Potassium Carbonate → 1-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid (rac)-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-indan-1-yl}-amide

HRID 2046572Notes

Reaction equation

HRID 2046572 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH:14]([NH:18][C:19]([C:21]2([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]3)O1.Br[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[C:34]=1[O:41][CH2:42][CH:43]([F:45])[F:44].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:40][C:35]1[C:34]([O:41][CH2:42][CH:43]([F:44])[F:45])=[C:33]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH:14]([NH:18][C:19]([C:21]2([NH:24][C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])[CH2:22][CH2:23]2)=[O:20])[CH2:13][CH2:12]3)[CH:38]=[C:37]([Cl:39])[CH:36]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 80271Tri-o-tolylphosphineHCID 441966871-Bromo-3,5-dichloro-2-(2,2-difluoroethoxy)benzeneHCID 893916181-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid [(rac)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yl]-amide

Product 1

HCID 601420251-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid (rac)-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-indan-1-yl}-amideYield 56%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

1-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid[(rac)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yl]-amide (intermediate A-1) (0.22 g, 502 μmol), 1-bromo-3,5-dichloro-2-(2,2-difluoro-ethoxy)-benzene (intermediate B-1) (169 mg, 552 μmol) and tri-o-tolylphosphine (30.6 mg, 100 μmol, eq: 0.2) were dissolved in THF (10.0 ml); then palladium(II)acetate (5.64 mg, 25.1 μmol, eq: 0.05) was added, followed by potassium carbonate (173 mg, 1.25 mmol), dissolved in water (1.0 ml). The reaction mixture was stirred at RT over night, then poured into H2O (50 ml) and extracted with EtOAc (2×25 mL). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (0.377 g) which was purified by flash chromatography (silica gel, 20 g, 10% to 50% EtOAc in heptane) to yield the title compound (0.15 g, 56%) as light yellow amorphous solid. MS: 535.1 (M−H−, 2Cl).

Workup

  1. extractionextracted with EtOAc (2×25 mL)
  2. dry with materialThe organic layers were dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customto give a crude product (0.377 g) which
  6. customwas purified by flash chromatography (silica gel, 20 g, 10% to 50% EtOAc in heptane)

Sources & evidence

ORD record
ord-c01c39b4db9942cb91a60592103298c6
Source dataset
uspto-grants-2013_11
Patent number
US08592426B2

Reaction notes

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