Citric Acid → (S)-tert-Butyl 2-((S)-2-(6-bromopyridin-3-yl)-1-cyanoethylcarbamoyl)piperidine-1-carboxylate

Temperatur

-78 °C

To a slurry of 2-bromo-5-methylpyridine (10.29 g) and N-bromosuccinimide (5.32 g) in carbon tetrachloride (150 mL) was added AIBN (200 mg) and the reaction vessel was purged with nitrogen. The reaction mixture was heated, under reflux, for 1.5 h then allowed to cool to room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 2-bromo-5-(bromomethyl)pyridine (4 g). This, together with tert-butyl 2-(diphenylmethyleneamino)acetate (4.71 g) and (2S,4S,5R)-2-((R)-allyloxy(quinolin-4-yl)methyl)-1-(anthracen-9-ylmethyl)-5-vinyl-1-azoniabicyclo[2.2.2]octane bromide (1.073 g) was dissolved in DCM (100 mL) and the solution was cooled to −78° C. under nitrogen. 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (5 mL) was added dropwise over 5 min and the mixture was stirred at −78° C. for 7 h then allowed to reach RT overnight. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The material obtained, (S)-tert-butyl 3-(6-bromopyridin-3-yl)-2-(diphenylmethyleneamino)propanoate (6 g), was dissolved in THF (75 mL) and to the solution was added citric acid (22 g) in water (75 mL). The mixture was stirred vigorously for 6 h then concentrated in vacuo and loaded onto an SCX cartridge. The cartridge was washed with water then methanol. The product was eluted with 10% ammonia in methanol. The solvent was removed in vacuo to give the sub-title compound (4.0 g).

1. waitto reach RT overnight
2. concentrationThe reaction mixture was concentrated in vacuo
3. custompartitioned between ethyl acetate and water
4. washThe ethyl acetate was washed with brine
5. dry with materialdried over magnesium sulfate
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customThe material obtained
9. stirringThe mixture was stirred vigorously for 6 h
10. concentrationthen concentrated in vacuo
11. washThe cartridge was washed with water
12. washThe product was eluted with 10% ammonia in methanol
13. customThe solvent was removed in vacuo

ORD-Eintrag

ord-d4b1715be58e4b69a2b96225156dafdb

Quelldatensatz

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07902181B2