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【结 构 式】

【药物名称】

【化学名称】5-[3-(2,4-Diaminopyrimidin-5-ylmethyl)-4-methoxyphenoxy]pentanoic acid

【CA登记号】

【 分 子 式 】C17H22N4O4

【 分 子 量 】346.38929

【开发单位】Harvard Medical School (Originator)

【药理作用】AIDS Medicines, ANTIINFECTIVE THERAPY, Treatment of Opportunistic Infections, Dihydrofolate Reductase (DHFR) Inhibitors

合成路线1

Protection of 4-methoxyphenol (I) with methyl chloroformate in the presence of pyridine affords the carbonate ester (II), which is condensed with dichloromethyl methyl ether and TiCl4 to yield alpha-chloro ether (III). Acidic hydrolysis of (III) with HCl furnishes aldehyde (IV), which is converted into the sodium phenoxide (V) by methanolysis of the carbonate ester (IV). Subsequent alkylation of (V) with p-methoxybenzyl bromide (VI) produces the p-methoxybenzyl ether (VII), which is condensed with 3-morpholinopropionitrile (VIII) employing a catalytic amount of NaOMe to give the morpholino acrylonitrile (IX). After conversion of (IX) to the 3-anilino acrylonitrile (X) upon heating with aniline hydrochloride, condensation with guanidine (XI) produces the diaminopyrimidine (XII). The p-methoxybenzyl group of (XII) is then cleaved by treatment with p-toluenesulfonic acid in MeOH, producing phenol (XIII). The sodium salt generated from phenol (XIII) and NaOEt is then alkylated with ethyl 5-bromopentanoate (XIV) to furnish ether (XV). Finally, alkaline hydrolysis of the ethyl ester group of (XV) leads to the title compound.

1 Rosowsky, A.; Queener, S.F.; Forsch, R.A.; Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines: Marked improvement in potency relative to trimethoprim and species selectivity. J Med Chem 2002, 45, 1, 233.
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) 32744 4-methoxyphenol 150-76-5 C7H8O2 详情 详情
(II) 59058 4-methoxyphenyl methyl carbonate C9H10O4 详情 详情
(III) 59059 3-[chloro(methoxy)methyl]-4-methoxyphenyl methyl carbonate C11H13ClO5 详情 详情
(IV) 59060 3-formyl-4-methoxyphenyl methyl carbonate C10H10O5 详情 详情
(V) 59061 sodium 3-formyl-4-methoxybenzenolate C8H7NaO3 详情 详情
(VI) 27490 1-(bromomethyl)-4-methoxybenzene C8H9BrO 详情 详情
(VII) 59062 2-methoxy-5-[(4-methoxybenzyl)oxy]benzaldehyde C16H16O4 详情 详情
(VIII) 31933 3-Morpholinopropionitrile; 3-(4-Morpholinyl)propanenitrile 4542-47-6 C7H12N2O 详情 详情
(IX) 59063 (Z)-2-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-3-(4-morpholinyl)-2-propenenitrile C23H26N2O4 详情 详情
(X) 59064 (Z)-3-anilino-2-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-2-propenenitrile C25H24N2O3 详情 详情
(XI) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(XII) 59065 2-amino-5-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-4-pyrimidinylamine; 5-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-2,4-pyrimidinediamine C20H22N4O3 详情 详情
(XIII) 59066 3-[(2,4-diamino-5-pyrimidinyl)methyl]-4-methoxyphenol C12H14N4O2 详情 详情
(XIV) 37151 ethyl 5-bromopentanoate 14660-52-7 C7H13BrO2 详情 详情
(XV) 59067 ethyl 5-{3-[(2,4-diamino-5-pyrimidinyl)methyl]-4-methoxyphenoxy}pentanoate C19H26N4O4 详情 详情
Extended Information