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【结 构 式】

【药物名称】SB-226882

【化学名称】4-[4-(4-Fluorophenyl)-1-(4-piperidinyl)-1H-imidazol-5-yl]-N-methylpyrimidine-2-amine

【CA登记号】180869-16-3

【 分 子 式 】C19H21FN6

【 分 子 量 】352.41782

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, p38 Protein Kinase Inhibitors

合成路线1

The condensation of pyruvic aldehyde dimethyl acetal (I) with dimethylformamide dimethyl acetal (II) afforded ketoenamine (III), which was condensed with N-methyl guanidine (IV) to give pyrimidine (V). Acid hydrolysis of the acetal function of (V) yielded pyrimidine carboxaldehyde (VI), which was converted to the imine (VIII) by treatment with 1-Boc-4-aminopiperidine (VII). Isonitrile (XII) was prepared by condensation of 4-fluorobenzaldehyde (IX) with formamide and p-thiocresol (X), followed by dehydration of the resulting formamide (XI) by means of POCl3 and Et3N. Reaction of isonitrile (XII) with imine (VIII) in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) produced imidazole (XIII). Finally, acid deprotection of the Boc group of (XIII) provided the title compound.

1 Adams, J.L.; Gallagher, T.F.; Garigipati, R.S.; Boehm, J.C.; Sisko, J.; Peng, Z.-Q.; Lee, J.C.-L. (SmithKline Beecham plc); Certain 1,4,5-tri-substd. imidazole cpds. useful as cytokine. EP 0809499; JP 1998512555; US 5593992; WO 9621452 .
2 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 .
3 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25433 1,1-dimethoxyacetone 6342-56-9 C5H10O3 详情 详情
(II) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(III) 25434 (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one C8H15NO3 详情 详情
(IV) 28411 N-Methylguanidine 598-12-9 C2H7N3 详情 详情
(V) 28412 4-(dimethoxymethyl)-N-methyl-2-pyrimidinamine C8H13N3O2 详情 详情
(VI) 28413 2-(methylamino)-4-pyrimidinecarbaldehyde C6H7N3O 详情 详情
(VII) 28414 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine 87120-72-7 C10H20N2O2 详情 详情
(VIII) 28415 tert-butyl 4-([(Z)-[2-(methylamino)-4-pyrimidinyl]methylidene]amino)-1-piperidinecarboxylate C16H25N5O2 详情 详情
(IX) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(X) 25437 4-methylphenylhydrosulfide 106-45-6 C7H8S 详情 详情
(XI) 25438 (4-fluorophenyl)[(4-methylphenyl)sulfanyl]methylformamide C15H14FNOS 详情 详情
(XII) 28416 4-Fluoro-alpha-(4-methylphenylsulfanyl)benzyl isocyanide C15H12FNS 详情 详情
(XIII) 28417 tert-butyl 4-[4-(4-fluorophenyl)-5-[2-(methylamino)-4-pyrimidinyl]-1H-imidazol-1-yl]-1-piperidinecarboxylate C24H29FN6O2 详情 详情

合成路线2

In a related procedure, condensation of 4-fluorobenzaldehyde (IX) with formamide and p-toluenesulfinic acid (XIV) produced the tosyl formamide (XV), which was dehydrated by means of POCl3 and Et3N to give isonitrile (XVI). Imidazole (XIII) was then obtained by reaction of this isonitrile with imine (VIII). Finally, the Boc protecting group of (XIII) was removed by acid treatment as above.

1 Adams, J.L.; Gallagher, T.F.; Garigipati, R.S.; Boehm, J.C.; Sisko, J.; Peng, Z.-Q.; Lee, J.C.-L. (SmithKline Beecham plc); Certain 1,4,5-tri-substd. imidazole cpds. useful as cytokine. EP 0809499; JP 1998512555; US 5593992; WO 9621452 .
2 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 .
3 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 28415 tert-butyl 4-([(Z)-[2-(methylamino)-4-pyrimidinyl]methylidene]amino)-1-piperidinecarboxylate C16H25N5O2 详情 详情
(IX) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(XIII) 28417 tert-butyl 4-[4-(4-fluorophenyl)-5-[2-(methylamino)-4-pyrimidinyl]-1H-imidazol-1-yl]-1-piperidinecarboxylate C24H29FN6O2 详情 详情
(XIV) 25593 4-methylbenzenesulfinic acid C7H8O2S 详情 详情
(XV) 25594 (4-fluorophenyl)[(4-methylphenyl)sulfonyl]methylformamide C15H14FNO3S 详情 详情
(XVI) 25595 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide C15H12FNO2S 详情 详情
Extended Information