Sodium Carbonate → 1-[4'-((1S)-1-{[(1S)-1-({[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]amino}carbonyl)-2-methylpropyl]amino}-2,2,2-trifluoroethyl)biphenyl-4-yl]cyclopropanecarboxylic acid

HRID 239863Notes

Reaction equation

HRID 239863 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:32]#[N:33])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])=[O:19])[CH:15]([CH3:17])[CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.OB(O)[C:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:45]([OH:47])=[O:46])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:32]([C@@H:21]([NH:20][C:18]([C@@H:14]([NH:13][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3([C:45]([OH:47])=[O:46])[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH:15]([CH3:17])[CH3:16])=[O:19])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=1[F:31])#[N:33]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 467396661-(4-Boronophenyl)cyclopropane-1-carboxylic acidHCID 68776812N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-L-valinamide

Product 1

HCID 426354851-[4'-((1S)-1-{[(1S)-1-({[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]amino}carbonyl)-2-methylpropyl]amino}-2,2,2-trifluoroethyl)biphenyl-4-yl]cyclopropanecarboxylic acid

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-L-valinamide (1 eq) in DMF (0.1M) were added 1-[4-(dihydroxyboryl)phenyl]cyclopropanecarboxylic acid (1.2 eq), Pd(dppf)Cl2 (0.05 eq) and 2M aqueous sodium carbonate (3 eq). The mixture was degassed by nitrogen bubbling for 5 min and heated to 90° C. for 2 h. The reaction mixture was cooled and diluted with EtOAc and 3N HCl was added to acidify the reaction mixture to pH 5. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and water, dried over Na2SO4 filtered and concentrated. The crude compound was purified by automated SiO2 flash chromatography system using solvent gradient of 40% EtOAc/Hex to 100% EtOAc/Hex.

Workup

  1. customThe mixture was degassed by nitrogen bubbling for 5 min
  2. temperatureThe reaction mixture was cooled
  3. additiondiluted with EtOAc and 3N HCl
  4. additionwas added
  5. extractionThe aqueous layer was extracted with EtOAc
  6. washThe combined organic layers were washed with brine and water
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude compound was purified by automated SiO2 flash chromatography system

Sources & evidence

ORD record
ord-d873e986cb134426bfc669efe88279f9
Source dataset
uspto-grants-2014_02
Patent number
US08642799B2

Reaction notes

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