Triethylamine → (R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide

In a 50 L glass reactor, dry methanol 21.43 L, containing 0.01% water, D-alaninamide hydrochloride (589.9 g; 4.72 mol), triethylamine (477.8 g; 4.72 mol) 4-(2-fluorobenzyloxy)benzaldehyde (1000 g, 4.33 mol) prepared as described in Example 23.1a) with GC purity 93.20 (area %, see Example 24A) and a content of 3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde of 0.43% by weight determined by GC (see Example 24B), and 3A° molecular sieves (430.62 g) are loaded under stirring and under nitrogen at room temperature. The mixture is heated up to 40° C. and stirred at this temperature for 4 hours. The reaction temperature is then lowered to 10° C. and sodium borohydride (82.58 g, 2.16 mol) is added portion wise in 30 min. The reaction mixture is warmed up to room temperature while stirring for additional 6 hours at 20±2° C. The reaction mixture is filtered and evaporated to dryness under vacuum. The residue is taken up with water (16 L) and toluene (14 L) at 60° C., the organic phase is separated and added with water (16 L). The two phases mixture is warmed up to 60° C.±2 under stirring. The organic phase is separated and added with water (16 L). The two phases mixture is warmed up to 60° C.±2 under stirring. The organic phase is dried by azeotropic distillation at about 60° C. under vacuum. The aqueous phases are combined together (solution A, about 50 L). The toluenic solution is gradually cooled to 10° C. The mixture is kept under stirring and under nitrogen at 10° C.±2 for 4 hours. The mixture is filtered and the cake is washed with cold (10° C.) toluene (2 L), dried under vacuum at room temperature to provide 393.3 g (1.31 mol; 30.3% yield) of (R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (I′b) as white solid.

1. customprepared
2. temperatureThe mixture is heated up to 40° C.
3. stirringstirred at this temperature for 4 hours
4. customis then lowered to 10° C.
5. temperatureThe reaction mixture is warmed up to room temperature
6. stirringwhile stirring for additional 6 hours at 20±2° C
7. filtrationThe reaction mixture is filtered
8. customevaporated to dryness under vacuum
9. customis taken up with water (16 L) and toluene (14 L) at 60° C.
10. customthe organic phase is separated
11. additionadded with water (16 L)
12. temperatureThe two phases mixture is warmed up to 60° C.±2
13. stirringunder stirring
14. customThe organic phase is separated
15. additionadded with water (16 L)
16. temperatureThe two phases mixture is warmed up to 60° C.±2
17. stirringunder stirring
18. customThe organic phase is dried by azeotropic distillation at about 60° C. under vacuum
19. temperatureThe toluenic solution is gradually cooled to 10° C
20. stirringunder stirring and under nitrogen at 10° C.±2 for 4 hours
21. filtrationThe mixture is filtered
22. washthe cake is washed with cold (10° C.) toluene (2 L)
23. customdried under vacuum at room temperature

ORD 기록

ord-811233ca905d42b1b5e1de25c4ac6b5a

출처 데이터셋

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08530701B2