Ethyl Acetate → 1-(4-methyl-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

HRID 1505199Notes

Reaction equation

HRID 1505199 reaction equation
Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([N:10]2[CH2:14][CH2:13][CH:12](O)C2)[CH:3]=1.Cl[C:17](Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:28]=[C:29]=[O:30].[NH2:31][C:32]1[C:37]2[O:38][CH2:39][C:40](=[O:42])[NH:41][C:36]=2[CH:35]=[CH:34][CH:33]=1.CCO[C:46]([CH3:48])=O>CN(C=O)C>[CH3:17][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:28][C:29]([NH:31][C:32]2[C:37]3[O:38][CH2:39][C:40](=[O:42])[NH:41][C:36]=3[CH:35]=[CH:34][CH:33]=2)=[O:30])=[C:4]([N:10]2[CH2:48][CH2:46][CH2:12][CH2:13][CH2:14]2)[CH:3]=1

Participants

7

Reactant 5

HCID 8857Ethyl Acetate3×HCID 94429TriphosgeneHCID 105034IsocyanateHCID 115934888-Amino-2H-1,4-benzoxazin-3(4H)-oneHCID 630834924-Chloro-2-(3-hydroxypyrrolidin-1-yl)benzonitrile

Product 1

HCID 534765861-(4-methyl-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)ureaYield 7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

Amine 2bh (1.08 g, 5.3 mmol) (Scheme 8) was dissolved in 40 ml of AcOEt and at 0° C. triphosgene (1.56 g, 5.4 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 15 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1f (1 g, 5.46 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 1/petroleum ether 9). The solvent was evaporated and the crude was dissolved in AcOEt (50 ml) and washed with water (1×30 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 150 mg of a white solid. Yield=7% 1HNMR (DMSO, 200 MHz) δ 1.63 (6H, m), 2.25 (3H, s), 2.76 (4H, m), 4.28 (2H, d, J=5.4 Hz), 4.61 (2H, s), 6.46 (1H, dd, J=7.8 Hz, J′=1.4 Hz), 6.81 (3H, m), 7.12 (2H, m), 7.75 (1H, dd, J=8.2 Hz, J′=1.6 Hz), 8.11 (1H, s), 10.66 (1H, bs); [M+1] 395.0 (C22H26N4O3 requires 394.5).

Workup

  1. additionwas added to the solution
  2. customthen evaporated
  3. dissolutionthe residue was dissolved in 15 ml of DMF
  4. temperaturethe mixture was warmed at 80° C. for 8 hours
  5. customThe solvent was evaporated
  6. dissolutionthe crude was dissolved in AcOEt (50 ml)
  7. washwashed with water (1×30 ml) and brine
  8. dry with materialThe organic phase was dried over sodium sulfate
  9. concentrationconcentrated under vacuum
  10. customThe purification of the crude residue by chromatographic column

Sources & evidence

ORD record
ord-82ba6ec4f08446f7ac29e4a15e35d344
Source dataset
uspto-grants-2015_12
Patent number
US09216975B2

Reaction notes

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