4-Aminobenzonitrile → HCID 59190809, compound

HRID 418333Notes

Reaction equation

HRID 418333 reaction equation
[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:14])C(O)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)(Cl)=[O:16].NC1C=[CH:26][C:23]([C:24]#[N:25])=[CH:22]C=1.CC[N:30]([CH:34]([CH3:36])[CH3:35])[CH:31](C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:24]([C:23]1[CH:26]=[CH:35][C:34]([NH:30][C:31](=[O:16])[CH2:14][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:36][CH:22]=1)#[N:25]

Participants

7

Reactant 4

HCID 133964-AminobenzonitrileHCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 11116940HCID 11116940, compound

Product 1

HCID 59190809HCID 59190809, compoundYield 85%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

3-Nitrophenyl-propionic acid (992 mg, 5.08 mmol) was suspended in toluene (10 mL). Thionyl chloride (1.82 mL, 25.0 mmol) was added dropwise and the resulting mixture was stirred at 110° C. for 1 h. The reaction mixture was concentrated and the residue was dissolved in dry dichloromethane (15 mL). To this solution was added 4-aminobenzonitrile (590 mg, 5.2 mmol) and Hunig's base (1.85 mL, 10.0 mmol). The reaction mixture was stirred for 4 h then diluted with ethyl acetate (150 mL) and quenched with NH4Cl (150 mL satd. aq.) The organic fraction was isolated and washed with brine (50 mL), dried with MgSO4 and concentrated. The residue was purified by flash chromatography using an ethyl acetate/hexane gradient to provide 1.273 g of N-(4-cyano-phenyl)-3-(3-nitro-phenyl)-propionamide (85% yield). This intermediate (103 mg, 0.35 mmol) was dissolved in methanol (5 mL) under an atmosphere of argon, and sodium borohydride (26.3 mg, 0.7 mmol) and Pd/C (20 mg) were added. The resulting mixture was stirred at room temperature for 1 h, filtered through celite, and concentrated. The residue was suspended in NH4Cl (20 mL, saturated aqueous), and this mixture was extracted with ethyl acetate (2×20 mL). The combined organic fractions were washed with brine (20 mL), dried and concentrated to provide 3-(3-amino-phenyl)-N-(4-cyano-phenyl)-propionamide (80 mg, 87% yield) which was used without further purification. This intermediate was converted to the title compound as described in example 20. MS, electrospray, 405 (M+H).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. dissolutionthe residue was dissolved in dry dichloromethane (15 mL)
  3. stirringThe reaction mixture was stirred for 4 h
  4. customquenched with NH4Cl (150 mL satd. aq.) The organic fraction
  5. customwas isolated
  6. washwashed with brine (50 mL)
  7. dry with materialdried with MgSO4
  8. concentrationconcentrated
  9. customThe residue was purified by flash chromatography

Sources & evidence

ORD record
ord-b717098b9daa4097a01b7008b331e0e2
Source dataset
uspto-grants-2012_01
Patent number
US08093266B2

Reaction notes

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