Raltitrexed, NSC-639186, ZN-D1694, ZD-1694, ICI-D-1694, D-1694, Tomudex

雷替曲塞Chemical Name: N-[5-[N-Methyl-N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)amino]-2-thenoyl]-L-glutamic acid
CAS No. 112887-68-0
项目整合开发状态: Launched-1996
项目研究机构: BTG (Originator), National Cancer Institute (Not Determined), AstraZeneca (Licensee), Ben Venue (Licensee)
合成路线:The acylation of diethyl L-glutamate (I) with 5-nitro-2-thienylcarbonyl chloride (II) in toluene gives N-(5-nitrothien-2-ylcarbonyl)-L-glutamic acid diethyl ester (III),which is reduced with sodium dithionite in ethanol/water to the corresponding amino compound (IV).The methylation of (IV) with methyl iodide and 2,6-lutidine yields the corresponding methylamine (V),which is condensed with 6-(bromomethyl)-2-methylquinazolin-4(3H)-one (VI) by means of 2,6-lutidine in hot DMF affording the diethyl ester (VIII) of D-1694.Finally,this compound is hydrolyzed with NaOH in ethanol/water.The bromomethyl quinazoline (VI) was obtained by selective radical bromination of 2,6-dimethylquinazolin-4(3H)-one (VII) with N-bromosuccinimide (NBS) and benzoyl peroxide in hot chloroform.