稠环的化合物中进行反应,然后再将1,2,4-三唑和氢化钠加到所得反应产物中进行反应:其中U表示卤原子,且L和M定义同上。
2.一种制备下列通式所示衍生物或其酸加成盐的方法:其中A为CH-或=N-,
L和M彼此相同或不同且各自表示氢原子或卤原子,和
R1意指5元杂环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基;或5元杂环的稠环,它可含有一个或多个除硫原子外的其它杂原子且具有一个取代基,并且具有可含一个或多个杂原子和一个取代基的芳香环;或其部分或全部被饱和的稠环,该方法包括,当制备衍生物或其酸加成盐时,将其相应的含有氰苯基取代的5元杂环的衍生物与叠氮化钠和盐酸三乙胺进行反应。
4.一种制备下列通式所示衍生物或其酸加成盐的方法:其中A为=CH-或=N-,
L和M彼此相同或不同,且各自表示氢原子或卤原子,和
R1意指5元杂环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基;或5元杂环的稠环,它可含有一个或多个除硫原子之外的其它杂原子且具有一个取代基,并且具有可含一个或多个杂原子和一个取代基的芳香环;或其部分或全部被饱和的稠环,该方法包括,在制备该衍生物或其酸加成盐时,将其相应的含卤代苯基取代的5元杂环衍生物与1,2,4-三唑和氢化钠进行反应。
6.按照权利要求1的制备化合物的方法,其中含5元杂环的化合物是4-(2,4-二氟苯基)噻唑,且2-卤代-苯乙酮为2-氯-2’,4’-二氟苯乙酮。
7.按照权利要求1的制备化合物的方法,其中含5元杂环的稠环的化合物为6-氰基苯并噻唑,且2-卤代-苯乙酮为2-氯-2’,4’-二氟苯乙酮。
8.一种制备1-(2,4-二氟苯基)-1-(6-氨基硫羰基苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇的方法,它包括将硫化氢气体与1-(2,4-二氟苯基)-1-(6-氰基苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇和三乙胺进行反应。
9.一种制备1-(2,4-二氟苯基)-1-(6-(4-甲基噻唑-2-基)-苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇的方法,它包括将碳酸氢钠和溴丙酮与1-(2,4-二氟苯基)-1-(6-氨基硫羰基苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇进行反应。
10.一种制备1-(2,4-二氟苯基)-1-6-(噻唑-1-基)-苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇的方法,它包括将1-(2,4-二氟苯基)-1-(6-氨基硫羰基苯并噻唑-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇与溴乙醛缩二甲醇进行反应。
11.一种制备1-(2,4-二氟苯基)-1-(4-(4-氨基甲酰基噻唑-2-基)-噻吩-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇的方法,它包括将1-(2,4-二氟苯基)-1-(4-氨基硫羰基噻吩-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇与α-溴乙基丙酮酸反应形成1-(2,4-二氟苯基)-1-(4-(4-乙氧羰基噻唑-2-基)-噻吩-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇,然后再将此化合物与氨进行反应。
12.一种制备1-(2,4-二氟苯基)-1-(4-(4-氰基噻唑-2-基)-噻吩-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇的方法,它包括将1-(2,4-二氟苯基)-1-(4-(4-氨基甲酰基噻唑-2-基)-噻吩-2-基)-2-(1H-1,2,4-三唑-1-基)乙醇与磷酰氯进行反应。
20.一种制备下列通式所示化合物或其盐的方法:其中R为低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,且Pr为羟基保护基,该方法包括将下列通式所示化合物在碱存在下与过氧酸进行反应:其中R、两个X和Pr定义同上,R2为低级烷基,且R3表示甲基或低级烷氧基。
22.一种制备下列通式所示化合物或其盐的方法:其中R意指低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,Pr为羟基保护基,且L为离去基团,该方法包括将下列通式所示化合物卤化,烷基磺化或芳基磺化:其中R、两个X和Pr定义同上。
23.一种制备下列通式所示化合物或其盐的方法:其中R为低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,且Pr为羟基保护基,且A为CH或氮原子,该方法包括将下列通式所示化合物与1,2,4-三唑或咪唑或其盐进行反应:其中R、两个X和Pr定义同上,且L表示离去基团。
24.一种制备下列通式所示化合物或其盐的方法:其中R为低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,且A为CH或氮原子,该方法包括解封下列通式所示化合物中的羟基保护基Pr:
其中R、两个X和A定义同上,且Pr为羟基保护基。
27.下列通式所示化合物或其盐:其中R为低级烷基,Pr表示羟基保护基,且L为离去基团。
29.下列通式所示化合物或其盐:其中R为低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,且Pr表示羟基保护基。
31.下列通式所示化合物或其盐:其中R为低级烷基,两个X彼此相同或不同且各自表示氢或卤原子,Pr表示羟基保护基,且A为CH或氮原子。
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- 1995-02-03 AU AU11556/95A patent/AU696640B2/en not_active Ceased
- 1995-02-03 EP EP95101489A patent/EP0667346A3/en not_active Ceased
- 1995-02-03 EP EP02003137A patent/EP1231210A3/en not_active Withdrawn
- 1995-02-03 EP EP03027431A patent/EP1394162A1/en not_active Withdrawn
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- 1995-02-06 NO NO19950425A patent/NO304430B1/no not_active IP Right Cessation
- 1995-02-06 CN CNA031451500A patent/CN1478778A/zh active Pending
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