反应详情

温度

5 °C

A 50 mL flask with mechanical stirrer, thermometer and N2 adapter was charged with 1.93 g (corrected for assay) of 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid (2.5 g, potency 77%) and 13.5 mL of dimethylformamide. The slurry was stirred 15 minutes and 1.94 grams of N-methylmorpholine (2.9 eq) was added. The mixture was cooled to 5° C. with an ice/water bath and chlorodimethoxytriazine (1.46 grams, 1.28 eq.) was added all at once. The mixture was stirred 40 minutes before L-glutamic acid diethyl ester (1.99 g, 1.28 eq) was added all at once. The reaction was allowed to warm to ambient temperature. The reaction was monitored by HPLC (reverse phase, gradient 20% to 46% acetonitrile:0.5% acetic acid buffer) and was complete in 1 hour at 23° C. The reaction mixture was transferred to a 250 mL Erlenmeyer flask containing 36 mL of deionized water and 18 mL of methylene chloride. The reaction flask was rinsed with 18 mL of methylene chloride which was added to the Erlenmeyer flask. The mixture was stirred 15 minutes and the layers were allowed to separate. The methylene chloride layer was concentrated from 46 grams to 13 grams using a rotary evaporator at reduced pressure at a bath temperature at 45° C. The concentrate was diluted with 55 mL of 3A alcohol, and concentrated again to 10 grams to remove methylene chloride. The concentrate was diluted to a total volume of 60 mL with 3A alcohol and the resulting solution was heated to 70° C. to 75° C. p-Toluenesulfonic acid (3.16 g, 2.57 eq.) dissolved in 55 mL of 3A alcohol were added over 30-90 minutes. The resulting slurry was refluxed for an hour. The slurry was cooled to ambient temperature and filtered using a 7 cm Buchner funnel. The wet cake was washed with 25 mL ethanol and dried in vacuo at 50° C. overnight to yield 3.66 grams of the title compound. Potency 95%

1. additionwas added all at once
2. temperatureto warm to ambient temperature
3. waitwas complete in 1 hour at 23° C
4. washThe reaction flask was rinsed with 18 mL of methylene chloride which
5. additionwas added to the Erlenmeyer flask
6. stirringThe mixture was stirred 15 minutes
7. customto separate
8. concentrationThe methylene chloride layer was concentrated from 46 grams to 13 grams
9. customa rotary evaporator at reduced pressure at a bath temperature at 45° C
10. additionThe concentrate was diluted with 55 mL of 3A alcohol
11. concentrationconcentrated again to 10 grams
12. customto remove methylene chloride
13. additionThe concentrate was diluted to a total volume of 60 mL with 3A alcohol
14. additionwere added over 30-90 minutes
15. temperatureThe resulting slurry was refluxed for an hour
16. temperatureThe slurry was cooled to ambient temperature
17. filtrationfiltered
18. washThe wet cake was washed with 25 mL ethanol
19. customdried in vacuo at 50° C. overnight