Ethyl cyanoacetate → 2-Cyano-3-(1-methyl-cyclopropyl)-acrylic acid ethyl ester

To 1-methylcyclopropane-methanol (Aldrich, 1.13 mL, 11.6 mmol) in 50 mL CH2Cl2 was added neutral alumina (2.5 g) and then PCC (2.5 g, 11.6 mmol), and the mixture stirred 3 h at ambient temperature. The mixture was filtered through a 1 cm plug of silica gel under vacuum, and rinsed with Et2O. The filtrate was concentrated to ca. 5 mL total volume. To the residue was added THF (10 mL), ethyl cyanoacetate (1.2 mL, 11.3 mmol), piperidine (5 drops), and finally acetic acid (5 drops). The whole was stirred at ambient temperature overnight, then partitioned between Et2O and sat. aq. NaHCO3. The phases were separated and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (10→15% EtOAc/hexanes) provided 0.53 g (25%) of the ester as a colorless oil that crystallized on standing, mp 35-37° C. 1H NMR (CDCl3) δ 6.99 (s, 1H), 4.27 (q, J=7.3 Hz, 2H), 1.55 (s, 3H), 1.32 (t, J=7.3 Hz, 3H), 1.14 (s, 2H), 1.07 (s, 2H). 13C NMR δ. 170.44, 162.90, 115.17, 103.69, 62.52, 21.24, 21.07 (2C), 20.71, 14.35. Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 66.86; H, 7.47; N, 7.70. 2-Aminomethyl-3-(1-methyl-cyclopropyl)-proplonic acid ethyl ester. To 2-cyano-3-(1-methyl-cyclopropyl)-acrylic acid ethyl ester (0.459, 2.51 mmol) in 16 mL EtOH:THF (1:1) was added RaNi (0.4 g), and the mixture was hydrogenated in a Parr shaker at 48 psi for 15.5 h. Pearlman's catalyst (0.5 g) was then added and hydrogenation was continued for an additional 15 h. The mixture was filtered and concentrated. Flash chromatography of the residue 2→3→4→5→6→8% MeOH/CH2Cl2 provided 0.25 g (54%) of the aminoester as a colorless oil. 1H NMR (CDCl3) δ 3.97 (m, 2H), 2.67 (m, 2H), 2.46 (m, 1H), 1.28 (d, J=7.3 Hz, 2H), 1.19 (bs, 2H), 1.09 (t, J=7.3 Hz, 3H), 0.85 (s, 3H), 0.04 (m, 4H). LRMS: m/z 186.1 (M+1). 2-Aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid. To a solution of 2-aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid ethyl ester (0.259, 1.35 mmol) in 10 mL methanol at 0° C. was added 10% aq. NaOH (10 mL). The mixture was stirred at ambient temperature overnight, then concentrated to remove the methanol. The residue was cooled to 0° C. and acidified to pH 2 with conc. HCl. After allowing to warm to ambient temperature the mixture was loaded onto DOWEX-50WX8-100 ion exchange resin and eluted with H2O until neutral to litmus. Elution was continued with 5% aq. NH4OH (100 mL) and the alkaline fractions concentrated to provide 0.15 g (71%) of the amino acid as a colorless solid. 1H NMR (CDCl3) δ 2.72 (m, 2H), 2.42 (m, 1H), 1.34 (dd, J=8.5, 13.9 Hz, 1H), 1.19 (dd, J=6.1, 13.9 Hz, 1H), 0.82 (s, 3H), 0.05 (m, 4H). LRMS: m/z 158.0 (M+1).

1. filtrationThe mixture was filtered through a 1 cm plug of silica gel under vacuum
2. washrinsed with Et2O
3. concentrationThe filtrate was concentrated to ca. 5 mL total volume
4. custompartitioned between Et2O and sat. aq. NaHCO3
5. customThe phases were separated
6. washthe organic phase washed with brine
7. dry with materialdried (MgSO4)
8. concentrationconcentrated

ORD record

ord-78c853cb32a740c294b24ddfaaaf872c

Source dataset

uspto-grants-2009_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07517909B2