CN106831609A - 一种6‑磺酸酯基嘧啶水杨酸类化合物及其制备方法和应用 - Google Patents
一种6‑磺酸酯基嘧啶水杨酸类化合物及其制备方法和应用 Download PDFInfo
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- CN106831609A CN106831609A CN201710003882.0A CN201710003882A CN106831609A CN 106831609 A CN106831609 A CN 106831609A CN 201710003882 A CN201710003882 A CN 201710003882A CN 106831609 A CN106831609 A CN 106831609A
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- phenyl
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- salicylic acid
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- -1 sulfonate group pyrimidine salicylic acid compounds Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 241000196324 Embryophyta Species 0.000 claims abstract description 46
- 108010000700 Acetolactate synthase Proteins 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 24
- 230000035772 mutation Effects 0.000 claims abstract description 23
- 239000003112 inhibitor Substances 0.000 claims abstract description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910005948 SO2Cl Inorganic materials 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 49
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 239000000460 chlorine Substances 0.000 claims description 16
- 238000006467 substitution reaction Methods 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 102000004190 Enzymes Human genes 0.000 claims description 10
- 108090000790 Enzymes Proteins 0.000 claims description 10
- 102220064956 rs200108320 Human genes 0.000 claims description 9
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 8
- 230000003197 catalytic effect Effects 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 4
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 4
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 3
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 3
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 3
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 3
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 claims description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 3
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 3
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 claims description 3
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 claims description 3
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 claims description 3
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 claims description 3
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 claims description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 3
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 3
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 claims description 3
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 claims description 3
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 3
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 claims description 3
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 3
- 229940126657 Compound 17 Drugs 0.000 claims description 3
- 229940126639 Compound 33 Drugs 0.000 claims description 3
- 229940127007 Compound 39 Drugs 0.000 claims description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 3
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 claims description 3
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- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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Abstract
本发明涉及除草剂领域,公开了一种6‑磺酸酯基嘧啶水杨酸类化合物及其制备方法和应用,该化合物具有式(1)所示的结构,制备6‑磺酸酯基嘧啶水杨酸类化合物的方法包括:(1)将式(2)所示结构的化合物与R2SO2Cl进行第一接触反应,得到式(3)所示的化合物;(2)将所述式(3)所示的化合物与三氟乙酸进行第二接触反应。本发明提供的6‑磺酸酯基嘧啶水杨酸类化合物对乙酰羟酸合成酶具有良好的抑制作用,同时针对乙酰羟酸合成酶抑制剂类除草剂产生抗性的杂草具有显著的反抗性抑制作用。从而能够防治乙酰羟酸合成酶突变导致的杂草抗性植株。
Description
技术领域
本发明涉及除草剂领域,具体地,涉及一种6-磺酸酯基嘧啶水杨酸类化合物及其制备方法和应用。
背景技术
乙酰羟酸合成酶(AHAS,Acetohydroxyacid Synthase)抑制类除草剂是通过抑制植物体内乙酰羟酸合成酶的活性以阻断关键支链氨基酸(缬氨酸、亮氨酸以及异亮氨酸)的合成,造成杂草的死亡,达到防治杂草的目的。
乙酰羟酸合成酶抑制类除草剂一直以低毒、高效、广谱等特性在农药市场中占据重要的地位。然而,由于在田间长期的不合理施用,且作用位点单一,该类抑制剂正面临着极为严重的杂草抗性问题,极大地限制了其未来的发展。因此,如何有效缓解其严重的抗药性问题成为了研究的热点。
