Hydrochloric Acid → 5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid

HRID 624948Notes

Reaction equation

Br[C:2]1[CH:3]=[CH:4][C:5]([C:17]([OH:19])=[O:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].[CH:20]1(B(O)O)[CH2:22][CH2:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C1(C)C=CC=CC=1.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH:20]1([C:2]2[CH:3]=[CH:4][C:5]([C:17]([OH:19])=[O:18])=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:22][CH2:21]1

Participants

Conditions

Temperature: 100 °C

Procedure

A mixture of 5-bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (501 mg, 1.43 mmol), cyclopropylboronic acid (CAN 411235-57-9, 184 mg, 2.15 mmol), palladium diacetate (CAN 3375-31-3, 16.1 mg, 71.6 μmol), tricyclohexylphosphine (CAN 2622-14-2, 8.03 mg, 28.6 μmol) and potassium phosphate (1.06 g, 5.01 mmol) in toluene/water (20/1 v/v, 10.5 mL) was stirred at 100° C. for 22 hours. After cooling the mixture was poured into ice-water (80 mL). 2 M Hydrochloric acid (25 mL) was added and the mixture was extracted with TBME, organic layers were washed twice with water, pooled, dried with Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient) to give the title compound (340 mg, 76%) as off-white solid; LC-MS (UV peak area, ESI) 96.6%, 310.0513 [M−H−].

Workup

temperatureAfter cooling the mixture
extractionthe mixture was extracted with TBME, organic layers
washwere washed twice with water
dry with materialdried with Na2SO4
filtrationfiltered
concentrationconcentrated in vacuo
customThe crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient)

Sources & evidence

ORD record: ord-d2d8320358524fae82af8d903cd1a0e9
Source dataset: uspto-grants-2016_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09303012B2

Reaction notes

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