Pivaloyl chloride → N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}acetamide

HRID 1435489

Reaction equation

HRID 1435489 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([C:28]1[N:8]([CH2:9][CH:10]2[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:21])[CH3:20])=[CH:3][C:2]=2[N:1]=1)([CH3:27])([CH3:24])[CH3:22]

Participants

5

Reactant 2

HCID 62493Pivaloyl chlorideHCID 57441085N-(3-Amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)acetamide

Product 1

HCID 57723211N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}acetamide

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

N-(3-Amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)acetamide (1.32 g, 4.44 mmol) was dissolved in 100 mL of DCM containing DMAP (108 mg, 0.89 mmol). Trimethylacetyl chloride (0.60 mL, 4.88 mmol) was added dropwise and the solution was stirred at rt for 2 h. The solution washed with saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. Part of the product precipitated during the washings and was filtered. The organic phase was evaporated and combined with the precipitate. The product was dissolved in 30 mL of AcOH and placed in 6 sealed tubes (5 mL/tube). Each tube was heated at 150° C. in a Personal Chemistry microwaves instrument for 2.5 h. The fractions were pooled and the solvent was evaporated. The product was dissolved in EtOAc and washed with aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was purified by flash chromatography on silica gel using acetone/hexanes (2:1) as eluent. Yield: 1.11 g (68%); 1H NMR (400 MHz, CD3OD) δ 1.40-1.49 (m, 2 H), 1.52 (s, 9 H), 1.60-1.65 (m, 2 H), 1.67-1.77 (m, 1 H), 1.96-2.06 (m, 3 H), 2.11 (s, 3 H), 2.15-2.23 (m, 1 H), 4.28 (d, J=7.62 Hz, 2 H), 7.35-7.39 (m, 1 H), 7.40-7.44 (m, 1 H), 7.85 (d, J=1.76 Hz, 1 H).

Workup

  1. washThe solution washed with saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution
  2. dry with materialdried over anhydrous Na2SO4
  3. customPart of the product precipitated during the washings
  4. filtrationwas filtered
  5. customThe organic phase was evaporated
  6. dissolutionThe product was dissolved in 30 mL of AcOH
  7. temperatureEach tube was heated at 150° C. in a Personal Chemistry microwaves instrument for 2.5 h
  8. customthe solvent was evaporated
  9. dissolutionThe product was dissolved in EtOAc
  10. washwashed with aqueous NaHCO3 solution, saturated aqueous NaCl solution
  11. dry with materialdried over anhydrous Na2SO4
  12. customThe product was purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-e5c3934385034e5bb7ce8cc91e71d662
Source dataset
uspto-grants-2009_11
Patent number
US07615642B2

Linked notes

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