CN102285937A - Method for synthesizing febuxostat - Google Patents
Method for synthesizing febuxostat Download PDFInfo
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- CN102285937A CN102285937A CN2011102711574A CN201110271157A CN102285937A CN 102285937 A CN102285937 A CN 102285937A CN 2011102711574 A CN2011102711574 A CN 2011102711574A CN 201110271157 A CN201110271157 A CN 201110271157A CN 102285937 A CN102285937 A CN 102285937A
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- febuxostat
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- synthetic method
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- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229960005101 febuxostat Drugs 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title abstract description 10
- 230000002194 synthesizing effect Effects 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 229910052751 metal Inorganic materials 0.000 claims abstract description 16
- 239000002184 metal Substances 0.000 claims abstract description 16
- -1 boric acid ester Chemical group 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 239000004327 boric acid Substances 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 238000010189 synthetic method Methods 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- 239000000010 aprotic solvent Substances 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 241000208140 Acer Species 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 2
- 125000000532 dioxanyl group Chemical group 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 description 3
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 230000003407 synthetizing effect Effects 0.000 description 3
- 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 2
- 201000005569 Gout Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- OGAZOYHQFBSRMC-UHFFFAOYSA-N ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(C=2C=C(C(OCC(C)C)=CC=2)C#N)=N1 OGAZOYHQFBSRMC-UHFFFAOYSA-N 0.000 description 2
- 229940013688 formic acid Drugs 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 2
- 231100000004 severe toxicity Toxicity 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003556 thioamides Chemical class 0.000 description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- SKJCWIFHLDWPEO-UHFFFAOYSA-N 3-benzyl-4-phenylbutan-2-one Chemical class C=1C=CC=CC=1CC(C(=O)C)CC1=CC=CC=C1 SKJCWIFHLDWPEO-UHFFFAOYSA-N 0.000 description 1
- HLLSOEKIMZEGFV-UHFFFAOYSA-N 4-(dibutylsulfamoyl)benzoic acid Chemical compound CCCCN(CCCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 HLLSOEKIMZEGFV-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 108010091383 Xanthine dehydrogenase Proteins 0.000 description 1
- 102000005773 Xanthine dehydrogenase Human genes 0.000 description 1
- 108010093894 Xanthine oxidase Proteins 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229960002708 antigout preparations Drugs 0.000 description 1
- QKLWAMMQKBOTCD-UHFFFAOYSA-N butane;diphenylphosphane Chemical compound CCCC.C=1C=CC=CC=1PC1=CC=CC=C1 QKLWAMMQKBOTCD-UHFFFAOYSA-N 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- FSRXIRGQJIHEFB-UHFFFAOYSA-N diphenylphosphane;ethane Chemical compound CC.C=1C=CC=CC=1PC1=CC=CC=C1 FSRXIRGQJIHEFB-UHFFFAOYSA-N 0.000 description 1
- ONDPGJBEBGWAKI-UHFFFAOYSA-N diphenylphosphane;propane Chemical compound CCC.C=1C=CC=CC=1PC1=CC=CC=C1 ONDPGJBEBGWAKI-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- WUOIAOOSKMHJOV-UHFFFAOYSA-N ethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CC)C1=CC=CC=C1 WUOIAOOSKMHJOV-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- NRXQIUSYPAHGNM-UHFFFAOYSA-N ioxynil Chemical compound OC1=C(I)C=C(C#N)C=C1I NRXQIUSYPAHGNM-UHFFFAOYSA-N 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000004144 purine metabolism Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention provides a method for synthesizing febuxostat. The method comprises the following steps of: (a) performing aromatic ring substitution reaction on a compound of a formula I to obtain a compound of a formula II; (b) performing halogen-metal exchange reaction on the compound of the formula II to obtain a compound of a formula III; (c) performing coupling reaction on the compound of the formula III and the compound of a formula VI under the action of a metal catalyst to obtain a compound of a formula IV; and (d) performing hydrolysis reaction on the compound of the formula IV to obtain the compound of a formula V, namely febuxostat, wherein X is I or Br; M is selected from boric acid ester or SnBu3; and R is H or an alkyl group. In the method, a convergent synthesis strategy is adopted, and a carbon-carbon bond is formed by applying metal catalyzed aromatic ring coupling reaction in a key step, so that a system in which a benzene ring is coupled with a thiazole ring is established. The method has the advantages of simple and short steps, high yield and low environmental pollution and can be suitable for industrial production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, relate more specifically to a kind of anti-gout drugs Febuxostat-2-[3-cyano group-4-(2-methyl propoxy-) phenyl]-synthetic method of 4-methyl-5 thiazol formic-acid.
