SYNTHESIS OF BORONIC ESTER AND ACID COMPOUNDS

摘要

The invention relates to the synthesis of boronic ester and acid compounds. More particularly, the invention provides improved synthetic processes for the large-scale production of boronic ester and acid compounds, including the peptide boronic acid proteasome inhibitor bortezomib.

主权项

1. A composition comprising an ether solvent that has low miscibility with water and at least about ten moles of a boronic ester compound of formula (I):wherein:
R1 is an optionally substituted aliphatic or aromatic group; R2 is hydrogen, a nucleofugic group, or an optionally substituted aliphatic or aromatic group; R3 is a nucleofugic group or an optionally substituted aliphatic or aromatic group; and R4 and R5 are together an optionally substituted aliphatic group, and R4 and R5, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring having 0 additional ring heteroatoms; and none of the variables R1-R5 is substituted with a heteroaromatic group; wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w; and wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture.