CN110156698A - 2-苯基-1，6-二氢嘧啶-5-甲酸衍生物的制备方法和用途 - Google Patents
2-苯基-1，6-二氢嘧啶-5-甲酸衍生物的制备方法和用途 Download PDFInfo
- Publication number
- CN110156698A CN110156698A CN201910489196.8A CN201910489196A CN110156698A CN 110156698 A CN110156698 A CN 110156698A CN 201910489196 A CN201910489196 A CN 201910489196A CN 110156698 A CN110156698 A CN 110156698A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- cyano
- dihydropyrimidine
- carboxylic acid
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 187
- AIWFLYGTAOUNIE-UHFFFAOYSA-N C1(=CC=CC=C1)C=1NCC(=CN=1)C(=O)O Chemical compound C1(=CC=CC=C1)C=1NCC(=CN=1)C(=O)O AIWFLYGTAOUNIE-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000012453 solvate Substances 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims description 79
- -1 4-Isopropoxy-3-cyanobenzamidine hydrochloride 4-isobutoxy-3-cyanobenzamidine hydrochloride 4-Isopentoxy-3-cyanobenzamidine hydrochloride Chemical compound 0.000 claims description 48
- 229920006391 phthalonitrile polymer Polymers 0.000 claims description 30
- OJFSUUSPNLGJDD-UHFFFAOYSA-N 6-oxo-1-phenylpyrimidine-5-carboxylic acid Chemical compound C1(=CC=CC=C1)N1C=NC=C(C1=O)C(=O)O OJFSUUSPNLGJDD-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- 201000005569 Gout Diseases 0.000 claims description 12
- QZWUBODXLCSKFB-UHFFFAOYSA-N C1(=CC=CC=C1)N1C=NC=C(C1=N)C(=O)O Chemical compound C1(=CC=CC=C1)N1C=NC=C(C1=N)C(=O)O QZWUBODXLCSKFB-UHFFFAOYSA-N 0.000 claims description 11
- 239000000543 intermediate Substances 0.000 claims description 10
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 201000001431 Hyperuricemia Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 7
- QESYLFCJDFCRIT-UHFFFAOYSA-N 4-hydroxybenzene-1,3-dicarbonitrile Chemical compound OC1=CC=C(C#N)C=C1C#N QESYLFCJDFCRIT-UHFFFAOYSA-N 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 238000006007 Sommelet synthesis reaction Methods 0.000 claims description 2
- 238000006136 alcoholysis reaction Methods 0.000 claims description 2
- 238000005915 ammonolysis reaction Methods 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 238000007265 chloromethylation reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- VXWYTPARKVGWFX-UHFFFAOYSA-N ethyl 4-chloro-2-phenylpyrimidine-5-carboxylate Chemical compound N1=C(Cl)C(C(=O)OCC)=CN=C1C1=CC=CC=C1 VXWYTPARKVGWFX-UHFFFAOYSA-N 0.000 claims 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract description 6
- 235000019253 formic acid Nutrition 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 170
- 239000007787 solid Substances 0.000 description 95
- 238000005160 1H NMR spectroscopy Methods 0.000 description 85
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 81
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 57
- 238000006243 chemical reaction Methods 0.000 description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 27
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 26
- 239000000243 solution Substances 0.000 description 21
- 239000012043 crude product Substances 0.000 description 17
- 238000000746 purification Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 12
- 108010093894 Xanthine oxidase Proteins 0.000 description 12
- 102100033220 Xanthine oxidase Human genes 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000011734 sodium Substances 0.000 description 10
- YTOJVXCVLBQYCZ-UHFFFAOYSA-N C1(=CC=CC=C1)OC(=O)C=1C(NC=CC1)=O Chemical compound C1(=CC=CC=C1)OC(=O)C=1C(NC=CC1)=O YTOJVXCVLBQYCZ-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 239000003826 tablet Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- CRXQCZULRYHWJG-UHFFFAOYSA-N phenyl 6-oxo-1H-pyrimidine-5-carboxylate Chemical compound C1(=CC=CC=C1)OC(=O)C1=CN=CNC1=O CRXQCZULRYHWJG-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229940075420 xanthine Drugs 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- LWDQPPLPHGXYLG-UHFFFAOYSA-N 1-(2,3,4-trimethoxyphenyl)propan-2-amine Chemical compound COC1=CC=C(CC(C)N)C(OC)=C1OC LWDQPPLPHGXYLG-UHFFFAOYSA-N 0.000 description 2
- MJIBJXKJBRLSQA-UHFFFAOYSA-N 1-(2,3,5-trimethoxyphenyl)propan-2-amine Chemical compound COC1=CC(CC(C)N)=C(OC)C(OC)=C1 MJIBJXKJBRLSQA-UHFFFAOYSA-N 0.000 description 2
- OASZJWLOOFXASO-UHFFFAOYSA-N 1-(2,3,6-trimethoxyphenyl)propan-2-amine Chemical compound COC1=CC=C(OC)C(OC)=C1CC(C)N OASZJWLOOFXASO-UHFFFAOYSA-N 0.000 description 2
- TVSIMAWGATVNGK-UHFFFAOYSA-N 1-(2,4,5-trimethoxyphenyl)propan-2-amine Chemical compound COC1=CC(OC)=C(OC)C=C1CC(C)N TVSIMAWGATVNGK-UHFFFAOYSA-N 0.000 description 2
- DDGNOUVDFKXADP-UHFFFAOYSA-N 1-(2,4,6-trimethoxyphenyl)propan-2-amine Chemical compound COC1=CC(OC)=C(CC(C)N)C(OC)=C1 DDGNOUVDFKXADP-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- IBQMHBGFMLHHLE-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester Chemical compound CCN(CC)CCCCCCCCOC(=O)C1=CC(OC)=C(OC)C(OC)=C1 IBQMHBGFMLHHLE-UHFFFAOYSA-N 0.000 description 2
- RCEFMOGVOYEGJN-UHFFFAOYSA-N 3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-1,4-dihydropyrimidin-2-one Chemical compound OC1=CC=CC=C1N1C(=O)NC(C=2C=C(C=CC=2)[N+]([O-])=O)=CC1 RCEFMOGVOYEGJN-UHFFFAOYSA-N 0.000 description 2
- FFJZKHGOZXZDFF-UHFFFAOYSA-N 3-cyano-4-propan-2-yloxybenzenecarboximidamide hydrochloride Chemical compound Cl.C(C)(C)OC1=C(C=C(C(=N)N)C=C1)C#N FFJZKHGOZXZDFF-UHFFFAOYSA-N 0.000 description 2
- LNKJESSHRFPVPE-UHFFFAOYSA-N 5-(diethylamino)pentyl 3,4,5-trimethoxybenzoate;hydrochloride Chemical compound Cl.CCN(CC)CCCCCOC(=O)C1=CC(OC)=C(OC)C(OC)=C1 LNKJESSHRFPVPE-UHFFFAOYSA-N 0.000 description 2
- AVTRLVGCVSFGCO-UHFFFAOYSA-N 6-(diethylamino)hexyl 3,4,5-trimethoxybenzoate Chemical compound CCN(CC)CCCCCCOC(=O)C1=CC(OC)=C(OC)C(OC)=C1 AVTRLVGCVSFGCO-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- JHZHWVQTOXIXIV-UHFFFAOYSA-N oxo-[[1-[3-[4-(oxoazaniumylmethylidene)pyridin-1-yl]propyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCCN1C=CC(=C[NH+]=O)C=C1 JHZHWVQTOXIXIV-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 2
- 229940048086 sodium pyrophosphate Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 2
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 2
- 229940116269 uric acid Drugs 0.000 description 2
- KQNBRMUBPRGXSL-UHFFFAOYSA-N 1-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1 KQNBRMUBPRGXSL-UHFFFAOYSA-N 0.000 description 1
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 1
- WZRKSPFYXUXINF-UHFFFAOYSA-N 1-(bromomethyl)-4-methylbenzene Chemical compound CC1=CC=C(CBr)C=C1 WZRKSPFYXUXINF-UHFFFAOYSA-N 0.000 description 1
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 1
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 1
- YLRBJYMANQKEAW-UHFFFAOYSA-N 1-bromo-4-(bromomethyl)benzene Chemical compound BrCC1=CC=C(Br)C=C1 YLRBJYMANQKEAW-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- UVRRJILIXQAAFK-UHFFFAOYSA-N 2-bromo-4-methylaniline Chemical compound CC1=CC=C(N)C(Br)=C1 UVRRJILIXQAAFK-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- IXDWSPYXCCAUAW-UHFFFAOYSA-N 2-oxo-1-phenylpyridine-3-carboxylic acid Chemical compound O=C1C(C(=O)O)=CC=CN1C1=CC=CC=C1 IXDWSPYXCCAUAW-UHFFFAOYSA-N 0.000 description 1
- USEGQJLHQSTGHW-UHFFFAOYSA-N 3-bromo-2-methylprop-1-ene Chemical compound CC(=C)CBr USEGQJLHQSTGHW-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010061619 Deformity Diseases 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010029148 Nephrolithiasis Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 206010048302 Tubulointerstitial nephritis Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000026816 acute arthritis Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229960002708 antigout preparations Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- DUEPRVBVGDRKAG-UHFFFAOYSA-N carbofuran Chemical compound CNC(=O)OC1=CC=CC2=C1OC(C)(C)C2 DUEPRVBVGDRKAG-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 231100000850 chronic interstitial nephritis Toxicity 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003684 drug solvent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- JSFILNWGTCTVNQ-ZRDIBKRKSA-N methyl (e)-3-[2-(4-bromophenoxy)-4-oxopyrido[1,2-a]pyrimidin-3-yl]-2-cyanoprop-2-enoate Chemical compound N1=C2C=CC=CN2C(=O)C(/C=C(C(=O)OC)\C#N)=C1OC1=CC=C(Br)C=C1 JSFILNWGTCTVNQ-ZRDIBKRKSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 208000016839 purine metabolism disease Diseases 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physical Education & Sports Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域，涉及2‑苯基‑1,6‑二氢嘧啶‑5‑甲酸衍生物的制备方法和用途。本发明提供了具有通式I所示的2‑苯基‑1,6‑二氢嘧啶‑5‑甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物，还提供了制备所述的2‑苯基‑1,6‑二氢嘧啶‑5‑甲酸衍生物或药学上可接受的盐的中间体，该中间体的结构如通式II、III或IV所示。其中，R1、R2、R3如权利要求和说明书所述。
