The synthetic method of deuterated dextromethorphan
A technology of dextromethorphan and deuterium, which is applied in organic chemistry methods, drug combinations, isotope introduction of heterocyclic compounds, etc., can solve problems such as slow metabolism, prolonged side effects, adverse events, etc.
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[0214] In one embodiment, such methods of preparation include the step of bringing into association the molecule to be administered with an ingredient such as a pharmaceutically acceptable carrier. In one embodiment, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with one or more liquid carriers, liposomes or finely divided solid carriers, and then, if desired, shaping the product.
[0215] In one embodiment, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as, but not limited to, capsules, sachets or tablets each containing a predetermined amount of the active ingredient; powders or granules; solutions in aqueous or non-aqueous liquids or Suspension; oil-in-water liquid emulsion; water-in-oil liquid emulsion; packaged in liposomes; or as a bolus injection, etc. In one embodiment, soft gelatin capsules are used to contai...
Embodiment 1
[0295] Synthesis of compounds of formula (I). Each reaction and numbered intermediate described below refers to the corresponding reaction and intermediate in Scheme 1 above.
[0296] Reaction (i) (intermediate d6-DM-J hydrochloride): A solution of dextromethorphan hydrobromide (1.1 kg, 2.97 mol, 1.0 equiv) in toluene (13.2 L, 12 v) was mixed with aqueous sodium hydroxide ( 1M concentration) mixed. After stirring, the organic phase was separated, washed with water to neutral pH and azeotropically dried. To the solution was added 1-chloroethyl chloroformate (0.552 kg, 3.86 mol, 1.3 equiv) and the mixture was stirred until the conversion was > 93%. The mixture was heated to 65-70°C and methanol (2.09 kg, 1.9 kg / kg) was added slowly. Heating was continued until the reaction conversion was > 98%. The reaction mixture was cooled and concentrated under vacuum until the methanol level dropped to NMT 100 ppm. Toluene (4.0 L, 3.6 v) was added and the mixture was concentrated again...
Embodiment 2
[0301] Synthesis of compounds of formula (IV). Each reaction and numbered intermediate described below refers to the corresponding reaction and intermediate in Scheme 3 above.
[0302] Reaction (v) (d6-DM hydrobromide monohydrate): All solutions were filtered using a 0.45 μm filter and all manipulations were performed in a class 100,000 clean room. Purified water (1.1 L, 4v) and d6-DM free base (277.4 g, 1.00 mol) were mixed in the reactor. A solution of hydrobromic acid (48% strength, 177.0 g, 1.05 mol) was added followed by purified water (0.28 L, 1 v). The resulting mixture was heated to 65-70°C until a solution formed, then cooled for crystallization. The mixture was heated and cooled for several cycles to optimize particle size and then cooled to ambient temperature. The product was isolated by filtration, washed with pure water, and dried at 40-45°C to obtain the compound of formula (IV). The compound of formula (IV) was obtained in 85.0% yield and 99.6% purity. HNM...
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