SB-435495
N-[2-(二乙胺基)乙基]-2-[2-(4-氟苯基磺酰)-5-(1-甲基-1H-吡哧唑-4-甲基)-4-氧基-1,4-二氢嘧啶-1-基]-N-[4'-(三氟甲基)双苯基-4-甲基]乙酰胺Chemical Name: N-[2-(Diethylamino)ethyl]-2-[2-(4-fluorobenzylsulfanyl)-5-(1-methyl-1H-pyrazol-4-ylmethyl)-4-oxo-1,4-dihydropyrimidin-1-yl]-N-[4'-(trifluoromethyl)biphenyl-4-ylmethyl]acetamide
CAS No. 304694-39-1, 304695-43-0 (4-methylbenzenesulfonate), 304694-45-9 (citrate), 304694-41-5 (hydrochloride), 304694-43-7 (tartrate)
项目整合开发状态: Phase I
项目研究机构: GlaxoSmithKline (Originator), Human Genome Sciences (Codevelopment)
合成路线:The Knoevenagel condensation of 1-methylpyrazole-4-carboxaldehyde (I) with malonic acid afforded the pyrazolylacrylic acid (II),which was further esterified with methanol and sulfuric acid,yielding ester (III).Catalytic hydrogenation of the unsaturated ester (III) in the presence of Pd/C gave the pyrazolylpropionate (IV).Claisen condensation of ester (IV) with methyl formate by using potassium tert-butoxide produced the (hydroxymethylene)propionate (V),which was subsequently cyclized with thiourea (VI) to furnish the thiouracil derivative (VII).Alkylation of (VII) with 4-fluorobenzyl chloride (VIII) gave rise to the thioether (IX).Regioselective alkylation of pyrimidine (IX) with tert-butyl iodoacetate produced the pyrimidinylacetate (X).The tert-butyl ester of (X) was then cleaved with trifluoroacetic acid yielding carboxylic acid (XI).
合成路线:Suzuki coupling between 4-bromobenzaldehyde (XII) and 4-trifluoromethylbenzeneboronic acid (XIII) produced the biphenyl compound (XIV).The reductive amination of aldehyde (XIV) with N,N-diethyl ethylenediamine (XV) gave diamine (XVI) (1).This was finally coupled with the intermediate carboxylic acid (XI) to afford the title amide.
📌 参考资料/链接：
参考文献标题:Pyrimidinone cpds.
文献作者:Ife,R.J.; Leach,C.A.; Smith,S.A.; Pinto,I.L.; Hickey,D.M.B.; Fenwick,A.E.(GlaxoSmithKline plc)
参考来源:EP 1175408; WO 0066567
📄 详细内容
合成路线:The Knoevenagel condensation of 1-methylpyrazole-4-carboxaldehyde (I) with malonic acid afforded the pyrazolylacrylic acid (II),which was further esterified with methanol and sulfuric acid,yielding ester (III).Catalytic hydrogenation of the unsaturated ester (III) in the presence of Pd/C gave the pyrazolylpropionate (IV).Claisen condensation of ester (IV) with methyl formate by using potassium tert-butoxide produced the (hydroxymethylene)propionate (V),which was subsequently cyclized with thiourea (VI) to furnish the thiouracil derivative (VII).Alkylation of (VII) with 4-fluorobenzyl chloride (VIII) gave rise to the thioether (IX).Regioselective alkylation of pyrimidine (IX) with tert-butyl iodoacetate produced the pyrimidinylacetate (X).The tert-butyl ester of (X) was then cleaved with trifluoroacetic acid yielding carboxylic acid (XI).
合成路线:Suzuki coupling between 4-bromobenzaldehyde (XII) and 4-trifluoromethylbenzeneboronic acid (XIII) produced the biphenyl compound (XIV).The reductive amination of aldehyde (XIV) with N,N-diethyl ethylenediamine (XV) gave diamine (XVI) (1).This was finally coupled with the intermediate carboxylic acid (XI) to afford the title amide.
参考文献标题:Inhibition of lipoprotein-associated phospholipase A2 - A novel approach for the treatment of atherosclerosis
文献作者:Smith,S.A.
参考来源:11th RSC-SCI Med Chem Symp (Sept 9 2001,Cambridge) 2001,Abst
产品链接: CAS No. 304694-39-1››