全球范围内,已有61个国家和地区报道了杂草对除草剂产生抗性的实例。其中,美国报道的抗性杂草数目达到了144种,紧随之后的是澳大利亚(62种)和加拿大(59种)。中国地区的抗性杂草实例在近20年来也被广泛报道,位列全球第五位(35种)。
乙酰羟酸合成酶抑制剂产生杂草抗性的主要原因是由于其作用位点的关键氨基酸残基发生单点突变。至今,有7个抗性突变位点在田间杂草中得到了证实,分别是Ala122、Pro197、Ala205、Asp376、Trp574、Ser653、Gly654(以拟南芥AHAS催化亚基的序列进行编号)。其中,Pro197位点的突变现象最为常见,突变类型最为广泛,一共涉及8种突变类型(P197A、P197T、P197S、P197R、P197Q、P197L、P197H和P197I)。在144种对乙酰羟酸合成酶抑制剂类除草剂具有抗性的杂草中,有70种抗性杂草属于P197突变型,占所有AHAS抗性杂草种群的一半,并且所产生的杂草抗性问题几乎涵盖了所有类型AHAS抑制剂。因此,基于该位点突变设计具有反抗性的抑制剂具有显著的现实意义。
发明内容
本发明的目的是:针对杂草对现有技术提供的乙酰羟酸合成酶抑制剂类除草剂产生抗性的缺陷,在保证对乙酰羟酸合成酶具有良好的抑制作用的前提下,提供一种针对乙酰羟酸合成酶抑制剂类除草剂产生抗性的杂草的反抗性抑制剂。
为了实现上述目的,第一方面,本发明提供一种6-磺酸酯基嘧啶水杨酸类化合物,该化合物具有式(1)所示的结构,
其中,R1选自H、C1-6的烷基、硝基和卤素中的至少一种;
R2选自取代或未取代的C1-10的烷基,取代或未取代的C6-20的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5~7元饱和或不饱和杂环,且其中的取代基选自卤素、C1-4的烷基、C1-4的烷氧基、硝基、三氟甲基和苯基中的至少一种;
R3和R4各自独立地为H、C1-3的烷基和卤素中的至少一种。
第二方面,本发明提供一种制备6-磺酸酯基嘧啶水杨酸类化合物的方法,该化合物具有式(1)所示的结构,该方法包括:
(1)将式(2)所示结构的化合物与R2SO2Cl进行第一接触反应,得到式(3)所示的化合物;
(2)将所述式(3)所示的化合物与三氟乙酸进行第二接触反应;
其中,R1、R2、R3和R4如本发明前述第一方面中所定义。
第三方面,本发明提供前述第一方面所述的6-磺酸酯基嘧啶水杨酸类化合物和/或前述第二方面所述的方法制备得到的6-磺酸酯基嘧啶水杨酸类化合物作为乙酰羟酸合成酶抑制剂的应用。
第四方面,本发明提供前述第一方面所述的6-磺酸酯基嘧啶水杨酸类化合物和/或前述第二方面所述的方法制备得到的6-磺酸酯基嘧啶水杨酸类化合物在防治由乙酰羟酸合成酶突变导致的杂草抗性植株中的应用。
本发明基于嘧啶水杨酸骨架结构作为药效团,得到了一类对Pro197Leu具有反抗性的含磺酸酯基嘧啶水杨酸的结构,并通过对其进一步的功能化修饰合成了一系列新型6-磺酸酯基嘧啶水杨酸类化合物。
本发明的所述6-磺酸酯基嘧啶水杨酸类化合物是兼备高抑制活性以及反抗性(抗性倍数(resistant factor)RF<1.00)的乙酰羟酸合成酶抑制剂,且对敏感型以及抗性杂草同时具有优异的防效。
具体地,本发明提供的6-磺酸酯基嘧啶水杨酸类化合物对乙酰羟酸合成酶具有良好的抑制作用,同时针对乙酰羟酸合成酶抑制剂类除草剂产生抗性的杂草具有显著的反抗性抑制作用。从而能够防治乙酰羟酸合成酶突变导致的杂草抗性植株。
本发明的其它特征和优点将在随后的具体实施方式部分予以详细说明。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是,此处所描述的具体实施方式仅用于说明和解释本发明,并不用于限制本发明。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
第一方面,本发明提供了一种6-磺酸酯基嘧啶水杨酸类化合物,该化合物具有式(1)所示的结构,
其中,R1选自H、C1-6的烷基、硝基和卤素中的至少一种;
R2选自取代或未取代的C1-10的烷基,取代或未取代的C6-20的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5~7元饱和或不饱和杂环,且其中的取代基选自卤素、C1-4的烷基、C1-4的烷氧基、硝基、三氟甲基和苯基中的至少一种;
R3和R4各自独立地为H、C1-3的烷基和卤素中的至少一种。
在R1中,所述“C1-6的烷基”表示,R1的碳原子总数为1-6。
所述“卤素”包括氟元素、氯元素、溴元素和碘元素。
在R2中,所述“取代或未取代的C1-10的烷基”表示,R2的碳原子总数为1-10。
在R2中,所述“取代或未取代的C6-20的芳基”表示,R2的碳原子总数为6-20,且至少还含有芳基,所述芳基包括苯基、萘基等。
在R2中,所述“取代或未取代的含有N、O和S中的至少一种杂原子的5~7元饱和或不饱和杂环”表示,R2为5~7元饱和或不饱和杂环,且其中的杂原子选自N、O和S中的至少一种,并且所述饱和或不饱和杂环可以为取代或未取代的。
在所述“取代或未取代”的定义中,若为取代的,则其中的取代基选自卤素、C1-4的烷基、C1-4的烷氧基、硝基、三氟甲基和苯基中的至少一种,并且,所述“C1-4的烷基”和“C1-4的烷氧基”表示其中的取代基的碳原子总数为1-4。
优选情况下,在式(1)中,R1选自H、C1-4的烷基和卤素中的至少一种;更优选地,R1选自H、甲基、乙基、正丙基、异丙基、正丁基、氟元素、氯元素、溴元素和碘元素中的至少一种;进一步优选地,R1选自H、甲基、乙基、异丙基、氟元素、氯元素和溴元素中的至少一种;特别优选地,R1选自H、甲基、乙基、氟元素、氯元素和溴元素中的至少一种。
优选情况下,在式(1)中,R2选自取代或未取代的C1-9的烷基,取代或未取代的C6-16的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5~6元饱和或不饱和杂环,且其中的取代基选自卤素、C1-4的烷基、C1-4的烷氧基、硝基、三氟甲基和苯基中的至少一种;更优选地,R2选自取代或未取代的C1-8的烷基,取代或未取代的C6-12的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5~6元不饱和杂环,且其中的取代基选自卤素、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基、硝基、三氟甲基和苯基中的至少一种;进一步优选地,R2选自取代或未取代的C1-7的烷基,取代或未取代的C6-10的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5元不饱和杂环,且其中的取代基选自氟元素、氯元素、溴元素、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、硝基、三氟甲基和苯基中的至少一种。
优选情况下,在式(1)中,R3和R4各自独立地为H、甲基、乙基、异丙基、氟、氯和溴中的至少一种;特别优选地,R3和R4各自独立地为H和/或甲基。
以下提供几种优选的具体实施方式说明本发明的6-磺酸酯基嘧啶水杨酸类化合物:
具体实施方式1:
在式(1)中,R1选自H、C1-4的烷基和卤素中的至少一种;
R2选自取代或未取代的C1-9的烷基,取代或未取代的C6-16的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5~6元饱和或不饱和杂环,且其中的取代基选自卤素、C1-4的烷基、C1-4的烷氧基、硝基、三氟甲基和苯基中的至少一种;
R3和R4各自独立地为H、甲基、乙基、异丙基、氟、氯和溴中的至少一种。
具体实施方式2:
在式(1)中,R1选自H、甲基、乙基、正丙基、异丙基、正丁基、氟元素、氯元素、溴元素和碘元素中的至少一种;
R2选自取代或未取代的C1-8的烷基,取代或未取代的C6-12的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5~6元不饱和杂环,且其中的取代基选自卤素、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基、硝基、三氟甲基和苯基中的至少一种;
R3和R4各自独立地为H、甲基、乙基、氯和溴中的至少一种。
具体实施方式3:
在式(1)中,R1选自H、C1-4的烷基和卤素中的至少一种;
R2选自取代或未取代的C1-7的烷基,取代或未取代的C6-16的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5~6元饱和或不饱和杂环,且其中的取代基选自卤素、C1-4的烷基、C1-4的烷氧基、硝基、三氟甲基和苯基中的至少一种;
R3和R4各自独立地为H、甲基、氯和溴中的至少一种。
具体实施方式4:
在式(1)中,R1选自H、甲基、乙基、异丙基、氟元素、氯元素和溴元素中的至少一种;特别优选地,R1选自H、甲基、乙基、氟元素、氯元素和溴元素中的至少一种;
在式(1)中,R2选自取代或未取代的C1-7的烷基,取代或未取代的C6-10的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5元不饱和杂环,且其中的取代基选自氟元素、氯元素、溴元素、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、硝基、三氟甲基和苯基中的至少一种;
