Toluene → (3R)-N-methylpiperidine-3-carboxamide

Temperature

2.5 °C

A solution of D-Cbz-Nipecotic acid ((R)-Piperidine-1,3,-dicarboxylic acid 1-benzyl ester) (1.32 g, 5.0 mmol) in toluene (25 mL) was treated with DMF (20 μL) followed by oxalyl chloride (646 μL, 7.5 mmol). The reaction mixture was stirred for 3 hr and evaporated to an oil. The crude acid chloride was then dissolved in THF (20 mL), cooled to 0-5° C., and treated with a 2 M THF solution of methylamine (7.5 mL, 15 mmol). The reaction mixture was stirred for 2 hr, allowed to warm to room temperature and evaporated in vacuo to afford solids which were filtered with the aid of water to afford Cbz-protected intermediate as a colorless solid (1.2 5 g, 91%). LC/MS 5.05 min, [M+1]+ 277. The CbZ-protected intermediate (1.0 g, 3.62 mmol) was dissolved in EtOH (50 mL), treated with a 10% palladium on carbon (50% water content) catalyst (750 mg) and hydrogenated at 60-70 psi hydrogen for 5 hr. The crude reaction mixture was then filtered through Celite, evaporated in vacuo, and redissolved in EtOH (10 mL) which was filtered through a nylon syringe filter to remove residual catalyst. Evaporation of the solution afforded crude product as a tacky solid (581 mg, 113%). LC/MS 0.68 min, [M+1]+ 143.

1. customevaporated to an oil
2. dissolutionThe crude acid chloride was then dissolved in THF (20 mL)
3. stirringThe reaction mixture was stirred for 2 hr
4. temperatureto warm to room temperature
5. customevaporated in vacuo
6. customto afford solids which
7. filtrationwere filtered with the aid of water
8. customto afford Cbz-
9. customLC/MS 5.05 min, [M+1]+ 277
10. customThe crude reaction mixture
11. filtrationwas then filtered through Celite
12. customevaporated in vacuo
13. dissolutionredissolved in EtOH (10 mL) which
14. filtrationwas filtered through a nylon syringe
15. filtrationfilter
16. customto remove residual catalyst
17. customEvaporation of the solution

ORD record

ord-6f1867aa42244473876cd67a30f475c0

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09029397B2