Description
技术领域
本发明属于医药技术领域，具体涉及2-苯基-1,6-二氢嘧啶-5-甲酸衍生物的制备方法和用途。
背景技术
痛风(Gout)是仅次于糖尿病的第二大代谢类疾病，发病原因是体内嘌呤代谢紊乱和(或)尿酸排泄减少，导致血液中的尿酸浓度偏高，进而造成痛风组织学改变。痛风的临床特点为高尿酸血症、反复发作的急性关节炎、痛风石沉积、痛风石性慢性关节炎和关节畸形、累及肾脏引起慢性间质性肾炎和肾结石等。随着经济发展，人们生活水平的提高，在全世界范围内，高尿酸血症和痛风的患病率呈上升趋势。目前，我国高尿酸血症患者约1.2亿，约占人口总数的10％。据调查有5％-12％的高尿酸血症患者最终发展为痛风，我国痛风病的患者数量约为1200万人。相关研究表明，痛风及高尿酸血症与许多其他类疾病，包括糖尿病、肥胖、高胰岛素血症、高血压等相关联。最值得注意的是高尿酸血症是引起心血管疾病发病的危险因素，严重的痛风病患者常常因心肌梗塞和外周动脉疾病而危及生命。因此，研发一类有较好抗高尿酸血症和痛风作用的药物，具有十分重要的现实意义
发明内容
本发明的目的是提供具有黄嘌呤氧化酶抑制活性的化合物及其药学上可接受的盐及其制备方法和在制备抗痛风药物中的用途。
本发明提供具有通式I所示的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物，
其中，
R1为H、C1-C6烷基、C2-C6烯基、取代或未取代的苄基，所述取代基为卤素、C1-C6烷基；
R2为H或C1-C6烷基；
R3为O或NH。
进一步地，
R1为H、C1-C6烷基、C2-C6烯基、取代或未取代的苄基，所述取代基为卤素、C1-C6烷基；
R2为H或C1-C4烷基；优选为H或甲基；
R3为O或NH。
具体地，本发明提供的具有黄嘌呤氧化酶抑制活性的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐，是下述化合物中的任一个：
4-甲基-2-(3-氰基-4-异丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-1)
4-甲基-2-(3-氰基-4-异丁氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-2)
4-甲基-2-(3-氰基-4-异戊氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-3)
4-甲基-2-(3-氰基-4-烯丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-4)
4-甲基-2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-5)
4-甲基-2-{3-氰基-4-[(3-甲基丁-2-烯-1-基)氧基]}苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-6)
4-甲基-2-(3-氰基-4-苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-7)
4-甲基-2-(3-氰基-4-对氟苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-8)
4-甲基-2-(3-氰基-4-对氯苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-9)
4-甲基-2-(3-氰基-4-对溴苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-10)
4-甲基-2-(3-氰基-4-对叔丁基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-11)
4-甲基-2-(3-氰基-4-对甲基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-12)
2-(3-氰基-4-异丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-1)
2-(3-氰基-4-异丁氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-2)
2-(3-氰基-4-异戊氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-3)
2-(3-氰基-4-烯丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-4)
2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-5)
2-{3-氰基-4-[(3-甲基丁-2-烯-1-基)氧基]}苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-6)
2-(3-氰基-4-苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-7)
2-(3-氰基-4-对氟苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-8)
2-(3-氰基-4-对氯苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-9)
2-(3-氰基-4-对溴苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-10)
2-(3-氰基-4-对叔丁基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-11)
2-(3-氰基-4-对甲基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-12)
2-(3-氰基-4-异戊氧基)苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸(TMC-3)
2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸(TMC-5)
2-(3-氰基-4-对溴苄氧基)苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸(TMC-10)
2-(3-氰基-4-对甲基苄氧基)苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸(TMC-12)
本发明还提供了一种制备所述的具有黄嘌呤氧化酶抑制活性的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐的中间体，该中间体的结构如通式II、III或IV所示：
其中，
R1为H、C1-C6烷基、C2-C6烯基、取代或未取代的苄基，所述取代基为卤素、C1-C6烷基；
R2为H或；R3为O、Cl、NH。
本发明优选具有通式II、III或IV所示的制备黄嘌呤氧化酶抑制活性的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐的中间体，
其中，
R1为H、C1-C6烷基、C2-C6烯基、取代或未取代的苄基，所述取代基为卤素、C1-C6烷基；
R2为H或C1-C4烷基，优选为H或甲基；R3为O、Cl、NH。
具体地，本发明提供了如下中间体：
本发明还提供了所述的具有黄嘌呤氧化酶抑制活性的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐的制备方法，步骤如下：
以水杨醛为起始原料，经氯甲基化、Sommelet反应和氰化得到共用中间体2,4-二氰基苯酚，2,4-二氰基苯酚和不同的卤代烃反应得到4-烷氧基-1,3苯二甲腈；相应的4-烷氧基-1,3苯二甲腈在甲醇钠催化下经醇解得到相应的亚胺酯，然后和氯化铵反应得到相应的4-烷氧基-3-氰基-苯甲脒盐酸盐；相应的4-烷氧基-3-氰基-苯甲脒盐酸盐与2-(1-乙氧基亚乙基)丙二酸二乙酯环合制得4-甲基-2-(3-氰基-4-烷氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯；相应的4-烷氧基-3-氰基-苯甲脒盐酸盐与乙氧甲叉环合制得4-甲基-2-(3-氰基-4-烷氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯；相应的4-甲基-2-(3-氰基-4-烷氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯经氯化亚砜氯代、氨水氨解得到4-甲基-2-(3-氰基-4-烷氧基)苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸乙酯；相应的乙酯经水解得到通式I所示化合物。
本发明提供了一种药物组合物，其包含有所述的具有黄嘌呤氧化酶抑制活性的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐，以及其衍生物、类似物、互变异构体、多晶型物、可药用的溶剂合物作为活性成分，以及可药用的辅料、载体、稀释剂等。
含有本发明化合物的药物组合物可以通过常规方法制备，例如在Remington:theScience and Practice of Pharmacy,19th Ed.,1995中描述。该组合物可以是常规的剂型如胶囊、片剂、粉末、溶液、混悬液、糖浆、气溶胶、或局部给药形式。它们可以含有适当的固体或液体载体，或在适当的无菌介质中形成注射溶液或混悬液。该组合物可以含有5-20％、优选0.5-10％重量的活性化合物,余量为可药用的载体、赋型剂、稀释剂、溶剂等。
典型的组合物含有式Ⅰ所示的化合物或其溶剂化物，以及可药用的赋型剂，其可以是载体或稀释剂，或被载体稀释，或被包装到载体中，其可以是胶囊、小袋、纸或其它容器的形式。当载体用作稀释剂时，它可以是固体、半固体或液体物质，其可以用作活性化合物的载体、赋型剂或介质。该活性化合物可以以在容器例如小袋中的颗粒状固体的形式被吸收。一些适合的载体为水、盐溶液、醇、聚乙二醇、聚羟基乙氧基化蓖麻油、花生油、椰揽油、明胶、乳糖、石膏粉、蔗糖、环糊精、直链淀粉、硬脂酸镁(magnesium sterate)、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素的低级烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸甘油单酯和甘油二酯、季成四醇脂肪酸酯、聚氧乙烯、羟基甲基纤维素和聚乙烯吡咯烷酮。同样地，载体或稀释剂可以包括任何本领域已知的缓释材料，如单硬脂酸甘油酯或二硬脂酸甘油酯，其单独使用或与蜡混合。制剂中还可以包括润湿剂，乳化剂，混悬剂，防腐剂，甜味剂或增香剂。可以通过本领域己知的方法配制本发明的制剂，以提供活性成分给药患者后的快速、持续或延迟释放。
该药物组合物可以是无菌的，并且如果需要可以与辅剂、乳化剂、缓冲剂和(或)着色剂等混合，只要其不与活性化合物反应。
可以以任何途径给药，只要其有效地将活性药物传送到适当的或所需的活性部位，例如口服，鼻腔，经皮，肺部，或肠胃外给药，例如直肠、贮库、皮下、静脉内、尿道内、肌肉内、鼻内、眼用溶液或油膏,优选通过口服途径给药。
如果固体载体用于口服给药，该制剂可以被压成片剂，或以粉末或小球形式装入胶囊中，或者制成锭剂或糖锭。如果使用液体载，该制剂可以是糖浆剂、乳剂、软明胶胶囊或无菌注射液，如水性或非水性液体混悬液或溶液。
对于鼻内给药，该制剂可以含有溶解或混悬于液体载体，尤其是水性载体中的式Ⅰ化合物，作为气溶胶给药。该载体可以含有添加剂，包括增溶剂如丙二醇，表面活性剂，吸收促进剂如卵磷脂(磷脂酚胆碱)或环糊精，或防腐剂如对羟基苯甲酸酯类。
对于肠胃外给药,特别适合的是注射溶液或混悬液，优选活性化合物溶剂于多羟基化蓖麻油中的水性溶液。
具有滑石和(或)碳水化合物载体或粘合剂等的片剂、糖衣丸或胶囊特别适合于口服给药。优选地，片剂、糖衣丸或胶囊的载体包括乳糖、玉米淀粉和(或)马铃薯淀粉。当可以使用加糖载体时，可以使用糖浆剂或酗剂。
本发明提供了所述的具有黄嘌呤氧化酶抑制活性的2-苯基-1.6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐及其组合物，所述的衍生物或药学上可接受的盐及其组合物能够用于制备治疗和(或)预防高尿酸血症和痛风病药物。
具体实施方式
下面的实施例将对本发明予以进一步的说明，但并不因此而限制本发明。
按照发明内容中所示流程制备。
实施例1.2,4-二醛基苯酚(M-2)的制备
于反应瓶中投入水杨醛(60g，0.39mol)，浓盐酸(390ml)，多聚甲醛(24.2g，0.64mol)，室温搅拌1h后滴加三氯氧磷(20ml)，控温0-10℃，约1h滴完，逐渐有大量固体析出，然后保温1h，室温搅拌过夜。反应结束后，滤出固体，用0.05％碳酸氢钠溶液洗涤滤饼，取滤饼，40℃真空干燥。在反应瓶中加入上述粗品、HMTA(74.7g，0.53mol)、50％乙酸水溶液280mL，回流反应1h。TLC监测反应，反应完后加入140ml浓盐酸，继续反应10min。将反应液缓慢倒入碎冰中，搅拌30min，抽滤，滤饼水洗，50℃真空干燥，得黄色粉末66g，收率89.5％。所得粗产品未经纯化直接用于下一步反应。
实施例2.2,4-二氰基苯酚(M-3)的制备
在反应瓶中投入M-2(66g，0.44mol)、盐酸羟胺(91.7g，1.32mol)、甲酸钠(110.7g，1.63mol)、NMP(30ml)，无水甲酸(400ml)，回流反应6h，反应过程中有大量固体析出，TLC监测反应，反应结束后，冷却至室温，10℃搅拌30min，抽滤，滤饼用水洗涤，烘干。所得粗品用50％乙醇重结晶，得34.5g白色固体，收率：54.5％。mp degraded at 190℃.1H NMR(600MHz,DMSO-d6)δ12.42(s,1H),8.27(s,1H),7.93(d,J＝8.7Hz,1H),7.15(d,J＝8.8Hz,1H).ESI-MS:m/z142.8[M-H]-.
实施例3.4-烷氧基-1,3-苯二甲腈(M-3-1)的制备
3.1 4-异丙氧基-1,3-苯二甲腈(M-3-1)的制备
在反应瓶中投入M-3(5g，0.035mol)、2-溴丙烷(5.5g，0.045mol)、碳酸钾(6.2g，0.045mol)、碘化钾(0.12g，0.0007mol)、DMF(30ml)，60℃反应3h，TLC监测，反应完成后，冷至室温，将反应液倒入水中，大量固体析出，搅拌30min，抽滤，滤饼水洗，烘干，所得粗品用乙醇重结晶，得白色固体5g，收率：77.9％，m.p.147.9-148.5℃.1H NMR(600MHz,DMSO-d6)δ8.36(d,J＝8.4Hz,1H),8.11(t,J＝8.5Hz,1H),7.55–7.35(m,1H),4.95(dt,J＝12.3,4.9Hz,1H),1.46–1.13(m,6H).ESI-MS:m/z 187.1[M+H]+.
3.2 4-异丁氧基-1,3-苯二甲腈(M-3-2)的制备
以溴代异丁烷为原料，制备方法同(M-3-A1)，得白色固体，收率：88.1％。m.p.129.6-130.1℃.1H NMR(600MHz,DMSO-d6)δ8.36(d,J＝2.1Hz,1H),8.11(dd,J＝8.9,2.1Hz,1H),7.42(d,J＝8.9Hz,1H),4.02(d,J＝6.4Hz,2H),2.07(dp,J＝13.3,6.6Hz,1H),1.00(d,J＝6.7Hz,6H).。ESI-MS:m/z 223.8[M+Na]+.
3.3 4-异戊氧基-1,3-苯二甲腈(M-3-3)的制备
以异戊烷为原料，制备方法同(M-3-1)，得白色固体，收率：66.6％。m.p.133.8-134.1℃.1H NMR(600MHz,DMSO-d6)δ8.36(d,J＝2.1Hz,1H),8.13(dd,J＝8.9,2.1Hz,1H),7.45(d,J＝8.9Hz,1H),4.26(t,J＝6.6Hz,2H),1.79(dp,J＝13.4,6.7Hz,1H),1.66(q,J＝6.7Hz,2H),0.94(d,J＝6.7Hz,6H).ESI-MS:m/z 215.7[M+H]+.
3.4 4-烯丙氧基-1,3-苯二甲腈(M-3-4)的制备
以烯丙基溴为原料，制备方法同(M-3-1)，得白色固体，收率：76.3％。m.p.200.4-201.1℃.1H NMR(600MHz,DMSO-d6)δ8.39(d,J＝2.1Hz,1H),8.14(dd,J＝8.9,2.2Hz,1H),7.43(d,J＝8.9Hz,1H),6.06(ddt,J＝17.3,10.5,5.2Hz,1H),5.47(dd,J＝17.2,1.7Hz,1H),5.34(dd,J＝10.6,1.5Hz,1H),4.86(d,J＝5.2Hz,2H).ESI-MS:m/z 185.3[M+H]+.
3.5 4-(2-甲基烯丙氧基)-1,3-苯二甲腈(M-3-5)的制备
以3-溴-2-甲基丙烯为原料，制备方法同(M-3-A1)，得白色固体，收率：73.3％。m.p.157.6-158.5℃.1H NMR(600MHz,DMSO-d6)δ8.41(d,J＝2.2Hz,1H),8.14(dd,J＝8.9,2.2Hz,1H),7.43(d,J＝9.0Hz,1H),5.13–5.09(m,1H),5.04(t,J＝1.5Hz,1H),4.78(s,2H),1.79(s,3H).ESI-MS:m/z 199.1[M+H]+.
3.6 4-[(3-甲基丁-2-烯-1-基)氧基]-1,3-苯二甲腈(M-3-6)的制备
以1-溴-3-甲基-2-丁烯为原料，制备方法同(M-3-1)，得白色固体，收率：61.2％.m.p.133.8-134.1℃.1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.2Hz,1H),8.14(dd,J＝8.9,2.1Hz,1H),7.44(d,J＝8.9Hz,1H),5.49–5.42(m,1H),4.82(d,J＝6.9Hz,2H),1.76(d,J＝15.9Hz,6H).ESI-MS:m/z 213.4[M+H]+.
