反应详情

To a suspension of 7,11-dichloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (34.0 g, 128.23 mmoles) in acetonitrile (300 mL) add methyl 2,2-dimethyl-3-(piperazin-1-yl)-propionate hydrochloride (2.1 equiv; 63.75 g, 269.29 mmoles) and potassium carbonate (4 equiv; 70.89 g, 512.93 mmoles). Heat the mixture at reflux overnight. Evaporate to dryness. Partition the residue between water (500 mL) and EtOAc (2×500 mL). Combine the organic layers and wash with water (500 mL) then brine. Dry over sodium sulfate, filter and evaporate to a brown oil. Add iso-hexane (˜150 mL) and a seed crystal of Preparation 50. Allow to crystallize over 2 h, then transfer the flask to a fridge and allow to stand. Collect the resulting heavy crystalline solid by filtration, washing with cold iso-hexane. Dry in a vacuum oven at 40° C. for 1 h, to give methyl 3-[4-(7-chloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (53.6 g, 97% yield). MS (m/z): 429.18 (M+1).

1. temperatureHeat the mixture
2. temperatureat reflux overnight
3. customEvaporate to dryness
4. customPartition the residue between water (500 mL) and EtOAc (2×500 mL)
5. washCombine the organic layers and wash with water (500 mL)
6. dry with materialDry over sodium sulfate
7. filtrationfilter
8. customevaporate to a brown oil
9. customAdd iso-hexane (˜150 mL) and a seed crystal of Preparation 50
10. customAllow to crystallize over 2 h
11. customCollect the resulting heavy crystalline solid
12. filtrationby filtration
13. washwashing with cold iso-hexane
14. customDry in a vacuum oven at 40° C. for 1 h