R3和R4各自独立地为H和/或甲基。
具体实施方式5:
本发明的6-磺酸酯基嘧啶水杨酸类化合物选自以下化合物中的至少一种:在式(1)中,
化合物1:R1为H,R2为苯基,R3和R4均为H;
化合物2:R1为H,R2为4-F-苯基,R3和R4均为H;
化合物3:R1为H,R2为4-Cl-苯基,R3和R4均为H;
化合物4:R1为H,R2为4-Br-苯基,R3和R4均为H;
化合物5:R1为H,R2为3-F-苯基,R3和R4均为H;
化合物6:R1为H,R2为3-Cl-苯基,R3和R4均为H;
化合物7:R1为H,R2为3-Br-苯基,R3和R4均为H;
化合物8:R1为H,R2为2-F-苯基,R3和R4均为H;
化合物9:R1为H,R2为2-Cl-苯基,R3和R4均为H;
化合物10:R1为H,R2为2-Br-苯基,R3和R4均为H;
化合物11:R1为H,R2为4-CH3-苯基,R3和R4均为H;
化合物12:R1为H,R2为3-CH3-苯基,R3和R4均为H;
化合物13:R1为H,R2为2-CH3-苯基,R3和R4均为H;
化合物14:R1为H,R2为4-NO3-苯基,R3和R4均为H;
化合物15:R1为H,R2为3-NO3-苯基,R3和R4均为H;
化合物16:R1为H,R2为2-NO3-苯基,R3和R4均为H;
化合物17:R1为H,R2为4-OCH3-苯基,R3和R4均为H;
化合物18:R1为H,R2为4-叔丁基-苯基,R3和R4均为H;
化合物19:R1为CH3,R2为苯基,R3和R4均为H;
化合物20:R1为CH3,R2为4-F-苯基,R3和R4均为H;
化合物21:R1为CH3,R2为4-Cl-苯基,R3和R4均为H;
化合物22:R1为CH3,R2为3-F-苯基,R3和R4均为H;
化合物23:R1为CH3,R2为3-Cl-苯基,R3和R4均为H;
化合物24:R1为CH3,R2为2-F-苯基,R3和R4均为H;
化合物25:R1为CH3,R2为2-Cl-苯基,R3和R4均为H;
化合物26:R1为H,R2为3,5-二氟-苯基,R3和R4均为H;
化合物27:R1为H,R2为2,4-二氟-苯基,R3和R4均为H;
化合物28:R1为H,R2为3,4-二氟-苯基,R3和R4均为H;
化合物29:R1为H,R2为3,4-二氯-苯基,R3和R4均为H;
化合物30:R1为H,R2为2,4-二氯-苯基,R3和R4均为H;
化合物31:R1为H,R2为4-氟-2-溴-苯基,R3和R4均为H;
化合物32:R1为H,R2为4-氟-3-氯-苯基,R3和R4均为H;
化合物33:R1为H,R2为4-氯-2-硝基-苯基,R3和R4均为H;
化合物34:R1为H,R2为2-氟-4-溴-苯基,R3和R4均为H;
化合物35:R1为H,R2为2-氟-4-甲基-苯基,R3和R4均为H;
化合物36:R1为H,R2为2-氟-4-氯-苯基,R3和R4均为H;
化合物37:R1为H,R2为2-溴-4-三氟甲基-苯基,R3和R4均为H;
化合物38:R1为H,R2为2-溴-5-三氟甲基-苯基,R3和R4均为H;
化合物39:R1为H,R2为2-硝基-4-三氟甲基-苯基,R3和R4均为H;
化合物40:R1为H,R2为2,4,6-三甲基-苯基,R3和R4均为H;
化合物41:R1为CH3,R2为3,4-二氟-苯基,R3和R4均为H;
化合物42:R1为CH3,R2为2,4-二氟-苯基,R3和R4均为H;
化合物43:R1为CH3,R2为2-氟-4-氯-苯基,R3和R4均为H;
化合物44:R1为CH3,R2为4-氟-3-氯-苯基,R3和R4均为H;
化合物45:R1为H,R2为R3和R4均为H;
化合物46:R1为H,R2为R3和R4均为H;
化合物47:R1为H,R2为R3和R4均为H;
化合物48:R1为H,R2为R3和R4均为H;
化合物49:R1为CH3,R2为R3和R4均为H;
化合物50:R1为CH3,R2为R3和R4均为H;
化合物51:R1为CH3,R2为R3和R4均为H;
化合物52:R1为H,R2为乙基,R3和R4均为H;
化合物53:R1为H,R2为环丙基,R3和R4均为H。
第二方面,本发明提供了一种制备6-磺酸酯基嘧啶水杨酸类化合物的方法,该化合物具有式(1)所示的结构,该方法包括:
(1)将式(2)所示结构的化合物与R2SO2Cl进行第一接触反应,得到式(3)所示的化合物;
(2)将所述式(3)所示的化合物与三氟乙酸进行第二接触反应;
其中,R1、R2、R3和R4如本发明前述第一方面中所定义。
在本发明的第二方面中,针对式(1)、式(2)和式(3)中的R1、R2、R3和R4基团的定义与本发明的第一方面中的相关定义完全相同,本发明在此不再赘述,本领域技术人员不应理解为对本发明的保护范围的限制。
优选地,所述第一接触反应在氢化钠存在下进行,所述第一接触反应的条件包括:温度为-10℃至45℃,时间为10~100min。
根据一种优选的具体实施方式,将式(2)所示结构的化合物与R2SO2Cl进行第一接触反应的步骤包括:在温度为-10℃至10℃下,将式(2)所示结构的化合物与氢化钠接触5-60min;然后在温度为5℃至45℃下,将所得混合物与R2SO2Cl进行第一接触反应。
在本发明中,所述第一接触反应可以在选自例如四氢呋喃、二氯甲烷、氯仿、甲苯、苯、对二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,4-二氧六环等溶剂存在下进行。
优选情况下,在步骤(1)中,在第一接触反应结束后,将所得混合物与饱和碳酸氢钠水溶液接触,然后采用例如乙酸乙酯进行萃取,干燥有机相后进行浓缩处理以得到式(3)所示的化合物。
优选地,所述第二接触反应的条件包括:温度为5℃至45℃,时间为30~400min。
在本发明中,所述第二接触反应可以在选自例如二氯甲烷、氯仿、甲苯、苯、对二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,4-二氧六环、四氢呋喃等溶剂存在下进行。
在本发明中,为了获得纯度更高的6-磺酸酯基嘧啶水杨酸类化合物,优选在所述步骤(2)之后,将获得的粗产物通过柱层析或重结晶等方法进行纯化处理。
在本发明的所述方法中,对其中的原料用量比例没有特别的限制,本领域技术人员根据目标产物的结构结合本领域的常规技术手段能够容易地获得合理的原料用量比例关系。本发明的制备例中示例性地给出了几种用量比例,本领域技术人员不应理解为对本发明的限制。
在本发明中,对所述式(2)所示结构的化合物的来源没有特别的限制,可以采用现有技术中的合成方法制备得到,也可以通过商购获得。本发明为了节约成本在制备例中示例性地提供了一种制备式(2)所示结构的化合物的方法,本领域技术人员不应理解为对本发明的限制。
优选地,本发明还提供了由前述第二方面所述的方法制备得到的6-磺酸酯基嘧啶水杨酸类化合物。
第三方面,本发明提供了前述第一方面所述的6-磺酸酯基嘧啶水杨酸类化合物和/或前述第二方面所述的方法制备得到的6-磺酸酯基嘧啶水杨酸类化合物作为乙酰羟酸合成酶抑制剂的应用。
第四方面,本发明提供了前述第一方面所述的6-磺酸酯基嘧啶水杨酸类化合物和/或前述第二方面所述的方法制备得到的6-磺酸酯基嘧啶水杨酸类化合物在防治由乙酰羟酸合成酶突变导致的杂草抗性植株中的应用。
优选地,所述由乙酰羟酸合成酶突变导致的杂草抗性植株中的抗性突变位点包括Ala122、Pro197、Ala205、Asp376、Trp574、Ser653和Gly654中的至少一种。特别地,前述抗性突变位点是以拟南芥AHAS催化亚基的序列进行编号的。其中,Ala表示丙氨酸;Pro表示脯氨酸;Asp表示天冬氨酸;Trp表示色氨酸;Ser表示丝氨酸;以及Gly表示甘氨酸。
优选地,所述由乙酰羟酸合成酶突变导致的杂草抗性植株中的抗性突变位点为Pro197。进一步优选地,所述由乙酰羟酸合成酶突变导致的杂草抗性植株的突变类型包括P197A、P197T、P197S、P197R、P197Q、P197L、P197H和P197I中的至少一种。
所述6-磺酸酯基嘧啶水杨酸类化合物既可以单独作为乙酰羟酸合成酶抑制剂或者防治由乙酰羟酸合成酶突变导致的杂草抗性植株,也可以与其它药剂进行复配使用。
本发明提供的6-磺酸酯基嘧啶水杨酸类化合物对乙酰羟酸合成酶具有良好的抑制作用,同时针对乙酰羟酸合成酶抑制剂类除草剂产生抗性的杂草具有显著的反抗性抑制作用。从而能够防治乙酰羟酸合成酶突变导致的杂草抗性植株。
以下将通过实例对本发明进行详细描述。以下实例中,在没有特别说明的情况下,使用的各种原料均来自商购,级别为分析纯。
制备例
(1)制备中间体2-2
将原料2-1(100mmol)溶于250mL的丙三醇中,向体系中通入CO2气体,100℃下反应24h。反应完全后将体系倾倒入1M稀盐酸溶液中,大量固体析出,抽滤,烘干,得中间体2-2。
具体地,以R1、R3和R4均为H时为例,所得中间体2-2的收率为89%;以R1为CH3,R3和R4均为H时为例,所得中间体2-2的收率为70%。
(2)制备中间体2-3
在氮气保护下控温于-10℃,500mL三颈瓶中将50mmol中间体2-2、二甲基氨基吡啶(DMAP,1mmol)溶于80mL干燥的乙二醇二甲醚中,缓慢加入丙酮(60mmol),恒温搅拌10min,将二氯亚砜(60mmol)以及30mL乙二醇二甲醚混合溶液缓慢滴加入体系,1h内滴加完毕,升至25℃后反应48h。反应完毕后,将体系倾倒入饱和碳酸氢钠水溶液中,待气泡释放完毕后,用乙酸乙酯萃取,干燥有机相,拌样,柱层析得白色固体2-3。
