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4-Bromobutyronitrile → (R)-tert-butyl 3-((R)-(3-chlorophenyl)(3-cyanopropoxy)methyl)piperidine-1-carboxylate

HRID 451908
Notes
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Reaction equation

HRID 451908 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]([OH:24])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:26][CH2:27][CH2:28][C:29]#[N:30].[NH4+].[Cl-]>CC#N.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]([O:24][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 214124-BromobutyronitrileHCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 44555022tert-Butyl (R)-3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate

Product 1

HCID 68714485(R)-tert-butyl 3-((R)-(3-chlorophenyl)(3-cyanopropoxy)methyl)piperidine-1-carboxylateYield 23.5%

Reagents, catalysts & solvents

2
HCID 6342AcetonitrileSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a suspension of NaH (763 mg, 19.1 mmol) and (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (1.55 g, 4.77 mmol) in CH3CN (20 mL) at 0-5° C. was added dropwise a solution of 4-bromobutyronitrile (3.17 g, 21.5 mmol) in CH3CN (5 mL), the reaction mixture was stirred for overnight at rt. The reaction mixture was poured into saturated aqueous NH4Cl, ethyl acetate (50 mL) was added. The organic layer was washed with water (3×20 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(3-cyanopropoxy)methyl)piperidine-1-carboxylate (0.44 g, 21% yield). 1H NMR (CD3OD, 400 MHz) δ 7.38-7.28 (m, 3H), 7.22 (m, 1H), 4.22 (m, 1H), 4.02 (d, 1H), 3.86 (d, 1H), 3.34 (m, 2H), 2.77 (q, 2H), 2.56 (t, 2H), 1.62 (m, 1H), 1.59 (m, 1H), 1.43 (s, 9H), 1.35-1.25 (m, 3H), 1.12 (d, 1H).

Workup

  1. additionwas added
  2. washThe organic layer was washed with water (3×20 mL) and brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-695bdd89cf9542e49e108f5ae34bf9c9
Source dataset
uspto-grants-2013_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08487108B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes