Diethyl Malonate → 2-(N-tert-butoxycarbonyl-4-butylamino)malonic acid diethyl ester

HRID 2050479Notes

Reaction equation

[Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCOC(C)=O.O>C(O)C>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([N:20]([CH2:21][CH2:22][CH2:23][CH3:24])[C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]

Participants

Conditions

Temperature: 60 °C

Procedure

Metallic sodium (0.28 g, 0.012 mol) is dissolved in absolute ethyl alcohol (EtOH) (9 ml) under nitrogen atmosphere. The mixture is heated to 60° C. and diethyl malonate (3.8 g, 0.024 mol) is then dripped therein. N-tert-butoxycarbonyl-4-chloro-butylamine (2.5 g, 0.012 mol) is then gradually added, at room temperature, to the resulting solution. The reaction mixture is stirred at room temperature for 2 hours and at the reflux temperature for 6 hours, and then poured into a mixture AcOEt/water (100 ml 1/1 v/v). The organic phase which is separated is then washed repeatedly with water and dried over MgSO4The solvent is removed under vacuum at 100° C. affording a crude oily product which is purified by reverse-phase HPLC on an RP-18 column eluting with an aqueous phase modified with CH3CN (45% by volume). The desired compound (1.31 g) is thus obtained as a pure product.

Workup

customThe organic phase which is separated
washis then washed repeatedly with water
customdried over MgSO4The solvent
customis removed under vacuum at 100° C.
customaffording a crude oily product which
customis purified by reverse-phase HPLC on an RP-18 column
washeluting with an aqueous phase

Sources & evidence

ORD record: ord-e8bfac0e121345aaa02fddcb3d932588
Source dataset: uspto-grants-1991_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US05013723

Reaction notes

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