具体地,以R1、R3和R4均为H时为例,所得中间体2-3的收率为96%;以R1为CH3,R3和R4均为H时为例,所得中间体2-3的收率为55%。
(3)制备中间体2-5
在250mL的反应瓶中将中间体2-3(30mmol),无水碳酸钾(60mmol)溶于50mL的N,N-二甲基甲酰胺中,25℃搅拌1h,将式2-4所示的化合物(共30mmol)平均分3次加入反应体系,升温至100℃,TLC跟踪至原料反应完全,停止反应,待反应体系冷却至25℃时倾倒入冰水中,大量白色固体析出,抽滤得白色粉末中间体2-5。
具体地,以R1、R3和R4均为H时为例,所得中间体2-5的收率为90%;以R1为CH3,R3和R4均为H时为例,所得中间体2-5的收率为87%。
(4)制备式(2)所示的化合物
控温于0℃,250mL的反应瓶中将式2-6所示的化合物(45mmol)溶于50mL的四氢呋喃中,平均分3次加入氢化钠(共45mmol),恒温反应30min,加入中间体2-5(30mmol),反应体系颜色逐渐变深,TLC跟踪至原料反应完全,加冰水淬灭反应,用乙酸乙酯萃取,干燥有机相,拌样,柱层析得无色油状物,即为式(2)所示的化合物。
具体地,以R1、R3和R4均为H时为例,所得式(2)所示的化合物的收率为80%;以R1为CH3,R3和R4均为H时为例,所得式(2)所示的化合物的收率为83%。
实施例
控温于0℃,50mL反应瓶中将式(2)所示的化合物(1mmol)溶于10mL的四氢呋喃中,加入氢化钠(1.5mmol),恒温反应30min,随后将R2SO2Cl(1mmol)缓慢滴加入体系,升温至25℃,TLC跟踪至原料反应完全,加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取,干燥有机相,减压蒸馏除去溶剂,得黄色油状物,即为式(3)所示的化合物,直接投入下一步反应中。
将式(3)所示的化合物溶于10mL的二氯甲烷中,缓慢加入三氟乙酸(TFA,5mmol),25℃反应,反应体系颜色逐渐变深,TLC跟踪至原料反应完全,减压蒸馏除去反应溶剂,拌样,柱层析,得到式(1)所示的6-磺酸酯基嘧啶水杨酸类化合物。
分别以表1中所示的R1和R2为例,且表1中的化合物中R3和R4均为H,说明本发明所得化合物的收率。
表1
以下提供表1中所示化合物的结构表征:
化合物1:m.p.135-136℃.1H NMR(600MHz,DMSO-d6)δ13.31(s,1H),7.88(d,J=7.8Hz,2H),7.84(dd,J=7.2,7.2Hz,1H),7.68(dd,J=7.8,7.8Hz,2H),7.54(dd,J=8.4,8.4Hz,1H),7.32(d,J=8.4Hz,1H),7.06(d,J=8.4Hz,1H),5.99(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H16N2O8S[M+Na]+455.0520.实测值455.0515.
化合物2:m.p.151-152℃.1H NMR(600MHz,DMSO-d6)δ13.31(s,1H),7.93(dd,J=9.0,4.8Hz,2H),7.57(dd,J=8.4,8.4Hz,1H),7.52(dd,J=9.0,9.0Hz,2H),7.33(d,J=8.4Hz,1H),7.12(d,J=8.4Hz,1H),5.99(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H15FN2O8S[M+Na]+473.0425.实测值473.0433.
化合物3:m.p.151-152℃.1H NMR(600MHz,DMSO-d6)δ13.33(s,1H),7.86(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,2H),7.58(dd,J=8.4,8.4Hz,1H),7.34(d,J=8.4Hz,1H),7.13(d,J=8.4Hz,1H),5.99(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H15ClN2O8S[M+H]+467.0310.实测值467.0303.
化合物4:m.p.153-154℃.1H NMR(600MHz,DMSO-d6)δ13.31(s,1H),7.89(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.57(dd,J=8.4,8.4Hz,1H),7.34(d,J=8.4Hz,1H),7.12(d,J=8.4Hz,1H),5.99(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H15BrN2O8S[M+H]+510.9805.实测值510.9803.
化合物5:m.p.136-137℃.1H NMR(600MHz,DMSO-d6)δ13.38(s,1H),7.85–7.64(m,4H),7.58(dd,J=7.8,7.8Hz,1H),7.35(d,J=7.8Hz,1H),7.14(d,J=7.8Hz,1H),6.00(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H15FN2O8S[M+H]+451.0606.实测值451.0605.
化合物6:m.p.114-115℃.1H NMR(600MHz,DMSO-d6)δ13.39(s,1H),7.93(d,J=6.0Hz,1H),7.90–7.81(m,2H),7.71(s,1H),7.57(dd,J=8.4,8.4Hz,1H),7.36(d,J=6.6Hz,1H),7.14(d,J=7.2Hz,1H),6.00(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H15ClN2O8S[M+H]+467.0310.实测值467.0311.
化合物7:m.p.91-92℃.1H NMR(600MHz,DMSO-d6)δ13.38(s,1H),8.06(d,J=7.8Hz,1H),7.98(s,1H),7.88(d,J=7.8Hz,1H),7.63(dd,J=8.4,8.4Hz,1H),7.58(dd,J=8.4,8.4Hz,1H),7.35(d,J=8.4Hz,1H),7.13(d,J=8.4Hz,1H),5.99(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H15BrN2O8S[M+H]+510.9805.实测值510.9804.
化合物8:m.p.139-140℃.1H NMR(600MHz,DMSO-d6)δ13.35(s,1H),7.91(d,J=4.8Hz,1H),7.81(t,J=7.2,7.2Hz,1H),7.65–7.50(m,2H),7.44(dd,J=7.8,7.8Hz,1H),7.34(d,J=8.4Hz,1H),7.07(d,J=8.4Hz,1H),5.99(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H15FN2O8S[M+Na]+473.0425.实测值473.0412.
化合物9:m.p.146-147℃.1H NMR(600MHz,DMSO-d6)δ13.38(s,1H),7.96(d,J=7.8Hz,1H),7.89–7.82(m,2H),,7.60(dd,J=7.2,7.2Hz,1H),7.51(dd,J=8.4,8.4Hz,1H),7.33(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),6.00(s,1H),3.75(s,6H).HRMS(MALDI):计算值C19H15ClN2O8S[M+H]+467.0310.实测值467.0308.
化合物10:m.p.134-136℃.1H NMR(600MHz,DMSO-d6)δ13.37(s,1H),8.05(d,J=7.8Hz,1H),7.96(d,J=7.8Hz,1H),7.74(dd,J=7.8,7.8Hz,1H),7.64(dd,J=7.8,7.8Hz,1H),7.50(dd,J=8.4,8.4Hz,1H),7.33(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),6.00(s,1H),3.76(s,6H).HRMS(MALDI):计算值C19H15BrN2O8S[M+H]+510.9805.实测值510.9801.
化合物11:m.p.155-156℃.1H NMR(600MHz,DMSO-d6)δ13.30(s,1H),7.76(d,J=8.2Hz,2H),7.54(dd,J=8.4,8.4Hz,1H),7.48(d,J=8.1Hz,2H),7.31(d,J=8.2Hz,1H),7.04(d,J=8.3Hz,1H),5.99(s,1H),3.74(s,6H),2.43(s,3H).HRMS(MALDI):计算值C20H18N2O8S[M+H]+447.0857.实测值447.0853.