3.7 4-苄氧基-1,3-苯二甲腈(M-3-7)的制备
以溴化苄为原料，制备方法同(M-3-1)，得白色固体，收率：80.1％。m.p.184.6-185.7℃.1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝2.2Hz,1H),8.15(dd,J＝8.9,2.2Hz,1H),7.53(d,J＝9.0Hz,1H),7.51–7.34(m,5H),5.40(s,2H).ESI-MS:m/z 235.4[M+H]+.
3.8 4-对氟苄氧基-1,3-苯二甲腈(M-3-8)的制备
以对氟溴苄为原料，制备方法同(M-3-1)，得白色固体，收率：43.8％。m.p.217.9-218.1℃.1H NMR(400MHz,DMSO-d6)δ8.41(d,J＝2.1Hz,1H),8.16(dd,J＝8.8,2.2Hz,1H),7.64(d,J＝8.1Hz,2H),7.51(d,J＝9.0Hz,1H),7.45(d,J＝8.1Hz,2H),5.38(s,2H).ESI-MS:m/z 253.3[M+Na]+.
3.9 4-对氯苄氧基-1,3-苯二甲腈(M-3-9)的制备
以对氯溴苄为原料，制备方法同(M-3-1)，得白色固体，收率：43.6％。m.p.217.3-218.8℃.1H NMR(400MHz,DMSO-d6)δ8.41(d,J＝2.2Hz,1H),8.16(dd,J＝8.9,2.1Hz,1H),7.72–7.60(m,2H),7.51(d,J＝8.9Hz,1H),7.48–7.40(m,2H),5.38(s,2H).ESI-MS:m/z269.0[M+H]+.
3.10 4-对溴苄氧基-1,3-苯二甲腈(M-3-10)的制备
以对溴溴苄为原料，制备方法同(M-3-1)，得白色固体，收率：86.2％。m.p.184.7-185.6℃.1H NMR(400MHz,DMSO-d6)δ8.41(d,J＝2.2Hz,1H),8.16(dd,J＝8.9,2.2Hz,1H),7.64(d,J＝8.0Hz,2H),7.48(dd,J＝25.6,8.5Hz,3H),5.38(s,2H).ESI-MS:m/z 313.1[M+H]+.
3.11 4-对叔丁基苄氧基-1,3-苯二甲腈(M-3-11)的制备
以对叔丁基溴苄为原料，制备方法同(M-3-1)，得白色固体，收率：77.4％。m.p.133.3-133.9℃.1H NMR(600MHz,DMSO-d6)δ8.40(d,J＝2.1Hz,1H),8.16(dd,J＝8.9,2.2Hz,1H),7.55(d,J＝9.0Hz,1H),7.46(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),5.36(s,2H),1.29(s,9H).ESI-MS:m/z 291.4[M+H]+.
3.12 4-对甲基苄氧基-1,3-苯二甲腈(M-3-12)的制备
以对甲基溴苄为原料，制备方法同(M-3-1)，得白色固体，收率：76.4％。m.p.174.5-175.9℃.1H NMR(600MHz,DMSO-d6)δ8.40(d,J＝2.1Hz,1H),8.15(dd,J＝8.9,2.1Hz,1H),7.52(d,J＝9.0Hz,1H),7.37(d,J＝8.0Hz,2H),7.24(d,J＝7.7Hz,2H),5.35(s,2H),2.32(s,3H).ESI-MS:m/z 249.2[M+H]+.
实施例4.4-烷氧基-3-氰基苯甲脒盐酸盐(M-4-s)的制备
4.1 4-异丙氧基-3-氰基苯甲脒盐酸盐(M-4-1)的制备
在反应瓶中依次投入4-异丙氧基-1,3-苯二甲腈(4g，0.021mol)、甲醇(120ml)、甲醇钠(0.17g，0.003mol)，25℃搅拌24h，TLC监测反应，若原料转化量小于50％，则继续反应直到转化量大于50％时，加入氯化铵(1.12g，0.021mol)，50℃反应4h，TLC监测，直至上一步生成的亚胺酯完全转化。反应液浓缩至干，加入乙酸乙酯打浆，抽滤，滤饼用乙酸乙酯洗涤，少量水淋洗，烘干，得白色固体3.4g，收率66.9％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.8.33(d,J＝2.5Hz,1H),8.20(dd,J＝9.1,2.5Hz,1H),7.48(d,J＝9.1Hz,1H),4.97(m,1H),1.37(d,J＝5.9Hz,6H).ESI-MS:m/z 204.4[M+H]+.
4.2 4-异丁氧基-3-氰基苯甲脒盐酸盐(M-4-2)的制备
以M-3-2为原料，制备方法同(M-4-1)，得白色固体，收率：42.2％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝2.6Hz,1H),8.18(dd,J＝8.8,2.6Hz,1H),7.48(d,J＝8.8Hz,1H),4.06(d,J＝6.4Hz,2H),2.10(m,1H),1.03(d,J＝6.6Hz,6H).ESI-MS:m/z 218.1[M+H]+.
4.3 4-异戊氧基-3-氰基苯甲脒盐酸盐(M-4-3)的制备
以M-3-3为原料，制备方法同(M-4-1)，得白色固体，收率：67.2％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(400MHz,DMSO-d6)δ8.30(d,J＝2.5Hz,1H),8.17(dd,J＝9.0,2.5Hz,1H),7.51(d,J＝9.0Hz,1H),4.30(t,J＝6.5Hz,2H),1.83(m,1H),1.70(q,J＝6.6Hz,2H),0.96(d,J＝6.6Hz,6H).ESI-MS:m/z 232.3[M+H]+.
4.4 4-烯异丙氧基-3-氰基苯甲脒盐酸盐(M-4-4)的制备
以M-3-4为原料，制备方法同(M-4-1)，得白色固体，收率：72.1％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝2.4Hz,1H),8.19(dd,J＝9.0,2.4Hz,1H),7.49(d,J＝9.0Hz,1H),6.09(m,1H),5.55–5.44(m,1H),5.37(m,1H),4.89(d,J＝5.2Hz,2H).ESI-MS:m/z 202.3[M+H]+.
4.5 4-[(2-甲基烯丙基)氧基]-3-氰基苯甲脒盐酸盐(M-4-5)的制备
以M-3-5为原料，制备方法同(M-4-1)，得白色固体，收率：68.1％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),8.21(d,J＝9.2Hz,1H),7.48(d,J＝9.2Hz,1H),5.11(s,1H),5.03(s,1H),4.80(s,2H),1.79(s,3H).ESI-MS:m/z216.2[M+H]+.
4.6 4-[(3-甲基丁-2-烯-1-基)氧基]-3-氰基苯甲脒盐酸盐(M-4-6)的制备
以M-3-6为原料，制备方法同(M-4-1)，得白色固体，收率：41.1％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(600MHz,DMSO-d6)δ8.34(d,J＝2.4Hz,1H),8.21(dd,J＝9.0,2.4Hz,1H),7.48(d,J＝9.0Hz,1H),5.46(t,J＝6.9Hz,1H),4.82(d,J＝6.8Hz,2H),1.75(dd,J＝10.5,1.4Hz,6H).ESI-MS:m/z 230.3[M+H]+.
4.7 4-苄氧基-3-氰基苯甲脒盐酸盐(M-4-7)的制备
以M-3-7为原料，制备方法同(M-4-1)，得白色固体，收率：24.6％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝2.2Hz,1H),8.12(dd,J＝8.9,2.2Hz,1H),7.50(d,J＝8.9Hz,1H),7.41(m,5H),5.37(s,2H).ESI-MS:m/z252.4[M+H]+.
4.8 4-(4-氟苄基)氧基-3-氰基苯甲脒盐酸盐(M-4-8)的制备
以M-3-8为原料，制备方法同(M-4-1)，得白色固体，收率：58.3％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝2.5Hz,1H),8.20(dd,J＝9.0,2.5Hz,1H),7.65–7.52(m,3H),7.28(m,2H),5.41(s,2H).ESI-MS:m/z270.2[M+H]+.
4.9 4-(4-氯苄基)氧基-3-氰基苯甲脒盐酸盐(M-4-9)的制备
以M-3-9为原料，制备方法同(M-4-1)，得白色固体，收率：54.2％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(400MHz,DMSO-d6)δ8.35(d,J＝2.4Hz,1H),8.21(dd,J＝9.0,2.4Hz,1H),7.56(m,5H),5.43(s,2H).ESI-MS:m/z 286.4[M+H]+
4.10 4-(4-溴苄基)氧基-3-氰基苯甲脒盐酸盐(M-4-10)的制备
以M-3-10为原料，制备方法同(M-4-1)，得白色固体，收率：73.9％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝2.4Hz,1H),8.16(dd,J＝9.0,2.4Hz,1H),7.65(d,J＝8.4Hz,2H),7.56(d,J＝9.0Hz,1H),7.47(d,J＝8.4Hz,2H),5.41(s,2H).ESI-MS:m/z 332.1[M+H]+.
4.11 4-(4-甲基苄基)氧基-3-氰基苯甲脒盐酸盐(M-4-11)的制备
以M-3-11为原料，制备方法同(M-4-1)，得白色固体，收率：53.1％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝2.5Hz,1H),8.15(dd,J＝9.0,2.5Hz,1H),7.59(d,J＝9.0Hz,1H),7.51–7.38(m,4H),5.38(s,2H),1.29(s,9H).ESI-MS:m/z 308.4[M+H]+.
4.12 4-(4-叔丁基苄基)氧基-3-氰基苯甲脒盐酸盐(M-4-A12)的制备
以M-3-A12为原料，制备方法同(M-4-A1)，得白色固体，收率：55.2％。所得粗品未经纯化直接进入下一步反应。m.p.>250℃.1H NMR(400MHz,DMSO-d6)δ8.28(d,J＝2.4Hz,1H),8.12(dd,J＝9.0,2.4Hz,1H),7.56(d,J＝9.0Hz,1H),7.39(d,J＝8.0Hz,2H),7.25(d,J＝8.0Hz,2H),5.37(s,2H),2.32(s,3H).ESI-MS:m/z 266.4[M+H]+.
实施例5.2-(1-乙氧基亚乙基)丙二酸二乙酯(M-230)的制备
在反应瓶中投入丙二酸二乙酯(20g，0.125mol)、三乙胺(25.3g，0.25mol)、氯化镁(11.9g，0.125mol)、乙腈(200ml)，降温至-5℃，缓慢滴加乙酰氯(10g，0.125mol)，控温-5℃，约30min滴完，保温1h后升至室温反应8h。TLC监测反应完后，用1N的HCl调pH至3左右，用乙醚萃取两次，合并有机相，用1N的HCl洗涤，无水硫酸钠干燥，蒸干，残余物用DMF溶解，加入溴乙烷(16.2g，0.148mol)、碳酸钾(21g，0.149mol)、碘化钾(2.1g，0.012mol)，60℃反应2h，TLC监测反应完成后，反应液冷至室温，加入水、乙醚，搅拌，分层，有机层用饱和食盐水洗涤，干燥，蒸干，得黄色油状物22g，柱层析纯化得7.4g浅黄色油状物，收率：25.8％。1HNMR(600MHz,DMSO-d6)δ4.14–4.03(m,6H),2.41(s,3H),1.21–1.12(m,9H).
实施例6.4-甲基-2-(3-氰基-4-烷氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-s)的制备
6.1 4-甲基-2-(3-氰基-4-异丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-1)的制备
在反应瓶中投入4-异丙氧基-3-氰基苯甲脒盐酸盐(1g，0.0042mol)、M-230(1.06g，0.0046mol)、新制乙醇钠的甲醇溶液(3g氢化钠(20％)低温下加入100ml乙醇中)(20ml)，回流反应2h，TLC监测反应完全后，将反应液冷至室温，向反应液中缓缓加入6N的HCl调pH至1，搅拌30min，抽滤，滤饼水洗，烘干，所得粗品用乙醇重结晶，得白色固体0.44g，收率：31.1％。m.p.205.6-207.8℃.1H NMR(600MHz,DMSO-d6)δ13.04(s,1H),8.48(d,J＝2.4Hz,1H),8.39(d,J＝9.1Hz,1H),7.46(d,J＝9.1Hz,1H),4.94(p,J＝6.0Hz,1H),4.29(q,J＝7.1Hz,2H),2.32(s,3H),1.36(d,J＝6.0Hz,6H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z342.3[M+H]+.
6.2 4-甲基-2-(3-氰基-4-异丁氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-2)的制备
以M-4-2为原料，制备方法同(MA-5-1)，得白色固体，收率：35.2％。m.p.172.8-178.7℃.1H NMR(600MHz,DMSO-d6)δ13.16(s,1H),8.61(s,1H),8.52(d,J＝2.4Hz,1H),8.44(d,J＝7.9Hz,1H),7.42(d,J＝9.1Hz,1H),4.25(q,J＝7.1Hz,2H),4.03(d,J＝6.5Hz,2H),2.32(s,3H),2.15–2.05(m,J＝6.6Hz,1H),1.29(t,J＝7.1Hz,3H),1.02(d,J＝6.7Hz,6H).ESI-MS:m/z 378.4[M+Na]+.
