7-Azaspiro[3.5]nonane-2,7-dicarboxylic acid, 7-(1,1-dimethylethyl) ester synthesis

Yield: 99%

Reaction Conditions:

Stage #1:2-cyano-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester with water;lithium hydroxide in ethanol for 4 h;Reflux;
Stage #2: with hydrogenchloride in water; pH=1 - 2

Steps:

35
Synthesis of 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid; tert-Butyl 2-cyano-7-azaspiro[3.5]nonane-7-carboxylate (1.5 g, 5.99 mmol) was dissolved in ethanol (40 mL) and water (40 mL). Lithium hydroxide (880 mg, 21 mmol) was added and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature. The ethanol was evaporated and the aqueous layer was acidified (pH 1-2) with 6N HCl. The aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried (MgSO₄), filtered and concentrated to give the title compound as a white solid (1.6 g, 99%). ¹H NMR (400 MHz, CDCl₃) δ ppm 3.34-3.41 (m, 2H), 3.27-3.34 (m, 2H), 3.10-3.21 (m, 1H), 2.12 (d, J=8.9 Hz, 4H), 1.58-1.63 (m, 2H), 1.52-1.58 (m, 2H), 1.47 (s, 9H). m/z 214 (MH⁺ minus t-Bu), 292 (MNa⁺).

References:

Pfizer Inc. US2010/113465, 2010, A1 Location in patent:Page/Page column 32