Morphine Series

The opium poppy Papaver somniferum contains two useful analgesic alkaloids, morphine and codeine, as well as thebaine, which not only may be 

One of the earliest attempts(68,69) at developing a nondependence-inducing morphine derivative resulted in the preparation of heroin (3,6-diacetylmor-phine or diamorphine) by acetylation of morphine. Reports of its reduced respiratory depression and dependence liability were soon shown to be mis-Ibunded, but its superior analgesic effects in animals and humans (twice morphine) are demonstrable. Pharmacological examination(70) of acyl derivatives of morphine showed that heroin and its higher and lower acyl homologs 

Codeine occurs in opium in relatively small amounts (—0.3%) and yet it is in great demand as an analgesic. Much of the morphine derived from opium is therefore converted by methylation to codeine. Conventional methylation techniques have been employed, including dimethyl sulfate, diazomethane, and phenyltrimethylammonium chloride. 

A series of C, to C12 straight-chain 3-O-alkyl analogs of morphine has been prepared 94 by conventional methods in an attempt to establish a relationship between lipophililicity and the rate of metabolism, particularly N-demethylation. No simple relationship was found. 

3-Morpholinoethylmorphine is known as pholcodine and has found wide application as an antitussive agent. Other series with basic (e.g., 1, R = CH2 CH2ND) or urethane (e.g., 1, R = CONHR ) 3-0- side chains have been reported/96  

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Rapoport, H., Naumann, R., Bissel, E.R., Bonner, R.M. The preparation of some dihydro ketones in the morphine series by Oppenauer oxidation, J. Org. Chem. 1950, 15, 1103-1107. 

Kametani<23) in 1977 reviewed the total synthesis of isoquinoline alkaloids, including alkaloids of the morphine series. 

Morphine, (+)-codeine, and (+)-heroin are all devoid of MHP (sc) antinociceptive activity/119 although (+)-morphine did show some central actions in rats when administered intracerebrally.(120) Compounds of the (+)-morphine series are related configurationally to (-)-sinomenine (53 of Chap. 3),(m) the absolute configuration of which has been demonstrated to be enantiomeric with that of natural (-)-morphine. 

By exploiting the work of Weller and Rapoport<56) in the natural (—)-morphine series, the NIH group was able to improve overall yields from sinomenine to unnatural opioids considerably.019 The availability of this unnatural series afforded a route to relatively large quantities of (+)-naloxone/128 also valuable for receptor studies. 

These hypotheses, although not always correct, have been of inestimable value in guiding tracer experiments on living plants. Experiments on the biosynthesis of berberine and related alkaloids have had, in addition to these guidelines, the benefit of the knowledge gained from previous tracer studies on the biosynthesis of the isoquinoline alkaloids of the papaverine and the morphine series, where it was known that two molecules of the aromatic amino acid, tyrosine, are built into these alkaloids via a pathway involving the intermediacy of norlaudanosoline (XCIV). 

In an investigation of new analgesic agents in the morphine series. Rapaport et a/. found it convenient to use the easily removable methoxymethyl ether as a blocking group. 

Hydrogenation of thebainone-B methine proceeds rapidly, with the absorption of two moles of hydrogen and production of /S-dihydro-thebainone dihydromethine [xvin] [20-21] this is the only case in morphine series in which reduction of an 8 14 double bond results in configuration of the asymmetric carbon atom C-14 in the abnormal manner. The possibility of thebainone-B methine having the isomeric structure [xix] is ruled out by the ultra-violet absorption spectrum, which is closely similar to that of /S-codeimethine [xx] and dissimilar from that of a-codeimethine [xxi] (Kg. 9) [21]. 

Attempts have been made to realize experimentally the conversion of laudanosine-type bases to bases of the aporphine and morphine series, so far without success. In an attempt to convert laudanosoline [xtx] to norglaucine [x ] it was discovered that the former is very readily oxidized to intractable materials, but that oxidation with chloranil [5-6] or tetrabromo-o-benzoquinone [7] affords, not the expected norglaucine, but 2 3 11 12-tetrahydro-8-methyldibenzotetrahydropyrrocolinium ohloride [xxi]. Protosinomenine [i] has been synthesized in two ways [3, 8], but the conditions required for the conversion of this base to sinomenine [iv] have not yet been realized and their discovery must be largely fortuitous [6],... 

Although the method of Gates gives, initially, a series of compounds epimeric at C-14 with those of the normal morphine series, a remarkable epimerization reaction has enabled a total synthesis of morphine to be achieved as follows [33]. 

ADDITION TO CHAPTER XXVII Elimination of the side-chain in the morphine series has now been accomplished without the production of a fully-aromatic phenanthrene derivative. The degradation of neopine dihydromethine [xvi] by heating the methiodide with sodium cycfohexyloxide in boiling cycfohexanol affords [xvni] [2] (see above addition to Chap. VI). 

Electrochemical determination of alkaloids of the morphine series 00CLY1075. 

Conversions of tosyl and mesyl derivatives of the morphine series. Synthesis of acetylthio and mercapto derivatives Bognar, Rezso Makleit, Sandor Mile, Terez... 

Elad D, Ginsburg D (1954) Syntheses in the morphine series 6. The synthesis of morphine. J Chem Soc 3052-3056... 

An improved procedure for the A-demethylation of tertiary amines, which was applied in the morphine series, utilizes phenyl chloroformate to obtain an intermediate carbamate which is then easily cleaved with a 1 1 mixture of 64 and 95% hydrazine. / -Nitrophenyl chloroformateor the milder vinyl chloroformate are sometimes preferred over phenyl chloroformate. 

Blount JF, Mohacsi E, Vane FM, Mannering GJ (1973) Isolation, X-ray analysis and synthesis of a metabolite of (-)-3-hydroxy-N-allylmorphinan. J Med Chem 16 352-355 Bogriar R, Gaal Gy, Kerekes P, Horvath G, Kovacs MT (1974) Hydroxyl group elimination in the morphine series. Org Prep Proc Int 6(6) 305-311 Brossi A, Teitel S (1970) Partial 0-demethylation of aromatic substituted 3,4-dihydroisoquino-Hnes. Helv Chim Acta 53 1779-1787... 

K. Bentley and D. Hardy, New potent analgesics in the morphine series, Proc. Chem. Soc., 1963, (July), 220. 

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