化合物12:m.p.116-117℃.1H NMR(600MHz,DMSO-d6)δ13.29(s,1H),7.71(s,1H),7.68–7.62(m,2H),7.60–7.51(m,2H),7.32(d,J=6.6Hz,1H),7.06(d,J=7.2Hz,1H),3.74(s,6H),2.40(s,3H).HRMS(MALDI):计算值C20H18N2O8S[M+Na]+469.0676.实测值469.0681.
化合物13:m.p.141-142℃.1H NMR(600MHz,DMSO-d6)δ13.31(s,1H),7.80(d,J=7.8Hz,1H),7.71(dd,J=7.8,7.8Hz,1H),7.57(d,J=7.8Hz,1H),7.49(dd,J=8.4,8.4Hz,1H),7.44(dd,J=7.8,7.8Hz,1H),7.30(d,J=8.2Hz,1H),6.91(d,J=8.3Hz,1H),5.99(s,1H),3.74(s,6H),2.66(s,3H).HRMS(MALDI):计算值C20H18N2O8S[M+H]+447.0857.实测值447.0856.
化合物14:m.p.141-142℃.1H NMR(600MHz,DMSO-d6)δ13.30(s,1H),8.46(d,J=7.2Hz,2H),8.13(d,J=3.6Hz,2H),7.60(dd,J=7.8,7.8Hz,1H),7.37(d,J=5.6Hz,1H),7.15(d,J=5.6Hz,1H),5.99(s,1H),3.75(s,6H).HRMS(MALDI):计算值C19H15N3O10S[M+H]+478.0551.实测值478.0551.
化合物15:m.p.144-145℃.1H NMR(600MHz,DMSO-d6)δ13.30(s,1H),8.66(d,J=7.2Hz,1H),8.48(s,1H),8.25(d,J=6.6Hz,1H),7.95(dd,J=7.8,7.8Hz,1H),7.60(dd,J=7.8,7.8Hz,1H),7.37(d,J=7.8Hz,1H),7.22(d,J=7.8Hz,1H),5.98(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H15N3O10S[M+H]+478.0551.实测值478.0551.
化合物16:m.p.137-138℃.1H NMR(600MHz,DMSO-d6)δ13.40(s,1H),8.22(d,J=7.2Hz,1H),8.09(d,J=7.2Hz,1H),8.02(d,J=7.2Hz,1H),7.93(d,J=6.0Hz,1H),7.57(dd,J=7.8,7.8Hz,1H),7.39(d,J=7.2Hz,1H),7.04(d,J=7.2Hz,1H),6.00(s,1H),3.76(s,6H).HRMS(MALDI):计算值C19H15N3O10S[M+H]+478.0551.实测值478.0551.
化合物17:m.p.134-135℃.1H NMR(600MHz,DMSO-d6)δ13.25(s,1H),7.78(d,J=9.0Hz,2H),7.54(dd,J=8.4,8.4Hz,1H),7.31(d,J=8.4Hz,1H),7.17(d,J=9.0Hz,2H),7.06(d,J=8.4Hz,1H),5.99(s,1H),3.87(s,3H),3.74(s,6H).HRMS(MALDI):计算值C20H18N2O9S[M+Na]+485.0625.实测值485.06121.
化合物18:m.p.135-136℃.1H NMR(600MHz,DMSO-d6)δ13.25(s,1H),7.80(d,J=8.4Hz,2H),7.69(d,J=8.4Hz,2H),7.55(dd,J=8.4,8.4Hz,1H),7.32(d,J=8.4Hz,1H),7.09(d,J=8.4Hz,1H),5.99(s,1H),3.75(s,6H),1.30(s,9H).HRMS(MALDI):计算值C23H24N2O8S[M+H]+489.1326.实测值489.1324.
化合物19:m.p.157-158℃.1H NMR(600MHz,DMSO-d6)δ13.11(s,1H),7.87(d,J=7.8Hz,1H),7.84(dd,J=7.2,7.2Hz,1H),7.68(dd,J=7.8,7.8Hz,2H),7.15(s,1H),6.87(s,1H),5.98(s,1H),3.74(s,6H),2.30(s,3H).HRMS(MALDI):计算值C20H18N2O8S[M+Na]+469.0676.实测值469.0672.
化合物20:m.p.155-156℃.1H NMR(600MHz,DMSO-d6)δ13.10(s,1H),7.96–7.86(m,2H),7.51(dd,J=8.4,8.4Hz,2H),7.16(s,1H),6.96(s,1H),5.98(s,1H),3.74(s,6H),2.33(s,3H).HRMS(MALDI):计算值C20H17FN2O8S[M+H]+465.0762.实测值465.0763.
化合物21:m.p.160-161℃.1H NMR(600MHz,DMSO-d6)δ13.11(s,1H),7.85(d,J=8.4Hz,2H),7.74(d,J=8.4Hz,2H),7.17(s,1H),6.98(s,1H),5.98(s,1H),3.74(s,6H),2.34(s,3H).HRMS(MALDI):计算值C20H17ClN2O8S[M+H]+481.0467.实测值481.0467.
化合物22:m.p.146-147℃.1H NMR(600MHz,DMSO-d6)δ13.15(s,1H),7.94–7.51(m,4H),7.17(s,1H),6.97(s,1H),5.98(s,1H),3.74(s,6H),2.33(s,3H).HRMS(MALDI):计算值C20H17FN2O8S[M+Na]+487.0582.实测值487.0576.
化合物23:m.p.147-148℃.1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),7.93(d,J=7.8Hz,1H),7.86(s,1H),7.84(d,J=7.2Hz,1H),7.71(dd,J=7.8,7.8Hz,1H),7.18(s,1H),6.98(s,1H),5.98(s,1H),3.75(s,6H),2.34(s,3H).HRMS(MALDI):计算值C20H17ClN2O8S[M+Na]+503.0286.实测值503.0281.
化合物24:m.p.154-155℃.1H NMR(600MHz,DMSO-d6)δ13.13(s,1H),7.90(dd,J=12.0,7.2Hz,1H),7.80(dd,J=7.2,7.2Hz,1H),7.63–7.52(dd,J=7.8,7.8Hz,1H),7.44(dd,J=7.8,7.8Hz,1H),7.16(s,1H),6.89(s,1H),5.98(s,1H),3.74(s,6H),2.30(s,3H).HRMS(MALDI):计算值C20H17FN2O8S[M+H]+465.0762.实测值465.0760.
化合物25:m.p.154-155℃.1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),7.96(d,J=7.8Hz,1H),7.90–7.79(m,2H),7.60(dd,J=7.2,7.2Hz,1H),7.16(s,1H),6.70(s,1H),5.99(s,1H),3.76(s,6H),2.25(s,3H).HRMS(MALDI):计算值C20H17ClN2O8S[M+H]+481.0467.实测值481.0465.
化合物26:m.p.130-131℃.1H NMR(600MHz,DMSO-d6)δ13.40(s,1H),7.87(dd,J=10.2,8.4Hz,1H),7.64–7.55(m,3H),7.37(d,J=8.4Hz,1H),7.20(d,J=8.4Hz,1H),5.99(s,1H),3.75(s,6H).HRMS(MALDI):计算值C19H14F2N2O8S[M+Na]+491.0331.实测值491.0343.
化合物27:m.p.159-160℃.1H NMR(600MHz,DMSO-d6)δ13.37(s,1H),7.87(dd,J=14.4,7.8Hz,1H),7.69(dd,J=9.0,9.0Hz,1H),7.56(dd,J=7.8,7.8Hz,1H),7.40–7.29(m,2H),7.15(d,J=8.3Hz,1H),5.99(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H14F2N2O8S[M+H]+469.0512.实测值469.0505.
