Cesium carbonate → 2-(6-(4-(3-Cyano-4-

HRID 1500203Notes

Reaction equation

HRID 1500203 reaction equation
Br[C:2]1[N:7]=[C:6]([CH:8]([OH:12])[C:9]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CCO.COCCOC.O.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:13]([C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[C:31]([F:32])([F:33])[F:34])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([CH:8]([OH:12])[C:9]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:14]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 898154332-(6-Bromopyridin-2-yl)-2-hydroxyacetamideHCID 89815591(4-(3-Cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid

Product 1

HCID 717351082-(6-(4-(3-Cyano-4-

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 86587095Dimethoxyethane ethanol waterSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 3-cyano-4-trifluoromethyl-1-fluorobenzene (70, g, 0.37, mol, Oakwood), 4-hydroxyphenylboronic acid (50, g, 0.36, mol, Boron Molecular), K2CO3, (70, g) and DMF/water (400, mL/40, mL) was heated to 100° C. for 3, h. After cooling to RT, the mixture was diluted with water (1, L) and extracted with EtOAc (1.5, L). The organic layer was washed with water (0.5, L) and brine, concentrated and purified by chromatographed over silica gel with 4% MeOH in chloroform to give (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid as pink solid (50, g, 45%). 1H NMR (400, MHz, CD3OD) 7.70-7.70, (3H, m), 7.35, (1H, d, J=2.4, Hz), 7.24, (1H, dd, J=2.2, & 8.8, Hz), 7.00, (2H, d, J=7.7, Hz). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17, mg, 0.022 mmol, Aldrich) was added to a mixture of 2-(6-bromopyridin-2-yl)-2-hydroxyacetamide (50, mg, 0.22, mmol), (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid (100, mg, 0.32, mmol) and cesium carbonate (140, mg, 0.43 mmol) in EtOH/DME/water (2, mL/2, mL/1, mL) at room temperature. The reaction mixture was flushed with argon, then, shaken at 90° C. for 3, h. After cooling to RT, the reaction was quenched with water (2, mL), and extracted with EtOAc (10 mL). The organic layer was separated, concentrated and purified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in water/0.1% TFA in ACN) to give 2-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2-hydroxyacetamide (Cpd. No. 6) as off-white solid (45, mg, 50%). LC/MS: m/z=414.1, [M+H]+, ; 1H NMR (400, MHz, DMSO-d6) 8.15, (2H, d, J=8.4, Hz), 7.93 (1H, d, J=9.2, Hz), 7.82-7.86, (3H, m), 7.37-7.45, (3H, m), 7.26, (2H, d, J=9.2, Hz), 4.95, (1H, s).

Workup

  1. customat room temperature
  2. customThe reaction mixture was flushed with argon
  3. temperatureAfter cooling to RT
  4. customthe reaction was quenched with water (2, mL)
  5. extractionextracted with EtOAc (10 mL)
  6. customThe organic layer was separated
  7. concentrationconcentrated
  8. custompurified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in water/0.1% TFA in ACN)

Sources & evidence

ORD record
ord-f1cb58d34c27481882818a0755f5e617
Source dataset
uspto-grants-2015_12
Patent number
US09206127B2

Reaction notes

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