反应详情

To a mixture of rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (40.5 mg, 0.10 mmol) and triethylamine (TEA, 20.0 mg, 0.20 mmol) in CH2Cl2 (1 mL) was added phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol) by injection, and the reaction mixture was stirred at rt for 20 min. 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (29.4 mg, 0.20 mmol) was then added. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which was diluted with MeOH and treated with PPTS (cat.) at 120° C. for 5 min with CEM microwave reactor. The reaction mixture was concentrated and diluted with CH2Cl2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (23.5 mg, 43.8%, 2 steps) as a white amorphous. HRMS (ES+) m/z Calcd for C27H32Cl2FN3O3+H [(M+H)+]: 536.1878; Found: 536.1879.

1. stirringThe reaction mixture was stirred at rt for another 30 min
2. concentrationthen concentrated
3. customto give the crude product (checked by LCMS) which
4. concentrationThe reaction mixture was concentrated
5. additiondiluted with CH2Cl2
6. washwashed with water and brine
7. customThe organic phase was separated
8. filtrationfiltered
9. dry with materialdried over Na2SO4
10. concentrationThe mixture was then concentrated
11. custompurified by RP-HPLC