Uses
Diethyl acetamidomalonate is a versatile building block used for the synthesis of various pharmaceutical and biologically active compounds. It is an intermediate for the preparation of Novobiocin analogues as potential heat shock protein 90 inhibitors. It is also used as a important intermediates in syntheses of vitamins B1 and B6, barbiturates, non-steroidal anti-inflammatory agents, other numerous pharmaceuticals.
Synthesis
Diethyl 2-aminomalonate hydrochloride (1.69 g, 8.0 mmol) and triethylamine (3.4 mL, 24 mmol, 3.0 eq.) were dissolved in dichloromethane (120 mL) at 0 °C. Acetyl chloride (0.57 mL, 8.0 mmol, 1.0 eq.) was added slowly and dropwise with stirring and the reaction mixture was gradually warmed to room temperature and stirred overnight. After completion of the reaction, the mixture was diluted with dichloromethane (100 mL) and washed sequentially with 1 M hydrochloric acid (3 x 60 mL). The aqueous phase was then back-extracted with dichloromethane (2 x 60 mL), the organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was removed by concentration under reduced pressure to give a pure white solid product. Yield: 1.68 g (96% yield). The product was characterized as follows: melting point 96 °C (literature value 97 °C); 1H NMR (300 MHz, CDCl3) δ [ppm]: 1.30 (t, J=7.1Hz, 6H, 7-CH3,9-CH3), 2.08 (s, 3H, 5-CH3), 4.27 (m, 4H, 6-CH2,8-CH2), 5.18 (d, J=7.1Hz, 1H), 5.18 (d, J=7.1Hz, 1H). 7.1 Hz, 1H, 2-CH), 6.67 (d, J=5.7 Hz, 1H, 2-NH); 13C NMR (75 MHz, CDCl3) δ [ppm]: 14.0 (q, C-7, C-9), 22.8 (q, C-5), 56.5 (d, C-2), 62.6 (t, C-6, C-8), 166.5 (s, C -1, C-3), 169.9 (s, C-4); high-resolution mass spectrometry (ESI+): 240.0842 calculated value for C9H15N5O+Na+, 240.0824 measured value.
References
[1] Patent: WO2013/26765, 2013, A1. Location in patent: Page/Page column 15-16
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 1011 - 1026
