Bortezomib intermediates II

Uses

(αS)-α-Amino-N-[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-benzenepropanamide Monohydrochloride is a Bortezomib (B675700) intermediate which is used in the evaluation of bone-targeted proteasome inhibitors for myeloma.

Synthesis

GENERAL METHODS: (S)-N-Boc-2-amino-3-methoxypropionic acid (4.73 g, 21.58 mmol) was dissolved in anhydrous CH2Cl2 (120 mL) and cooled to -10 °C. HOBt (4.38 g, 32.37 mmol) and EDCI (6.2 g, 32.37 mmol) were added sequentially and stirred for 10 minutes. Intermediate 5 (8.19 g, 21.58 mmol) and DIPEA (9.77 g, 75.53 mmol) were then added. The reaction mixture was stirred at -10 °C for 1 hour, followed by continued stirring at room temperature for 15 hours. After completion of the reaction, the organic phase was washed sequentially with 10% hydrochloric acid, 5% NaHCO3 solution and brine and dried over anhydrous Na2SO4. Filtered and concentrated, the crude product obtained was directly used in the next step of the reaction. The borate ester prepared above was dissolved in ethyl acetate (30 mL) and ethyl acetate solution (55 mL) of 4.5 mol/L HCl was added slowly and dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The ethyl acetate was removed by evaporation under reduced pressure. Methyl tert-butyl ether (MTBE) was added to the residue and filtered to give the glassy solid product 3a (7.8 g, 89.7% yield). The product was confirmed by 1H NMR (400 MHz, DMSO) and MS (ESI) characterization.

References

[1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 3975 - 3981
[2] Journal of Medicinal Chemistry, 2018,