Toluene → N-((5-(4-cyano-3-fluorophenyl)pyridin-3-yl)(cyclopropyl)-methyl)ethanesulfonamide

HRID 1897779Notes

Reaction equation

HRID 1897779 reaction equation
[F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:16]=O)[CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:18]([S:20]([NH2:23])(=[O:22])=[O:21])[CH3:19].[NH4+].[Cl-].[C:26]1([CH3:32])C=CC=C[CH:27]=1>C(OCC)(=O)C.[Cl-].[Na+].O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH:32]3[CH2:26][CH2:27]3)[NH:23][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH:13]=[N:12][CH:11]=2)=[CH:9][C:2]=1[F:1])#[N:5]

Participants

8

Reactant 4

HCID 1140TolueneHCID 25517Ammonium ChlorideHCID 73702EthanesulfonamideHCID 595784372-Fluoro-4-(5-formyl-pyridin-3-yl)-benzonitrile

Product 1

HCID 49820125N-((5-(4-cyano-3-fluorophenyl)pyridin-3-yl)(cyclopropyl)-methyl)ethanesulfonamideYield 30%

Reagents, catalysts & solvents 3

HCID 11026Titanium isopropoxideCatalystHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
-36 °C

Procedure

Titanium isopropoxide (0.98 mL, 3.36 mmol) was added to a mixture of 2-fluoro-4-(5-formyl-pyridin-3-yl)-benzonitrile (380 mg, 1.68 mmol) and ethanesulfonamide (183 mg, 1.68 mmol) in toluene (14 mL) at RT. The resulting mixture was heated to reflux for 2 h. After concentration, the residue was dissolved in THF (10 mL) and a solution of c-PrMgBr (0.5 M in THF, 16.8 mL, 8.40 mmol) was added dropwise at −40° C., and the resulting mixture was stirred at −36° C. for 1 h. Saturated NH4Cl solution was added to the reaction mixture. The resulting mixture was diluted with ethyl acetate and brine, and subsequently filtered. The organic layer was separated to concentrate and purified by flash column (10% MeOH/DCM=0-30%) to give the title compound (185 mg, 30%); ESI-MS m/z: 360 [M+1]+, 1HNMR (MeOD, 400 MHz) δ ppm 8.85 (1H, d, J=2.0 Hz), 8.72 (1H, d, J=2.0 Hz), 8.25 (1H, t, J=2.0 Hz), 7.94 (1H, d, J=8.0 Hz), 7.82-7.77 (2H, m), 3.95 (1H, d, J=9.2 Hz), 3.89 (3H, s), 3.07-2.96 (2H, m), 1.34-1.29 (1H, m), 1.31 (1H, t, J=7.2 Hz), 0.81-0.76 (1H, m), 0.67-0.62 (2H, m), 0.55-0.51 (1H, m)

Workup

  1. temperatureThe resulting mixture was heated
  2. temperatureto reflux for 2 h
  3. concentrationAfter concentration
  4. dissolutionthe residue was dissolved in THF (10 mL)
  5. filtrationsubsequently filtered
  6. customThe organic layer was separated
  7. concentrationto concentrate
  8. custompurified by flash column (10% MeOH/DCM=0-30%)

Sources & evidence

ORD record
ord-b3edc9351e914b8784d851bf16f98c51
Source dataset
uspto-grants-2013_08
Patent number
US08519142B2

Reaction notes

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