480848, SB-480848, -Drug Synthesis Database

【结构式】

【药物名称】480848, SB-480848

【化学名称】N-[2-(Diethylamino)ethyl]-2-[2-(4-fluorobenzylsulfanyl)-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-y]-N-[4'-(trifluoromethyl)-1,1'-biphenyl-4-ylmethyl]acetamide

【CA登记号】356057-34-6, 356057-36-8 (mono HCl salt)

【分子式】C₃₆H₃₈F₄N₄O₂S

【分子量】666.78746

【开发单位】GlaxoSmithKline (Originator), Human Genome Sciences (Originator)

【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Lipoprotein Associated Phospholipase 2 (Lp-PLA2) Inhibitors

合成路线1 合成路线2

合成路线1

Condensation between ethyl 2-oxocyclopentanecarboxylate (I) and thiourea (II) gives rise to the thiouracil derivative (III) (1,2). This is then alkylated with 4-fluorobenzyl chloride (IV) to yield thioether (V). Subsequent alkylation of (V) with tert-butyl iodoacetate (VI) furnishes adduct (VII). Further acidic cleavage of the tert-butyl ester group of (VII) leads to carboxylic acid (VIII) (2,3). Alternatively, intermediate (VIII) is prepared by alkylation of (V) with triflate (IX), followed by alkaline hydrolysis of the resultant methyl ester (X)

参考文献中间体

【1】 The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2003, 13, 6, 1067.
【2】 Ife, R.J.; Leach, C.A.; Hickey, D.M.B.; Pinto, I.L.; Smith, S.A.; Stanway, S.J. (GlaxoSmithKline plc); Pyrimidine-4-one derivs. as LDL-PLA 2 inhibitors. EP 1263740; JP 2003523335; US 2002103213; US 6649619; WO 0160805 .
【3】 Mulholland, K.R.; Ross, A.R.; Smith, G.E.; Slater, G.R. (GlaxoSmithKline plc); Novel processes. WO 0316287 .

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)	29947	ethyl 2-oxocyclopentanecarboxylate	611-10-9	C₈H₁₂O₃	详情	详情
(II)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(III)	63490	2-sulfanyl-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one		C₇H₈N₂OS	详情	详情
(IV)	12354	4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene	352-11-4	C₇H₆ClF	详情	详情
(V)	63491	2-{[(4-fluorophenyl)methyl]sulfanyl}-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one		C₁₄H₁₃FN₂OS	详情	详情
(VI)	24735	tert-Butyl 2-iodoacetate		C₆H₁₁IO₂	详情	详情
(VII)	63492	1,1-dimethylethyl 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetate		C₂₀H₂₃FN₂O₃S	详情	详情
(VIII)	63494	2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid		C₁₆H₁₅FN₂O₃S	详情	详情
(IX)	63493	methyl 2-{[(trifluoromethyl)sulfonyl]oxy}acetate		C₄H₅F₃O₅S	详情	详情
(X)	63495	methyl 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetate		C₁₇H₁₇FN₂O₃S	详情	详情

合成路线2

Suzuki coupling between 4-bromobenzaldehyde (XI) and 4-trifluoromethylbenzeneboronic acid (XII) affords the biphenylyl aldehyde (XIII). This is then reductively aminated with N,N-diethylethylenediamine (XIV) and NaBH4 to produce diamine (XV) (1,3). Finally, coupling between amine (XV) and carboxylic acid (VIII) leads to the title carboxamide

参考文献中间体

【1】 The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2003, 13, 6, 1067.
【2】 Ife, R.J.; Leach, C.A.; Hickey, D.M.B.; Pinto, I.L.; Smith, S.A.; Stanway, S.J. (GlaxoSmithKline plc); Pyrimidine-4-one derivs. as LDL-PLA 2 inhibitors. EP 1263740; JP 2003523335; US 2002103213; US 6649619; WO 0160805 .
【3】 Mulholland, K.R.; Ross, A.R.; Smith, G.E.; Slater, G.R. (GlaxoSmithKline plc); Novel processes. WO 0316287 .

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)	63494	2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid		C₁₆H₁₅FN₂O₃S	详情	详情
(XI)	22231	4-Bromobenzaldehyde	1122-91-4	C₇H₅BrO	详情	详情
(XII)	48639	4-(Trifluoromethyl)phenylboronic acid		C₇H₆BF₃O₂	详情	详情
(XIII)	53051	4-[4-(trifluoromethyl)phenyl]benzaldehyde	n/a	C₁₄H₉F₃O	详情	详情
(XIV)	12420	N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine	100-36-7	C₆H₁₆N₂	详情	详情
(XV)	53052	N-[2-(diethylamino)ethyl]-N-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}amine; N~1~,N~1~-diethyl-N~2~-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1,2-ethanediamine	n/a	C₂₀H₂₅F₃N₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)