Dimethylformamide → 2-(3-Allyl-3-methyl-2,4-dioxo-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxyphenyl) acetamide

HRID 343185Notes

Reaction equation

HRID 343185 reaction equation
[CH2:1]([C:4]([CH3:11])([C:8]([OH:10])=O)[C:5]([OH:7])=O)[CH:2]=[CH2:3].C[N:13](C=O)C.C(Cl)(=O)C(Cl)=O.[CH:23]([N:26]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[C:27](=[O:36])[CH2:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:25])[CH3:24]>C(Cl)Cl.C1COCC1>[CH2:1]([C:4]1([CH3:11])[C:5](=[O:7])[N:29]([CH2:28][C:27]([N:26]([CH:23]([CH3:25])[CH3:24])[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:13][C:8]1=[O:10])[CH:2]=[CH2:3]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 126302202-Allyl-2-methyl malonic acidHCID 53747552N-Isopropyl-N-(4-methoxy-phenyl)-2-phenylamino acetamide

Product 1

HCID 676971062-(3-Allyl-3-methyl-2,4-dioxo-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxyphenyl) acetamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 3.04 g (19.2 mmol) of 2-allyl-2-methyl malonic acid, prepared as in Part A, in 50 mL of DCM at 0° C. is added 7 mL of DMF, followed by 6.7 mL (76.8 mmol) of oxalyl chloride. The resulting solution is stirred 1 h at RT, then the solvent and excess oxalyl chloride is removed in vacuo. The residue is dissolved in 100 mL of THF and added dropwise to a stirring solution of 5.0 g (16.0 mmol) of N-Isopropyl-N-(4-methoxy-phenyl)-2-phenylamino acetamide, prepared as in Intermediate 44, in 300 mL of THF maintained at 0° C. The resulting mixture is stirred at RT for 30 min then refluxed for 16 h. The solvents were removed in vacuo and the residue poured into 200 mL of 1H HCl and extracted with EtOAc (2×100 mL). The organics were washed with NaHCO3 (1×100 mL), brine (1×100 mL), dried over MgSO4, and the solvent removed in vacuo. Purification of the brown oil by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 4.0 g of 2-(3-Allyl-3-methyl-2,4-dioxo-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxyphenyl) acetamide: 1H NMR (CDCl3, 300 MHz) δ9.53 (s, 1H), 7.27-6.85 (m, 8H), 5.67-5.60 (m, 1H), 5.05-4.93 (m, 2H), 4.73 (d, 1H, J=17), 4.50-4,45 (d, 1H, J=16), 3.77 (s, 3H), 3.60 (d, 1H, J=17), 2.1 (s, 1H), 1.46 (s, 2H), 1.09-1.03 (m, 6H).

Workup

  1. customthe solvent and excess oxalyl chloride is removed in vacuo
  2. dissolutionThe residue is dissolved in 100 mL of THF
  3. temperaturemaintained at 0° C
  4. stirringThe resulting mixture is stirred at RT for 30 min
  5. temperaturethen refluxed for 16 h
  6. customThe solvents were removed in vacuo
  7. additionthe residue poured into 200 mL of 1H HCl
  8. extractionextracted with EtOAc (2×100 mL)
  9. washThe organics were washed with NaHCO3 (1×100 mL), brine (1×100 mL)
  10. dry with materialdried over MgSO4
  11. customthe solvent removed in vacuo
  12. customPurification of the brown oil by silica gel flash column chromatography

Sources & evidence

ORD record
ord-0c8d8282bb2d4f0eae4e2ef28313bb70
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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