Bromoacetonitrile → (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate

HRID 2039900Notes

Reaction equation

HRID 2039900 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([OH:23])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:27][C:28]#[N:29]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:27][C:28]#[N:29])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1

Participants

5

Reactant 3

HCID 11534Bromoacetonitrile2×HCID 24758Sodium hydride2×HCID 58017388(R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate

Product 1

HCID 67365681(R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylateYield 150.7%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A solution of (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (55 g, 0.156 mol) in acetonitrile (1.2 L) was cooled to 0° C., NaH (19.2 g, 0.48 mol, 60% in oil) was added in portions, then the mixture was stirred at rt for 1 hr. The mixture was cooled to −20° C. and bromoacetonitrile (57.7 g, 0.48 mol) was added dropwise. After 0.5 hr, additional NaH (19.2 g, 0.48 mol, 60% in oil) and bromoacetonitrile (57.7 g, 0.48 mol) was added. TLC showed 80% of the starting material was reacted. The reaction was quenched with saturated NH4Cl solution (200 mL), water (1 L) was added. Acetonitrile was removed by reduced pressure, CH2Cl2 (1 L) was added, the aqueous layer was back extracted with CH2Cl2 (3×500 mL), dried over Na2SO4 and concentrated in vacuo to give the crude (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (90 g), which was used for the next step without further purification.

Workup

  1. temperatureThe mixture was cooled to −20° C.
  2. waitAfter 0.5 hr
  3. customwas reacted
  4. customThe reaction was quenched with saturated NH4Cl solution (200 mL), water (1 L)
  5. additionwas added
  6. customAcetonitrile was removed by reduced pressure, CH2Cl2 (1 L)
  7. additionwas added
  8. extractionthe aqueous layer was back extracted with CH2Cl2 (3×500 mL)
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-6e515269af2445659065c40965fc3c77
Source dataset
uspto-grants-2013_11
Patent number
US08580823B2

Reaction notes

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