Spiro[9H-fluorene-9,4'-piperidine]-1'-carboxylic acid, 2,7-dibromo-, 1,1-dimethylethyl ester synthesis

Yield:1616113-98-4 61%

Reaction Conditions:

Stage #1: 2,7-dibromo-9H-fluorenewith sodium hydride in tetrahydrofuran;mineral oil at 0 - 20; for 0.5 h;
Stage #2: N-(tert-butyloxycarbonyl)bis(2-chloroethyl)amine in tetrahydrofuran;mineral oil at 0; for 4 h;Reflux;

Steps:

I Step I: tert-Butyl 2,7-dibromospiro[fluorene-9,4'-piperidine]- -carboxylate. Intermediate AG5

Step I: tert-Butyl 2,7-dibromospiro[fluorene-9,4'-piperidine]- -carboxylate. Intermediate AG5 To a cold (0°C) stirred solution of 2,7-dibromo-9H-fluorene (7.500 g, 23.15 mmol) in THF (38 mL) is added NaH in oil (3.7 g, 146.5 mmol) in portions. Cooling bath is removed, mixture stirred at RT for 30 min (rapid evolution of hydrogen gas observed) cooled back to 0°C. A solution of tert-butyl N,N-bis(2-chloroethyl)carbamate (4.00 g, 16.52 mmol) in THF (6.0 mL) is then added. The reaction mixture is slowly warmed to reflux and stirred for 4 h (bath temp. 75°C). The final reaction mixture is cooled to RT, quenched slowly by pouring onto crushed ice, extracted with Et20 (2 x 100 mL). The combined organic extracts are washed with brine, dried over Na₂S0₄ and concentrated. The residue is purified on Biotage Snap silica gel cartridge (340 g) using a gradient of EtOAc in Hex (0% to 10%, 6 CV and 10%) as eluent to afford the title compound (5.00 g, 61%) as an orange solid. ^XH NMR (400 MHz, CDC1₃) δ 7.71 (d, J = 1.7 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.49 (dd, J = 7.9, 1.5 Hz, 2H), 3.92 - 3.72 (m, 4H), 1.94 - 1.74 (m, 4H), 1.53 (s, 9H).

References:

WO2014/100158,2014,A1 Location in patent:Page/Page column 92-93