Propanedioyl dichloride → 2-(7,8-Difluoro-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide

HRID 343158Notes

Reaction equation

HRID 343158 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])=[C:4]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:3]=1.[C:32](Cl)(=[O:37])[CH2:33][C:34](Cl)=[O:35]>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[N:9]([CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[O:12])[C:32](=[O:37])[CH2:33][C:34](=[O:35])[N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1

Participants

4

Reactant 2

HCID 74269Propanedioyl dichlorideHCID 539192522-(4,5-Difluoro-2-phenylamino-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide

Product 1

HCID 676973252-(7,8-Difluoro-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamideYield 35.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

A solution of 5.62 g 2-(4,5-difluoro-2-phenylamino-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, (13.2 mmol) in 50 mL of tetrahydrofuran is transferred to an addition funnel. A solution of 1.60 mL of malonyl dichloride (16.53 mmol, 1.25 equiv) in 50 mL tetrahydrofuran is transferred to a separate addition funnel. Each solution of each reagent is simultaneously added dropwise over 20 min. to 250 mL of tetrahydrofuran at ambient temperature under nitrogen with vigorous agitation. After stirring 16 hrs. at ambient temperature, the reaction mixture is concentrated in vacuo. The residue is purified on flash grade silica gel using 40-50% ethyl acetate in hexane. The appropriate fractions were combined, evaporated in vacuo, dried under high vacuum for 2 hrs., and then triturated with hexane. The hexane is removed in vacuo and the residual solid is dried under high vacuum to provide 2.340 g of 2-(7,8-Difluoro-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an off-white solid: 1H NMR (300 MHz, CDCl3) δ7.37 (m, 7H), 7.15 (m, 1H), 7.01 (m, 2H), 6.76 (dd, 1H, J=7.8, 11.1), 5.04 (m, 1H), 4.36 (d, 1H, J=16.3), 4.00 (d, 1H, J=16.5), 3.89 (s, 3H), 3.62 (d, 1H, J=12.2), 3.54 (d, 1H, J=12.2), 1.14 (m, 6H); low resolution MS (FAB)m/e 494 (MH+).

Workup

  1. customis transferred to an addition funnel
  2. concentrationat ambient temperature, the reaction mixture is concentrated in vacuo
  3. customThe residue is purified on flash grade silica gel using 40-50% ethyl acetate in hexane
  4. customevaporated in vacuo
  5. customdried under high vacuum for 2 hrs
  6. custom, and then triturated with hexane
  7. customThe hexane is removed in vacuo
  8. customthe residual solid is dried under high vacuum

Sources & evidence

ORD record
ord-471fac2e90404b3688966d848c703593
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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