Hydrochloric Acid → HCID 86703583, compound

HRID 1849709Notes

Reaction equation

HRID 1849709 reaction equation
[N:1]1([S:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[C:14](Cl)[C:13]([O:17][CH2:18][C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][OH:30])([CH2:22]5)[CH2:20]3)[CH2:26]4)=[CH:12][C:11]=2[F:31])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[N:1]1([S:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[C:14]([CH:33]3[CH2:35][CH2:34]3)[C:13]([O:17][CH2:18][C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][OH:30])([CH2:22]5)[CH2:20]3)[CH2:26]4)=[CH:12][C:11]=2[F:31])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 62657Potassium Phosphate, Tribasic2×HCID 2760897Cyclopropylboronic acid2×HCID 20066521Tri(cyclohexyl)phosphine tetrafluoroborate2×HCID 86703581HCID 86703581, compound

Product 1

HCID 86703583HCID 86703583, compoundYield 53%

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A degassed mixture of N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((3-(hydroxymethyl)adamantan-1-yl)methoxy)benzamide (0.51 g, 1.04 mmol), cyclopropylboronic acid (0.89 g, 10.4 mmol), tricyclohexylphosphine tetrafluoroborate (0.23 g, 0.62 mmol), potassium phosphate (tribasic, 1.10 g, 5.20 mmol), water (3.0 mL), and tetrahydrofuran (3.0 mL) in toluene (15 mL) was added palladium (II) acetate (0.070 g, 0.31 mmol). The resulting mixture was refluxed under nitrogen for 18 hours. The reaction mixture was cooled to ambient temperature and added additional cyclopropylboronic acid (0.89 g, 10.40 mmol), tricyclohexylphosphine tetrafluoroborate (0.23 g, 0.62 mmol), and potassium phosphate (tribasic, 1.10 g, 5.20 mmol), and then refluxed under nitrogen for 10 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (80 mL) and water (50 mL), acidified with 1 M aqueous hydrochloric acid solution. The organic layer was washed with 1 M aqueous hydrochloric acid solution (20 mL) and brine (2×50 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (1:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the title compound (0.27 g, 53%): 1H NMR (300 MHz, DMSO-d6) δ 11.56 (br s, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.90 (d, J=13.0 Hz, 1H), 4.38-4.31 (m, 1H), 4.01 (t, J=7.5 Hz, 4H), 3.64 (s, 2H), 3.02-2.96 (m, 2H), 2.19-2.06 (m, 2H), 2.06-1.94 M, 3H), 1.64-1.47 (m, 6H), 1.45-1.32 (m, 6H), 0.92-0.83 (m, 2H), 0.96-0.61 (m, 2H); MS (ES+) m/z 493.2 (M+1).

Workup

  1. temperatureThe resulting mixture was refluxed under nitrogen for 18 hours
  2. temperaturerefluxed under nitrogen for 10 hours
  3. temperatureThe reaction mixture was cooled to ambient temperature
  4. washThe organic layer was washed with 1 M aqueous hydrochloric acid solution (20 mL) and brine (2×50 mL)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by silica gel column chromatography (1:1 hexanes

Sources & evidence

ORD record
ord-b5c6f4582011415c8e922c14682e0989
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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