Water → HCID 68155891, compound

Temperature

77.5 °C

To a solution of ethyl 1-[(2-amino-5-chloro-phenyl)methyl]-4-methyl-pyrrole-2-carboxylate (20 g, 68.3 mmoles) in dimethyl sulfoxide (60 mL) add potassium t-butoxide (8.4 g, 74.9 mmoles) in DMSO (40 mL) and heat the reaction mixture to 75-80° C. for 1-2 hr. Add water (200 mL) slowly, cool to room temperature, and stir for 1-2 hr. Filter the solids, wash the filtercake with water (75 mL), and transfer the solids to a clean reaction vessel. Add THF (100 mL) and heat the reaction mixture to 30-35° C. until the solids dissolve. Add DCM (350 mL) and continue to stir at 30-35° C. for 1-2 hr. Add 1N hydrochloric acid (250 mL) and continue to stir at 30-35° C. for 1-2 hr. Separate the layers, wash the organic layer with 1N hydrochloric acid (250 mL) followed by a 25% aqueous solution of sodium chloride (50 mL), and concentrate the solution, at below 50° C., to arrive at a volume of approximately 25 mL. Add ethanol (50 mL), concentrate the solution, at below 50° C., to arrive at a volume of approximately 25 mL, and add additional ethanol (50 mL). Concentrate the solution, at below 50° C., to arrive at a volume of approximately 25 mL, heat the reaction mixture to 45-50° C., and stir for 1-2 hr. Cool the reaction mixture to 5-10° C. with stirring for 2-3 hr., and filter the resulting solids. Rinse the filtercake with ethanol (25 mL) and dry in an oven at less than 50° C. under reduced pressure to give 7-chloro-2-methyl-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one as an off-white solid (14.9 g, 99.9% purity, 88.5% yield).

1. filtrationFilter the solids
2. washwash the filtercake with water (75 mL)
3. temperatureAdd THF (100 mL) and heat the reaction mixture to 30-35° C. until the solids
4. dissolutiondissolve
5. stirringto stir at 30-35° C. for 1-2 hr
6. additionAdd 1N hydrochloric acid (250 mL)
7. stirringto stir at 30-35° C. for 1-2 hr
8. customSeparate the layers
9. washwash the organic layer with 1N hydrochloric acid (250 mL)
10. concentrationconcentrate the solution
11. customat below 50° C.
12. concentrationAdd ethanol (50 mL), concentrate the solution
13. customat below 50° C.
14. additionadd additional ethanol (50 mL)
15. concentrationConcentrate the solution
16. customat below 50° C.
17. temperatureheat the reaction mixture to 45-50° C.
18. stirringstir for 1-2 hr
19. temperatureCool the reaction mixture to 5-10° C.
20. stirringwith stirring for 2-3 hr
21. filtration, and filter the resulting solids
22. washRinse the filtercake with ethanol (25 mL)
23. customdry in an oven at less than 50° C. under reduced pressure

ORD record

ord-40cb065791e541b5802269de3cdaf981

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08314092B2