Even though many of the syntheses have been known since the middle of the 20th century, researchers are still working today to further develop the synthesis of Dextromethorphan and, for example, to make it more environmentally friendly. This includes the synthesis by means of ionic liquids. Racemate separation
Since only one of the stereoisomers has the desired effect, the separation of a racemic mixture of hydroxy N- methyl morphinan using tartaric acid and subsequent methylation of the hydroxyl group is a suitable method. By using (D)-tartrate, the (+)-isomer remains as the product. This synthetic pathway was patented by Roche in 1950. Traditional synthesis
The traditional synthetic route uses Raney nickel and has been further improved over time, for example by the use of ibuprofen and AlCl3. Overall, it is a cost-effective method with moderate reaction conditions that is easy to handle and suitable for industrial production. Grewes cyclization
Grewes cyclization is easier to handle in terms of the chemicals used, produces higher yields and higher purity of the product. Improved Grewes cyclization
Formylation prior to cyclization avoids ether cleavage as a side reaction and yields higher than without N-substitution or N-methylation. In this example, the purification was done by formation of a brucine salt. This process has also been patented by Roche. History
The racemic parent compound racemorphan was first described in a Swiss and US patent application from Hoffmann-La Roche in 1946 and 1947, respectively; a patent was granted in 1950.
Dextromethorphan is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. It is in the morphinan class of medications with sedative, dissociative, and stimulant properties (at lower doses). Dextromethorphan does not have a significant affinity for the mu-opioid receptor activity typical of morphinan compounds and exerts its therapeutic effects through several other receptors. In its pure form, dextromethorphan occurs as a white powder.Dextromethorphan is also used recreationally. When exceeding approved dosages, dextromethorphan acts as a dissociative hallucinogen. It has multiple mechanisms of action, including actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor agonist. Dextromethorphan and its major metabolite, dextrorphan, also block the NMDA receptor at high doses, which produces effects similar to other dissociative anesthetics such as ketamine, nitrous oxide, and phencyclidine. It was patented in 1949 and approved for medical use in 1953. Medical uses
Cough suppression
The primary use of dextromethorphan is as a cough suppressant, for the temporary relief of cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold), as well as those resulting from inhaled particle irritants. Pseudobulbar affect
In 2010, the FDA approved the combination drug dextromethorphan/quinidine for the treatment of pseudobulbar affect (uncontrollable laughing/crying). Dextromethorphan is the actual therapeutic agent in the combination; quinidine merely serves to inhibit the enzymatic degradation of dextromethorphan and thereby increase its circulating concentrations via inhibition of CYP2D6.