6.3 4-甲基-2-(3-氰基-4-异戊氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-3)的制备
以M-4-3为原料，制备方法同(MA-5-1)，得白色固体，收率：33.3％。m.p.168.5-172.7℃.1H NMR(600MHz,DMSO-d6)δ13.05(s,1H),8.47(d,J＝2.3Hz,1H),8.40(d,J＝9.3Hz,1H),7.44(d,J＝9.1Hz,1H),4.31–4.23(m,4H),2.31(s,3H),1.82(dp,J＝13.4,6.7Hz,1H),1.69(q,J＝6.6Hz,2H),1.28(t,J＝7.1Hz,3H),0.96(d,J＝6.7Hz,6H).ESI-MS:m/z 370.4[M+H]+.
6.4 4-甲基-2-(3-氰基-4-烯丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-4)的制备
以M-4-4为原料，制备方法同(MA-5-1)，得白色固体，收率：35.2％。m.p.209.3-210.7℃.1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),8.64(s,1H),8.55(d,J＝2.3Hz,1H),8.46(d,J＝9.1Hz,1H),7.45(d,J＝9.1Hz,1H),6.09(ddt,J＝17.3,10.5,5.1Hz,1H),5.49(dd,J＝17.2,1.7Hz,1H),5.36(dd,J＝10.6,1.5Hz,1H),4.87(d,J＝5.2Hz,2H),4.26(q,J＝7.1Hz,2H),2.36(s,3H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z 340.2[M+H]+.
6.5 4-甲基-2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-5)的制备
以M-4-5为原料，制备方法同(MA-5-1)，得白色固体，收率：37.3％。m.p.199.7-201.3℃.1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),8.63(s,1H),8.55(d,J＝2.3Hz,1H),8.50–8.38(m,1H),7.43(d,J＝9.1Hz,1H),5.12(s,1H),5.04(s,1H),4.77(s,2H),4.26(q,J＝7.1Hz,2H),2.39(s,3H),1.81(s,3H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z 354.3[M+H]+.
6.6 4-甲基-2-{3-氰基-4[(3-甲基丁-2-烯-1-基)氧基]}苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-6)的制备
以M-4-6为原料，制备方法同(MA-5-1)，得白色固体，收率：32.1％。m.p.204.3-205.9℃.1H NMR(600MHz,DMSO-d6)δ13.17(s,1H),8.63(s,1H),8.53(d,J＝2.3Hz,1H),8.49–8.42(m,1H),7.46(d,J＝9.0Hz,1H),5.49(ddt,J＝8.2,5.5,1.4Hz,1H),4.82(d,J＝6.8Hz,2H),4.26(q,J＝7.1Hz,2H),2.41(s,3H),1.77(dd,J＝13.2,1.3Hz,6H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z367.9[M+H]+.
6.7 4-甲基-2-(3-氰基-4-苄氧基苯基)-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-7)的制备以M-4-7为原料，制备方法同(MA-5-1)，得白色固体，收率：49.5％。m.p.215.7-217.9℃.1H NMR(600MHz,DMSO-d6)δ13.17(s,1H),8.62(s,1H),8.55(d,J＝2.4Hz,1H),8.45(d,J＝9.0Hz,1H),7.54(d,J＝9.1Hz,1H),7.50(d,J＝6.8Hz,2H),7.44(t,J＝7.6Hz,2H),7.38(t,J＝7.3Hz,1H),5.40(s,2H),4.25(q,J＝7.1Hz,2H),2.37(s,3H),1.28(t,J＝7.1Hz,3H).ESI-MS:m/z 390.4[M+H]+.
6.8 4-甲基-2-(3-氰基-4-对氟苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-8)的制备
以M-4-8为原料，制备方法同(MA-5-1)，得白色固体，收率：47.5％。m.p.197.4-200.8℃.1H NMR(600MHz,DMSO-d6)δ8.49(s,1H),8.41(s,1H),7.63–7.50(m,3H),7.28(t,J＝8.9Hz,2H),5.38(s,2H),4.28(q,J＝7.1Hz,2H),2.31(s,3H),1.28(t,J＝7.1Hz,3H).ESI-MS:m/z 408.2[M+H]+.
6.9 4-甲基-2-(3-氰基-4-对氯苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-9)的制备
以M-4-9为原料，制备方法同(MA-5-1)，得白色固体，收率：28.8％。m.p.198.4-201.3℃.1H NMR(600MHz,DMSO-d6)δ13.07(s,1H),8.50(d,J＝2.3Hz,1H),8.40(d,J＝8.7Hz,1H),7.66–7.63(m,2H),7.52–7.49(m,1H),7.46(d,J＝8.1Hz,2H),5.38(s,2H),4.28(q,J＝7.1Hz,2H),2.31(s,3H),1.28(t,J＝7.1Hz,3H).ESI-MS:m/z 424.9[M+H]+.
6.10 4-甲基-2-(3-氰基-4-对溴苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-10)的制备
以M-4-10为原料，制备方法同(MA-5-1)，得白色固体，收率：31.3％。m.p.199.7-203.3℃.1H NMR(600MHz,DMSO-d6)δ13.04(s,1H),8.46(d,J＝2.3Hz,1H),8.37(d,J＝8.7Hz,1H),7.63–7.60(m,2H),7.49–7.46(m,1H),7.43(d,J＝8.1Hz,2H),5.35(s,2H),4.25(q,J＝7.1Hz,2H),2.28(s,3H),1.25(t,J＝7.1Hz,3H).ESI-MS:m/z 467.5[M+H]+.
6.11 4-甲基-2-(3-氰基-4-对叔丁基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-11)的制备
以M-4-11为原料，制备方法同(MA-5-1)，得白色固体，收率：32.9％。m.p.208.5-212.0℃.1H NMR(600MHz,DMSO-d6)δ13.19(s,1H),8.62(s,1H),8.55(d,J＝2.4Hz,1H),8.46(dd,J＝9.2,2.4Hz,1H),7.55(d,J＝9.1Hz,1H),7.49–7.41(m,4H),5.35(s,2H),4.26(q,J＝7.1Hz,2H),2.29(s,3H),1.29(m,12H).ESI-MS:m/z 446.3[M+H]+.
6.12 4-甲基-2-(3-氰基-4-对甲基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(MA-5-12)的制备
以M-4-A12为原料，制备方法同(MA-5-1)，得白色固体，收率：35.6％。m.p.197.8-203.1℃.1H-NMR(400MHz,DMSO-d6)δ8.54(d,J＝2.3Hz,1H),8.44(dd,J＝9.0,2.4Hz,1H),7.55(d,J＝9.1Hz,1H),7.39(d,J＝8.1Hz,2H),7.24(d,J＝8.0Hz,2H),5.36(s,2H),4.26(q,J＝7.1Hz,2H),2.65(s,3H),2.32(s,3H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z 405.1[M+H]+.
实施例7.2-(3-氰基-4-烷氧基苯基)-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(MB-5-s)的制备
7.1 2-(3-氰基-4-异丙氧基苯基)-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(MB-5-1)的制备
以4-异丙氧基-3-氰基苯甲脒盐酸盐和乙氧甲叉为原料，制备方法同(MA-5-1)，得白色固体，收率：43.1％。m.p.199.8-201.1℃.1H NMR(600MHz,DMSO-d6)δ13.14(s,1H),8.61(s,1H),8.51(d,J＝2.4Hz,1H),8.46–8.40(m,1H),7.45(d,J＝9.2Hz,1H),4.94(hept,J＝6.1Hz,1H),4.25(q,J＝7.1Hz,2H),1.36(d,J＝6.0Hz,6H),1.28(t,J＝7.1Hz,3H).ESI-MS:m/z 350.7[M+Na]+.
7.2 2-(3-氰基-4-异丁氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(MB-5-2)的制备
以M-4-2为原料，制备方法同(MA-5-1)，得白色固体，收率：51.3％。m.p.207.5-209.8℃.1H NMR(600MHz,DMSO-d6)δ13.16(s,1H),8.61(s,1H),8.52(d,J＝2.4Hz,1H),8.44(d,J＝7.9Hz,1H),7.42(d,J＝9.1Hz,1H),4.25(q,J＝7.1Hz,2H),4.03(d,J＝6.5Hz,2H),2.15–2.05(m,J＝6.6Hz,1H),1.29(t,J＝7.1Hz,3H),1.02(d,J＝6.7Hz,6H).ESI-MS:m/z342.4[M+H]+.
7.3 2-(3-氰基-4-异戊氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(MB-5-3)的制备
以M-4-3为原料，制备方法同(MB-5-1)，得白色固体，收率：35.0％。m.p.190.7-193.4℃.1H NMR(600MHz,DMSO-d6)δ13.17(s,1H),8.63(s,1H),8.53(d,J＝2.4Hz,1H),8.46(d,J＝9.1Hz,1H),7.47(d,J＝9.1Hz,1H),4.26(dt,J＝19.9,6.8Hz,4H),1.82(dp,J＝13.3,6.7Hz,1H),1.69(q,J＝6.7Hz,2H),1.28(t,J＝7.1Hz,3H),0.96(d,J＝6.6Hz,6H).ESI-MS:m/z 378.6[M+Na]+.
7.4 2-(3-氰基-4-烯丙氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(MB-5-4)的制备
以M-4-4为原料，制备方法同(MB-5-1)，得白色固体，收率：51.3％。m.p.209.3-210.7℃.1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),8.64(s,1H),8.55(d,J＝2.3Hz,1H),8.46(d,J＝9.1Hz,1H),7.45(d,J＝9.1Hz,1H),6.09(ddt,J＝17.3,10.5,5.1Hz,1H),5.49(dd,J＝17.2,1.7Hz,1H),5.36(dd,J＝10.6,1.5Hz,1H),4.87(d,J＝5.2Hz,2H),4.26(q,J＝7.1Hz,2H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z 347.8[M+Na]+.
7.5 2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(M B-5-5)的制备
以M-4-5为原料，制备方法同(MB-5-1)，得白色固体，收率：62.5％。m.p.199.7-201.3℃.1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),8.63(s,1H),8.55(d,J＝2.3Hz,1H),8.50–8.38(m,1H),7.43(d,J＝9.1Hz,1H),5.12(s,1H),5.04(s,1H),4.77(s,2H),4.26(q,J＝7.1Hz,2H),1.81(s,3H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z 340.4[M+H]+。
7.6 2-{3-氰基-4[(3-甲基丁-2-烯-1-基)氧基]}苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(M B-5-6)的制备
以M-4-6为原料，制备方法同(MB-5-1)，得白色固体，收率：38.4％。m.p.204.3-205.9℃.1H NMR(600MHz,DMSO-d6)δ13.17(s,1H),8.63(s,1H),8.53(d,J＝2.3Hz,1H),8.49–8.42(m,1H),7.46(d,J＝9.0Hz,1H),5.49(ddt,J＝8.2,5.5,1.4Hz,1H),4.82(d,J＝6.8Hz,2H),4.26(q,J＝7.1Hz,2H),1.77(dd,J＝13.2,1.3Hz,6H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z 376.3[M+Na]+。
7.7 2-(3-氰基-4-苄氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(M B-5-7)的制备
以M-4-7为原料，制备方法同(MB-5-1)，得白色固体，收率：80.0％。m.p.215.7-217.9℃.1H NMR(600MHz,DMSO-d6)δ13.17(s,1H),8.62(s,1H),8.55(d,J＝2.4Hz,1H),8.45(d,J＝9.0Hz,1H),7.54(d,J＝9.1Hz,1H),7.50(d,J＝6.8Hz,2H),7.44(t,J＝7.6Hz,2H),7.38(t,J＝7.3Hz,1H),5.40(s,2H),4.25(q,J＝7.1Hz,2H),1.28(t,J＝7.1Hz,3H).ESI-MS:m/z 376.3[M+Na]+。
7.8 2-(3-氰基-4-对氟苄氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(M B-5-8)的制备
以M-4-8为原料，制备方法同(MB-5-1)，得白色固体，收率：46.9％。m.p.207.9-211.3℃1H NMR(600MHz,DMSO-d6)δ13.19(s,1H),8.63(s,1H),8.55(d,J＝2.4Hz,1H),8.47(d,J＝9.0Hz,1H),7.62–7.48(m,3H),7.28(t,J＝8.9Hz,2H),5.39(s,2H),4.26(q,J＝7.1Hz,2H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z 394.2[M+H]+。
7.9 2-(3-氰基-4-对氯苄氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(M B-5-9)的制备
以M-4-9为原料，制备方法同(MB-5-1)，得白色固体，收率：37.5％。m.p.226.1-227.7℃.1H NMR(600MHz,DMSO-d6)δ13.20(s,1H),8.63(s,1H),8.56(d,J＝2.4Hz,1H),8.46(d,J＝9.0Hz,1H),7.60–7.43(m,5H),5.41(s,2H),4.26(q,J＝7.1Hz,2H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z410.7[M+H]+。
7.10 2-(3-氰基-4-对溴苄氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(MB-5-10)的制备
以M-4-10为原料，制备方法同(MB-5-1)，得白色固体，收率：70.9％。m.p.221.4-223.5℃.1H NMR(600MHz,DMSO-d6)δ13.20(s,1H),8.63(s,1H),8.56(d,J＝2.2Hz,1H),8.46(d,J＝9.1Hz,1H),7.65(d,J＝8.3Hz,2H),7.57–7.39(m,3H),5.39(s,2H),4.26(q,J＝7.1Hz,2H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z 476.9[M+Na]+。
7.11 2-(3-氰基-4-对叔丁基苄氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(MB-5-11)的制备
以M-4-11为原料，制备方法同(MB-5-1)，得白色固体，收率：66.1％。m.p.221.5-222.0℃.1H NMR(600MHz,DMSO-d6)δ13.19(s,1H),8.62(s,1H),8.55(d,J＝2.4Hz,1H),8.46(dd,J＝9.2,2.4Hz,1H),7.55(d,J＝9.1Hz,1H),7.49–7.41(m,4H),5.35(s,2H),4.26(q,J＝7.1Hz,2H),1.29(s,12H).ESI-MS:m/z 454.3[M+Na]+。
7.12 2-(3-氰基-4-对甲基苄氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(MB-5-12)的制备
以M-4-12为原料，制备方法同(MB-5-1)，得白色固体，收率：44.4％。m.p.211.8-213.3℃.1H NMR(600MHz,DMSO-d6)δ8.84(s,1H),8.58(d,J＝8.0Hz,2H),7.52(d,J＝1.6Hz,1H),7.42–7.36(m,2H),7.25(d,J＝7.1Hz,2H),5.32(s,2H),4.32(q,J＝7.1Hz,2H),2.32(s,3H),1.33(t,J＝7.1Hz,3H).ESI-MS:m/z 390.3[M+H]+.
