Bromoacetonitrile → (R)-tert-butyl 3-((R)-(3-chlorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate

HRID 2039878Notes

Reaction equation

HRID 2039878 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:22])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:26][C:27]#[N:28])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1

Participants

4

Reactant 3

HCID 11534Bromoacetonitrile2×HCID 24758Sodium hydride2×HCID 445550221-Piperidinecarboxylic acid, 3-[(R)-(3-chlorophenyl)hydroxymethyl]-, 1,1-dimethylethyl ester, (3R)-

Product 1

HCID 67364989(R)-tert-butyl 3-((R)-(3-chlorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylateYield 100.9%

Procedure

To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (32.5 g, 0.1 mol), NaH (12 g, 0.3 mol) was added at 0° C. The mixture was stirred for 1 h at room temperature. The mixture was cooled to −40° C., then bromoacetonitrile (35.7 g, 0.3 mol) was added drop wise. The mixture was stirred an additional 0.5 h at −20° C. HPLC indicated the reaction was ˜30% complete. The addition of NaH and bromoacetonitrile was repeated two more times. HPLC indicated the reaction was ˜60% completed. The reaction was quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated to give the crude product as brown oil (36.8 g), which was used for the next step without purification.

Workup

  1. temperatureThe mixture was cooled to −40° C.
  2. stirringThe mixture was stirred an additional 0.5 h at −20° C
  3. customThe reaction was quenched with sat. NH4Cl
  4. extractionThe mixture was extracted with CH2Cl2
  5. dry with materialThe organic layer was dried over Na2SO4
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-476e02508aaf4b11a27cbf742d5a5b85
Source dataset
uspto-grants-2013_11
Patent number
US08580823B2

Reaction notes

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