Tetrahydrofuran → (RS)-N-(3,5-Difluoro-benzyl)-2-methyl-N'-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-malonamide

HRID 2223243Notes

Reaction equation

HRID 2223243 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=O.O1CCCC1.[NH2:23][CH:24]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]2[CH:37]=[CH:38][CH:39]=[CH:40][C:27]=2[N:26]([CH3:41])[C:25]1=[O:42].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[F:17][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([F:1])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([NH:23][CH:24]1[C:25](=[O:42])[N:26]([CH3:41])[C:27]2[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=2[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:30]1)=[O:11]

Participants

6

Reactant 5

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27296813-Amino-1-methyl-5-phenyl-1H-benzo[E][1,4]diazepin-2(3H)-oneHCID 21091473N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid

Product 1

HCID 10005794(RS)-N-(3,5-Difluoro-benzyl)-2-methyl-N'-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-malonamideYield 67%

Procedure

To a solution of 0.073 g (0.3 mmol) N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid in 5 ml of tetrahydrofuran 0.080 g (0.3 mmol) of (3RS)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 0.058 g (0.3 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 0.040 g (0.3 mmol) of 1-hydroxybenzotrizole hydrate and 0.039 g (0.3 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. After concentration in vacuo 0.5 N HCl (5 ml) was added and the mixture was extracted with dichloromethane (three times 5 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate=3:1) to yield 0.099 g (67%) of the diastereomeric mixture of title compound as white solid.

Workup

  1. concentrationAfter concentration in vacuo 0.5 N HCl (5 ml)
  2. additionwas added
  3. extractionthe mixture was extracted with dichloromethane (three times 5 ml)
  4. extractionThe combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution
  5. dry with materialdried (MgSO4)
  6. customevaporated on the rotary evaporator
  7. customThe residue was purified by flash chromatography (hexane/ethyl acetate=3:1)

Sources & evidence

ORD record
ord-46c3212a4869473ebf7b964c54473a60
Source dataset
uspto-grants-2008_05
Patent number
US07375099B2

Reaction notes

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