化合物28:m.p.155-156℃.1H NMR(600MHz,DMSO-d6)δ13.37(s,1H),8.01(dd,J=7.8,7.8Hz,1H),7.79–7.73(m,2H),7.59(dd,J=8.4,8.4Hz,1H),7.35(d,J=8.4Hz,1H),7.18(d,J=8.4Hz,1H),5.99(s,1H),3.75(s,6H).HRMS(MALDI):计算值C19H14F2N2O8S[M+H]+469.0512.实测值469.0505.
化合物29:m.p.133-134℃.1H NMR(600MHz,DMSO-d6)δ13.38(s,1H),8.05(s,1H),7.95(d,J=8.4Hz,1H),7.80(d,J=8.4Hz,1H),7.60(dd,J=8.4,8.4Hz,1H),7.36(d,J=8.4Hz,1H),7.19(d,J=7.8Hz,1H),5.99(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H14Cl2N2O8S[M+H]+500.9921.实测值500.9918.
化合物30:m.p.156-157℃.1H NMR(600MHz,DMSO-d6)δ13.39(s,1H),8.10(s,1H),7.92(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.54(dd,J=8.4,8.4Hz,1H),7.35(d,J=8.4Hz,1H),6.98(d,J=8.4Hz,1H),6.00(s,1H),3.75(s,6H).HRMS(MALDI):计算值C19H14Cl2N2O8S[M+H]+500.9921.实测值500.9918.
化合物31:m.p.151-152℃.1H NMR(600MHz,DMSO-d6)δ13.37(s,1H),8.09(d,J=8.4Hz,1H),8.01(dd,J=9.0,5.4Hz,1H),7.68–7.42(m,2H),7.34(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),6.00(s,1H),3.76(s,6H).HRMS(MALDI):计算值C19H14BrFN2O8S[M+H]+528.9711.实测值528.9705.
化合物32:m.p.116-118℃.1H NMR(600MHz,DMSO-d6)δ13.37(s,1H),8.07(d,J=6.3Hz,1H),7.93–7.84(m,1H),7.73(dd,J=9.0,9.0Hz,1H),7.60(dd,J=8.4,8.4Hz,1H),7.36(d,J=8.4Hz,1H),7.18(d,J=8.4Hz,1H),6.00(s,1H),3.75(s,6H).HRMS(MALDI):计算值C19H14ClFN2O8S[M+H]+485.0216.实测值485.0212.
化合物33:m.p.146-147℃.1H NMR(600MHz,DMSO-d6)δ13.46(s,1H),8.79(s,1H),8.32(d,J=8.4Hz,1H),8.23(d,J=8.4Hz,1H),7.60(dd,J=8.4,8.4Hz,1H),7.42(d,J=8.4Hz,1H),7.15(d,J=8.4Hz,1H),6.00(s,1H),3.76(s,6H).HRMS(MALDI):计算值C19H14ClN3O10S[M+H]+512.0167.实测值512.0154.
化合物34:m.p.160-161℃.1H NMR(600MHz,DMSO-d6)δ13.40(s,1H),8.00(d,J=9.6Hz,1H),7.76–7.64(m,2H),7.58(dd,J=8.4,8.4Hz,1H),7.36(d,J=8.4Hz,1H),7.15(d,J=8.4Hz,1H),6.00(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H14BrFN2O8S[M+Na]+550.9530.实测值550.9518.
化合物35:m.p.157-158℃.1H NMR(600MHz,DMSO-d6)δ13.33(s,1H),7.67(dd,J=7.8,7.8Hz,1H),7.55(dd,J=8.4,8.4Hz,1H),7.43(d,J=11.4Hz,1H),7.33(d,J=8.4Hz,1H),7.25(d,J=8.4Hz,1H),7.06(d,J=8.4Hz,1H),5.99(s,1H),3.74(s,6H),2.43(s,3H).HRMS(MALDI):计算值C20H17FN2O8S[M+H]+465.0762.实测值465.0757.
化合物36:m.p.152-153℃.1H NMR(600MHz,DMSO-d6)δ13.38(s,1H),7.88(d,J=9.2Hz,1H),7.80(dd,J=7.8,7.8Hz,1H),7.61–7.52(m,2H),7.36(d,J=8.4Hz,1H),7.16(d,J=8.4Hz,1H),5.99(s,1H),3.74(s,6H).HRMS(MALDI):计算值C19H14ClFN2O8S[M+H]+485.0216.实测值485.0214.
化合物37:m.p.155-157℃.1H NMR(600MHz,DMSO-d6)δ13.40(s,1H),8.30(d,J=8.4Hz,1H),8.13(d,J=8.4Hz,1H),8.08(s,1H),7.55(dd,J=8.4,8.4Hz,1H),7.37(d,J=8.4Hz,1H),6.99(d,J=8.3Hz,1H),6.00(s,1H),3.75(s,6H).HRMS(MALDI):计算值C20H14BrF3N2O8S[M+H]+578.9679.实测值578.9671.
化合物38:m.p.159-161℃.1H NMR(600MHz,DMSO-d6)δ13.40(s,1H),8.46(s,1H),8.15(d,J=8.4Hz,1H),8.02(d,J=8.4Hz,1H),7.54(dd,J=8.4,8.4Hz,1H),7.36(d,J=8.4Hz,1H),6.96(d,J=8.4Hz,1H),6.00(s,1H),3.76(s,6H).HRMS(MALDI):计算值C20H14BrF3N2O8S[M+H]+578.9679.实测值578.9672.
化合物39:m.p.160-161℃.1H NMR(600MHz,DMSO-d6)δ13.43(s,1H),8.51(s,1H),8.01(d,J=8.4Hz,1H),7.98(d,J=8.4Hz,1H),7.59(dd,J=8.4,8.4Hz,1H),7.40(d,J=8.4Hz,1H),7.11(d,J=8.4Hz,1H),6.00(s,1H),3.76(s,6H).HRMS(MALDI):计算值C20H14F3N3O10S[M+H]+546.0430.实测值546.0416.
化合物40:m.p.149-150℃.1H NMR(600MHz,DMSO-d6)δ13.25(s,1H),7.49(dd,J=8.4,8.4Hz,1H),7.31(d,J=8.4Hz,1H),7.16(s,2H),6.81(d,J=8.4Hz,1H),5.99(s,1H),3.75(s,6H),2.48(s,6H),2.31(s,3H).HRMS(MALDI):计算值C22H22N2O8S[M+H]+475.1170.实测值475.1165.
化合物41:m.p.137-138℃.1H NMR(600MHz,DMSO-d6)δ13.13(s,1H),7.99(dd,J=7.2,7.2Hz,1H),7.85–7.51(m,2H),7.18(s,1H),7.03(s,1H),5.98(s,1H),3.75(s,6H),2.35(s,3H).HRMS(MALDI):计算值C20H16F2N2O8S[M+Na]+505.0488.实测值505.0481.
化合物42:m.p.158-159℃.1H NMR(600MHz,DMSO-d6)δ13.14(s,1H),7.86(dd,J=14.4,7.8Hz,1H),7.68(dd,J=9.0,9.0Hz,1H),7.33(dd,J=8.4,7.2Hz,1H),7.17(s,1H),6.98(s,1H),5.97(s,1H),3.74(s,6H),2.33(s,3H).HRMS(MALDI):计算值C20H16F2N2O8S[M+Na]+505.0488.实测值505.0479.
化合物43:m.p.157-158℃.1H NMR(600MHz,DMSO-d6)δ13.17(s,1H),7.87(d,J=10.2Hz,1H),7.79(dd,J=7.8,7.8Hz,1H),7.53(d,J=8.4Hz,1H),7.18(s,1H),7.01(s,1H),5.98(s,1H),3.74(s,6H),2.33(s,3H).HRMS(MALDI):计算值C20H16ClFN2O8S[M+Na]+521.0192.实测值521.0185.