Background technology
Gout claims hyperuricemia again, is the disease that the purine metabolism obstacle causes, along with the raising of people's living standard, its sickness rate is more and more higher, is classified as one of big chronic disease of 21 centurys 20 by United Nations.And Febuxostat is a kind of selectivity XOD/xanthine dehydrogenase inhibitor of new high efficiency, can reduce the intravital uric acid level of goat patient effectively, obviously improves the symptom of patient with gout.At present, the traditional structure synthetizing thiazolium method of the most of employing of the synthetic method of Febuxostat through reporting, common synthetic route long (generally more than six steps), and also the conversion of functional group is very loaded down with trivial details in the wherein related molecule; Secondly, the starting raw material of multiple synthetic route costs an arm and a leg, even in some step, need to use severe toxicity, corrodibility and the stronger chemical reagent of contaminative such as sodium cyanide, trifluoroacetic acid, urotropine, hydrogen sulfide, thiophosphoric anhydride, operator and environment are had bigger disadvantageous effect.In addition, some reaction needed is used diazotization reaction, should not control in the operation of extensive reaction, and this makes suitability for industrialized production relatively more difficult.And the total recovery of the synthetic method of existing bibliographical information is lower, generally is lower than 30%, and this also makes it be not suitable for suitability for industrialized production.
In traditional synthetic method, make up in molecule and when introducing cyano group: JP06345724, EP0513379A1, WO9209279, CN101386604 disclose in raw material by existing two substituting groups on the phenyl ring, connect cyano group it is positioned; JP10139770 discloses in intermediate by the existing leavings group on the phenyl ring, and it is carried out substitution reaction; WO9209279 carries out diazotization reaction to the amino on the phenyl ring in raw material or intermediate; This several method all will adopt prussiates such as hypertoxic potassium cyanide, sodium cyanide, and the security of technology is very low, and environment damage is very big.
When making up ring closure reaction generation thiazole ring, utilize sulfo-reagent to change into thioamides to the cyano group in raw material or the intermediate: US20050075503, US2005027128 disclose to use and fed hydrogen sulfide pressurization preparation in solution, react very dangerous, corrodibility is strong, environmental disruption is big, is unfavorable for amplifying producing; CN101391988 discloses one kettle way reaction synthetizing thiazolium ring, avoid using hydrogen sulfide, but raw materials cost is higher; CN101412699 discloses use HCl/DMF system synthetizing thiazolium ring, avoids the using gas operation, and yield is higher, but reaction time is very long, and aftertreatment is loaded down with trivial details.When the acid amides on raw material or the intermediate phenyl ring was changed into thioamides, JP06293746 disclosed the thiophosphoric anhydride that uses severe toxicity, is unfavorable for scale production.
When introducing aldehyde radical on the phenyl ring of the intermediate after making up thiazole ring: JP11060552, JP1045733 disclose the use polyphosphoric acid and have made solvent, produce polymerization in the reaction process and become sticky thickly, are unfavorable for stirring and yield is low, and impurity is more, is unfavorable for producing; CN101412699 discloses the use trifluoroacetic acid and has made solvent, and yield significantly improves, but trifluoroacetic acid Costco Wholesale height, be difficult to reclaim and corrodibility very strong, security is low; CN102002017 discloses use mixing acid and has made solvent, but acid pollution does not still improve.
On traditional structure thiazole ring method, need repeatedly carry out functional group's conversion, change loaded down with trivial detailsly, increased reactions steps, generally need more than six steps, for example, just be synthesized to final compound through the reaction of nine steps in the Chinese Medicine magazine [2009,40 (1): 1-5].
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides a kind of novel synthesis of Febuxostat of suitable suitability for industrialized production, this method steps is brief, total recovery is high, and less to the influence of operator and environment.
