Piritrexim, 301U74, NSC-351521, BW-301U, -Drug Synthesis Database

【结构式】

【药物名称】Piritrexim, 301U74, NSC-351521, BW-301U

【化学名称】6-(2,5-Dimethoxyphenylmethyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
　　　　　　2,4-Diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine

【CA登记号】72732-56-0, 79483-69-5 (isethionate)

【分子式】C₁₇H₁₉N₅O₂

【分子量】325.37328

【开发单位】GlaxoSmithKline (Originator), Ilex Oncology (Licensee)

【药理作用】Bladder Cancer Therapy , Oncolytic Drugs, Antimetabolites, Dihydrofolate Reductase (DHFR) Inhibitors

合成路线1 合成路线2

合成路线1

The synthesis of [14C]-labeled piritrexim has been described: The condensation of 2,5-dimethoxybenzaldehyde (I) with acetone in aqueous NaOH gives 4-(2,5-dimethoxyphenyl)-3-(E)-buten-2-one (II), which is hydrogenated with H2 over Pd/C in methanol to give 4-(2,5-dimethoxyphenyl)-2-butanone (III). The condensation of (III) with malononitrile (IV) by means of acetic acid-sodium acetate in refluxing toluene yields 2-cyano-5-(2,5-dimethoxyphenyl)-3-methyl-2-pentenenitrile (V), which is condensed with acetic acid diethoxymethyl ester (VI) at 105 C to afford the corresponding diethoxymethyl derivative (VII). The cyclization of (VII) with 32% HBr in acetic acid affords 2-bromo-5-(2,5-dimethoxybenzyl)-4-methylpyridine-3-carbonitrile (VIII), which is finally cyclized again with [14C]-labeled guanidine (IX) by means of NaH in refluxing tert-butyl alcohol.

参考文献中间体

【1】 Wisowaty, J.C.; Darnofall, M.E.; Hill, J.A.; Synthesis of carbon-14 labelled piritrexim - A potential anticancer agent. J Label Compd Radiopharm 1993, 33, 12, 1119.

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)	10174	2,5-Dimethoxybenzaldehyde	93-02-7	C₉H₁₀O₃	详情	详情
(II)	10175	(E)-4-(2,5-Dimethoxyphenyl)-3-buten-2-one		C₁₂H₁₄O₃	详情	详情
(III)	10176	4-(2,5-Dimethoxyphenyl)-2-butanone		C₁₂H₁₆O₃	详情	详情
(IV)	12061	Malononitrile	109-77-3	C₃H₂N₂	详情	详情
(V)	10177	2-[3-(2,5-Dimethoxyphenyl)-1-methylpropylidene]malononitrile		C₁₅H₁₆N₂O₂	详情	详情
(VI)	17661	Diethoxymethyl acetate	14036-06-7	C₇H₁₄O₄	详情	详情
(VII)	10178	2-[2-(2,5-Dimethoxybenzyl)-3,3-diethoxy-1-methylpropylidene]malononitrile		C₂₀H₂₆N₂O₄	详情	详情
(VIII)	10179	2-Bromo-5-(2,5-dimethoxybenzyl)-4-methylnicotinonitrile		C₁₆H₁₅BrN₂O₂	详情	详情
(IX)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(IX)	44601	guanidine		CH₅N₃	详情	详情

合成路线2

The reaction of 2,5-dimethoxybenzaldehyde (I) with ethyl acetoacetate (II) in a mixture of piperidine and glacial acetic acid in refluxing benzene gives ethyl alpha-acetyl-beta-(2,5-dimethoxyphenyl)acrylate (III), which is hydrogenated in a Parr low-pressure apparatus using 5% palladium on charcoal catalyst in ethyl acetate to yield ethyl alpha-acetyl-(2,5-dimethoxyphenyl)propionate (IV). The condensation of the propionate (IV) with 2,4.6-triaminopyrimidine in diphenylether at 195-230 C provides 2,4-diamino-7,8-dihydro-6-(2,5-dimethoxybenzyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidine (VI). The key intermediate (VI) is converted to the 7-chloro compound (VII) by treatment with a 1:1 complex of N,N-dimethylformamide thionyl chloride, and finally (VII) is hydrogenolyzed with palladium on charcoal in the presence of potassium hydroxide to yield BW-301 U.

参考文献中间体

【1】 Grivsky, E.M.; et al.; Synthesis and antitumor activity of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine. J Med Chem 1980, 23, 3, 327-329.
【2】 Sigel, C.W.; BW-301 U. Drugs Fut 1985, 10, 2, 108.

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)	10174	2,5-Dimethoxybenzaldehyde	93-02-7	C₉H₁₀O₃	详情	详情
(II)	11819	ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate	141-97-9	C₆H₁₀O₃	详情	详情
(III)	28975	ethyl (Z)-2-acetyl-3-(2,5-dimethoxyphenyl)-2-propenoate		C₁₅H₁₈O₅	详情	详情
(IV)	28976	ethyl 2-(2,5-dimethoxybenzyl)-3-oxobutanoate		C₁₅H₂₀O₅	详情	详情
(V)	28977	2,6-diamino-4-pyrimidinylamine	1004-38-2	C₄H₇N₅	详情	详情
(VI)	28978	2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one		C₁₇H₁₉N₅O₃	详情	详情
(VII)	28979	2-amino-7-chloro-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin-4-ylamine		C₁₇H₁₈ClN₅O₂	详情	详情

Extended Information