化合物44:m.p.136-137℃.1H NMR(600MHz,DMSO-d6)δ13.16(s,1H),8.05(d,J=5.4Hz,1H),7.87(d,J=6.6Hz,1H),7.72(dd,J=8.4,8.4Hz,1H),7.19(s,1H),7.04(s,1H),5.98(s,1H),3.75(s,6H),2.35(s,3H).HRMS(MALDI):计算值C20H16ClFN2O8S[M+Na]+521.0192.实测值521.0191.
化合物45:m.p.122-123℃.1H NMR(600MHz,DMSO-d6)δ13.33(s,1H),8.50(s,1H),7.89(dd,J=4.8,3.2Hz,1H),7.56(dd,J=8..44,8Hz,1H),7.42(d,J=4.8Hz,1H),7.33(d,J=8.4Hz,1H),7.05(d,J=8.4Hz,1H),6.00(s,1H),3.75(s,6H).HRMS(MALDI):计算值C17H14N2O8S2[M+H]+439.0270.实测值439.0259.
化合物46:m.p.135-137℃.1H NMR(600MHz,DMSO-d6)δ13.26(s,1H),8.48(s,1H),7.83(s,1H),7.57(dd,J=8.4,8.4Hz,1H),7.32(d,J=8.4Hz,1H),7.18(d,J=8.4Hz,1H),6.00(s,1H),3.88(s,3H),3.75(s,6H).HRMS(MALDI):计算值C17H16N4O8S[M+H]+437.0767.实测值437.0763.
化合物47:m.p.166-167℃.1H NMR(600MHz,DMSO-d6)δ13.31(s,1H),7.65(dd,J=8.4,8.4Hz,1H),7.41(d,J=8.4Hz,1H),7.35(d,J=8.4Hz,1H),6.01(s,1H),3.75(s,6H),2.39(s,3H),2.15(s,3H).HRMS(MALDI):计算值C18H17N3O9S[M+H]+452.0758.实测值452.0754.
化合物48:m.p.136-137℃.1H NMR(400MHz,DMSO-d6)δ13.51(s,1H),7.55(dd,J=8.4,8.4Hz,1H),7.44-7.41(m,5H),7.33(d,J=7.8Hz,1H),7.20(d,J=7.8Hz,1H),6.01(s,1H),4.99(s,2H),3.77(s,6H).HRMS(MALDI):计算值C20H18N2O8S[M+H]+447.0857.实测值447.0849.
化合物49:m.p.122-123℃.1H NMR(600MHz,DMSO-d6)δ13.14(s,1H),8.24(d,J=4.8Hz,1H),7.79(d,J=3.2Hz,1H),7.29(dd,J=4.2,4.2Hz,1H),7.17(s,1H),6.89(s,1H),5.98(s,1H),3.75(s,6H),2.32(s,3H).HRMS(MALDI):计算值C17H14N2O8S2[M+H]+453.0421.实测值453.0421.
化合物50:m.p.161-162℃.1H NMR(600MHz,DMSO-d6)δ13.13(s,1H),8.48(s,1H),7.88(d,J=1.8Hz,1H),7.41(d,J=3.2Hz,1H),7.15(s,1H),6.84(s,1H),5.98(s,1H),3.75(s,6H),2.31(s,3H).HRMS(MALDI):计算值C18H16N2O8S2[M+Na]+453.0421.实测值453.0423.
化合物51:m.p.176-177℃.1H NMR(600MHz,DMSO-d6)δ13.27(s,1H),7.24(s,1H),7.18(s,1H),6.00(s,1H),3.75(s,6H),2.39(s,3H),2.38(s,3H),2.16(s,3H).HRMS(MALDI):计算值C19H19N3O9S[M+H]+466.0915.实测值466.0915.
化合物52:m.p.129-130℃.1H NMR(600MHz,DMSO-d6)δ13.53(s,1H),7.61(dd,J=8.4,8.4Hz,1H),7.37(d,J=4.8Hz,1H),7.35(d,J=4.8Hz,1H),6.02(s,1H),3.77(s,6H),3.58(q,J=7.3Hz,2H),1.36(t,J=7.3Hz,3H).HRMS(MALDI):计算值C15H16N2O8S[M+H]+385.0700.实测值385.0695.
化合物53:m.p.123-124℃.1H NMR(600MHz,DMSO-d6)δ13.50(s,1H),7.61(dd,J=8.4,8.4Hz,1H),7.39(d,J=8.4Hz,1H),7.36(d,J=8.4Hz,1H),6.01(s,1H),3.77(s,6H),3.00(td,J=7.8,4.2Hz,1H),1.22–1.15(m,2H),1.08–1.03(m,2H).HRMS(MALDI):计算值C16H16N2O8S[M+H]+397.0700.实测值397.0700.
测试例
本测试例用于测定对照药剂、实施例制备得到的化合物1-53对野生型乙酰羟酸合成酶以及P197L突变体的抑制活性,本测试例中使用的酶为野生型乙酰羟酸合成酶及其P197L突变体,从拟南芥中(plasmids pET28a(+)-AtAHAS以及pET28a(+)-AtAHAS-P197L)表达制得,具体的制备方法为文献Triazolopyrimidines as New Herbicidal Lead forCombating Weed Resistance Associated with Acetohydroxyacid Synthase Mutation,Yu Chao Liu etc.J.Agric.Food Chem.05Jun 2016提供的方法。
具体的活性试验方法为:
野生型拟南芥AtAHAS和突变型P197L分别由质粒pET28a(+)-AtAHAS和pET28a(+)-AtAHAS-P197L表达获得。
化合物用DMSO溶解。化合物抑制活性测定实验采用96孔酶标板。在各孔中分别加入反应缓冲液(1mM ThDP,10mM MgCl2,10μM FAD,50mM磷酸缓冲液,pH为7.5,100mM丙酮酸),各种浓度的化合物,最后加入AHAS酶液,反应开始。把96孔板在37℃下孵育60min后,加入10μL的硫酸溶液(3mol/L)终止反应,然后在60℃下孵育15min,使乙酰乳酸转化为3-羟基-2-丁酮。最后加入100μL的5%α-萘酚(溶于NaOH)和100μL的0.5%肌酸,把96孔板放在60℃中继续孵育15min,进行显色反应。最后将96孔板放在酶标仪上,在λ=525nm处测定吸光度。
化合物的抑制常数Ki app值通过下面方程拟合得到:
νi=ν∞+(ν0-ν∞)/(1+[I]/Ki app)
νi和ν0分别表示在抑制剂存在和不存在情况下的酶的速率(这里可以用相对活性表示);[I]表示抑制剂的浓度;Ki app为apparent Ki,即表观抑制常数,也就是在抑制剂抑制了AHAS酶50%的活性时所对应的浓度。如果测定结果表明,在饱和的抑制剂浓度下,酶几乎没有活性,可以令ν∞=0,再拟合方程求出Ki app值。
测试结果列于表2中,并且,表2中的对照药剂AA的结构式如下:
表2
a RF=Ki,WT/Ki,P197L(抗性倍数)
