Mechanistic Studies-the DDQ Oxidation

Oxidation of the A-ring lactam is dearly the key step in the finasteride process. Although this reaction could have been optimized through trial and error, experiments designed to provide insight into the mechanism gave us the understanding needed to identify the best conditions most effidently. 

Reinvestigating the reaction of cyclohexanone silyl enol ether 22 with DDQ, adducts were also observed [26]. At 25 °C, both C-C and C-0 adducts (75 and 76) were formed along with the dehydrogenation products 23 and 77. The ratio of 

Physical chemical studies provided insight into the mechanism of the reactions and aided in optimization of key parameters. The order of the reaction in BSTFA, 

The dehydrogenation reaction was generally monitored by taking samples for reversed phase H PLC analysis. Diode array detectors for H PLC were relatively new at that time and proved valuable for quickly getting structural information on products of the reaction produced under different conditions. Key reaction parameters for adduct formation, overall concentration, BSTFA, TfOH, and DDQ charges, were optimized using a thermostated HPLC autosampler to sample reactions directly for analysis. Comparison of reaction profiles provided rate and reaction time information that was used to select a more limited number of reaction conditions that were scaled up to compare yields. 

Clearly, our effort toward understanding the course of the dehydrogenation reaction was key in achieving optimal performance for production. The understanding of this reaction, however, goes beyond the finasteride process changing the way that we think about quinone oxidations. 

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