| DESCRIPTION |
Another case study was presented at the Barcelona meeting by author. She described the process development for a new class of retinoid-X receptor (RXR) agonists for treatment of type 2 diabetes. Author described the synthesis of a compound identified as 411629, which is an analog of bexarotene, a "L" product already on the market for the treatment of T-cell lymphoma. 411629 consists of a tetrahydronaphthalene subunit connected by a cyclopropane bridge to a para-substituted pyridylcarboxylic acid.
The first-generation synthesis had nine steps, with a 12% overall yield. The intermediates required chromatographic purification. And incorporation of the cyclopropane ring represented half of the total synthesis cost. In the synthesis of the tetrahydronaphthalene subunit, "E" scientists were able to increase the two-step yield from 48% to 98% by making the key Friedel-Crafts alkylation catalytic in AlCl3, Faul said. They improved the selectivity in the synthesis of the pyridylcarboxy ester subunit. The two subunits were then coupled by a nitromethane-mediated Friedel-Crafts acylation reaction. Taking advantage of both the pyridine nitrogen and para-substituted carboxy ester functionality, the scientists incorporated the cyclopropane ring by chelate-controlled addition of CH3MgCl to the ketone, followed by treatment of the olefin with trimethylsulfoxonium ylide. This second-generation synthesis took eight weeks to devise. It consisted of seven steps with a 24% overall yield and required no chromatographic purification. It has been used to produce the compound in kilogram quantities for clinical development. In addition, the chemistry developed for this process was valuable in identification of a second generation of RXR agonists for preclinical evaluation
|