The technical solution used in the present invention is: the invention provides a kind of synthetic method of Febuxostat, may further comprise the steps:
(a) make formula 
The substitution reaction of compound generation aromatic nucleus obtain formula
Compound;
(b) make the formula of gained in the step (a) Compound obtain formula through halogen-metal exchange reaction
Compound;
(c) make the formula of gained in the step (b) 
Compound and formula
Compound linked reaction takes place under the effect of metal catalyst obtains formula
Compound;
(d) make the formula of gained in the step (c) 
Compound obtain formula through hydrolysis reaction
The compound Febuxostat;
Wherein X is I, Br;
M is selected from boric acid ester or SnBu
3
R is H or alkyl.
Further, in step (a), formula 
Compound under the condition that alkali exists, in aprotic solvent,, obtain formula with 2-methyl isophthalic acid-propyl alcohol generation aromatic nucleus substitution reaction
Compound.
Further, above-mentioned alkali is selected from sodium, potassium, liquefied ammonia, sodium hydrogen, lithium diisopropylamine, hexamethyl two silica-based amido lithiums, sodium hexamethyldisilazide; Above-mentioned aprotic solvent is selected from N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, ether, methyl tertiary butyl ether, dioxane, toluene, tetrahydrofuran (THF), methyl-sulphoxide or its arbitrary combination.
Again further, in step (b), formula 
Compound and metal exchange reagent in aprotic solvent, carry out halogen-metal exchange reaction and obtain formula
Compound.
Preferably, formula
Compound carry out halogen-metal exchange reaction, can be under protection of nitrogen gas under-78-100 ℃, carry out 1-20 hour.
Further, aprotic solvent is the inferior maple of diformazan, dioxane, toluene, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, N in step (b), dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone or its arbitrary combination.
Further, in step (c), linked reaction is carried out in aprotic solvent under the condition that alkali exists.
Further, alkali is selected from yellow soda ash, salt of wormwood, sodium acetate, potassium acetate, lithium hydroxide, hydrated barta, sodium hydroxide, triethylamine, cesium fluoride, Potassium monofluoride, tetra-n-butyl Neutral ammonium fluoride, tetrabutylammonium chloride, cesium carbonate, salt of wormwood, alkoxyl group negative ion or its arbitrary combination in step (c); Aprotic solvent is selected from dioxane, toluene, acetonitrile, N, dinethylformamide, methyl-sulphoxide, N,N-dimethylacetamide, N-Methyl pyrrolidone, dimethylamine, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride or its arbitrary combination.
Preferably, in the step (c), metal catalyst can be that palladium catalyst (0 valency or II valency) or other can play the metal catalyst of suitable catalytic effect, for example, four triphenyl phosphorus palladiums, palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, two (tricyclohexyl phosphine) palladium, two (tri-butyl phosphine) palladium, two (Er Ya Benzyl benzylacetones) palladium, two (triphenyl is seen) dichloride, three (dibenzalacetones), two palladiums, two (tricyclohexyl phosphine) palladium chloride, (1, the 5-cyclooctadiene) palladium chloride, two (1, two (diphenylphosphine) ethane of 2-) palladium, two (tri-o-tolyl phosphine) palladium chloride, 1, two (diphenylphosphine butane) palladium chlorides of 4-, 1, two (diphenylphosphine) propane of 3-) palladium chloride, 1,2-two (diphenylphosphino) ethane palladium chloride, palladium carbon, cupric iodide or Nickel Chloride or the like.
Again further, in step (d), formula
The compound reaction that under alkaline condition, in the mixing solutions of methyl alcohol and tetrahydrofuran (THF), is hydrolyzed, employed alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide.
Compared with prior art, the present invention has following advantage: avoid using the strong acid make solvent, reduced the dangerous of reaction and to the corrosion of equipment; Avoid using gas to participate in reaction, reduced the loaded down with trivial details property of operation, improved reaction safety; Avoid using hypertoxicity materials such as prussiate and non-oxidation two sulphur, safe; Avoided traditional structure thiazole ring method, adopted the catalytic aromatic ring coupling of palladium to introduce thiazole ring, synthesis step is short, only needs for 4 steps can synthesize final compound Febuxostat, and total recovery can reach more than 40%.
Embodiment
Below in conjunction with specific embodiment the present invention is described in further detail.
