A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5. The optimization of each step is described at length. The main focus of the paper is the study of the RCM step and the description of the main problems faced when scaling up to pilot scale this highly powerful but very challenging synthetic operation. Eventually, the RCM reaction was smoothly scaled up to produce >400 kg of cyclized product.
The reduction of conjugated aldehydes and ketones by sodium borohydride leads, in general, to substantial amounts of fully saturated alcohol products. In alcohol solvents the formation of saturated /3-alkoxy alcohols (involving solvent addition to the double bond) is observed. This product is enhanced by added solvent conjugate base and depressed by addition of trialkyl borate. The structural features which control the extent of simple carbonyl reduction, 1,4 reduction, and solvent addition have been examined, as well as the effects of different solvents on the course of the reaction.Sodium borohydride reduction of carbon-carbon double bonds has been observed in conjugated esters,3 nitroalkenes,4 and enol acetates.6 These examples are apparently widely regarded as exceptions to the general rule that double bonds are inert to sodium borohydride. Based on the early literature report6 that crotonaldehyde, cinnamaldehyde, and mesityl oxide yield only allylic alcohols with this reagent, most recent textbooks7 either state or imply that carbonyl-conjugated double bonds are unaffected by sodium borohydride. Conversely, lithium aluminum hydride is often viewed as a less selective reagent based on the well-documented complete reduction of cinnamyl derivatives.8
Based on the hypothesis that analgetic activity is a dissociable feature of the cannabinoid molecule, we examined modifications of the side chain, the phenolic moiety, and, most significantly, structures that lack the benzopyran functionality present in THC and (—)‐9‐nor‐9β‐hydroxyhexahydrocannabinol (HHC). A new grouping, the 1‐methyl‐4‐phenylbutyloxy C‐3 side chain, elaborates a unique lipopholic region. Replacement of the phenol substituent produced several derivatives which retain analgetic activity in the codeine potency range. Introduction of a weakly basic nitrogen at C‐5 and deletion of the axial methyl group in the B ring, two structural changes forbidden by traditional cannabinoid SAR, resulted in a unique family of benzoquinolines with potent analgetic activity. The prototype of this series, levonantradol, exhibits potent and stereospecific analgetic and antiemetic activity.
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