实施例8.2-(3-氰基-4-烷氧基苯基)-4-氯嘧啶-5-甲酸乙酯(MC-6-s)的制备
8.1 2-(3-氰基-4-异戊氧基)苯基-4-氯嘧啶-5-甲酸乙酯(MC-6-3)的制备
在反应瓶中投入2-(3-氰基-4-异戊氧基苯基)-6-氧代-1,6-二氢吡啶-5-甲酸乙酯(4.7g，0.013mol)、DMF(25ml)，搅拌至溶清，室温下滴加氯化亚砜(4.7g，0.039mol)，约30min滴完，室温下继续反应2h，TLC监测反应，反应完后，将反应液缓缓倒入0℃的10％碳酸钾溶液(100ml)中，大量固体析出，搅拌30min，抽滤，烘干，得淡黄色固体3.8g，收率77.3％。高温下变质，未测熔点。1H NMR(600MHz,DMSO-d6)δ9.21(s,1H),8.56(dd,J＝9.0,2.2Hz,1H),8.52(d,J＝2.3Hz,1H),7.45(d,J＝9.1Hz,1H),4.39(q,J＝7.1Hz,2H),4.27(t,J＝6.6Hz,2H),1.84(dp,J＝13.4,6.7Hz,1H),1.70(q,J＝6.7Hz,2H),1.37(t,J＝7.1Hz,3H),0.97(d,J＝6.7Hz,6H).ESI-MS:m/z 374.2[M+H]+.
8.2 2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-4-氯嘧啶-5-甲酸乙酯(MC-6-5)的制备
以MB-5-5为原料，制备方法同(MC-6-3)，得白色固体，收率87.1％。高温下变质，未测熔点。1H NMR(600MHz,DMSO-d6)δ9.19(s,1H),8.60–8.48(m,2H),7.41(d,J＝8.8Hz,1H),5.08(d,J＝53.7Hz,2H),4.73(s,2H),4.37(q,J＝7.1Hz,2H),1.80(s,3H),1.34(t,J＝7.1Hz,3H).ESI-MS:m/z 358.3[M+H]+.
8.3 2-(3-氰基-4-对溴苄氧基)苯基-4-氯嘧啶-5-甲酸乙酯(MC-6-10)的制备
以MB-5-10为原料，制备方法同(MC-6-3)，得白色固体，收率88.9％。高温下变质，未测熔点。1H NMR(600MHz,DMSO-d6)δ9.25(s,1H),8.66–8.60(m,2H),7.71–7.63(m,2H),7.55(dd,J＝8.4,1.1Hz,1H),7.51–7.43(m,2H),5.40(s,2H),4.39(q,J＝7.1Hz,2H),1.36(t,J＝7.1Hz,3H).ESI-MS:m/z 472.7[M+H]+.
8.4 2-(3-氰基-4-对甲基苄氧基)苯基-4-氯嘧啶-5-甲酸乙酯(MC-6-12)的制备
以MB-5-12为原料，制备方法同(MC-6-3)，得白色固体，收率81.1％。高温下变质，未测熔点。1H NMR(600MHz,DMSO-d6)δ9.24(s,1H),8.66–8.55(m,2H),7.57(dd,J＝8.7,0.8Hz,1H),7.40(d,J＝8.0Hz,2H),7.25(d,J＝7.7Hz,2H),5.36(s,2H),4.39(q,J＝7.1Hz,2H),2.32(s,3H),1.36(t,J＝7.1Hz,3H).ESI-MS:m/z 408.3[M+H]+.
实施例9.2-(3-氰基-4-烷氧基)苯基-4-氨基嘧啶-5-甲酸乙酯(MC-7-s)的制备
9.1 2-(3-氰基-4-异戊氧基)苯基-4-氨基嘧啶-5-甲酸乙酯(MC-7-3)的制备
在反应瓶中投入2-(3-氰基-4-异戊氧基苯基)-4-氯嘧啶-5-甲酸乙酯(3.7g，0.01mol)、四氢呋喃(20ml)、浓氨水(30ml)，室温下搅拌2h，TLC监测反应进程，反应完后，将反应液蒸干，加入乙醇打浆，抽滤，滤饼烘干，得白色固体3.2g，收率91.2％。m.p.108.1–109.7℃.1H NMR(600MHz,DMSO-d6)δ8.83(s,1H),8.57(dd,J＝8.9,2.2Hz,1H),8.55(d,J＝2.2Hz,1H),8.09(s,1H),7.71(s,1H),7.42(d,J＝9.0Hz,1H),4.32(q,J＝7.1Hz,2H),4.25(t,J＝6.6Hz,2H),1.83(dp,J＝13.4,6.7Hz,1H),1.69(q,J＝6.7Hz,2H),1.33(t,J＝7.1Hz,3H),0.96(d,J＝6.7Hz,6H).ESI-MS:m/z 355.6[M+H]+.
9.2 2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-4-氨基嘧啶-5-甲酸乙酯(MC-7-5)的制备
以MC-6-5为原料，制备方法同(MC-7-3)，得白色固体，收率93.9％。m.p.131.2–133.3℃.1H NMR(600MHz,DMSO-d6)δ8.84(s,1H),8.59–8.53(m,2H),8.09(s,1H),7.72(s,1H),7.43–7.37(m,1H),5.09(d,J＝61.8Hz,2H),4.74(s,2H),4.32(q,J＝7.1Hz,2H),1.82(t,J＝1.2Hz,3H),1.33(t,J＝7.1Hz,3H).ESI-MS:m/z 339.4[M+H]+.
9.3 2-(3-氰基-4-对溴苄氧基)苯基-4-氨基嘧啶-5-甲酸乙酯(MC-7-10)的制备
以MC-6-10为原料，制备方法同(MC-7-3)，得白色固体，收率72.3％。m.p.189.8–191.2℃.1H NMR(600MHz,DMSO-d6)δ8.84(s,1H),8.63–8.54(m,2H),8.10(s,1H),7.73(s,1H),7.68–7.62(m,2H),7.53–7.41(m,3H),5.36(s,2H),4.32(q,J＝7.1Hz,2H),1.33(t,J＝7.1Hz,3H).ESI-MS:m/z 453.7[M+H]+.
9.4 2-(3-氰基-4-对甲基苄氧基)苯基-4-氨基嘧啶-5-甲酸乙酯(MC-7-12)的制备
以MC-6-12为原料，制备方法同(MC-7-3)，得白色固体，收率86.5％。m.p.183.8–185.3℃.1H NMR(600MHz,DMSO-d6)δ8.84(s,1H),8.58(d,J＝8.0Hz,2H),8.10(s,1H),7.72(s,1H),7.52(d,J＝1.6Hz,1H),7.42–7.36(m,2H),7.25(d,J＝7.8Hz,2H),5.32(s,2H),4.32(q,J＝7.1Hz,2H),2.32(s,3H),1.33(t,J＝7.1Hz,3H).ESI-MS:m/z 389.4[M+H]+.
实施例10.4-甲基-2-(3-氰基-4-烷氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-s)
10.1 4-甲基-2-(3-氰基-4-异丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-1)的制备
在反应瓶中投入4-甲基-2-(3-氰基-4-异丙氧基苯基)-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯(0.4g，0.0011mol)、1M氢氧化锂水溶液(4ml)、乙醇(2ml)、四氢呋喃(2ml)，50℃反应3h，TLC监测反应，反应完成后，冷却至室温，向反应液中加入1N的HCl调pH至2-3，有大量固体析出，继续搅拌1h，抽滤，滤饼水洗，烘干，用50％四氢呋喃水溶液重结晶，得0.34g白色固体，收率93.2％。m.p.>250℃。1H NMR(600MHz,DMSO-d6)δ8.53(d,J＝2.4Hz,1H),8.43(dd，J＝9.1，2.4Hz,1H),7.51(d,J＝9.1Hz,1H),4.96(hept,J＝6.3Hz,1H),2.65(s,3H),1.37(d,J＝6.0Hz,6H).13C NMR(101MHz,DMSO)δ165.95,163.19,162.67,159.67,155.74,135.72,134.79,124.00，116.11,114.68,113.97,102.07,72.81,21.97.ESI-HRMS:Calcd.for C16H15N3O4[M–H]-312.0990,found:312.1027.
10.2 4-甲基-2-(3-氰基-4-异丁氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-2)的制备
以MA-5-2为原料，制备方法同(TMA-1)，得白色固体，收率：94.4％。m.p.>250℃.1HNMR(600MHz，DMSO-d6)δ8.54(d,J＝2.4Hz,1H),8.44(dd,J＝9.0,2.4Hz,1H),7.47(d,J＝9.1Hz,1H),4.05(d,J＝6.5Hz,2H),2.65(s,3H),2.11(hept,J＝6.7Hz,1H),1.03(d,J＝6.7Hz,6H).13C NMR(101MHz,DMSO)δ166.66,164.87,163.75,158.94,156.34,135.78,134.47,124.14,115.74,113.95,111.98,101.60,75.76,28.01,25.58,19.11.ESI-HRMS:Calcd.for C17H17N3O4[M–H]-326.1219,found:326.1200.
10.3 4-甲基-2-(3-氰基-4-异戊氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-3)的制备
以MA-5-3为原料，制备方法同(TMA-1)，得白色固体，收率：96.1％。m.p.>250℃.1HNMR(600MHz,DMSO-d6)δ8.53(d,J＝2.4Hz,1H),8.45(dd,J＝9.0,2.4Hz,1H),7.49(d,J＝9.0Hz,1H),4.29(t,J＝6.6Hz,2H),2.65(s,3H),1.83(dq,J＝13.3,6.7Hz,1H),1.70(q,J＝6.6Hz,2H),0.97(d,J＝6.7Hz,6H).13C NMR(101MHz,DMSO)δ166.80,166.18,163.44,158.27,156.13,135.75,134.49,124.68,115.99,113.85,110.83,101.40,68.59,37.37,25.09,23.10,22.83.ESI-HRMS:Calcd.for C18H19N3O4[M–H]-340.1376,found:340.1352.
10.4 4-甲基-2-(3-氰基-4-烯丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-4)的制备
以MA-5-4为原料，制备方法同(TMA-1)，得白色固体，收率：96.2％。m.p.>250℃.1HNMR(600MHz,DMSO-d6)δ8.58(d,J＝2.3Hz,1H),8.49(dd,J＝9.0,2.4Hz,1H),7.44(d,J＝9.1Hz,1H),6.09(ddt,J＝17.3,10.4,5.1Hz,1H),5.56–5.43(m,1H),5.35(dt,J＝10.7,1.5Hz,1H),4.86(d,J＝5.2Hz,2H),2.68(s,3H).13C NMR(101MHz,DMSO)δ169.85,166.67,166.55,162.71,156.93,135.68,134.53,132.64,125.86,118.92,116.08,114.03,109.94,101.39,70.13,22.88.ESI-HRMS:Calcd.for C16H13N3O4[M–H]-310.0906,found:310.0894.
10.5 4-甲基-2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-5)的制备
以MA-5-5为原料，制备方法同(TMA-1)，得白色固体，收率：91.1％。m.p.>250℃.1HNMR(600MHz,DMSO-d6)δ8.55(d,J＝2.4Hz,1H),8.43(dd,J＝9.0,2.4Hz,1H),7.46(d,J＝9.1Hz,1H),5.14(s,1H),5.07–5.02(m,1H),4.79(s,2H),2.65(s,3H),1.82(s,3H).13C NMR(101MHz,DMSO)δ165.94,163.08,162.67,162.35,155.73,139.96,135.70,134.56,124.54,115.89,114.29,113.56,101.63,72.74,19.44.ESI-HRMS:Calcd.for C17H15N3O4[M–H]-324.1063,found:324.1030.
