Codeine formation from morphine

Lotsch J, Rohrbacher M, Schmidt H, Doehring A, Brockmoller J, Geisslinger G (2009) Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation Pain 144 119-124... 

Semi-Synthetic Transformations of the Morphine Alkaloids Although it has been synthesised (ref 61), (now by four distinct routes) morphine (63), a powerful analgesic is readily available from the natural source, opium obtained from Papaver somniferum as the major alkaloid present (approx. 10%) and indeed the first to be isolated by Serturner in 1803, while the methyl ether, codeine (64) which comprises only 0.5% is relatively weakly active. Thebaine (65) a third component of opium is non-analgesic but is important as an intermediate for the formation of codeine, a somewhat scarce commodity (ref. 62) but a valuable mild analgesic and anti-tussive in great demand. It is best prepared from morphine by methylation with phenyl trimethylammonium ethoxide the by-product consisting of dimethylaniline (ref.63). 

Morphine and codeine are members of the large and diverse group of benzylisoquinoline alkaloids, of which morphine and sanguinarine share a common biosynthetic pathway, beginning with the condensation of two L-Tyr derivatives to produce the central precursor (S)-norcoclaurine yields (S)-reticuline, the last common intermediate in the biosynthesis of both sanguinarine and morphine. Berberine bridge enzyme (BBE) catalyzes the conversion of (S)-reticuline to (S)-scoulerine, the first committed step in the sanguinarine pathway. Alternatively, (S)-reticuline can be isomerized to its (R)-epimer as the first step in the formation of morphine. Since the pathway from tyrosine to (S)-reticuline is also known at the enzyme level, the conversion of L-tyrosine to macarpine involves a total of 19 enzymes which are now at least partially characterized. 

Figure 6.13. Formation of morphine and codeine from thebaine (Gruetzmann and Schroeter,...

Morphine and codeine biosynthesis (Samuelsson, 1999 Herbert et al., 2000 Novak et al., 2000) Studies on the biosynthesis of morphine have been carried out mainly on cell cultures mainly of Coptis japonica and species of Thalictrum. Two enzymes (tyrosine decarboxylase and phenolase) catalyze the formation of dopamine from one molecule tyrosine. Dopamine is also the key intermediate in the biosynthesis of mescaline. 

Klein applied gas chromatography. 3-0-acetylmorphine results from an incomplete esterification of morphine with acetic anhydride and the amount may be of value for forensic purposes. Because of the very small amounts present in heroin, the compound was derivatized with hepta-fluorobutyric anhydride and gas chromatographed with a Ni electron capture detector on a 3 1 OV-17 on Gas Chrom Q packed column at 230°C using chlorpromazine as an internal standard. The heptafluorobutyric anhydride derivatives were extracted quantitatively from the reaction mixture with light petroleum and were stable for several hours in this solvent. However, it was recommended that upon formation, the analysis should be completed without delay. The analysis was carried out with 1-10 mg heroin samples and the amount of 3-0-acetylmorphine varied from 0.1 to 2 %, acetylcodeine from 3 to 15, morphine and codeine from 0.01 to 0.5. ... 

Much of the beneht in solubihty enhancement from salt formation is attributable to the change in solution pH caused by the presence of the counterion. This occurs because the ionization and solubility of acidic drugs (such as barbiturates and non-steroidal anti-inflammatory drugs) increases in basic conditions but decreases in acidic conditions. This behavior is exemplified by derivations of the Henderson-Hasselbalch equations (37.2) and (37.3). The opposite situation occurs for basic drugs such as chlorpromazine, morphine and codeine, which are more soluble in acidic conditions. 

Energetic reduction with lithium aluminum hydride led to the reduction of the carbonyl group with the formation of the correct alcohol epimer, as expected from the steric hindrance presented by the benzene ring, and to removal of the aromatic bromine. This last reaction is a noteworthy example of the removal of aromatically bound halogen without reduction of either an allyhc hydroxyl or a double bond. The codeine so produced (CCCLXXXIII) was then demethylated to morphine (CCCLXXXIV) by short heating to 220° with pyridine hydrochloride. 

An early key intermediate in benzylisoquinoline biosynthesis is (57), which by decarboxylation affords (59) this in turn leads to (61) and on to alkaloids (Scheme 2). Confirmation of this pathway has come from a study using cell-free preparations of P. somniferum stems and seed capsules. It was found that this preparation catalysed the formation of (57), (59), and (61) from dopamine (54) plus 3,4-dihydroxyphenylpyruvic acid (55) without the addition of 5-adenosyl-methionine, NADPH, and pyridoxal phosphate, the reaction stopped at (57). The formation of the alkaloids reticuline, thebaine, codeine, and morphine, produced by whole plants, could not be detected with this cell-free system. The results confirm not only the intermediacy of (57) and (59) in benzylisoquinoline biosynthesis, but also the involvement of (54) and (55). 

The conversion of reticuline (44) into morphinan alkaloids, which occurs with loss of tritium from C-1 in P. somniferum (see above)," has been observed also for the formation of thebaine (46) in P. bracteatum, a plant which produces this alkaloid but not codeine or morphine. Radioactive 1,2-dehydroreticuline (47) labelled both reticuline (44) and thebaine (46), whilst radioactive reticuline again labelled thebaine (46). ° Codeinone (48) and codeine (50) are biosynthetic intermediates between thebaine (46) and morphine (51) in P. somniferum, and it was shown that (48) was efficiently reduced to (50) in P. bracteatumf It is apparent that alkaloid biosynthesis in the two plants is similar, with the important difference that in P. bracteatum the enzymes which effect demethylation of (46) are missing, and so biosynthesis goes no further than thebaine (46). 

Alkaloids of the morphinane group. If the tetrahydroisoquinoline alkaloid norlaudanosoline is written in such a way that part of the molecule is rotated around the dotted line (Fig. 280), the relationship to the morphinane-type alkaloids becomes obviously. The actual precursor of these compounds, however, is (R)-reticuline. It is probably attacked by a phenol oxidase (C 2.3.1) yielding a biradical which is stabilized by the formation of the dienone (- -)-salutaridine. After reduction of (-j-)-salutaridine closure of a new 0-heterocyclic ring results in the formation of thebaine. The alkaloids codeine and morphine are synthesized from thebaine in Papaver somniferum,... 

Finally Fairbairn and El-Masry (1968) succeeded in proving the existence of bound alkaloids in poppy seeds. Poppy seeds normally contain only traces of alkaloids. The authors discovered alkaloidlike substances, codeine among them, after acid hydrolysis or pepsin digestion of ground seeds. These compounds were radioactive if the maturing capsule had been fed radioactive morphine. They also reported formation of these alkaloidlike compounds as a result of the action of a crude enzyme preparation from the plant upon morphine. 

Moving forward from 59, six steps were required to convert this compound to 60. Vicinal dihydroxylation of the olefin was followed by oxidative cleavage of the intermediate diol using lead tetraacetate. Reductive amina-tion of the resulting aldehyde with methylamine, followed by acylation of the intermediate secondary amine gave the desired carbamate. Swern oxidation of the secondary alcohol, followed by enol ether formation gave 60. Elimination of -toluenesulfinic acid from 60 provided 61. Oxidation of this dienol ether to dienone 62 was followed by release of the secondary amine, followed by a conjugate addition reaction to establish the critical C-N bond. The remainder of the synthesis followed known chemistry. The mixture of enones 63 was converted to codeinone (35), codeine (3) and then morphine (1). 

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