Synthesis of boronic ester and acid compounds

A large-scale process for forming a compound of formula (XIV):

• or a boronic acid anhydride thereof, said process comprising:
• (a) providing a boron “ate” complex of formula (XV):
• wherein:
• R3 is a nucleofugic group;
• Y is a nucleofugic group;
• and
• M+ is an alkali metal;
• (b) contacting the boron “ate” complex of formula (XV) with a Lewis acid under conditions that afford a boronic ester compound of formula (XVI):
• said contacting step being conducted in a reaction mixture comprising an ether solvent that has low miscibility with water, 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;
• (c) treating the boronic ester compound of formula (XVI) with a reagent of formula M1-N(G)2, where M1 is an alkali metal and each G individually or together is an amino group protecting group, to form a compound of formula (XVII):
• (d) removing the G groups to form a compound of formula (XVIII):
• or an acid addition salt thereof;
• (e) coupling the compound of formula (XVIII) with a compound of formula (XIX);
• wherein:
• P1 is a cleavable amino group protecting moiety;
• and
• X is OH or a leaving group;
• to form a compound of formula (XX):
• wherein P1 is as defined above;
• (f) removing the protecting group P1 to form a compound of formula (XXI):
• or an acid addition salt thereof;
• (g) coupling the compound of formula (XXI) with a reagent of formula (XXII)
• wherein X is a QH or a leaving group, to form a compound of formula (XXIII):
• (h) deprotecting the boronic acid moiety to form the compound of formula (XIV) or a boronic acid anhydride thereof.