Potassium Phosphate, Tribasic → Ethyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorobenzoate

HRID 515235Notes

Reaction equation

HRID 515235 reaction equation
Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:19])[S:9](=[O:18])(=[O:17])[N:10]([CH2:11][CH:12]3[CH2:14][C:13]3([F:16])[F:15])[C:5]2=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1[C:26]([F:34])=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:13]1([F:16])[CH2:14][CH:12]1[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([C:27]3[C:26]([F:34])=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:23]([O:22][CH2:20][CH3:21])=[O:24])=[CH:3][CH:4]=2)[N:8]([CH3:19])[S:9]1(=[O:18])=[O:17]

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 447176532-Fluoro-3-(ethoxycarbonyl)benzeneboronic acidHCID 866879055-Chloro-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide

Product 1

HCID 68245322Ethyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorobenzoate

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

5-chloro-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (29-1) (2.2 g, 7.1 mmol, 1.0 eq), [3-(ethoxycarbonyl)-2-fluorophenyl]boronic acid (3.0 g, 14 mmol, 2.0 eq), tripotassium phosphate (3.0 g, 14.2 mmol, 2.0 eq), S-Phos (0.29 g, 0.71 mmol, 0.1 eq), and palladium(II) acetate (0.080 mg, 0.36 mmol, 0.05 eq) were combined in THF (15 mL) and water (2 mL). The resulting mixture was heated at 75° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (100 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (120 g SiO2, 0-60% EtOAc in hexanes) to afford ethyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorobenzoate (37-1) as a yellow solid. LRMS m/z (M+H) 442.2 found, 442.1 required.

Workup

  1. temperatureto cool to room temperature
  2. washwashed with water (10 mL) and brine (10 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude residue was purified by flash chromatography (120 g SiO2, 0-60% EtOAc in hexanes)

Sources & evidence

ORD record
ord-547f57e1d9984bdf98ac510bfc52ae11
Source dataset
uspto-grants-2015_08
Patent number
US09108937B2

Reaction notes

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