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
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Publication Number
US-8569483-B2
Publication Date
2013-10-29
Expiration Date
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 document describes a process for preparing bazedoxifene (1-{4-[2-(azepan-1-yl)ethoxy]benzyl}-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol, formula 9) and its acetate salt. The process converts 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (formula 3) with the ester of a sulphonic acid of 2-(4-bromomethyl)phenoxyethanol (formula 18) to an isolated pure ester sulphonic intermediate (formula 2).
The process includes treating the ester intermediate with hexamethylenimine to obtain a benzylated azepane indole intermediate (formula 8) and purification involving hydrochloride salt formation and liberation of a pure free base. Catalytic debenzylation of the benzylated azepane indole intermediate (formula 8) in the presence of palladium-carbon provides the bazedoxifene free base (formula 9) with high HPLC purity.
In an alternative option, the ester intermediate (formula 2) can be first debenzylated to a hydroxy sulfonate intermediate (formula 19), followed by reaction with hexamethylenimine and isolation of bazedoxifene free base (formula 9) with the stated purity and impurity profile. The free base can optionally be converted to its acetate salt.
The document contrasts the described route with prior art routes, including routes employing hazardous reagents such as LAH and CBr4/BF3·etherate, and emphasizes improved yield/purity and reduced specific impurities corresponding to formulas 22 and 23. It also emphasizes formation of a higher-purity hydrochloride salt of intermediate 8.
Claims Coverage
The document provides one independent claim for the overall preparation process of bazedoxifene and its acetate salt. Across that independent claim, the stated inventive features include the stepwise conversion from the named indole (formula 3) using the named sulfonate ester (formula 18), isolation of an ester intermediate (formula 2), azepane formation with hexamethylenimine to obtain intermediate (formula 8) followed by purification via hydrochloride salt formation and base liberation, catalytic debenzylation with palladium-carbon to obtain bazedoxifene free base (formula 9) with the stated HPLC impurity characteristics, and optional conversion to the acetate salt.
Stepwise sulfonate-ester alkylation to isolate ester intermediate
Reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (formula 3) with the ester of a sulphonic acid of 2-(4-bromomethyl)phenoxyethanol (formula 18) to obtain a pure ester of the sulphonic acid intermediate (formula 2).
Hexamethylenimine conversion to azepane benzylated intermediate and purification via hydrochloride salt
Treating the ester intermediate so obtained (formula 2) with hexamethylenimine to obtain 1-{4-[2-(azepan-1-yl)ethoxy]benzyl}-5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (formula 8), then purifying by forming its hydrochloride salt and liberating pure free base.
Catalytic debenzylation to obtain bazedoxifene free base with low C-alkylated impurity
Catalytically debenzylating the purified intermediate (formula 8) in the presence of palladium-carbon to obtain bazedoxifene free base (formula 9) with high stated HPLC purity and a C-alkylated impurity below the detectable limit.
Optional route through hydroxy sulfonate and optional conversion to acetate salt
Optionally debenzylating the ester intermediate (formula 2) to obtain the hydroxy sulfonate intermediate (formula 19), followed by reaction with hexamethylenimine to isolate bazedoxifene free base (formula 9), and optionally converting the free base to its acetate salt.
Overall, the independent claim covers a stepwise process that converts the named indole precursor (formula 3) with a specific sulfonate ester (formula 18) to isolate intermediate (formula 2), forms the benzylated azepane indole intermediate (formula 8) with hexamethylenimine and purifies it via hydrochloride salt formation and base liberation, then uses palladium-carbon debenzylation to produce bazedoxifene free base (formula 9) with high HPLC purity and low or undetectable C-alkylated impurity, with an optional alternative pathway via hydroxy sulfonate intermediate (formula 19) and optional conversion to the acetate salt.
Stated Advantages
Improved yield/purity compared with prior art routes.
Reduced specific impurities, including impurities corresponding to formulas 22 and 23.
Formation of a higher-purity hydrochloride salt of intermediate 8.
Bazedoxifene free base purity greater than 99.8% by HPLC with a C-alkylated impurity below the detectable limit.
Bazedoxifene acetate salt obtained as part of the process.
Documented Applications
Preparation of bazedoxifene (formula 9) and its acetate salt using the described process and intermediates (formulas 2, 8, and optionally 19).
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