反应详情

4-amino-2,5-difluoro-benzoic acid (Rare Chemicals GmbH; 450 mg, 2.6 mmol), (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 473 mg, 2.73 mmol), HATU (1.08 g 2.86 mmol) and DIPEA (2.25 mL, 13 mmol) were combined in DMF (10 mL) and stirred at room temperature for 4 hours. The solvent was evaporated and the residue dissolved in MeOH and added to an SCX-2 column (20 g), pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material dissolved in DCM and purified on a silica column eluting with 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to a yellow gum. Diethylether was added and re-evaporated and dried under high vacuum to yield the title compound as a yellow gum, which slowly crystallised to a cream solid (550 mg, 83%)

1. customThe solvent was evaporated
2. dissolutionthe residue dissolved in MeOH
3. additionadded to an SCX-2 column (20 g), pre-wet with MeOH (2 column volumes)
4. customThe column was flushed with MeOH (2 column volumes)
5. washeluted with 2M ammonia in MeOH
6. additionProduct containing fractions
7. customevaporated
8. dissolutionthe resultant material dissolved in DCM
9. custompurified on a silica column
10. washeluting with 5% 2M ammonia in MeOH/DCM
11. additionFractions containing product
12. customevaporated to a yellow gum
13. additionDiethylether was added
14. customre-evaporated
15. customdried under high vacuum