4-Methylmorpholine → HCID 20814055, compound

HRID 896374Notes

Reaction equation

HRID 896374 reaction equation
[CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:15][C:16]3[N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]4[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:18]=4[N:17]=3)[C:5]2=[O:33])[CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(Cl)Cl.O>[CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:15][C:16]3[N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]4[CH:26]=[CH:27][C:28]([CH2:30][OH:31])=[CH:29][C:18]=4[N:17]=3)[C:5]2=[O:33])[CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 4311764Sodium borohydrideHCID 22349289HCID 22349289, compound

Product 1

HCID 20814055HCID 20814055, compoundYield 53%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a cooled (0° C.) solution of 2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid (77 mg, 0.17 mmol) and N-methyl morpholine (23 μL, 0.21 mmol) in DCM (3 mL) was added isobutyl chloroformate (27 μL, 0.21 mmol. The mixture was allowed to warm to room temperature and stirred for 2 hrs. After concentration and trituration with ethyl acetate the solid was removed by filtration and the filtrate concentrated in vacuo. The residue containing the mixed anhydride was dissolved in THF (3 mL) and added to a stirred and cooled (0° C.) solution of sodium borohydride (65 mg, 1.7 mmol) in water. The mixture was allowed to warm to room temperature and stirred for 3 hrs., followed by quenching with satd. Na/K tartrate and stirring overnight. The mixture was extracted with ethyl acetate (3×10 mL), the combined organic phases washed with brine and dried (MgSO4). Purification by flash chromatography (eluent 2%, 5% methanol in DCM) afforded 3-cyclopropyl-1-[5-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-1H-quinazoline-2,4-dione (39 mg, 52%) as a white solid.

Workup

  1. concentrationAfter concentration and trituration with ethyl acetate the solid
  2. customwas removed by filtration
  3. concentrationthe filtrate concentrated in vacuo
  4. additionThe residue containing the mixed anhydride
  5. dissolutionwas dissolved in THF (3 mL)
  6. additionadded to
  7. stirringa stirred
  8. temperatureto warm to room temperature
  9. stirringstirred for 3 hrs
  10. customby quenching with satd
  11. stirringNa/K tartrate and stirring overnight
  12. extractionThe mixture was extracted with ethyl acetate (3×10 mL)
  13. washthe combined organic phases washed with brine
  14. dry with materialdried (MgSO4)
  15. customPurification by flash chromatography (eluent 2%, 5% methanol in DCM)

Sources & evidence

ORD record
ord-f742f2ac66374e1d893be66aceee1ea4
Source dataset
uspto-grants-2005_07
Patent number
US06919331B2

Reaction notes

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