Example: Febuxostat-2-[3-cyano group-4-(2-methyl propoxy-) phenyl]-4-methyl-5 thiazol formic-acid synthetic
Synthesizing of 5-iodo-2-isobutyl phenyl ether nitrile
(2.8 mL, 30.2 mmol) are dissolved among the 50 mL DMF with 2-methyl isophthalic acid-propyl alcohol, are chilled to 0 ℃, add NaH(1.21 g, 30.2 mmol), stirred 30 minutes, add 2-fluoro-5 ioxynil (5.0 g, 20.2 mmol), rise to room temperature, stirring is spent the night.Add entry (100 mL), ethyl acetate (100 mL) extraction three times, organic phase is washed 2 times with saturated nacl aqueous solution (150 mL), anhydrous sodium sulfate drying, filter, concentrate silicagel column purifying (sherwood oil: ethyl acetate=20:1 wash-out), concentrate and obtain weak yellow liquid (5.78 g, 95% yield).
1
H-NMR（d-DMSO,?400?MHz）：1.00(d,?6H,?J=6.8),?2.05(m,?1H),3.90(d,?2H,?J=6.8),?7.06(d,?1H,?J=8.8),?7.93(dd,?1H),?8.04(d,?1H,?J=2.4)。
Synthesizing of 3-cyano-4-isobutoxy phenylo boric acid pinacol ester
Under nitrogen protection, to above-mentioned synthetic 5-iodo-2-isobutyl phenyl ether nitrile (4.9 g, 16 mmol), connection boric acid pinacol ester (8.3 g, 32 mmol), potassium acetate (4.8 g, 49 mmol) and DMSO(150 mL) mixed solution in add PdCl
2
(dppf) (1.32 g, 1.6 mmol) are heated to 80 ℃, and stirring is spent the night.Add entry (300 mL), with ethyl acetate (150 mL) extraction four times, after merging organic phase, with the saturated nacl aqueous solution washing once, anhydrous sodium sulfate drying filters, filtrate concentrates, silicagel column purifying (sherwood oil: ethyl acetate=20:1 wash-out), concentrate and obtain colourless liquid (3.53g, 72% yield).
1
H-NMR（d-DMSO,400?MHz）：1.00(d,?6H,?J=6.8),?1.28(s,?12H),?2.05(m,?1H),?3.94(d,?2H,?J=6.4),?7.25(d,?1H,?J=8.4),?7.84(d,?1H,?J=1.2),?7.88(dd,?1H)。
Synthesizing of 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid ethyl ester
Under nitrogen protection; to above-mentioned synthetic 3-cyano-4-isobutoxy phenylo boric acid pinacol ester (2.8g; 9.3 mmol), 2-bromo-4-methylthiazol ethyl formate (3.0 g; 12 mmol), 2N sodium carbonate solution (18.5 mL; 37 mmol) add four triphenyl phosphorus palladium (1.08 g and in the mixed solution of dioxane (200 mL); 0.93 mmol), gained solution is heated to 80 ℃, stirring is spent the night.Reaction solution is concentrated into dried, silicagel column purifying (sherwood oil: ethyl acetate=20:1 and 10:1 wash-out) concentrates and to obtain white solid (2.4g, 75% yield).
1
H-NMR（d-DMSO,?400?MHz）：1.02(d,?6H,?J=6.8),?1.30(t,?3H),?2.09(m,?1H),?2.68(s,?3H),?4.01(d,?2H,?J=6.4),?4.30(dd,?2H),?7.38(d,?1H,?J=8.8),?8.25(dd,?1H),?8.32(d,?1H,?J=2.4)。
Synthesizing of 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid (Febuxostat)
With above-mentioned synthetic 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid ethyl ester (100 mg, 0.29 mmol) be dissolved in the mixed solution of methyl alcohol and tetrahydrofuran (THF), add 1N NaOH(0.6 mL, 0.58 mmol), be heated to 70 ℃, stirred 3 hours.Mixed solution is concentrated into dried, add entry (10 mL), methylene dichloride (20 mL) extraction three times, organic phase is abandoned it, and water, extracts three times with methylene dichloride (20 mL) to 1-2 with 1N salt acid for adjusting pH value, the organic phase anhydrous sodium sulfate drying, filter, concentrate and obtain white solid (85 mg, 93% yield).
