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 239863Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 239863
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]

Komponenten

6

Edukt 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

Produkt 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

Reagenzien, Katalysatoren, Lösungsmittel 2

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

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

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.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-d873e986cb134426bfc669efe88279f9
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08642799B2

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