Methadone synthesis

Replacement of one of the phenyl groups by an alkyl group of similar bulk, on the other hand, alters the biologic activity in this series. Alkylation of phenylacetonitrile with isopropyl bromide affords the substituted nitrile, 136. Treatment of the anion prepared from 136 with strong base with 2-dimethylamino-l-chloropropane gives isoaminile (137). It is of note that alkylation of this halide, isomeric with that used in the early methadone synthesis, is apparently unaccompanied by isomer formation. Isoaminile is an agent with antitussive activity. 

Synthesis of the intermediate aminonitrile for methadone by (I r giospecific route served to confirm the structure. Alkyla-I Lon of diphenylacetonitrile with l-chloro-2-propanol affords the. ilcohol, 120, free of isomeric products (although it is possible here, too, to imagine cyclization of the halide prior to alkyla-lion). The hydroxyl is then converted to the bromide (121) by... 

Pain research is a traditional and well established field within the pharmaceutical industry. Beginning with the isolation of morphine in a small pharmacy by Adam Serturner (1806), the next major breakthrough in pain treatment was achieved by the synthesis of acetylsalicylic acid by Felix Hoffmann in the Bayer Laboratories in Wuppertal (1897). Further outstanding contributions by the pharmaceutical industry were the first fully synthetic opioids pethidine (1939) and methadone (1946). Continued efforts up to now have resulted in many potent and clinically accepted analgesics with reasonable side effects and covering nearly all facets of pain treatment. However, pain treatment is far from being satisfactory in respect to more complex pain states, e.g. neuropathy, visceral pain or migraine. 

An interesting example of yield and selectivity increases in the synthesis of a methadone intermediate (184) has been described by Poupaert et al.2s 1 The yield is higher (86%) and the selectivity 184/185 increased compared to the method using toluene and NaH. In fact, the improvement is probably due to a difference in reactivity of the aziridinium ion intermediate. 

Resolution of a cheap racemate at the start of a synthesis is economically advantageous if it can be demonstrated that chirality is not lost in the subsequent stages. Moreover, optical purity can be enhanced by purification of intermediates during the total synthesis. This strategy of resolution at the beginning has been applied to a new synthesis of optically active methadones and levo-a-acetylmethadol (LAAM) (16). 

Synthesis of single-enantiomer methadones has also been achieved using the chiral pool approach. Thus, Barnett and Smirz obtained ( )-(+)-l-dimethylamino-2-propanol (18) from (-)-... 

An alternative approach for the synthesis of levomethadone uses lipase-catalyzed resolution of a cheap23 starting material, (R,S)-dimcthylaminopropan-2-ol (18) (Scheme 29.6), and demonstration that configurational integrity is maintained during the subsequent steps of the total synthesis. Our approach has also led to the synthesis of d-methadone and of LAAM 16. 

The resulting products were then converted into both (R) and (.S )-methadone, following largely the literature procedures with careful monitoring of the optical activity for each stage of the synthesis (Scheme 29.7). 

Use Synthesis of methadone, other chemical syntheses. Combining the properties of tertiary amine and secondary alcohol. 

The original synthesis yielded both methadone and its 5-methyl position isomer isomethadone (Fig. 5-11), which is also an effective pain-relieving compound not used in the United States. 

Dual action of methadone on 5-HT synthesis and metabolism Ahtee, Liisa Carlsson, Arvid... 

The synthesis is likewise simple. Alkylation of diphenylacetonitrile is followed by a Grignard reaction, and separation of the enantiomers is achieved with (+)-tartaric acid. Global production of racemic methadone has increased steadily over the last two decades, and reaches an annual amount of 35-45 tonnes. [82]... 

Uses Preparation of diphenylacetic acid synthesis of antispasmodics intermediate for methadone herbicide Manuf./Distrib. Aldrich http //www.sigma-aldrich.conr, Alfa Chem http //www.alfachem.homepage.com-, D O http //www.dochem.com-, DSM Andeno BV Fluka http //www.sigma-aldrich.com Kira R.W. Greeff http //www.pechiney-chemicals.com-, Schweizerhall http //www.susinc.com-. Sigma Spectrum Quality Prods. 

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