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

HRID 588902Notes

Reaction equation

HRID 588902 reaction equation
Br[C:2]1[C:3]([Cl:32])=[CH:4][C:5]([O:30][CH3:31])=[C:6]([NH:8][C@@H:9]([CH3:29])[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:33]1(B(O)O)[CH2:35][CH2:34]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:32][C:3]1[C:2]([CH:33]2[CH2:35][CH2:34]2)=[CH:7][C:6]([NH:8][C@@H:9]([CH3:29])[C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:16][CH2:17]2)=[O:11])=[C:5]([O:30][CH3:31])[CH:4]=1

Participants

7

Reactant 3

HCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 117610822HCID 117610822, compound

Product 1

HCID 117611000(S)-tert-Butyl 3-(4-(2-((4-chloro-5-cyclopropyl-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylateYield 62%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of (S)-tert-butyl 3-(4-(2-((5-bromo-4-chloro-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (700 mg, 1.32 mmol), cyclopropylboronic acid (114 mg, 1.32 mmol), Pd(OAc)2 (15 mg, 0.066 mmol), tricyclohexylphosphine (37 mg, 0.132 mmol), K3PO4.3H2O (974 mg, 4.62 mmol) in DMF (10 mL) and H2O (0.5 mL) was stirred under argon at 80° C. for 16 h. The mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/dichloroethane=1:100) to afford the desired product (400 mg, 62%). ESI-MS m/z: 493.2[M+H]+.

Workup

  1. temperatureto cool to RT
  2. custompartitioned between ethyl acetate and water
  3. washThe organic layer was washed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by flash column chromatography on silica gel (methanol/dichloroethane=1:100)

Sources & evidence

ORD record
ord-57218fcbb1aa4417a977f4047cdaa3c1
Source dataset
uspto-grants-2016_01
Patent number
US09227978B2

Reaction notes

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