反应详情

温度

140 °C

Dissolve methyl 2,2-dimethyl-3-(piperazin-1-yl)-propanoate dihydrochloride (1.49 g, 5.47 mmoles) in water and absorb onto an SCX2 column. Wash the column with methanol and elute methyl 2,2-dimethyl-3-piperazin-1-yl-propanoate with 2M ammonia in methanol. Remove the methanol in vacuo and add the methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate to acetonitrile (12 mL). Add 2,11-dichloro-7-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.85 g, 3.22 mmoles) and sodium bicarbonate (0.405 g, 4.83 mmoles) to the acetonitrile solution. Heat and stir in the microwave for 30 minutes at 140° C. Cool to room temperature, absorb the reaction mixture onto silica and purify by chromatography (gradient elution with EtOAc/isohexane 0:100% to 100:0%). Collect the fractions containing product and evaporate the solvent in vacuo and dissolve the residue in methanol (10 mL) and add lithium hydroxide (0.235 g, 9.65 mmoles). Heat and stir the methanolic solution in the microwave for 12.5 minutes at 140° C. Cool to room temperature and acidify with acetic acid and then evaporate the solvent under reduced pressure. Dissolve the residue in excess 2M HCl (aq) and then evaporated to dryness. Dissolve the residue in water and immobilise onto a macroporous polystyrene hydrogen carbonate (PL-HCO3) resin. Wash the resin with water and elute from the resin with 2M HCl (aq). Evaporate the solution to dryness to give 3-[4-(2-chloro-7-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoic acid dihydrochloride (0.177 g; 11.28% yield). MS (m/z): 415.18 (M+1).

1. customabsorb onto an SCX2 column
2. washWash the column with methanol
3. washelute methyl 2,2-dimethyl-3-piperazin-1-yl-propanoate with 2M ammonia in methanol
4. customRemove the methanol in vacuo
5. additionadd the methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate to acetonitrile (12 mL)
6. temperatureHeat
7. temperatureCool to room temperature
8. customabsorb the reaction mixture onto silica
9. custompurify by chromatography (gradient elution with EtOAc/isohexane 0:100% to 100:0%)
10. customCollect the fractions
11. additioncontaining product
12. customevaporate the solvent in vacuo
13. dissolutiondissolve the residue in methanol (10 mL)
14. temperatureHeat
15. stirringstir the methanolic solution in the microwave for 12.5 minutes at 140° C
16. temperatureCool to room temperature
17. customevaporate the solvent under reduced pressure
18. dissolutionDissolve the residue in excess 2M HCl (aq)
19. customevaporated to dryness
20. dissolutionDissolve the residue in water
21. washWash the resin with water
22. washelute from the resin with 2M HCl (aq)
23. customEvaporate the solution to dryness