1
H-NMR（d-DMSO,400MHz）：1.02(d,?6H,?J=6.8),?2.09(m,?1H),?2.66(s,?3H),?4.01(d,?2H,?J=6.4),?7.37(d,?1H,?J=8.8),?8.22(dd,?1H),?8.28(d,?1H,?J=2),?13.40(s,?1H)。
Claims (10)
1. the synthetic method of a Febuxostat is characterized in that, may further comprise the steps:
(a) make formula
The substitution reaction of compound generation aromatic nucleus obtain formula
Compound;
(b) make the described formula of gained in the step (a)
Compound obtain formula through halogen-metal exchange reaction
Compound;
(c) make the described formula of gained in the step (b)
Compound and formula
Compound linked reaction takes place under the effect of metal catalyst obtains formula
Compound;
(d) make the described formula of gained in the step (c)
Compound obtain formula through hydrolysis reaction
The compound Febuxostat;
Wherein X is I, Br;
M is selected from boric acid ester or SnBu
3
R is H or alkyl.
2. the synthetic method of Febuxostat according to claim 1 is characterized in that: in step (a), and described formula
Compound under the condition that alkali exists, in aprotic solvent,, obtain described formula with 2-methyl isophthalic acid-propyl alcohol generation aromatic nucleus substitution reaction
Compound.
3. the synthetic method of Febuxostat according to claim 2, it is characterized in that: described alkali is selected from sodium, potassium, liquefied ammonia, sodium hydrogen, lithium diisopropylamine, hexamethyl two silica-based amido lithiums, sodium hexamethyldisilazide; Described aprotic solvent is selected from N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, ether, methyl tertiary butyl ether, dioxane, toluene, tetrahydrofuran (THF), methyl-sulphoxide or its arbitrary combination.
4. the synthetic method of Febuxostat according to claim 1 is characterized in that: in step (b), and described formula
Compound and metal exchange reagent in aprotic solvent, carry out halogen-metal exchange reaction and obtain described formula
Compound.
5. the synthetic method of Febuxostat according to claim 4 is characterized in that: described halogen-metal exchange reaction carried out 1-20 hour under-78-100 ℃ under protection of nitrogen gas.
6. the synthetic method of Febuxostat according to claim 4, it is characterized in that: described aprotic solvent is the inferior maple of diformazan, dioxane, toluene, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone or its arbitrary combination.
7. the synthetic method of Febuxostat according to claim 1 is characterized in that: in step (c), described linked reaction is carried out in aprotic solvent under the condition that alkali exists.
8. the synthetic method of Febuxostat according to claim 7, it is characterized in that: described alkali is selected from yellow soda ash, salt of wormwood, sodium acetate, potassium acetate, lithium hydroxide, hydrated barta, sodium hydroxide, triethylamine, cesium fluoride, Potassium monofluoride, tetra-n-butyl Neutral ammonium fluoride, tetrabutylammonium chloride, cesium carbonate, salt of wormwood, alkoxyl group negative ion or its arbitrary combination; Described aprotic solvent is selected from dioxane, toluene, acetonitrile, N, dinethylformamide, methyl-sulphoxide, N,N-dimethylacetamide, N-Methyl pyrrolidone, dimethylamine, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride or its arbitrary combination.
9. the synthetic method of Febuxostat according to claim 1 is characterized in that: in the step (c), described metal catalyst is (0) valency or (II) valency palladium catalyst, palladium carbon, cupric iodide or Nickel Chloride.
10. the synthetic method of Febuxostat according to claim 1 is characterized in that: in step (d), and described formula
The compound reaction that under alkaline condition, in the mixing solutions of methyl alcohol and tetrahydrofuran (THF), is hydrolyzed, employed alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide.
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| CN109293597A (en) * | 2018-10-29 | 2019-02-01 | 安徽省庆云医药股份有限公司 | A kind of preparation method of Febuxostat |
| CN110878064A (en) * | 2019-11-06 | 2020-03-13 | 武汉光谷亚太医药研究院有限公司 | High-yield synthesis method of certain specific impurity of febuxostat |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104130170A (en) * | 2014-08-11 | 2014-11-05 | 济南大学 | Synthesis method of 4-Hydroxythiobenzamide |
| CN109293597A (en) * | 2018-10-29 | 2019-02-01 | 安徽省庆云医药股份有限公司 | A kind of preparation method of Febuxostat |
| CN109293597B (en) * | 2018-10-29 | 2022-05-10 | 安徽省庆云医药股份有限公司 | Preparation method of febuxostat |
| CN110878064A (en) * | 2019-11-06 | 2020-03-13 | 武汉光谷亚太医药研究院有限公司 | High-yield synthesis method of certain specific impurity of febuxostat |
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