Isobutyronitrile → HCID 89906823, compound

HRID 629085Notes

Reaction equation

HRID 629085 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[C:13](Cl)=[N:14][CH:15]=[C:16]([CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18].[C:33](#[N:37])[CH:34]([CH3:36])[CH3:35]>C1COCC1>[Br:11][C:12]1[C:13]([C:34]([C:33]#[N:37])([CH3:36])[CH3:35])=[N:14][CH:15]=[C:16]([CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18]

Participants

5

Reactant 3

HCID 6559IsobutyronitrileHCID 3251421Potassium bis(trimethylsilyl)amideHCID 867025955-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 89906823HCID 89906823, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-70 °C

Procedure

KHMDS 1 M in THF (1.517 mL) was added dropwise to a mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 200 mg, 0.506 mmol) and isobutyronitrile (52 mg, 0.758 mmol) in THF (5 mL) at −78° C. under a nitrogen atmosphere. The RM was stirred at −70° C. for 1 h, and allowed to warm to RT overnight. The RM was quenched with water and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure. The residue was purified by flash chromatography (RediSep® Silica gel column, 24 g, EtOAc/n-hexane, isocratic 1:3) to afford 5-bromo-6-(2-cyanopropan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (122 mg, 0.285 mmol) together with pyrimidine-5-boronic acid (53 mg, 0.427 mmol), Na2CO3 (0.427 mL, 0.855 mmol), PdCl2(dppf) (11 mg, 0.014 mmol) and dioxane (1.6 mL) were added to a vial, which was sealed, evacuated/purged with argon. The RM was stirred at 90° C. for 3 h, cooled to RT, treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 24 g, MeOH/DCM, isocratic 5:95) to afford the title product as a yellow solid. UPLC-MS (Condition 2) tR=1.05 min, m/z=428.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.72 (s, 6H) 7.38 (d, J=8.99 Hz, 2H) 7.80-7.91 (m, 2H) 8.26 (d, J=1.96 Hz, 1H) 8.96 (d, J=0.78 Hz, 2H) 9.18 (d, J=1.95 Hz, 1H) 9.30 (s, 1H) 10.64 (s, 1H).

Workup

  1. temperatureto warm to RT overnight
  2. customThe RM was quenched with water
  3. extractionextracted with EtOAc
  4. dry with materialThe combined extracts were dried over Na2SO4
  5. filtrationfiltered
  6. customthe filtrate was evaporated off under reduced pressure
  7. customThe residue was purified by flash chromatography (RediSep® Silica gel column, 24 g, EtOAc/n-hexane, isocratic 1:3)

Sources & evidence

ORD record
ord-e4548e7b42b54dce9bbd50df15f701c1
Source dataset
uspto-grants-2016_04
Patent number
US09315489B2

Reaction notes

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