反应详情

In a reaction vessel under nitrogen charge a solution of ethyl 1-(5-chloro-2-nitrobenzyl)-4-methyl-1H-pyrrole-2-carboxylate (100.0 g, 310 mmoles) in THF (800 mL) and add zinc dibromide (0.22 equiv; 15.4 g, 68.4 mmoles) with stirring at room temperature. Charge a slurry of 5% platinum(S)/charcoal (13.3 g) in THF (25 mL), and place the vessel under hydrogen at 380 kPa. Hydrogenate at room temperature for 30 hr. to 40 hr., monitoring formation of a partially hydrogenated intermediate and filter over diatomite. Rinse the filter aid with THF (300 mL) and concentrate the filtrate, at below 40° C., to arrive at a volume of approximately 200 mL. Add DCM (250 mL), concentrate the solution, at below 40° C., to arrive at a volume of approximately 200 mL, and add additional DCM (600 mL). This process can be repeated as necessary to remove undesired levels of THF from the reaction mixture. Charge water (500 mL), separate the layers, and wash the organic layer with water (300 mL), followed by 25% aqueous solution of sodium chloride (250 mL). Concentrate the solution, 40° C., to arrive at a volume of approximately 200 mL, add heptane (400 mL), and concentrate the solution, at below 40° C., to arrive at a volume of approximately 200 mL. Add heptane (400 mL) and heat the reaction mixture to 40-45° C. with stirring for 2-3 hr. Cool the reaction mixture to 5-10° C. and continue stirring at this temperature for 1-2 hr. Filter the resulting solids and dry in an oven at less than 50° C. under reduced pressure to give ethyl 1-(2-amino-5-chlorobenzyl)-4-methyl-1H-pyrrole-2-carboxylate (81.4 g, 95.8% purity, 85.9% yield) as a yellow solid.

1. waitto 40 hr
2. filtrationfilter over diatomite
3. washRinse the filter aid with THF (300 mL)
4. concentrationconcentrate the filtrate
5. customat below 40° C.
6. concentrationAdd DCM (250 mL), concentrate the solution
7. customat below 40° C.
8. additionadd additional DCM (600 mL)
9. customto remove undesired levels of THF from the reaction mixture
10. customCharge water (500 mL), separate the layers
11. washwash the organic layer with water (300 mL)
12. concentrationConcentrate the solution, 40° C.
13. additionadd heptane (400 mL)
14. concentrationconcentrate the solution
15. customat below 40° C.
16. temperatureAdd heptane (400 mL) and heat the reaction mixture to 40-45° C.
17. stirringwith stirring for 2-3 hr
18. temperatureCool the reaction mixture to 5-10° C.
19. stirringcontinue stirring at this temperature for 1-2 hr
20. filtrationFilter the resulting solids
21. customdry in an oven at less than 50° C. under reduced pressure