-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】5-[4-Methoxy-9(R)-methyl-6,7,8,9-tetrahydro[1,3]dioxolo[4,5-h]isoquinolin-8-ylmethyl]pyrimidine-2,4-diamine

【CA登记号】562856-94-4

【分子式】C₁₇H₂₁N₅O₃

【分子量】343.38862

【开发单位】Roche (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Dihydrofolate Reductase (DHFR) Inhibitors

合成路线1

Condensation of guanidine nitrate (I) with (ethoxymethylene)malononitrile (II) in the presence of NaOEt yields 2,4-diaminopyrimidine-5-carbonitrile (III). Reduction of nitrile (III) by means of Raney nickel in formic acid leads to aldehyde (IV), which is further reduced to alcohol (V) by means of NaBH4. Treatment of alcohol (V) with HBr in AcOH gives the bromide (VI), which is condensed with pyridine in DMF to form the crystalline pyridinium salt (VII). Finally, displacement of compound (VII) with the tetrahydroisoquinoline (VIII), followed by resolution by chiral HPLC, furnishes the title compound.

参考文献中间体

【1】 Gerber, P.; Wyss, P.C.; Hartman, P.G.; Hubschwerlen, C.; Locher, H.; Marty, H.-P.; Stahl, M.; Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening. J Med Chem 2003, 46, 12, 2304.

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)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(II)	13017	Ethoxymethylenemalononitrile; 2-(Ethoxymethylene)malononitrile	123-06-8	C₆H₆N₂O	详情	详情
(III)	64871	2,4-diamino-5-pyrimidinecarbonitrile		C₅H₅N₅	详情	详情
(IV)	26525	2,4-diamino-5-pyrimidinecarbaldehyde		C₅H₆N₄O	详情	详情
(V)	64872	(2,4-diamino-5-pyrimidinyl)methanol		C₅H₈N₄O	详情	详情
(VI)	64873	5-(bromomethyl)-2,4-pyrimidinediamine		C₅H₇BrN₄	详情	详情
(VII)	64874	1-[(2,4-diamino-5-pyrimidinyl)methyl]pyridinium bromide		C₁₀H₁₂BrN₅	详情	详情
(VIII)	64875	methyl 9-methyl-6,7,8,9-tetrahydro[1,3]dioxolo[4,5-h]isoquinolin-4-yl ether; 9-methyl-4-(methyloxy)-6,7,8,9-tetrahydro[1,3]dioxolo[4,5-h]isoquinoline		C₁₂H₁₅NO₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)