Triethylamine → HCID 136351296, compound

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of methyl (2S)-2-[N-(α-methyl-L-γ-glutamyl) amino]-4-(1-methoxycarbonylmethyltetrazol-5-yl)butyrate (0.220 g, 0.575 mmol) in anhydrous DMF (3.5 ml) cooled to 0° C. under nitrogen was added p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid (0.171 g, 0.46 mmol), prepared as described in Example 13(5), followed by diethyl phosphorocyanidate (0.164 g, 1.01 mmol) and triethylamine (0.102 g, 1.01 mmol) to give a clear solution after about 1 minute. The reaction mixture was stirred at 0° C. for 10 minutes, the ice-bath was then removed and stirring was continued for 21/2 hours under nitrogen before being partitioned between ethyl acetate (80 ml) and water (80 ml). The two layers were separated and the aqueous layer was washed with ethyl acetate (2×80 ml). The organics were combined and succesively washed with 10% aqueous citric acid (80 ml), saturated aqueous sodium bicarbonate (80 ml) and dilute brine (80 ml), dried (Na2SO4) and concentrated in vacuo to a yellow glass. This was dissolved in dichloromethane-methanol and to this solution silica gel (Merck Art 7734, 1.2 g) was added. The solvents were removed in vacuo to give a free running powder which was placed on a silica gel column made up in ethyl acetate. Elution of the column with ethyl acetate (~100 ml) and then with a gradient of methanol in chloroform (2 to 3%) afforded a pale yellow solid which reprecipitated from dichloromethane (10 ml)-methanol (2 ml)/hexanes to give the title compound as a white solid (0.143 g). Because of the low yield, the initial aqueous washing and the citric acid washings, obtained during the work-up, were combined and then extracted with ethyl acetate (2×150 ml), dried (Na2SO4) and concentrated in vacuo to give methyl (2S)-2-{N-{N-{p[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)-amino]benzoyl}-α-methyl-L-γ-glutamyl}amino}-4-(1-methoxycarbonylmethyltetrazol-5-yl)butyrate as a white solid. Purification as described above afforded an additional 0.060 g of the product, m.p. 197°-200° C.;

Provenance & Evidence