Synthetic route for the preparation of α-amino boronic acid derivatives via substituted alk-1-ynes

A process for producing bortezomib N-(pyrazin-2-yl)carbonyl-L-phenylalanine-L-leucine boronic acid), comprising the steps of:

• a) providing a compound of formula VI
• wherein:
• R1 is isopropyl;
• R2 and R3 cooperatively form a part of a 5-membered ring representing 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane;
• X is a halogen selected from the group consisting of CI, Br and I;
• and
• * indicates a chiral center;
• wherein said process of providing said compound of formula VI comprises the steps of:
• (i) providing a compound of formula V
• wherein R1, R2, R3 and X are defined as above;
• (ii) converting said compound of formula V to compound of formula VI by hydrogenation, and
• (iii) optionally applying enantiomeric resolution in order to obtain enantiomerically pure compound of formula VI;
• b) converting said compound of formula VI to compound of formula VIII
• wherein R1, R2 and R3 and R′ are defined as above;
• A is an anion selected from the group of anions consisting of Cl−, Br−, HSO4−, CH3COO−, CF3COO− and R′SO3−, wherein R′ represents alkyl or aryl;
• and
• * indicates a chiral center;
• or free amine thereof,
• by a process comprising the steps of:
• (i) converting the compound of formula VI to compound of formula VII
• wherein R1, R2 and R3 are defined as above, and
• PM is an amino group protecting moiety, wherein PM is selected from the group consisting of tert-butanesulfinyl, tosyl, p-nitrobenzenesulfonyl, carbobenzyloxy, t-butyloxycarbonyl, benzyl, p-methoxybenzyl, dimethoxybenzyl, p-hydroxybenzyl, 9-phenylfluoren-9-yl, fluorenyl, diphenylmethyl, ferrocenylmethyl and 4-methyltrityl, and x=1 and y=1, or PM is SiR″3, wherein R″ represents alkyl and x=0 and y=2;
• and
• * indicates a chiral center;
• by substituting X of the compound of formula VI with a protected amino group, and
• (ii) subjecting the compound of formula VII to cleavage of protection groups to yield the compound of formula VIII;
• c) obtaining an enantiomerically pure compound of formula VIII by enantiomeric resolution,
• d) converting the enantiomerically pure compound of formula VIII to a compound of formula XII:
• by a process comprising the steps of either:
• (i) coupling the enantiomerically pure compound of formula VIII with the compound of formula XI
• to give the compound of formula XII;
• or
• (i)′ coupling the enantiomerically pure compound of formula VIII with the compound of formula XIII
• to give the compound of formula XIV
• (ii)′ deprotecting the amino group moiety to yield the compound of formula XV
• and,
• (iii)′ coupling the compound of formula XV with a compound of formula XVI
• to give the compound of formula XII;
• and
• e) deprotecting the compound of formula XII to yield bortezomib.