Potassium Phosphate, Tribasic → HCID 86703557, compound

HRID 1849867Notes

Reaction equation

HRID 1849867 reaction equation
Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([CH3:28])[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:29]1(B(O)O)[CH2:31][CH2:30]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:29]1([C:2]2[C:3]([O:16][CH2:17][C:18]3([CH3:28])[CH2:19][CH2:20][C:21]4([O:22][CH2:23][CH2:24][O:25]4)[CH2:26][CH2:27]3)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:31][CH2:30]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborateHCID 86703556HCID 86703556, compound

Product 1

HCID 86703557HCID 86703557, compoundYield 100%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of tert-butyl 5-chloro-2-fluoro-4-((8-methyl-1,4- dioxaspiro[4.5]decan-8-yl)-methoxy)benzoate (0.28 g, 0.67 mmol), cyclopropylboronic acid (0.08 g, 1.00 mmol), potassium phosphate (0.57 g, 2.68 mmol) and tricyclohexylphosphine tetrafluoroborate (0.05 g, 0.14 mmol) in toluene (3 mL) and water (0.3 mL) under a nitrogen atmosphere was added palladium acetate (0.016 g, 0.07 mmol). The reaction mixture was heated at 130° C. for 30 minutes in the microwave and then cooled to ambient temperature. Water (20 mL) was added and the mixture extracted with ethyl acetate (2×15 mL), the combined organics were washed with brine (10 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) afforded tert-butyl 5-cyclopropyl-2-fluoro-4-((8-methyl-1,4-dioxaspiro[4.5]-decan-8-yl)methoxy)benzoate (0.28 g, 0.67 mmol) which was used directly into the next step. To a solution of this compound (0.28 g, 0.67 mmol) in dichloromethane (5 mL), was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and then directly purified by column chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.071 g, 28%). 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=8.3 Hz, 1H), 6.51 (d, J=12.5 Hz, 1H), 3.85-3.76 (m, 2H), 2.58-2.29 (m, 4H), 2.06-1.73 (m, 5H), 1.55 (s, 9H), 1.28 (s, 3H), 0.91-0.82 (m, 2H), 0.64-0.57 (m, 2H).

Workup

  1. temperaturecooled to ambient temperature
  2. extractionthe mixture extracted with ethyl acetate (2×15 mL)
  3. washthe combined organics were washed with brine (10 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification of the residue by column chromatography (5% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-1c0971b8e85c4625a4467f0ea01212e8
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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