SB-226882, -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

【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.

参考文献中间体

【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

Drug NewChemical Entity Original Patent(1)