Abstract The quinazoline-based inhibitor of thymidylate synthase, Raltitrexed, was synthesized from 2, 5-thiophenedicarboxylic acid via mono-coupling with diethyl l-glutamate, modified Curtius reaction, N-methylation, removal of Boc-protecting group, condensation with (bromomethyl) quinazolinone and saponification in 18.2% overall yield.
[Marsham, Peter R.; Hughes, Leslie R.; Jackman, Ann L.; Hayter, Anthony J.; Oldfield, John; et al. Journal of Medicinal Chemistry, 1991 , vol. 34, # 5 p. 1594 - 1605]
![diethyl N-[5-[N-(tert-butoxycarbonyl)-N-methylamino]-2-thenoyl]-L-glutamate Structure](https://image.chemsrc.com/caspic/398/132463-33-3.png)
![Diethyl N-[5-methylamino-2-thenoyl]-L-glutamate Structure](https://image.chemsrc.com/caspic/095/112889-02-8.png)
![Diethyl N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N-methylamino]-2-thenoyl]-L-glutamate Structure](https://image.chemsrc.com/caspic/067/132463-02-6.png)