Process for the preparation of bazedoxifene acetate and intermediates thereof

Inventors

Divi, Murali Krishna Prasad • Padakandla, Gundu Rao • Rao, Bolneni Nageswara • Suresh, Dandu Venkata

Assignees

Divis Laboratories Ltd

Abstract

A novel process is described for the preparation of pharmaceutically useful compounds such as 1-{4-[2-(azepan-1-yl)ethoxy]benzyl}-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol acetic acid commonly known as bazedoxifene acetate of the formula-1 using 2-(4-{[5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl}phenoxy)ethyl-4-methylbenzenzene-1-sulfonate (formula 2a).

Core Innovation

The patent describes prior synthetic routes to bazedoxifene acetate, including approaches that proceed through indole intermediates and sulfonate-related transformations, and identifies drawbacks in those routes. In particular, impurity formation is discussed, including a reduced-purity outcome and the presence of undesired C-alkylated impurity (formula-24). The patent positions the problem as improving the synthesis of bazedoxifene acetate while controlling impurities and improving industrial operability versus prior use of hazardous reagents.

The invention improves the synthesis by key N-alkylation of an indole intermediate (formula-3) using a sulfonate electrophile (formula-18, with X defined as tosyl/mesyl/benzenesulfonyl) to form a sulfonate intermediate (formula-2a). The patent describes that this step yields a high-purity product and reduces the C-alkylated impurity (formula-24). The sulfonate intermediate (formula-2a) is then converted to bazedoxifene via intermediate-8 or intermediate-19, followed by deprotection to bazedoxifene free base (formula-9) and acetylation to bazedoxifene acetate (formula-1).

In addition, the patent discloses preparation of the sulfonate electrophile (formula-18) from 4-(2-hydroxyethyloxy)benzaldehyde (formula-15) through sulfonylation, reduction to a hydroxymethyl precursor (formula-17), and bromination to bromomethyl sulfonate (formula-18). The document reports that impurity control eliminates impurities of formulas-22 and 23 and highlights improved industrial operability compared with prior use of hazardous reagents such as LAH, CBr4, and BF3 etherate.

Claims Coverage

The document includes one independent claim and one dependent claim. The claims cover a multi-step process for preparing the sulfonic acid ester of 2-(4-bromomethyl)phenoxy ethanol (formula 18) as an intermediate for a specified indole-based compound, with one claim narrowing the sulphonic acid chlorides used in step (a).

Overall, the claims focus on preparing the bromomethyl sulfonate (formula 18) through conversion of the benzaldehyde derivative to a sulphonic acid ester (formula 16), reduction to a hydroxymethyl derivative (formula 17), and bromination with phosphorus tribromide to isolate the bromomethyl sulfonate (formula 18). The dependent claim narrows the set of permissible sulphonic acid chlorides for the ester-forming step.

Stated Advantages

Documented Applications