反应详情

温度

78 °C

Alternatively the title compound may be prepared by the following procedure. Charge the 3-amino-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester prepared in preparation 37, diiodomethane, and acetonitrile to a 22 L round-bottom flask equipped with an addition funnel, thermocouple, overhead stirrer, and condenser. Dilute isoamyl nitrite with heptane and charge the resulting solution to the addition funnel. Warm the reaction mixture to 78° C. Add 0.65 L of the isoamyl nitrite solution over 1.75 hours, at which point vigorous evolution of nitrogen is observed. Suspend the addition of the isoamyl nitrite solution for about 20 minutes to allow the off-gassing to subside. Add the remainder of the isoamyl nitrite solution over 15 minutes. Stir the reaction mixture at reflux for an additional 2 hours, then cool to room temperature. Remove the solvent under reduced pressure and dilute the resulting concentrate with a mixture of 0.2 L pentane and 0.2 L methylene chloride. Pour the resulting mixture onto a 4 kg column of silica gel that is pre-wetted with cyclohexane. Elute the column with 5′ gallons of cyclohexane, and discard the eluent. Next, elute the column with 6 gallons of a 1:1 mixture of cyclohexane:methylene chloride, followed by 5 gallons of 3:2 cyclohexane:methylene chloride. Combine these fractions and remove the solvent under reduced pressure. Suspend the resulting solid in 0.5 L of heptane and stir for 45 minutes. Collect the product by filtration, rinse with heptane, and vacuum-dry at 40° C. to afford the title compound (432.8 g) in 57.6% yield. Mass spectrum (m/e): 333.0 (M+1).

1. customequipped with an addition funnel
2. temperatureat reflux for an additional 2 hours
3. temperaturecool to room temperature
4. customRemove the solvent under reduced pressure
5. additiondilute the resulting
6. concentrationconcentrate with a mixture of 0.2 L pentane and 0.2 L methylene chloride
7. additionPour the resulting mixture onto a 4 kg column of silica gel that
8. washElute the column with 5′ gallons of cyclohexane
9. washNext, elute the column
10. additionwith 6 gallons of a 1:1 mixture of cyclohexane
11. customremove the solvent under reduced pressure
12. stirringstir for 45 minutes
13. customCollect the product
14. filtrationby filtration
15. washrinse with heptane
16. customvacuum-dry at 40° C.