Tricyclohexylphosphine → tert-Butyl 3-(4-(3-(4-chloro-5-cyclopropyl-2-hydroxyphenyl)propanoyl)piperazin-1-yl)azetidine-1-carboxylate

HRID 588866Notes

Reaction equation

HRID 588866 reaction equation
Br[C:2]1[C:3]([Cl:31])=[CH:4][C:5]([O:29]C)=[C:6]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:7]=1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:31][C:3]1[C:2]([CH:32]2[CH2:34][CH2:33]2)=[CH:7][C:6]([CH2:8][CH2:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:19]3)[CH2:16][CH2:17]2)=[O:11])=[C:5]([OH:29])[CH:4]=1

Participants

7

Reactant 3

HCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 90455837HCID 90455837, compound

Product 1

HCID 131734452tert-Butyl 3-(4-(3-(4-chloro-5-cyclopropyl-2-hydroxyphenyl)propanoyl)piperazin-1-yl)azetidine-1-carboxylateYield 77.4%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

A mixture of tert-butyl 3-(4-(3-(5-bromo-4-chloro-2-methoxyphenyl)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (280 mg, 0.54 mmol), cyclopropylboronic acid (185 mg, 2.2 mmol), K3PO4.3H2O (444 mg, 1.9 mmol), tricyclohexylphosphine (30 mg, 0.1 mmol), Pd(OAc)2 (24 mg, 0.11 mmol) in toluene (10 mL) and water (1 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=60:1) to afford the desired product (194 mg, 75% yield). ESI-MS m/z: 477.3[M+H]+.

Workup

  1. temperatureat reflux under argon for 16 h
  2. concentrationconcentrated in vacuo
  3. customThe residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=60:1)

Sources & evidence

ORD record
ord-c52e1cf44fd149d7997a3ffdd90baae1
Source dataset
uspto-grants-2016_01
Patent number
US09227978B2

Reaction notes

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