【药物名称】Raltitrexed, NSC-639186, ZN-D1694, ZD-1694, ICI-D-1694, D-1694, Tomudex
化学结构式(Chemical Structure):
参考文献No.7178
标题:Anti-tumor quinazolines
作者:Hughes, L.R. (AstraZeneca plc; National Research Development Corp.)
来源:EP 0239362; GB 2188319; JP 1989125373; US 4992550; US 5081124; US 5187167
合成路线图解说明:

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.

参考文献No.291113
标题:Tomudex (TM)
作者:Lohmeyer, M.; Casta馿r, J.
来源:Drugs Fut 1995,20(4),371
合成路线图解说明:

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.

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