Cesium carbonate → Methyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-fluorobenzoate

HRID 515219Notes

Reaction equation

HRID 515219 reaction equation
Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:12][CH:13]3[CH2:15][C:14]3([F:17])[F:16])[S:7](=[O:11])(=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:16][C:14]1([F:17])[CH2:15][CH:13]1[CH2:12][N:6]1[C:5]2[CH:18]=[CH:19][C:2]([C:22]3[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=3[F:20])[C:27]([O:29][CH3:30])=[O:28])=[CH:3][C:4]=2[N:8]([CH3:9])[S:7]1(=[O:11])=[O:10]

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 230053662-Fluoro-5-(methoxycarbonyl)benzeneboronic acidHCID 682450025-Bromo-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

Product 1

HCID 67411528Methyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-fluorobenzoate

Reagents, catalysts & solvents 4

HCID 178418851HCID 178418851, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

5-bromo-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (4-1) (100 mg, 0.28 mmol, 1 eq), [2-fluoro-5-(methoxycarbonyl)phenyl]boronic acid (84 mg, 0.43 mmol, 1.5 eq), cesium carbonate (185 mg, 0.57 mmol, 2.0 eq) and bis(tri-t-butylphosphine)palladium(0) (29 mg, 0.06 mmol, 0.2 eq) were combined in dioxane (1.5 mL) and water (0.3 mL). The resulting mixture was heated in the microwave at 100° C. for 10 minutes. The reaction mixture was diluted with EtOAc (10 mL), washed with water (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (12 g SiO2, 0-70% EtOAc in hexanes) to afford methyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-fluorobenzoate (17-1) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.14 (dd, J=1.6, 6.0 Hz, 1 H); 8.01 (m, 1 H); 7.21 (m, 2 H); 6.95 (t, J=1.2 Hz, 1 H); 6.90 (d, J=6.4 Hz, 1 H); 3.94 (s, 3 H); 3.91 (d, J=5.6 Hz, 2 H); 3.33 (s, 3 H); 2.14 (m, 1 H); 1.64 (m, 1 H); 1.39 (m, 1 H).

Workup

  1. washwashed with water (2 mL) and brine (2 mL)
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude residue was purified by flash chromatography (12 g SiO2, 0-70% EtOAc in hexanes)

Sources & evidence

ORD record
ord-fd38925c2cb943349b06e77c1c30b641
Source dataset
uspto-grants-2015_08
Patent number
US09108937B2

Reaction notes

Loading…