10.6 4-甲基-2-{3-氰基-4[(3-甲基丁-2-烯-1-基)氧基]苯基}-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-6)的制备
以MA-5-6为原料，制备方法同(TMA-1)，得白色固体，收率：96.2％。m.p.>250℃。1HNMR(600MHz,DMSO-d6)δ8.73(s,1H),8.54(d,J＝2.4Hz,1H),8.47(dd,J＝9.0,2.4Hz,1H),7.49(d,J＝9.1Hz,1H),5.49(t,J＝6.8Hz,1H),4.84(d,J＝6.8Hz,2H),2.75(s,3H),1.78(dd,J＝12.5,1.3Hz,6H).13C NMR(101MHz,DMSO)δ166.10,164.68,160.24,140.98,136.87,135.79,125.46,119.83,117.14,115.46,113.19,102.78,68.03,27.05,19.75,19.70.ESI-HRMS:Calcd.for C18H17N3O4[M–H]-340.1292,found:340.1300.
10.7 4-甲基-2-(3-氰基-4-苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-7)的制备
以MA-5-7为原料，制备方法同(TMA-1)，得白色固体，收率：94.7％。m.p.>250℃.1HNMR(400MHz,DMSO-d6)δ8.55(d,J＝2.4Hz,1H),8.44(dd,J＝9.0,2.4Hz,1H),7.56(d,J＝9.1Hz,1H),7.51(d,J＝7.1Hz,2H),7.45(t,J＝7.3Hz,2H),7.38(t,J＝7.2Hz,1H),5.41(s,2H),2.65(s,3H).13C NMR(101MHz,DMSO)δ166.00,163.13,161.16,158.65,155.81,135.95,135.75,134.65,129.11,128.82,128.20,124.75,115.98,114.43,101.77,71.27.Calcd.for C20H15N3O4[M–H]-360.1063,found:360.1022.
10.8 4-甲基-2-[3-氰基-4-(4-氟苄氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-8)的制备
以MA-5-8为原料，制备方法同(TMA-1)，得白色固体，收率：88.9％。m.p.>250℃.1HNMR(600MHz,DMSO-d6)δ8.46(d,J＝2.4Hz,1H),8.35(dd,J＝9.0,2.4Hz,1H),7.57(dd,J＝8.5,2.8Hz,2H),7.45(d,J＝9.2Hz,1H),7.38(d,J＝8.1Hz,2H),5.30(s,2H),2.41(s,3H).13C NMR(101MHz,DMSO)δ168.83,166.02,163.29,162.88,155.82,135.70,135.38,134.57,132.04,130.29,128.52,124.93,122.03,115.90,114.32,101.75,70.45,23.04.ESI-HRMS:Calcd.for C20H14FN3O4[M–H]-378.0896,found:378.0902.
10.9 4-甲基-2-[3-氰基-4-(4-氯苄氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-9)的制备
以MA-5-9为原料，制备方法同TMA-1，得白色固体，收率：94.2％。m.p.>250℃.1HNMR(600MHz,DMSO-d6)δ8.55(d,J＝2.4Hz,1H),8.44(dd,J＝9.0,2.4Hz,1H),7.66(dd,J＝8.5,2.8Hz,2H),7.54(d,J＝9.2Hz,1H),7.47(d,J＝8.1Hz,2H),5.39(s,2H),2.51(s,3H).
10.10 4-甲基-2-[3-氰基-4-(4-溴苄氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-10)的制备
以MA-5-10为原料，制备方法同(TMA-1)，得白色固体，收率：94.1％。m.p.>250℃.1H NMR(600MHz,DMSO-d6)δ8.55(d,J＝2.4Hz,1H),8.44(dd,J＝9.0,2.4Hz,1H),7.66(dd,J＝8.5,2.8Hz,2H),7.54(d,J＝9.2Hz,1H),7.47(d,J＝8.1Hz,2H),5.39(s,2H),2.51(s,3H).13C NMR(101MHz,DMSO)δ169.96,167.14,164.41,164.00,156.94,136.82,136.50,135.70,133.17,131.41,129.64,126.05,123.15,117.02,115.45,102.88,71.58,24.16.ESI-HRMS:Calcd.for C20H14BrN3O4[M–H]-438.0095,found:438.0064.
10.11 4-甲基-2-[3-氰基-4-(4-叔丁基苄氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-11)的制备
以MA-5-11为原料，制备方法同(TMA-1)，得白色固体，收率：91.8％。m.p.>250℃.1H NMR(600MHz,DMSO-d6)δ8.55(d,J＝2.4Hz,1H),8.46(dd,J＝9.0,2.4Hz,1H),7.57(d,J＝9.1Hz,1H),7.45(q,J＝8.5Hz,4H),5.36(s,2H),2.65(s,3H),1.29(s,9H).13C NMR(101MHz,DMSO)δ166.78,166.07,163.18,155.97,151.37,135.77,134.65,132.91,128.18,125.86,124.80,116.02,114.34,101.68,71.15,34.83,31.55,22.90.ESI-HRMS:Calcd.forC24H23N3O4[M–H]-416.1616,found:416.1605.
10.12 4-甲基-2-[3-氰基-4-(4-甲基苄氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMA-12)的制备
以MA-5-12为原料，制备方法同(TMA-1)，得白色固体，收率：89.9％。m.p.>250℃.1H-NMR(400MHz,DMSO-d6)δ8.54(d,J＝2.3Hz,1H),8.44(dd,J＝9.0,2.4Hz,1H),7.55(d,J＝9.1Hz,1H),7.39(d,J＝8.1Hz,2H),7.24(d,J＝8.0Hz,2H)，5.36(s，2H)，2.65(s，3H)，2.32(s，3H).13C-NMR(101MHz，DMSO)δ165.97,164.91,163.19，155.95,138.20,135.87,134.82,132.89,129.64,128.39,124.52,115.97,114.39,101.69,71.25,21.27.ESI-HRMS:Calcd.for C21H17N3O4[M–H]-374.1146,found:374.1159.
实施例11.2-(3-氰基-4-烷氧基苯基)-6-氧代-1,6-二氢吡啶-5-甲酸(TMBs)
11.1 2-(3-氰基-4-异丙氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸(TMB-1)的制备
以2-(3-氰基-4-异丙氧基苯基)-6-氧代-1,6-二氢吡啶-5-甲酸乙酯为原料，制备方法同(TMA-1)，得白色固体，收率：89.1％。m.p.238.5-240.8.1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.53(d,J＝2.4Hz,1H),8.45(dd,J＝9.1,2.4Hz,1H)，7.50(d,J＝9.1Hz,1H),4.96(p,J＝6.0Hz,1H),1.37(d,J＝6.0Hz,6H).13C NMR(101MHz,DMSO)δ166.97,164.98,162.84,159.08,156.47,135.75,134.82,124.09,116.03,114.74,111.95,102.18,72.88,21.97.IR(KBr):cm-1 3432,5154,2244,1732,1643,1556,1290,946.ESI-HRMS:Calcd.forC15H13N3O4[M–H]-298.0906,found:298.0934.
11.2 2-(3-氰基-4-异丁氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸(TMB-2)的制备
以MB-5-2为原料，制备方法同(TMA-1)，得白色固体，收率：82.1％。m.p.231.6-232.4.1H NMR(600MHz,DMSO-d6)δ8.68(d,J＝1.3Hz,1H),8.54(d,J＝2.3Hz,1H),8.46(dd,J＝9.1,2.4Hz,1H),7.45(d,J＝8.8Hz,1H),4.04(d,J＝6.5Hz,2H),2.10(dt,J＝13.3,6.6Hz,1H),1.02(d,J＝6.7Hz,6H).13C NMR(151MHz,DMSO)δ164.90,164.44,163.79,163.55,158.81,135.88,134.56,124.09,115.78,114.03,111.82,101.59,75.76,28.01,19.14.IR(KBr):cm-13406,3071,2230,1709,1645,1566,1291,1009.ESI-HRMS:Calcd.ForC16H15N3O4[M–H]-312.0990,found:312.0987.
11.3 2-(3-氰基-4-异戊氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸(TMB-3)的制备
以MB-5-3为原料，制备方法同(TMA-1)，得白色固体，收率：83.2％。m.p.229.6-231.4℃.1H NMR(600MHz,DMSO-d6)δ8.71(s,1H),8.52(d,J＝2.4Hz,1H),8.45(dd,J＝9.0,2.4Hz,1H),7.48(d,J＝9.1Hz,1H),4.28(t,J＝6.6Hz,2H),1.82(dp,J＝13.4,6.7Hz,1H),1.69(d,J＝6.7Hz,2H),0.96(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO)δ166.92,164.95,163.67,158.99,156.43,135.74,134.50,124.22,115.83,113.92,111.88,101.56,68.66,37.35,25.09,22.81.IR(KBr):cm-13462,3079,2233,1709,1643,1564,1291,974.ESI-HRMS:Calcd.for C17H17N3O4[M–H]-326.1146,found:326.1181.
11.4 2-(3-氰基-4-烯丙氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸(TMB-4)的制备
以MB-5-4为原料，制备方法同(TMA-1)，得白色固体，收率：81.1％。m.p.226.2-229.5℃。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.55(d,J＝2.4Hz,1H),8.46(dd,J＝9.0,2.4Hz,1H),7.46(d,J＝9.2Hz,1H),6.10(ddd,J＝22.4,10.4,5.1Hz,1H),5.49(dd,J＝17.2,1.7Hz,1H),5.36(dd,J＝10.6,1.5Hz,1H),4.88(d,J＝5.2Hz,2H).IR(KBr):cm-13462,2081,2234,1706,1644,1566,1297,985.ESI-HRMS:Calcd.for C15H11N3O4[M–H]-296.0677,found:296.0695.
11.5 2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-5)的制备
以MB-5-5为原料，制备方法同(TMA-1)，得白色固体，收率：87.8％。m.p.>250℃。1HNMR(600MHz,DMSO-d6)δ8.64(s,1H),8.58(d,J＝2.2Hz,1H),8.53(dd,J＝9.0,2.3Hz,1H),7.42(d,J＝9.0Hz,1H),5.13(s,1H),5.03(s,1H),4.76(s,2H),1.80(s,3H).13C NMR(101MHz,DMSO)δ170.21,166.14,162.84,160.22,155.22,140.02,135.50,134.30,126.56,116.02,114.21,113.47,110.74,101.57,72.66,19.44.IR(KBr):cm-1 3451,2232,1626,1563,1300,1004.ESI-HRMS:Calcd.for C16H13N3O4[M–H]-310.0833,found:310.0850.
11.6 2-{3-氰基-4[(3-甲基丁-2-烯-1-基)氧基]苯基}-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-6)的制备
以MB-5-6为原料，制备方法同(TMA-1)，得白色固体，收率：79.1％。m.p.>250℃。1HNMR(600MHz,DMSO-d6)δ8.73(s,1H),8.54(d,J＝2.4Hz,1H),8.47(dd,J＝9.0,2.4Hz,1H),7.49(d,J＝9.1Hz,1H),5.49(t,J＝6.8Hz,1H),4.84(d,J＝6.8Hz,2H),1.78(dd,J＝12.5,1.3Hz,6H).13C NMR(101MHz,DMSO)δ164.97,163.55,159.11,139.85,135.74,134.66,124.33,118.70,116.01,114.33,112.06,101.65,66.90,25.92,18.62.IR(KBr):cm-13463,3076,2233,1711,1642,1564,1286,969.ESI-HRMS:Calcd.for C17H15N3O4[M–H]-324.0990,found:324.1007.
11.7 2-(3-氰基-4-苄氧基)苯基-6-氧代-1,6-二氢吡啶-5-甲酸(TMB-7)的制备
以MB-5-7为原料，制备方法同(TMA-1)，得白色固体，收率：83.9％。m.p.>250℃。1HNMR(600MHz,DMSO-d6)δ8.72(s,1H),8.55(d,J＝2.4Hz,1H),8.46(dd,J＝9.0,2.4Hz,1H),7.57(d,J＝9.1Hz,1H),7.51(d,J＝7.0Hz,2H),7.44(t,J＝7.5Hz,2H),7.41–7.35(m,1H),5.41(s,2H).13C NMR(101MHz,DMSO)δ166.68,164.96,163.31,159.09,156.67,135.91,135.80,134.68,129.10,128.83,128.19,124.75,115.90,114.49,112.17,101.88,71.31.IR(KBr):cm-1 3461,3076,2231,1699,1632,1564,1290,1013.ESI-HRMS:Calcd.forC19H13N3O4[M–H]-346.0833,found:346.0822.