从上表所示的结果可以得知,本发明的含磺酸酯的嘧啶水杨酸类化合物对于野生型乙酰羟酸合成酶以及P197L突变体具有酶抑制活性。
并且,本发明提供的含磺酸酯的嘧啶水杨酸类化合物的抗性倍数均低于对照药剂,且小于等于1.00。部分化合物的抗性倍数维持在0.01~0.10倍,说明其具有较高的反抗性。
从上表中的结果可以看出,本发明所涉及的具有高抑制活性以及反抗性的含磺酸酯嘧啶水杨酸类衍生物可用于抗性杂草的治理。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
Claims (10)
1.一种6-磺酸酯基嘧啶水杨酸类化合物,该化合物具有式(1)所示的结构,
其中,R1选自H、C1-6的烷基、硝基和卤素中的至少一种;
R2选自取代或未取代的C1-10的烷基,取代或未取代的C6-20的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5~7元饱和或不饱和杂环,且其中的取代基选自卤素、C1-4的烷基、C1-4的烷氧基、硝基、三氟甲基和苯基中的至少一种;
R3和R4各自独立地为H、C1-3的烷基和卤素中的至少一种。
2.根据权利要求1所述的化合物,其中,在式(1)中,
R1选自H、C1-4的烷基和卤素中的至少一种;
R2选自取代或未取代的C1-7的烷基,取代或未取代的C6-16的芳基,取代或未取代的含有N、O和S中的至少一种杂原子的5~6元饱和或不饱和杂环,且其中的取代基选自卤素、C1-4的烷基、C1-4的烷氧基、硝基、三氟甲基和苯基中的至少一种;
R3和R4各自独立地为H、甲基、乙基、异丙基、氟、氯和溴中的至少一种。
3.根据权利要求1所述的化合物,其中,该化合物选自以下化合物中的至少一种:在式(1)中,
化合物1:R1为H,R2为苯基,R3和R4均为H;
化合物2:R1为H,R2为4-F-苯基,R3和R4均为H;
化合物3:R1为H,R2为4-Cl-苯基,R3和R4均为H;
化合物4:R1为H,R2为4-Br-苯基,R3和R4均为H;
化合物5:R1为H,R2为3-F-苯基,R3和R4均为H;
化合物6:R1为H,R2为3-Cl-苯基,R3和R4均为H;
化合物7:R1为H,R2为3-Br-苯基,R3和R4均为H;
化合物8:R1为H,R2为2-F-苯基,R3和R4均为H;
化合物9:R1为H,R2为2-Cl-苯基,R3和R4均为H;
化合物10:R1为H,R2为2-Br-苯基,R3和R4均为H;
化合物11:R1为H,R2为4-CH3-苯基,R3和R4均为H;
化合物12:R1为H,R2为3-CH3-苯基,R3和R4均为H;
化合物13:R1为H,R2为2-CH3-苯基,R3和R4均为H;
化合物14:R1为H,R2为4-NO3-苯基,R3和R4均为H;
化合物15:R1为H,R2为3-NO3-苯基,R3和R4均为H;
化合物16:R1为H,R2为2-NO3-苯基,R3和R4均为H;
化合物17:R1为H,R2为4-OCH3-苯基,R3和R4均为H;
化合物18:R1为H,R2为4-叔丁基-苯基,R3和R4均为H;
化合物19:R1为CH3,R2为苯基,R3和R4均为H;
化合物20:R1为CH3,R2为4-F-苯基,R3和R4均为H;
化合物21:R1为CH3,R2为4-Cl-苯基,R3和R4均为H;
化合物22:R1为CH3,R2为3-F-苯基,R3和R4均为H;
化合物23:R1为CH3,R2为3-Cl-苯基,R3和R4均为H;
化合物24:R1为CH3,R2为2-F-苯基,R3和R4均为H;
化合物25:R1为CH3,R2为2-Cl-苯基,R3和R4均为H;
化合物26:R1为H,R2为3,5-二氟-苯基,R3和R4均为H;
化合物27:R1为H,R2为2,4-二氟-苯基,R3和R4均为H;
化合物28:R1为H,R2为3,4-二氟-苯基,R3和R4均为H;
化合物29:R1为H,R2为3,4-二氯-苯基,R3和R4均为H;
化合物30:R1为H,R2为2,4-二氯-苯基,R3和R4均为H;
化合物31:R1为H,R2为4-氟-2-溴-苯基,R3和R4均为H;
化合物32:R1为H,R2为4-氟-3-氯-苯基,R3和R4均为H;
化合物33:R1为H,R2为4-氯-2-硝基-苯基,R3和R4均为H;
化合物34:R1为H,R2为2-氟-4-溴-苯基,R3和R4均为H;
化合物35:R1为H,R2为2-氟-4-甲基-苯基,R3和R4均为H;
化合物36:R1为H,R2为2-氟-4-氯-苯基,R3和R4均为H;
化合物37:R1为H,R2为2-溴-4-三氟甲基-苯基,R3和R4均为H;
化合物38:R1为H,R2为2-溴-5-三氟甲基-苯基,R3和R4均为H;
化合物39:R1为H,R2为2-硝基-4-三氟甲基-苯基,R3和R4均为H;
化合物40:R1为H,R2为2,4,6-三甲基-苯基,R3和R4均为H;
化合物41:R1为CH3,R2为3,4-二氟-苯基,R3和R4均为H;
化合物42:R1为CH3,R2为2,4-二氟-苯基,R3和R4均为H;
化合物43:R1为CH3,R2为2-氟-4-氯-苯基,R3和R4均为H;
化合物44:R1为CH3,R2为4-氟-3-氯-苯基,R3和R4均为H;
化合物45:R1为H,R2为R3和R4均为H;
化合物46:R1为H,R2为R3和R4均为H;
化合物47:R1为H,R2为R3和R4均为H;
化合物48:R1为H,R2为R3和R4均为H;
化合物49:R1为CH3,R2为R3和R4均为H;
化合物50:R1为CH3,R2为R3和R4均为H;
化合物51:R1为CH3,R2为R3和R4均为H;
化合物52:R1为H,R2为乙基,R3和R4均为H;
化合物53:R1为H,R2为环丙基,R3和R4均为H。
4.一种制备6-磺酸酯基嘧啶水杨酸类化合物的方法,该化合物具有式(1)所示的结构,该方法包括:
(1)将式(2)所示结构的化合物与R2SO2Cl进行第一接触反应,得到式(3)所示的化合物;
(2)将所述式(3)所示的化合物与三氟乙酸进行第二接触反应;
其中,R1、R2、R3和R4如前述权利要求1-3中任意一项所定义。
5.根据权利要求4所述的方法,其中,所述第一接触反应在氢化钠存在下进行,所述第一接触反应的条件包括:温度为-10℃至45℃,时间为10~100min。
6.根据权利要求4所述的方法,其中,所述第二接触反应的条件包括:温度为5℃至45℃,时间为30~400min。
7.权利要求1-3中任意一项所述的6-磺酸酯基嘧啶水杨酸类化合物和/或权利要求4-6中任意一项所述的方法制备得到的6-磺酸酯基嘧啶水杨酸类化合物作为乙酰羟酸合成酶抑制剂的应用。
8.权利要求1-3中任意一项所述的6-磺酸酯基嘧啶水杨酸类化合物和/或权利要求4-6中任意一项所述的方法制备得到的6-磺酸酯基嘧啶水杨酸类化合物在防治由乙酰羟酸合成酶突变导致的杂草抗性植株中的应用。
9.根据权利要求8所述的应用,其中,所述由乙酰羟酸合成酶突变导致的杂草抗性植株中的抗性突变位点包括Ala122、Pro197、Ala205、Asp376、Trp574、Ser653和Gly654中的至少一种。
10.根据权利要求8所述的应用,其中,所述由乙酰羟酸合成酶突变导致的杂草抗性植株中的抗性突变位点为Pro197;优选地,
所述由乙酰羟酸合成酶突变导致的杂草抗性植株的突变类型包括P197A、P197T、P197S、P197R、P197Q、P197L、P197H和P197I中的至少一种。
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