TERT-BUTYL 1-OXA-4,9-DIAZASPIRO[5.5]UNDECANE-9-CARBOXYLATE

Synthesis

The reaction was carried out in 12 batches as follows: borane-dimethyl sulfide complex (10 M, dissolved in dimethyl sulfide, 75 mL, 750 mmol) was slowly added dropwise to a solution of tert-butyl 3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (50 g, 180 mmol) in tetrahydrofuran (1.5 L). The reaction mixture was heated at reflux for 6 h at 70 °C, followed by stirring for 10 h at 25 °C. Upon completion of the reaction, the reaction was quenched with methanol (500 mL) and stirring was continued at 25 °C for 30 min, after which it was concentrated under reduced pressure. The resulting white solid was dissolved in methanol (1 L), N,N'-dimethylethane-1,2-diamine (65 g, 740 mmol) was added, and heated at reflux for 16 hours at 70 °C. Twelve batches of the reaction mixture were combined and concentrated in vacuum to give a pale yellow oil. This oily substance was dissolved in dichloromethane (4 L), washed with aqueous ammonium chloride (4 x 2 L), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was ground with petroleum ether (500 mL) at 25°C for 30 min to give a white solid product (304 g). The milled filtrate was concentrated under vacuum and the residue was ground with petroleum ether (200 mL) at 25 °C for 36 h to give additional white solid product (135 g). Total yield: 439 g, 1.71 mol, 77%. lcms m/z 257.2 [M + H]+. 1H NMR (400 MHz, CDCl3) δ 3.85-3.59 (m, 4H), 3.14 (br dd, J = 11,11 Hz, 2H), 2.84 (dd, J = 4.9,4.6 Hz, 2H), 2.68 (s , 2H), 2.02-1.84 (br m, 2H), 1.47-1.33 (m, 2H), 1.45 (s, 9H).

References

[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7458 - 7461
[2] Patent: WO2017/21805, 2017, A1. Location in patent: Page/Page column 83; 85
[3] Patent: US2018/208608, 2018, A1. Location in patent: Paragraph 0243; 0244; 0246
[4] Patent: WO2015/185207, 2015, A1. Location in patent: Page/Page column 190; 191
[5] Patent: WO2015/185208, 2015, A1. Location in patent: Page/Page column 147; 148