Morphine, Morphinan, and Benzomorphan 4-Phenylpiperidines

It is generally accepted that the narcotic analgesics do not in fact interfere with the pain as such rather, these compounds change the perception of the pain. In other words, the patient may come to regard pain with detachment. This very mechanism may be responsible for one of the major drawbacks of the narcotic 286 

Although morphine has been prepared by total synthesis, the complexity of the molecule makes such an approach unattractive on a commercial scale. The drug in fact is obtained by fractionation of opium obtained from the poppy morphine in turn is used as starting material for various derivatives. If it were not for the importance of these drugs in the clinic, some progress might have been made in eradication of the plant. 

Catalytic reduction of codeine (2) affords the analgesic dihydrocodeine (7) Oxidation of the alcohol at 6 by means of the Oppenauer reaction gives hydrocodone (9)an agent once used extensively as an antitussive. It is of note that treatment of codeine under strongly acidic conditions similarly affords hydrocodone by a very unusual rearrangement of an allyl alcohol to the corresponding enol, followed by ketonization. 

When morphine is subjected to a similar reduction-oxidation sequence (1- 10), there is obtained hydromorphone (10).  

The prototype of this series is synthesized by first reacting morphine with cyanogen bromide. This reagent in effect serves to replace the methyl group by cyano. Hydrolysis of the intermediate (11) affords desmethylmorphine (12). Alkylation of the last with allyl bromide affords nalorphine (13).  

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