[1-(tert-Butoxycarbonylamino-methyl)-cyclohexyl]-acetic acid

Chemical Properties

White powder

Uses

Protected Gabapentin (G117250). Amino acid structurally related to γ-Aminobutyric Acid (GABA), designed to cross the blood brain barrier. Used as an anticonvulsant.

Synthesis

Example 39: Synthesis of [1-(tert-butoxycarbonylamino - methyl) - cyclohexyl] - acetic acid; 2-(1-(aminomethyl)cyclohexyl)acetic acid (10.0 g, 58.4 mmol) was dissolved in tetrahydrofuran (280 mL) and 1N sodium hydroxide solution (128.5 mL) was added. The reaction mixture was cooled to 0°C and di-tert-butyl dicarbonate (14.0 g, 1.1 eq.) was added in batches under vigorous stirring. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. Subsequently, the tetrahydrofuran was removed by evaporation and the aqueous layer was washed with ethyl acetate (3 x 50 mL). The aqueous layer was acidified with potassium dihydrogen phosphate (44 g) and foam generation was observed. Gradually, the foam was replaced by a white precipitate. Stirring of the mixture was continued for 2 hours, during which time potassium dihydrogen phosphate (1 g) was slowly added. The precipitate was collected by filtration and washed with water to afford the target product 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid (15.2 g, 96% yield). Mass spectrum (MS): 272.1 (corresponds to C14H25NO4, [M+H]+); Melting point: 181 °C (decomposition); Elemental analysis (C14H25NO4) (calculated values) C: 59.52, H: 9.36, N: 4.76; (measured values) C: 59.51, H: 9.03, N: 4.87. IR spectrum (KBr, cm-1): 3413, 3054, 2933 (broad peaks), 1709, 1666, 1531, 1248; 1H NMR (CDCl3) δ 1.27-1.58 (multiple peaks, 19H), 2.29 (single peak, 2H), 3.12 (double peaks, 2H, J = 6.8 Hz), 4.97 (broad peak, 1H).

References

[1] Patent: EP1157000, 2005, B1
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1479 - 1486
[3] Patent: WO2016/123533, 2016, A1. Location in patent: Page/Page column 40
[4] Patent: US2006/46967, 2006, A1. Location in patent: Page/Page column 134
[5] Patent: US2003/176504, 2003, A1