11.8 2-[3-氰基-4-(4-氟苄氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-8)的制备
以MB-5-8为原料，制备方法同(TMA-1)，得白色固体，收率：81.9％。m.p.>250℃。1HNMR(600MHz,DMSO-d6)δ8.72(s,1H),8.57(d,J＝2.4Hz,1H),8.49(dd,J＝9.0,2.4Hz,1H),7.57(td,J＝6.4,1.6Hz,3H),7.29(t,J＝8.9Hz,2H),5.39(s,2H).13C NMR(101MHz,DMSO)δ165.32,163.73,163.08,161.31,159.56,135.77,134.61,132.23,130.67,130.59,125.48,116.10,115.95,115.88,114.47,101.81,70.59.IR(KBr):cm-13452,3080,2233,1698,1632,1565,1299,1011.ESI-HRMS:Calcd.for C19H12FN3O4[M–H]-364.0739,found:364.0731.
11.9 2-[3-氰基-4-(4-氯苄氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-9)的制备
以MB-5-9为原料，制备方法同(TMA-1)，得白色固体，收率：89.1％。m.p.>250℃.1HNMR(600MHz,DMSO-d6)δ8.71(s,1H),8.58(s,1H),8.52–8.46(m,1H),7.66–7.42(m,5H),5.41(s,2H).13C NMR(101MHz,DMSO)δ169.06,165.89,162.82,160.13,156.06,135.66,135.09,134.49,133.46,130.09,129.16,126.49,116.04,114.40,111.33,101.78,70.41.IR(KBr):cm-13460,3086,2230,1696,1631,1565,1295,1012.ESI-HRMS:Calcd.forC19H12ClN3O4[M–H]-380.0444,found:380.0420.
11.10 2-[3-氰基-4-(4-溴苄氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-10)的制备
以MB-5-10为原料，制备方法同(TMA-1)，得白色固体，收率：90.1％。m.p.>250℃1HNMR(600MHz,DMSO-d6)δ8.73(s,1H),8.57(d,J＝2.4Hz,1H),8.48(dd,J＝9.0,2.4Hz,1H),7.72–7.62(m,2H),7.56(d,J＝9.1Hz,1H),7.51–7.41(m,2H),5.40(s,2H).13C NMR(101MHz,DMSO)δ169.12,165.95,162.89,160.20,156.12,135.73,135.15,134.55,133.53,130.15,129.22,126.55,116.10,114.46,111.39,101.84,70.47.IR(KBr):cm-1 3461,3079,2229,1700,1631,1565,1295,1009.ESI-HRMS:Calcd.for C19H12BrN3O4[M–H]-423.9938,found:423.9913.
11.11 2-[3-氰基-4-(4-叔丁基苄氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-11)的制备
以MB-5-11为原料，制备方法同(TMA-1)，得白色固体，收率：90.9％。m.p.>250℃。1H-NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.64–8.51(m,2H),7.60–7.17(m,5H),5.27(s,2H),1.29(s,9H).13C-NMR(101MHz,DMSO)δ173.66,172.09,162.19,161.13,159.83,151.17,134.63,133.37,128.12,125.79,116.99,115.93,113.50,100.83,70.65,34.79,31.56.IR(KBr):cm-1 3453,2962,2231,1605,1476,1282,1007.ESI-HRMS:Calcd.for C23H21N3O4[M–H]-402.1459,found:402.1466.
11.12 2-[3-氰基-4-(4-甲基苄氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸(TMB-12)的制备
以MB-5-12为原料，制备方法同(TMA-1)，得白色固体，收率：89.9％。m.p.>250℃。1H-NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.56(s,1H),8.47(d,J＝9.1Hz,1H),7.57(d,J＝9.1Hz,1H),7.39(d,J＝7.8Hz,2H),7.25(d,J＝8.1Hz,2H),5.37(s,2H),2.32(s,3H).13C-NMR(101MHz,DMSO)δ169.02,165.87,162.80,160.11,156.02,135.64,135.06,134.47,133.44,130.06,129.13,126.46,116.02,114.38,111.31,101.76,70.39,25.59.IR(KBr):cm-1 3423,3075,2229,1702,1631,1563,1298,1015.ESI-HRMS:Calcd.for C20H15N3O4[M–H]-360.0990,found:360.0969.
实施例12.2-(3-氰基-4-烷氧基)苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸(TMC-s)
12.1 2-(3-氰基-4-异戊氧基)苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸(TMC-3)的制备
以2-(3-氰基-4-异戊氧基)苯基-4-氨基嘧啶-5-甲酸乙酯为原料，制备方法同(TMA-1)，最后调pH时改用醋酸，得白色固体，收率：83.1％。m.p.>250℃.1H NMR(600MHz,DMSO-d6)δ8.80(s,1H),8.65–8.48(m,2H),8.24(s,1H),7.98(s,1H),7.44(d,J＝8.8Hz,1H),4.26(t,J＝6.6Hz,2H),1.83(dp,J＝13.4,6.8Hz,1H),1.70(q,J＝6.6Hz，2H),0.96(d，J＝6.7Hz,6H).13C NMR(151MHz,DMSO)δ167.64,163.06,162.88,162.82,158.75,135.26,133.96,129.28,116.39,113.72,103.50,101.28,68.34,37.43,25.09,22.86.ESI-HRMS:Calcd.for C17H18N4O3[M+H]+327.1452,found:327.1412.
12.2 2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸(TMC-5)的制备
以MC-7-5为原料，制备方法同(TMC-3)，得白色固体，收率：79.2％。m.p.>250℃.1HNMR(600MHz,DMSO-d6)δ8.76(s,1H),8.71–8.49(m,3H),8.24(s,1H),7.46(d,J＝9.0Hz,1H),5.14(s,1H),5.04(s,1H),4.77(s,2H),1.82(s,3H).13C NMR(151MHz,DMSO)δ165.99，161.93，161.70，160.19，155.33，139.03，138.98，134.26，133.13,115.10,113.17,112.43,102.67,100.51,71.58,18.41.ESI-HRMS:Calcd.for C16H14N4O3[M–H]-309.0993,found:309.0989.
12.3 2-[3-氰基-4-(4-溴苄氧基)]苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸(TMC-10)的制备
以MC-7-10为原料，制备方法同TMC-3，得白色固体，收率：77.3％。m.p.>250℃.1HNMR(400MHz,DMSO-d6)δ8.80–8.75(m,1H),8.67–8.46(m,3H),8.21(s,1H),7.65(d,J＝8.4Hz,2H),7.55(d,J＝8.9Hz,1H),7.48(d,J＝8.4Hz,2H),5.38(s,2H).13C NMR(101MHz,DMSO)δ166.79,162.99,162.79,135.46,134.40,132.05,130.37,122.02,116.11,114.43,103.87,101.81,70.44.ESI-HRMS:Calcd.for C19H13BrN4O3[M–H]-423.0098,found:423.0063.
12.4 2-[3-氰基-4-(4-甲基苄氧基)]苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸(TMC-12)的制备
以MC-7-12为原料，制备方法同(TMC-3)，得白色固体，收率：80.0％。m.p.>250℃.1H NMR(600MHz,DMSO-d6)δ8.79(s,1H),8.58(d,J＝8.4Hz,2H),8.41(s,1H),8.10(s,1H),7.55(d,J＝8.9Hz,1H),7.40(d,J＝7.7Hz,2H),7.25(d,J＝7.7Hz,2H),5.33(s,2H),2.32(s,3H).13C NMR(101MHz,DMSO)δ167.21,163.02,162.79,157.05,138.17,135.28,134.19,132.99,129.63,128.40,116.28,114.34,103.69,101.69,71.15,21.27.ESI-HRMS:Calcd.for C20H16N4O3[M–H]-359.1150,found:359.1124.
实施例13.化合物TMC-3片剂的制备
处方组成及含量
包衣液处方：
欧巴代(03B28796) 21g
95％乙醇 适量
制成约 430ml
工艺
将己过100目筛的辅料与主药过60目筛混合,以95％乙醇制软材，以18目筛制粒,60℃通风干燥,以16目筛整粒后与硬脂酸镁混合均匀,以φ6mm浅凹冲打片。
包衣溶液的配制：在适宜容器中加入适量的95％乙醇，开动搅拌机，将处方量的欧巴代(03B28796)固体粉末均匀的加入到旋涡中，同时尽量避免有粉末漂浮在液体表面，必要时，可以提高转速以保持适当的旋涡，待所有的欧巴代(03B28796)全部加入后，降低搅拌速度，使旋涡消失，继续搅拌45min，即得。
薄膜包衣片的制备：将片芯置包衣锅内，保持温度60℃±5℃，进行包衣，即得。
实施例14.目标化合物的黄嘌呤氧化酶抑制活性研究
1.试验材料
1.1试剂：黄嘌呤氧化酶(Sigma,USA)、黄嘌呤(98.0％，百灵威)、焦磷酸钠(99.0％，天津市博迪化工有限公司)、乙二胺四乙酸二钠(99.0％，天津市博迪化工有限公司)
1.2仪器：电子分析天平(AR1140型)，电热恒温水浴锅(DK-98-1型)，酶标仪(Varioskan Flash型)
1.3受试样品：阳性药别嘌呤醇，所制备化合物
2.试验方法
2.1配制方法
缓冲液的配制：0.1mol/L焦磷酸钠0.3mmol/L EDTA二钠，pH值8.3
化合物溶液配制：将相应的化合物先配制成0.1mM的DMSO溶液，然后用缓冲液稀释成所需要的浓度进行测试
黄嘌呤溶液配制：精密称取黄嘌呤30.42mg，置100mL量瓶中，先加入2mL的1M氢氧化钠溶液溶清，然后加入缓冲液稀释至刻度，得到浓度为2000μM的母液。依据需求用缓冲液稀释，体外活性测试黄嘌呤溶液浓度为500μM
2.2酶活力检测方法
向96孔板中依次加入缓冲液67μL，黄嘌呤氧化酶溶液40μL，抑制剂溶液53μL，25℃孵育15min后加入黄嘌呤溶液40μL(由于加入黄嘌呤反应即开始，所以加样应迅速且立刻测试，防止反应速率出现下降)，之后每30s检测一次295nm处检测吸光度。空白组采用相应的药物溶剂做为对照。
V＝(A2-A1)/T抑制率＝(v空白-v测试)/v空白x 100％
以10μM为初筛浓度，对抑制率大于50％的化合物进行IC50测试。
2.2统计学方法
全部资料采用SPSS(17.0)统计软件包进行检验分析。结果用平均值±标准误差表示，组间均数比较进行方差齐性分析，并进行Dunnett’s test分析方法进行组间比较
3.实验结果：
实验结果表明，所合成的28个目标化合物均显示出较强的黄嘌呤氧化酶抑制活性(实验数据见表1)。
表1 28个样品对黄嘌呤氧化酶活性的影响(M±SD)
Claims (10)
1.具有通式I所示的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物，
其中，
R1为H、C1-C6烷基、C2-C6烯基、取代或未取代的苄基，所述取代基为卤素、C1-C6烷基；
R2为H或C1-C6烷基；
R3为O或NH。
2.具有通式II或III所示的制备2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物的中间体，
其中，
R1为H、C1-C6烷基、C2-C6烯基、取代或未取代的苄基，所述取代基为卤素、C1-C6烷基；
R2为H或C1-C6烷基；
R3为O、Cl、NH。
3.如权利要求1所述的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物或权利要求2所述的中间体，
其中，R2为H或C1-C4烷基。
4.权利要求1所述的具有通式I所示的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物，选自：
4-甲基-2-(3-氰基-4-异丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-(3-氰基-4-异丁氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-(3-氰基-4-异戊氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-(3-氰基-4-烯丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-{3-氰基-4-[(3-甲基丁-2-烯-1-基)氧基]}苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-(3-氰基-4-苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-(3-氰基-4-对氟苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-(3-氰基-4-对氯苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-(3-氰基-4-对溴苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-(3-氰基-4-对叔丁基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
4-甲基-2-(3-氰基-4-对甲基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-异丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-异丁氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-异戊氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-烯丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-{3-氰基-4-[(3-甲基丁-2-烯-1-基)氧基]}苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-对氟苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-对氯苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-对溴苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-对叔丁基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-对甲基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-异戊氧基)苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸
2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-对溴苄氧基)苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸
2-(3-氰基-4-对甲基苄氧基)苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸。
5.权利要求2所述的制备2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物的中间体，选自：
4-异丙氧基-1,3苯二甲腈
4-异丁氧基-1,3苯二甲腈
4-异戊氧基-1,3苯二甲腈
4-烯丙氧基-1,3苯二甲腈
4-(2-甲基烯丙氧基)-1,3苯二甲腈
4-[(3-甲基丁-2-烯-1-基)氧基]-1,3苯二甲腈
4-苄氧基-1,3苯二甲腈
4-对氟苄氧基-1,3苯二甲腈
4-对氯苄氧基-1,3苯二甲腈
4-对溴苄氧基-1,3苯二甲腈
4-对叔丁基苄氧基-1,3苯二甲腈
4-对甲基苄氧基-1,3苯二甲腈
4-异丙氧基-3-氰基苯甲脒盐酸盐
4-异丁氧基-3-氰基苯甲脒盐酸盐
