SB-435495, -Drug Synthesis Database

【结构式】

【药物名称】SB-435495

【化学名称】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

【CA登记号】304694-39-1, 304695-43-0 (4-methylbenzenesulfonate), 304694-45-9 (citrate), 304694-41-5 (hydrochloride), 304694-43-7 (tartrate)

【分子式】C₃₈H₄₀F₄N₆O₂S

【分子量】720.8391

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

【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

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).

参考文献中间体

【1】 Smith, S.A.; Inhibition of lipoprotein-associated phospholipase A2 - A novel approach for the treatment of atherosclerosis. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst .
【2】 Ife, R.J.; Leach, C.A.; Smith, S.A.; Pinto, I.L.; Hickey, D.M.B.; Fenwick, A.E. (GlaxoSmithKline plc); Pyrimidinone cpds.. EP 1175408; WO 0066567 .

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)	53042	1-methyl-1H-pyrazole-4-carbaldehyde	n/a	C₅H₆N₂O	详情	详情
(II)	53043	(E)-3-(1-methyl-1H-pyrazol-4-yl)-2-propenoic acid	n/a	C₇H₈N₂O₂	详情	详情
(III)	53044	methyl (E)-3-(1-methyl-1H-pyrazol-4-yl)-2-propenoate	n/a	C₈H₁₀N₂O₂	详情	详情
(IV)	53045	methyl 3-(1-methyl-1H-pyrazol-4-yl)propanoate	n/a	C₈H₁₂N₂O₂	详情	详情
(V)	53046	methyl (Z)-3-hydroxy-2-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-propenoate	n/a	C₉H₁₂N₂O₃	详情	详情
(VI)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VII)	53047	5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone	n/a	C₉H₁₀N₄OS	详情	详情
(VIII)	12354	4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene	352-11-4	C₇H₆ClF	详情	详情
(IX)	53048	2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4(1H)-pyrimidinone	n/a	C₁₆H₁₅FN₄OS	详情	详情
(X)	53049	tert-butyl 2-[2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-oxo-1(4H)-pyrimidinyl]acetate	n/a	C₂₂H₂₅FN₄O₃S	详情	详情
(XI)	53050	2-[2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-oxo-1(4H)-pyrimidinyl]acetic acid	n/a	C₁₈H₁₇FN₄O₃S	详情	详情

合成路线2

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.

参考文献中间体

【1】 Smith, S.A.; Inhibition of lipoprotein-associated phospholipase A2 - A novel approach for the treatment of atherosclerosis. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst .
【2】 Ife, R.J.; Leach, C.A.; Smith, S.A.; Pinto, I.L.; Hickey, D.M.B.; Fenwick, A.E. (GlaxoSmithKline plc); Pyrimidinone cpds.. EP 1175408; WO 0066567 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	53050	2-[2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-oxo-1(4H)-pyrimidinyl]acetic acid	n/a	C₁₈H₁₇FN₄O₃S	详情	详情
(XII)	22231	4-Bromobenzaldehyde	1122-91-4	C₇H₅BrO	详情	详情
(XIII)	48639	4-(Trifluoromethyl)phenylboronic acid		C₇H₆BF₃O₂	详情	详情
(XIV)	53051	4-[4-(trifluoromethyl)phenyl]benzaldehyde	n/a	C₁₄H₉F₃O	详情	详情
(XV)	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
(XVI)	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)