Dimethyl malonate → [[[(3S)-Hexahydro-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-azepin-3-yl]amino][(2-methyl-5-benzofuranyl)amino]methylene]propanedioic acid dimethyl ester

HRID 1264633Notes

Reaction equation

HRID 1264633 reaction equation
[H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([N:22]=[C:23]=S)=[CH:18][C:16]=2[CH:17]=1.[NH2:25][C@H:26]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]([CH2:33][C:34]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[C:27]1=[O:41]>CN(C=O)C.[Hg](Cl)Cl>[CH3:8][O:7][C:5](=[O:6])[C:4](=[C:23]([NH:25][C@H:26]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]([CH2:33][C:34](=[O:35])[N:36]2[CH2:37][CH2:38][CH2:39][CH2:40]2)[C:27]1=[O:41])[NH:22][C:19]1[CH:20]=[CH:21][C:15]2[O:14][C:13]([CH3:12])=[CH:17][C:16]=2[CH:18]=1)[C:3]([O:10][CH3:11])=[O:9]

Participants

7

Reactant 4

HCID 7943Dimethyl malonateHCID 24758Sodium hydrideHCID 120478195-Isothiocyanato-2-methylbenzofuranHCID 12047820(S)-1-[(3-amino-hexahydro-2-oxo-1H-azepin-1-yl)acetyl]pyrrolidine

Product 1

HCID 70030842[[[(3S)-Hexahydro-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-azepin-3-yl]amino][(2-methyl-5-benzofuranyl)amino]methylene]propanedioic acid dimethyl esterYield 40%

Reagents, catalysts & solvents 2

HCID 24085Mercuric ChlorideCatalystHCID 6228DimethylformamideSolvent

Procedure

Sodium hydride (95%, 11 mg, 0.44 mmol) was added to a solution of dimethyl malonate (40 mg, 0.30 mmol) in DMF (1.5 mL) at 0° C. The resulting mixture was warmed to room temperature, 2-methyl-5-isothiocyanatobenzofuran (56 mg, 0.30 mmol) was then added, and the resulting solution was stirred at at room temperature for 30 minutes. To the solution was then added 1-[[(3S)-3-aminohexahydro-2-oxo-1H-azepin-1-yl]acetyl]pyrrolidine (71 mg, 0.30 mmol) followed by mercury (II) chloride (82 mg, 0.30 mmol). The resulting dark mixture was stirred at room temperature for 2 h, then filtered through CELITE. The filtrate was concentrated, and the residue was purified by flash chromatography (silica, 1 to 5% methanol/dichloromethane) to afford the title compound as a pale yellow solid (63 mg, 40%): MS (ESI, pos. ion spectrum) m/z 527, HPLC (method A): tR 3.5 min.

Workup

  1. stirringThe resulting dark mixture was stirred at room temperature for 2 h
  2. filtrationfiltered through CELITE
  3. concentrationThe filtrate was concentrated
  4. customthe residue was purified by flash chromatography (silica, 1 to 5% methanol/dichloromethane)

Sources & evidence

ORD record
ord-72c666fe3752479fae806bb1a6491453
Source dataset
uspto-grants-2003_04
Patent number
US06544981B2

Reaction notes

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