The general procedure for the synthesis of 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid from methyl chloroformate-9-fluorenylmethyl and 4-amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid was as follows: 4-amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5 g, 20.5 mmol) was dissolved in THF (300 mL), an aqueous solution of Na2CO3 (6.45 g, 61.5 mmol, 3.0 eq.) was added (64.5 mL) and cooled to 0 °C. A THF solution (30 mL) of methyl 9-fluorenyl chloroformate (5.3 g, 30.7 mmol, 1.5 eq.) was added slowly and dropwise. The reaction mixture was gradually warmed to 25 °C and stirring was continued for 12 hours. After completion of the reaction, the reaction solution was carefully acidified with 1 M HCl and the crude product was extracted three times with EtOAc. The organic layers were combined, dried with Na2SO4, concentrated and purified by combiflash column chromatography (eluent: 0 to 10% MeOH/DCM) to afford the target product 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butyloxycarbonyl)piperidine-4-carboxylic acid (4.02 g, 42% yield). The product was confirmed by 1H NMR, 13C NMR and HRMS characterization.
