Teleha, Christopher A., et al. Organic Process Research & Development 18.12 (2014): 1630-1640.
The scale-up of the CCR-2 antagonist succinate 1 to a 600 g quantity of sufficient purity for planned studies is described. The formation process involves a novel strategy that exploits the lactone 16 formed upon alkylation with Tert-Butyl(2-Iodoethoxy)Dimethylsilane. Reduction of the lactone afforded the diol 20, which was subjected to diastereoselective seleno-oxidation or bromo-oxidation to provide the bicyclic ether core. This work reveals a detailed interpretation of the stereochemical consequences of the selenization/halogenation reactions, as well as an X-ray structure of the selenide 22a to confirm the stereochemical assignments. The oxyhalogenation results also indicate that selenium can be removed from the process. Reduction of 22a/c and reoxidation of the alcohol in 21 using diatomaceous earth-modified Jones conditions afforded the acid 5 from 12 in 25% overall yield. The final steps included coupling of the acid 5 with the amine 6, Boc deprotection of 26, reductive amination with 4, chromatographic enrichment of the desired diastereomer 3, and succinate formation, completing the synthesis of the final compound 1 in 10 steps (starting from step 12) in 13% overall yield.
A solution of LHMDS in THF (1 M, 6.97 L, 6.97 mol) was cooled to -70 °C and treated with a solution of 12 (763.5 g, 3.16 mol) in THF (800 mL) at < -68 °C for 2 h. The resulting solution was stirred at < -68 °C for 45 min. A solution of tert-butyl(2-iodoethoxy)dimethylsilane (1.267 kg, 4.426 mol) in THF (800 mL) was added at ~ -66 °C over 1 h 50 min. The reaction mixture was stirred at -66 °C for 45 minutes. The reaction was warmed to -15 °C by adding room temperature IPA to a cooling bath. Once the reaction reached this temperature, the reaction was checked by NMR and HPLC and found to be complete. The reactants were poured into a mixture of aqueous HCl (concentrated, 500 mL) and ~4 L of ice. While the mixture was stirred, additional concentrate was added. HCl (250 mL) and ice (2 L) (pH now 8) were added and finally concentrated. HCl (250 mL) was added to achieve an aqueous pH of 2. The lower aqueous layer was separated and extracted with toluene (1.5 L). The combined organic layers were washed with 1 L of brine and the organic layer was diluted with toluene (~7.5 L) until two layers were clearly present when washed with water (1.5 L). The organic layer was washed with brine (1 L) and the resulting organic layer was clear. The organic layer was washed with brine (1 L) and dried over MgSO4.
Cha, Jacob Y., John TS Yeoman, and Sarah E. Reisman. Journal of the American Chemical Society 133.38 (2011): 14964-14967.
