Process for the preparation of benzylbenzene SGLT2 inhibitors
Provided are methods of making compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides synthetic intermediates useful for preparing such compounds.
1. A composition comprising
a compound of formula Ia having the structure:
in an amount of at least 95% of the composition,
side-product A having the structure:
in an amount of less than about 1% of the composition, and
side-product B having the structure:
in an amount of less than about 3% of the composition,
wherein the composition is prepared by the method comprising:
(a) forming a first reaction mixture comprising a compound of Formula IIa:
an alkyl-magnesium complex selected from the group consisting of C 1 -C 4 alkylmagnesium chloride, C 1 -C 4 alkylmagnesium bromide, di(C 1 -C 4 alkyl)magnesium, C 3 -C 7 cycloalkylmagnesium chloride, C 3 -C 7 cycloalkylmagnesium bromide, and di(C 3 -C 7 cycloalkyl)magnesium, and
a first organic solvent,
wherein the ratio of the alkyl-magnesium complex to the compound of Formula IIa is less than or equal to 1.0 (mol/mol), and
wherein the first reaction mixture is at a temperature of less than about −50° C., to afford ara intermediate compound,
(b) forming a second reaction mixture comprising the intermediate compound, a second organic solvent, and a compound of Formula IIIa:
to afford the compound of Formula Ia wherein R 4 is OH,
(c) forming a third reaction mixture comprising a C 1 -C 3 alkylhydroxy, a strong acid and the compound of Formula Ia wherein R 4 is OH, thereby forming the compound of Formula Ia wherein R 4 is C 1 -C 3 alkoxy; and
(d) forming a fourth reaction mixture comprising a reducing agent and the compound of Formula Ia wherein R 4 is C 1 -C 3 alkoxy, thereby preparing the compound of Formula Ia wherein R 4 is H, and
wherein
X is iodo,
R 1 is chloro,
R 2 is H,
R 3 is (C 3 -C 6 cycloalkoxy)C 1 -C 3 alkoxy,
R 4 is selected from the group consisting of H, OH and C 1 -C 3 alkoxy, and
R b is a protecting group.
2. The composition of claim 1 , comprising
the compound of formula Ia having the structure:
in an amount of at least 95% of the composition,
side-product A having the structure:
in an amount of less than about 1% of the composition, and
side-product B having the structure:
in an amount of less than about 3% of the composition.