Doxepin synthesis

Applications to Doxepin Synthesis. The next synthetic objective to be discussed is doxepin (75). The structure of doxepin is shown below. Doxepin (also marketed as Adapin or Sinequan) is a tricyclic heterocyclic compound that is widely prescribed. Doxepin is prepared in very large quantities using a traditional Friedel-Crafts methodology. Of importance from the point of view of synthetic planning is that doxepin is sold as a mixture of E- and Z- double bond isomers. This leads to a simplification of the synthesis of doxepin. 

The transformation of the seven-membered ring lactone into an ether and the deoxygenation of the phenol both have extensive literature precedent. Once this is successful, we will then have prepared an advanced intermediate in the industrial synthesis of doxepin. 

Doxepin (Ila) was marketed this year as a mixture of cis and trans isomers (acid catalyzed equilibration in the final step of the synthesis gave a cis to trans ratio of approximately 15 85), This drug was compared with eimitriptyline eind found to be clinically similar in its properties. Side effects were due to its anticholinergic properties. Several clinical studies with doxepin showed that the drug was a good antidepressant. One report stated that there was noticeable sedation while others claimed only mild side effects. ... 

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