Potassium Carbonate → 1-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid {(rac)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide

HRID 2046574Notes

Reaction equation

HRID 2046574 reaction equation
Br[C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:12]([C:14]3([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:8][C:9]=2[CH:10]=1.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:54]1[CH:59]=[C:58]([Cl:60])[CH:57]=[C:56]([F:61])[C:55]=1[C:62]1[N:66]=[C:65]([CH3:67])[O:64][N:63]=1>CS(C)=O.O.[Pd](Cl)Cl>[Cl:60][C:58]1[CH:57]=[C:56]([F:61])[C:55]([C:62]2[N:66]=[C:65]([CH3:67])[O:64][N:63]=2)=[C:54]([C:2]2[CH:3]=[N:4][C:5]3[CH:6]([NH:11][C:12]([C:14]4([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:15]4)=[O:13])[CH2:7][CH2:8][C:9]=3[CH:10]=2)[CH:59]=1

Participants

9

Reactant 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 684506413-(2-Bromo-4-chloro-6-fluorophenyl)-5-methyl-1,2,4-oxadiazoleHCID 893915111-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-3-bromo-6,7-dihydro-5H-[1]pyrindin-7-yl)-amide

Product 1

HCID 601423031-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid {(rac)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amideYield 50.2%

Reagents, catalysts & solvents 3

HCID 24290Palladium ChlorideCatalyst2×HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent2×

Conditions

Temperature
90 °C

Procedure

1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-3-bromo-6,7-dihydro-5H-[1]pyrindin-7-yl)-amide (intermediate A-5) (0.2 g, 510 μmol), potassium acetate (150 mg, 1.53 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (155 mg, 612 μmol) were dissolved in DMSO (8.0 ml). The reaction vessel was closed and evacuated, then charged with argon; this procedure was repeated five times. After 10 minutes (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) (18.7 mg, 25.5 μmol, eq: 0.05) was added and the reaction mixture was stirred at 90° C. for 1.5 hours. After cooling to RT, potassium carbonate (141 mg, 1.02 mmol), dissolved in water (1.0 ml) and 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B-2) (164 mg, 561 μmol) were added, followed by (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) (18.7 mg, 25.5 μmol, eq: 0.05). This reaction mixture was stirred at 80° C. for 3 hours, then poured into H2O (50 ml) and extracted with CH2Cl2 (3×25 ml). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (0.364 g), which was purified by flash chromatography (silica gel, 20 g, 0% to 2% MeOH in CH2Cl2) to yield the title compound (0.134 g, 50%) as light grey solid. MS: 524.1 (MH+, 1Cl).

Workup

  1. customThe reaction vessel was closed
  2. customevacuated
  3. additioncharged with argon
  4. temperatureAfter cooling to RT
  5. stirringThis reaction mixture was stirred at 80° C. for 3 hours
  6. extractionextracted with CH2Cl2 (3×25 ml)
  7. dry with materialThe organic layers were dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto give a crude product (0.364 g), which
  11. customwas purified by flash chromatography (silica gel, 20 g, 0% to 2% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-c9931be9eabf4e10bc20bb39911c8679
Source dataset
uspto-grants-2013_11
Patent number
US08592426B2

Reaction notes

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