Potassium Phosphate, Tribasic → Tert-butyl 3-((2-cyclopropyl-5-fluoro-4-(methoxycarbonyl)-phenoxy)methyl)azetidine-1-carboxylate

HRID 1849875Notes

Reaction equation

HRID 1849875 reaction equation
Cl[C:2]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([F:25])=[CH:17][C:3]=1[O:4][CH2:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:26]1([C:2]2[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([F:25])=[CH:17][C:3]=2[O:4][CH2:5][CH:6]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)[CH2:28][CH2:27]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborateHCID 86703759Tert-butyl 3-((2-chloro-5-fluoro-4-(methoxycarbonyl)phenoxy)methyl)azetidine-1-carboxylate

Product 1

HCID 86703760Tert-butyl 3-((2-cyclopropyl-5-fluoro-4-(methoxycarbonyl)-phenoxy)methyl)azetidine-1-carboxylateYield 83%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of tert-butyl 3-((2-chloro-5-fluoro-4-(methoxycarbonyl)- phenoxy)methyl)-azetidine-1-carboxylate (1.2 g, 3.2 mmol), cyclopropylboronic acid (415 mg, 4.8 mmol), potassium phosphate (2.04 g, 9.6 mmol) and tricyclohexylphosphine tetrafluoroborate (118 mg, 0.32 mmol) in toluene (20 mL) and water (1 mL) under a nitrogen atmosphere was added palladium acetate (36 mg, 0.16 mmol). The reaction mixture was heated to 100° C. for 16 h and then cooled to ambient temperature. The mixture was quenched by water (50 mL) and extracted with ethyl acetate (50 mL×3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column (eluting with petroleum ether/ethyl acetate, from 10/1 to 2/1) to afford target compound (1.0 g, 83%) as a pale yellow solid. LCMS (ESI) m/z: 324.3 [M−56+H]+.

Workup

  1. temperaturecooled to ambient temperature
  2. customThe mixture was quenched by water (50 mL)
  3. extractionextracted with ethyl acetate (50 mL×3)
  4. washthe combined organic layers were washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting residue was purified by silica gel column (eluting with petroleum ether/ethyl acetate, from 10/1 to 2/1)

Sources & evidence

ORD record
ord-b2ebd6d581f34c54a71d1843386a2bec
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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