Sodium hydride → N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine

HRID 475916Notes

Reaction equation

HRID 475916 reaction equation
Cl[C:2]1[N:11]=[C:10]([N:12]([CH2:14][CH3:15])[CH3:13])[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[N:3]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1.[H-].[Na+]>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH:32][C:2]3[N:11]=[C:10]([N:12]([CH2:14][CH3:15])[CH3:13])[C:9]4[CH2:8][CH2:7][CH2:6][CH:5]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:4]=4[N:3]=3)=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 580753532-chloro-N-ethyl-N-methyl-8-phenyl-5,6,7,8-tetrahydroquinazolin-4-amineHCID 580757574-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline

Product 1

HCID 58075270N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamineYield 33.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 2-chloro-N-ethyl-N-methyl-8-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine (42.9 mg, 0.142 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (31.8 mg, 0.142 mmol) in THF (2 mL) was added 60% suspension of sodium hydride in mineral oil (6.82 mg, 0.284 mmol). The reaction mixture was heated with stirring in a capped vial at 80° C. for 1.5 h. The reaction mixture was carefully partitioned between an aqueous solution of ammonium chloride and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by reverse-phase preparative HPLC to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine (31.6 mg, 0.048 mmol, 33.5% yield) as brown oil. LC-MS (M+H)+=489.2. 1H NMR (500 MHz, CDCl3) δ ppm 11.50 (1H, br s), 7.74 (1H, d, J=1.2 Hz), 7.39 (1H, dd, J=8.5, 2.1 Hz), 7.29 (2H, dd, J=4.9, 2.7 Hz), 7.21-7.27 (2H, m), 7.12-7.19 (3H, m), 7.07 (1H, d, J=1.5 Hz), 4.20 (1H, t, J=7.0 Hz), 3.80 (3H, s), 3.68-3.78 (2H, m, J=13.8, 7.0, 7.0, 7.0, 7.0 Hz), 3.31 (3H, s), 2.64-2.82 (2H, m), 2.27 (1H, ddd, J=13.3, 7.5, 5.2 Hz), 1.88-1.99 (1H, m), 1.74-1.85 (1H, m), 1.54-1.67 (1H, m), 1.34 (3H, t, J=7.0 Hz).

Workup

  1. temperatureThe reaction mixture was heated
  2. customThe reaction mixture was carefully partitioned between an aqueous solution of ammonium chloride and dichloromethane
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with dichloromethane
  5. dry with materialThe combined organic extracts were dried over anhydrous magnesium sulfate
  6. filtrationfiltered
  7. customThe solvent was removed in vacuum
  8. customthe residue was purified by reverse-phase preparative HPLC

Sources & evidence

ORD record
ord-722249db679d42229c70413d484bc769
Source dataset
uspto-grants-2014_01
Patent number
US08637525B2

Reaction notes

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