Water → (R)-tert-butyl 3-((3-chloropyridin-2-yl)amino)piperidine-1-carboxylate

HRID 588356Notes

Reaction equation

HRID 588356 reaction equation
Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CCC([O-])(C)C.[Na+].[NH2:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.O>C1(C)C=CC=CC=1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2].CCCCCCC>[Cl:8][C:7]1[C:2]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[N:3][CH:4]=[CH:5][CH:6]=1

Participants

8

Reactant 4

HCID 962WaterHCID 1501974tert-butyl (3R)-3-aminopiperidine-1-carboxylateHCID 2733478Sodium 2-methylbutan-2-olateHCID 70163262-Bromo-3-chloropyridine

Product 1

HCID 117652951(R)-tert-butyl 3-((3-chloropyridin-2-yl)amino)piperidine-1-carboxylateYield 73%

Reagents, catalysts & solvents 3

HCID 178482626HCID 178482626, compoundCatalystHCID 1140TolueneSolventHCID 8900HeptaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 2-bromo-3-chloropyridine (203.8 g, 1.06 moles), sodium tert-amylate (147 g, 1.27 moles), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (249.5 g, 1.25 moles) in toluene (2 L) was heated to 80° C. To this solution was added chloro(di-2-norbornylphosphino)(2-dimethylaminoferrocen-1-yl) palladium (II) (6.1 g, 10.06 mmol) followed by heating to 105° C. and holding for 3 h. The reaction mixture was cooled to room temperature, 1 L of water was added, then the biphasic mixture was filtered through Celite®. After layer separation, the organic phase was washed with 1 L of water followed by treatment with 60 g of Darco® G-60 at 50° C. The mixture was filtered through Celite®, and concentrated to a final total volume 450 mL, resulting in the precipitation of solids. To the slurry of solids was added 1 L of heptane. The solids were collected via filtration and then dried to afford the title compound as a dull orange solid (240.9 g, 73% yield).

Workup

  1. temperatureby heating to 105° C.
  2. temperatureThe reaction mixture was cooled to room temperature
  3. filtrationthe biphasic mixture was filtered through Celite®
  4. customAfter layer separation
  5. washthe organic phase was washed with 1 L of water
  6. customfollowed by treatment with 60 g of Darco® G-60 at 50° C
  7. filtrationThe mixture was filtered through Celite®
  8. concentrationconcentrated to a final total volume 450 mL
  9. customresulting in the precipitation of solids
  10. filtrationThe solids were collected via filtration
  11. customdried

Sources & evidence

ORD record
ord-aaa9c93d4b8f477c948f3c347f81565c
Source dataset
uspto-grants-2016_01
Patent number
US09227956B2

Reaction notes

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