6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid

Application

6-BOC-6-azaspiro[2.5]octane-1-carboxylic acid is an important pharmaceutical intermediate and a key raw material for the synthesis of many drugs and excipients. It is used in the preparation of tyrosine kinases and some protein kinase inhibitors.

Synthesis

Step 3: 6-tert-butyl 1-ethyl 6-azaspiro[2.5]octane-1,6-dicarboxylate (500 mg, 1.76 mmol) was dissolved in ethanol (8 mL) and a solution of sodium hydroxide (212 mg, 5.3 mmol) in water (4 mL) was added. The reaction mixture was stirred at 15°C for 12 hours. After completion of the reaction, the solvent was removed by evaporation under reduced pressure. The residue was dissolved in water and slowly acidified with dilute hydrochloric acid (0.5 M) under cooling in an ice bath to pH ~ 4. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (390 mg, 83% yield) as a white solid.1H NMR (400 MHz, CDCl3): δ 3.52-3.42 (m, 3H), 3.38-3.35 (m, 1H), 1.75- 1.72 (m, 2H), 1.58-1.56 (m, 1H), 1.46-1.43 (m, 11H), 1.23-1.21 (m, 1H), 1.02-1.01 (m, 1H).

References

[1] Patent: WO2015/949, 2015, A1. Location in patent: Page/Page column 117-118
[2] Patent: WO2013/127269, 2013, A1. Location in patent: Page/Page column 189; 190