-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】4-[4-(4-Fluorophenyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine

【CA登记号】180869-35-6

【分子式】C₂₂H₂₇FN₆

【分子量】394.49909

【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3

合成路线1

Two related syntheses have been reported for this compound. The intermediate alpha-tosyl-(4-fluorobenzyl)isonitrile (V) was prepared by condensation of 4-fluorobenzaldehyde (I), p-toluenesulfinic acid (II) and formamide (III) in the presence of chlorotrimethylsilane (1-4), followed by dehydration of the resulting formamide derivative (IV) with POCl3 and triethylamine.

参考文献中间体

【1】 Sisko, J.; A one-pot synthesis of 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-amino-4-pyrimidinyl)imidazole: A potent inhibitor of P38 MAP kinase. J Org Chem 1998, 63, 13, 4529.
【2】 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 .
【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)	12337	4-fluorobenzaldehyde	459-57-4	C₇H₅FO	详情	详情
(II)	25593	4-methylbenzenesulfinic acid		C₇H₈O₂S	详情	详情
(IV)	25594	(4-fluorophenyl)[(4-methylphenyl)sulfonyl]methylformamide		C₁₅H₁₄FNO₃S	详情	详情
(V)	25595	4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide		C₁₅H₁₂FNO₂S	详情	详情

合成路线2

In the original procedure, pyruvic aldehyde dimethyl acetal (VI) was condensed with N,N-dimethylformamide dimethyl acetal to give enaminoketone (VII). Subsequent reaction of (VII) with guanidine (VIII) provided 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (IX), which was hydrolyzed to the corresponding aldehyde (X) with 3 N HCl at 48 C. This was condensed with 4-amino-2,2,6,6-tetramethylpiperidine (XI) to produce imine (XII). Finally, reaction between imine (XII) and tosyl isonitrile (V) in the presence of K2CO3 generated the target imidazole.

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】 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 .
【3】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	25595	4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide		C₁₅H₁₂FNO₂S	详情	详情
(VI)	25433	1,1-dimethoxyacetone	6342-56-9	C₅H₁₀O₃	详情	详情
(VII)	25434	(E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one		C₈H₁₅NO₃	详情	详情
(VIII)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(IX)	25435	4-(dimethoxymethyl)-2-pyrimidinylamine		C₇H₁₁N₃O₂	详情	详情
(X)	25436	2-amino-4-pyrimidinecarbaldehyde		C₅H₅N₃O	详情	详情
(XI)	25596	2,2,6,6-tetramethyl-4-piperidinamine	36768-62-4	C₉H₂₀N₂	详情	详情
(XII)	25597	4-[[(2,2,6,6-tetramethyl-4-piperidinyl)imino]methyl]-2-pyrimidinamine		C₁₄H₂₃N₅	详情	详情

合成路线3

A new procedure, which avoided the unstable pyrimidine aldehye (X), started by condensing pyruvic aldehyde (XIII) with aminopiperidine (XI). The resulting imine (XIV) was reacted with tosyl isonitrile (V) to form the acetyl imidazole (XV). Subsequent treatment of (XV) with N,N-dimethylformamide dimethyl acetal gave enaminoketone (XVI), which was then condensed with guanidine (VIII) to produce the required pyrimidine ring.

参考文献中间体

【1】 Sisko, J.; A one-pot synthesis of 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-amino-4-pyrimidinyl)imidazole: A potent inhibitor of P38 MAP kinase. J Org Chem 1998, 63, 13, 4529.
【2】 Sisko, J. (SmithKline Beecham plc); Novel synthesis. US 5917043; WO 9723479 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	25595	4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide		C₁₅H₁₂FNO₂S	详情	详情
(VIII)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(XI)	25596	2,2,6,6-tetramethyl-4-piperidinamine	36768-62-4	C₉H₂₀N₂	详情	详情
(XIII)	25598	2-oxopropanal	78-98-8	C₃H₄O₂	详情	详情
(XIV)	25599	1-[(2,2,6,6-tetramethyl-4-piperidinyl)imino]acetone		C₁₂H₂₂N₂O	详情	详情
(XV)	25600	1-[4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-1H-imidazol-5-yl]-1-ethanone		C₂₀H₂₆FN₃O	详情	详情
(XVI)	25601	(E)-3-(dimethylamino)-1-[4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-1H-imidazol-5-yl]-2-propen-1-one		C₂₃H₃₁FN₄O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)