SB-239063, -Drug Synthesis Database

【结构式】

【药物名称】SB-239063

【化学名称】trans-4-[4-(4-Fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazol-1-yl]cyclohexanol
　　　　　　trans-4-(4-Fluorophenyl)-1-(4-hydroxycyclohexyl)-5-(2-methoxypyrimidin-4-yl)imidazole

【CA登记号】193551-21-2

【分子式】C₂₀H₂₁FN₄O₂

【分子量】368.41437

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Antipsoriatics, Cerebrovascular Diseases, Treatment of, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, DERMATOLOGIC DRUGS, NEUROLOGIC DRUGS, RESPIRATORY DRUGS, Stroke, Treatment of, IL-1 Inhibitors, p38 Protein Kinase Inhibitors, TNF-alpha Antagonists

合成路线1 合成路线2

合成路线1

The condensation of p- fluorobenzaldehyde (I) with p-toluenesulfinic acid (II) in the presence of camphorsulfonic acid in formamide produced the tosylmethyl formamide (III). This was dehydrated to the required isocyanide (IV) using POCl3 and Et3N in cold dimethoxyethane.

参考文献中间体

【1】 Adams, J.L.; Garigipati, R.S. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0883402; WO 9725047 .
【2】 Adams, J.L.; Garigipati, R.S.; Sorenson, M.E. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0889726; JP 2000503304; WO 9725048 .
【3】 Boehm, J.C.; Garigipati, R.S.; Adams, J.L. (SmithKline Beecham Corp.); Novel cycloalkyl substd. imidazoles. EP 1019396; WO 9901452 .

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
(III)	25594	(4-fluorophenyl)[(4-methylphenyl)sulfonyl]methylformamide		C₁₅H₁₄FNO₃S	详情	详情
(IV)	25595	4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide		C₁₅H₁₂FNO₂S	详情	详情

合成路线2

Condensation of pyruvic aldehyde dimethyl acetal (V) with dimethylformamide dimethyl acetal produced enamino ketone (VI). Cyclization of (VI) with thiourea (VII), followed by methylation with iodomethane furnished the (methylsulfanyl)pyrimidine (VIII). Acid hydrolysis of the dimethyl acetal gave rise to aldehyde (IX). Cyclohexanedione monoketal (X) was converted to oxime (XI) and then hydrogenated to give amine (XII). This was condensed with aldehyde (IX) yielding imine (XIII). Reaction of imine (XIII) with sulfonyl isocyanide (IV) gave rise to imidazole (XIV). The methylsulfanyl group of (XIV) was then oxidized to sulfone (XV) employing oxone®. Further displacement of the methylsulfonyl group of (XV) with NaOMe produced the methoxy pyrimidine (XVI). After ketal (XVI) hydrolysis, reduction of the resulting ketone (XVII) with NaBH4 furnished the title alcohol.

参考文献中间体

【1】 Adams, J.L.; Garigipati, R.S.; Sorenson, M.E. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0889726; JP 2000503304; WO 9725048 .
【2】 Adams, J.L.; Garigipati, R.S. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0883402; WO 9725047 .
【3】 Boehm, J.C.; Garigipati, R.S.; Adams, J.L. (SmithKline Beecham Corp.); Novel cycloalkyl substd. imidazoles. EP 1019396; WO 9901452 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	25595	4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide		C₁₅H₁₂FNO₂S	详情	详情
(V)	25433	1,1-dimethoxyacetone	6342-56-9	C₅H₁₀O₃	详情	详情
(VI)	25434	(E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one		C₈H₁₅NO₃	详情	详情
(VII)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VIII)	41422	methoxy[2-(methylsulfanyl)-4-pyrimidinyl]methyl methyl ether; 4-(dimethoxymethyl)-2-(methylsulfanyl)pyrimidine		C₈H₁₂N₂O₂S	详情	详情
(IX)	41423	2-(methylsulfanyl)-4-pyrimidinecarbaldehyde		C₆H₆N₂OS	详情	详情
(X)	11377	1,4-Dioxaspiro[4.5]decan-8-one	4746-97-8	C₈H₁₂O₃	详情	详情
(XI)	41424	1,4-dioxaspiro[4.5]decan-8-one oxime		C₈H₁₃NO₃	详情	详情
(XII)	41425	1,4-dioxaspiro[4.5]dec-8-ylamine; 1,4-dioxaspiro[4.5]decan-8-amine		C₈H₁₅NO₂	详情	详情
(XIII)	41426	N-(1,4-dioxaspiro[4.5]dec-8-yl)-N-[(Z)-[2-(methylsulfanyl)-4-pyrimidinyl]methylidene]amine; N-[(Z)-[2-(methylsulfanyl)-4-pyrimidinyl]methylidene]-1,4-dioxaspiro[4.5]decan-8-amine		C₁₄H₁₉N₃O₂S	详情	详情
(XIV)	41427	4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-(methylsulfanyl)pyrimidine; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl sulfide		C₂₂H₂₃FN₄O₂S	详情	详情
(XV)	41428	4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-(methylsulfonyl)pyrimidine; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl sulfone		C₂₂H₂₃FN₄O₄S	详情	详情
(XVI)	41429	4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl ether; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-methoxypyrimidine		C₂₂H₂₃FN₄O₃	详情	详情
(XVII)	41430	4-[4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)-1H-imidazol-1-yl]cyclohexanone		C₂₀H₁₉FN₄O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)