4-异戊氧基-3-氰基苯甲脒盐酸盐
4-烯丙氧基-3-氰基苯甲脒盐酸盐
4-(2-甲基烯丙氧基)-3-氰基苯甲脒盐酸盐
4-[(3-甲基丁-2-烯-1-基)氧基]-3-氰基苯甲脒盐酸盐
4-苄氧基-3-氰基苯甲脒盐酸盐
4-对氟苄氧基-3-氰基苯甲脒盐酸盐
4-对氯苄氧基-3-氰基苯甲脒盐酸盐
4-对溴苄氧基-3-氰基苯甲脒盐酸盐
4-对叔丁基苄氧基-3-氰基苯甲脒盐酸盐
4-对甲基苄氧基-3-氰基苯甲脒盐酸盐
4-甲基-2-(3-氰基-4-异丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-(3-氰基-4-异丁氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-(3-氰基-4-异戊氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-(3-氰基-4-烯丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-{3-氰基-4-[(3-甲基丁-2-烯-1-基)氧基]}苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-(3-氰基-4-苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-(3-氰基-4-对氟苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-(3-氰基-4-对氯苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-(3-氰基-4-对溴苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-(3-氰基-4-对叔丁基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
4-甲基-2-(3-氰基-4-对甲基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-异丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-异丁氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-异戊氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-烯丙氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-{3-氰基-4-[(3-甲基丁-2-烯-1-基)氧基]}苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-对氟苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-对氯苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-对溴苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-对叔丁基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-对甲基苄氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-异戊氧基)苯基-4-氯嘧啶-5-甲酸乙酯
2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-4-氯嘧啶-5-甲酸乙酯
2-(3-氰基-4-对溴苄氧基)苯基-4-氯嘧啶-5-甲酸乙酯
2-(3-氰基-4-对甲基苄氧基)苯基-4-氯嘧啶-5-甲酸乙酯
2-(3-氰基-4-异戊氧基)苯基-4-亚氨基-1,6-二氢嘧啶-5-甲酸乙酯
2-[3-氰基-4-(2-甲基烯丙氧基)]苯基-4-亚氨基-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-对溴苄氧基)苯基-4-亚氨基-1,6-二氢嘧啶-5-甲酸乙酯
2-(3-氰基-4-对甲基苄氧基)苯基-4-亚氨基-1,6-二氢嘧啶-5-甲酸乙酯。
6.一种药物组合物，包含权利要求1、3或4所述的通式I所示的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物和药学上可接受的载体。
7.一种权利要求1或3所述的通式I所示的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐的制备方法，其特征在于：
以水杨醛为起始原料，经氯甲基化、Sommelet反应和氰化得到共用中间体2,4-二氰基苯酚，2,4-二氰基苯酚和不同的卤代烃反应得到4-烷氧基-1,3苯二甲腈；相应的4-烷氧基-1,3苯二甲腈在甲醇钠催化下经醇解得到相应的亚胺酯，然后和氯化铵反应得到相应的4-烷氧基-3-氰基-苯甲脒盐酸盐；相应的4-烷氧基-3-氰基-苯甲脒盐酸盐与2-(1-乙氧基亚乙基)丙二酸二乙酯环合制得4-甲基-2-(3-氰基-4-烷氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯；相应的4-烷氧基-3-氰基-苯甲脒盐酸盐与乙氧甲叉环合制得4-甲基-2-(3-氰基-4-烷氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯；相应的4-甲基-2-(3-氰基-4-烷氧基)苯基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯经氯化亚砜氯代、氨水氨解得到4-甲基-2-(3-氰基-4-烷氧基)苯基-6-亚氨基-1,6-二氢嘧啶-5-甲酸乙酯；相应的乙酯经水解得到通式I所示化合物。
8.权利要求1、3或4所述的通式I所示的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物或权利要求6所述的药物组合物在制备预防或治疗高尿酸血症药物中的应用。
9.权利要求1、3或4所述的通式I所示的2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物或权利要求6所述的药物组合物在制备抗痛风的药物中的应用。
10.权利要求2、3或5所述的中间体在制备2-苯基-1,6-二氢嘧啶-5-甲酸衍生物或药学上可接受的盐、异构体、多晶型物、可药用的溶剂化物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910489196.8A CN110156698B (zh) | 2019-06-06 | 2019-06-06 | 2-苯基-1，6-二氢嘧啶-5-甲酸衍生物的制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910489196.8A CN110156698B (zh) | 2019-06-06 | 2019-06-06 | 2-苯基-1，6-二氢嘧啶-5-甲酸衍生物的制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110156698A true CN110156698A (zh) | 2019-08-23 |
| CN110156698B CN110156698B (zh) | 2020-10-13 |
Family
ID=67627866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910489196.8A Active CN110156698B (zh) | 2019-06-06 | 2019-06-06 | 2-苯基-1，6-二氢嘧啶-5-甲酸衍生物的制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110156698B (zh) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112209886A (zh) * | 2020-11-09 | 2021-01-12 | 沈阳药科大学 | 2-(3-氰基-4-烷氧基)苯基嘧啶衍生物及其制备方法和用途 |
| CN112979559A (zh) * | 2021-03-08 | 2021-06-18 | 沈阳药科大学 | 2-苯基嘧啶甲酸衍生物及其制备方法和应用 |
| CN113004208A (zh) * | 2021-03-08 | 2021-06-22 | 沈阳药科大学 | 一种抑制黄嘌呤氧化酶活性的化合物及制备方法和应用 |
| CN113620829A (zh) * | 2020-05-07 | 2021-11-09 | 鲁南制药集团股份有限公司 | 一种非布司他中间体化合物 |
| CN114539158A (zh) * | 2020-11-24 | 2022-05-27 | 沈阳药科大学 | 一种FXIa抑制剂类化合物及其制备方法和用途 |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03261785A (ja) * | 1989-12-15 | 1991-11-21 | Smith Kline Ltd | ピリミドピリミジン誘導体 |
| CN101010300A (zh) * | 2004-08-27 | 2007-08-01 | 安斯泰来制药株式会社 | 2－苯基吡啶衍生物 |
| CN101282934A (zh) * | 2005-10-07 | 2008-10-08 | 安斯泰来制药株式会社 | 三芳基羧酸衍生物 |
| CN103068807A (zh) * | 2010-08-27 | 2013-04-24 | 帝人制药株式会社 | 通过使用钯化合物的偶合法的苯基取代杂环衍生物的制备方法 |
| CN108484494A (zh) * | 2018-06-15 | 2018-09-04 | 沈阳药科大学 | 2-氧代-1,2-二氢吡啶-4-甲酸类化合物 |
| CN108689948A (zh) * | 2018-06-04 | 2018-10-23 | 沈阳药科大学 | 6-(3,4-取代苯基)-2-巯基嘧啶-4-甲酸类化合物及其制备方法和用途 |
| CN108929275A (zh) * | 2018-06-14 | 2018-12-04 | 沈阳药科大学 | 6-(3,4-取代苯基)-3-氧代-2,3-二氢哒嗪-4-酰肼类化合物及其用途 |
| WO2019069973A1 (ja) * | 2017-10-04 | 2019-04-11 | 日本たばこ産業株式会社 | 含窒素ヘテロアリール化合物およびその医薬用途 |
-
2019
- 2019-06-06 CN CN201910489196.8A patent/CN110156698B/zh active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03261785A (ja) * | 1989-12-15 | 1991-11-21 | Smith Kline Ltd | ピリミドピリミジン誘導体 |
| CN101010300A (zh) * | 2004-08-27 | 2007-08-01 | 安斯泰来制药株式会社 | 2－苯基吡啶衍生物 |
| CN101282934A (zh) * | 2005-10-07 | 2008-10-08 | 安斯泰来制药株式会社 | 三芳基羧酸衍生物 |
| CN103068807A (zh) * | 2010-08-27 | 2013-04-24 | 帝人制药株式会社 | 通过使用钯化合物的偶合法的苯基取代杂环衍生物的制备方法 |
| WO2019069973A1 (ja) * | 2017-10-04 | 2019-04-11 | 日本たばこ産業株式会社 | 含窒素ヘテロアリール化合物およびその医薬用途 |
| CN111148735A (zh) * | 2017-10-04 | 2020-05-12 | 日本烟草产业株式会社 | 含氮杂芳基化合物及其药物用途 |
| CN108689948A (zh) * | 2018-06-04 | 2018-10-23 | 沈阳药科大学 | 6-(3,4-取代苯基)-2-巯基嘧啶-4-甲酸类化合物及其制备方法和用途 |
| CN108929275A (zh) * | 2018-06-14 | 2018-12-04 | 沈阳药科大学 | 6-(3,4-取代苯基)-3-氧代-2,3-二氢哒嗪-4-酰肼类化合物及其用途 |
| CN108484494A (zh) * | 2018-06-15 | 2018-09-04 | 沈阳药科大学 | 2-氧代-1,2-二氢吡啶-4-甲酸类化合物 |
Non-Patent Citations (1)
| Title |
|---|
| 梁勇等: ""2_苯基_5_吡啶基_1_3_4_省略_合物的合成及黄嘌呤氧化酶抑制活性"", 《中国药物化学杂志》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113620829A (zh) * | 2020-05-07 | 2021-11-09 | 鲁南制药集团股份有限公司 | 一种非布司他中间体化合物 |
| CN113620829B (zh) * | 2020-05-07 | 2024-05-31 | 鲁南制药集团股份有限公司 | 一种非布司他中间体化合物 |
| CN112209886A (zh) * | 2020-11-09 | 2021-01-12 | 沈阳药科大学 | 2-(3-氰基-4-烷氧基)苯基嘧啶衍生物及其制备方法和用途 |
| CN114539158A (zh) * | 2020-11-24 | 2022-05-27 | 沈阳药科大学 | 一种FXIa抑制剂类化合物及其制备方法和用途 |
| CN114539158B (zh) * | 2020-11-24 | 2023-12-08 | 沈阳药科大学 | 一种FXIa抑制剂类化合物及其制备方法和用途 |
| CN112979559A (zh) * | 2021-03-08 | 2021-06-18 | 沈阳药科大学 | 2-苯基嘧啶甲酸衍生物及其制备方法和应用 |
| CN113004208A (zh) * | 2021-03-08 | 2021-06-22 | 沈阳药科大学 | 一种抑制黄嘌呤氧化酶活性的化合物及制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110156698B (zh) | 2020-10-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110156698B (zh) | 2-苯基-1，6-二氢嘧啶-5-甲酸衍生物的制备方法和用途 | |
| DE60216094T2 (de) | Modulatoren der peroxisom-proliferator-aktivierten rezeptoren (ppar) | |
| KR20200013058A (ko) | Ssao 억제제 | |
| EP2408753A2 (en) | Compounds and methods for treating mammalian gastrointestinal microbial infections | |
| SK280584B6 (sk) | Spôsob prípravy arylpiperazinylových heterocyklick | |
| JP2000516593A (ja) | 糖尿病及び肥満症の治療に用いられる選択的β▲下３▼作動物質としての置換スルホンアミド | |
| WO2009047240A1 (en) | Indole derivatives useful as ppar activators | |
| EP1539724B1 (en) | Amino benzothiazole compounds with nos inhibitory activity | |
| RU2448966C1 (ru) | Полиморфная форма | |
| JP2000515133A (ja) | 血糖降下性および脂質低下性の化合物 | |
| CN110156757B (zh) | 四氮唑类黄嘌呤氧化酶抑制剂化合物及其制备方法和用途 | |
| JP2001525399A (ja) | 選択的β３アドレナリン作動性作動薬 | |
| CN110156769B (zh) | 具有黄嘌呤氧化酶抑制活性的化合物及其制备方法和应用 | |
| WO2009147121A1 (en) | Carboxyl substituted indoles for use as ppar alpha modulators | |
| CN112778318B (zh) | 抑制黄嘌呤氧化酶活性的嘧啶并吡唑类衍生物及制备方法和应用 | |
| WO2011065420A1 (ja) | ６－置換－１－メチル－１ｈ－ベンズイミダゾール誘導体の製造法及びその製造中間体 | |
| CN112209886A (zh) | 2-(3-氰基-4-烷氧基)苯基嘧啶衍生物及其制备方法和用途 | |
| CN101463031B (zh) | 吲唑及四氢吲唑类化合物及其制法和其药物组合物与用途 | |
| CN113004188B (zh) | 一种吲哚衍生物及制备方法和应用 | |
| JP6050315B2 (ja) | Ｓ１ｐ１受容体アゴニストとしての新規なピペリジニルモノカルボン酸 | |
| CN113173917B (zh) | 1-烷基-5-四唑基/嘧啶酮基-1h-吲哚-3-甲腈类化合物及其制备方法和应用 | |
| CN113173918B (zh) | N-吲哚-1,6-二氢嘧啶-4-羧酰胺衍生物及其制备方法和应用 | |
| CN113004187B (zh) | 一种具有抑制有机阴离子转运体1活性的化合物及制备方法和应用 | |
| US7163953B2 (en) | Benzylether derivatives | |
| EP3411366B1 (en) | Method for the production of pomalidomide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |