Triethylamine → HCID 136351296, compound

Temperature

0 °C

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.;

1. customprepared
2. customto give a clear solution after about 1 minute
3. customthe ice-bath was then removed
4. stirringstirring
5. custom2 hours
6. custombefore being partitioned between ethyl acetate (80 ml) and water (80 ml)
7. customThe two layers were separated
8. washthe aqueous layer was washed with ethyl acetate (2×80 ml)
9. washsuccesively washed with 10% aqueous citric acid (80 ml), saturated aqueous sodium bicarbonate (80 ml) and dilute brine (80 ml)
10. dry with materialdried (Na2SO4)
11. concentrationconcentrated in vacuo to a yellow glass
12. dissolutionThis was dissolved in dichloromethane-methanol and to this solution silica gel (Merck Art 7734, 1.2 g)
13. additionwas added
14. customThe solvents were removed in vacuo
15. customto give a free running powder which
16. washElution of the column with ethyl acetate (~100 ml)
17. customwith a gradient of methanol in chloroform (2 to 3%) afforded a pale yellow solid which
18. customreprecipitated from dichloromethane (10 ml)-methanol (2 ml)/hexanes

ORD record

ord-86865902d40f44f690888e5c81773b5e

Source dataset

uspto-grants-1998_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05747499