On the Graphic Formula of Morphine and a Rational Nomenclature of Morphine Derivatives

Abstract

It is well known that the constitution of morphine is now fully established after about seventy years of the most skilful chemical investigations crowned by the synthesis of codeine by Gates et al. 1.

Details

Author: H. Baggesgaard Rasmussen, Jorgen Berger
Pages: 30 to 32
Creation Date: 1955/01/01

On the Graphic Formula of Morphine and a Rational Nomenclature of Morphine Derivatives

H. Baggesgaard Rasmussen
Jorgen Berger
The Royal Danish School of Pharmacy, Department of Organic Chemistry, Copenhagen, Denmark

It is well known that the constitution of morphine is now fully established after about seventy years of the most skilful chemical investigations crowned by the synthesis of codeine by Gates et al. [1] .

The usual graphic formula is based upon a phenanthrene skeleton, the middle of which is fused with a piperidine ring. The numbering of the atoms usually follows the classical numbering employed by Graebe and Liebermann for the 10 C-atoms in the phenanthrene nucleus (Fig. 1); the remaining four C-atoms are given the numbers 11-14 incl. ( Knorr and Hürlein[2] ). The nitrogen atom generally has no number. This numbering can be found in all the classical papers concerning the structure of morphine and also in the graphic formula proposed by Cahn and Robinson (Fig. 8).

Another method of numbering is found in Patterson and Capell: The Ring Index, New York 1940, No. 3094, where morphine is considered as being derivative of imino-ethano-phenanthrene-furan (Fig. 2). Schaumann[3] has given another graphic formula in which he considered the piperidine nucleus as being the most important analgiphoric group and emphasizes this in the formula (Fig. 3).

The synthesis of morphinan (Figs. 6 and 7) and its derivatives by Grewe et al. [4] has given us the nucleus of all compounds in the morphine group; the graphic formula used by these scientists is based upon the old phenanthrene formula for morphine.

Since the middle of the 'thirties it has been the custom ( Wieland and Dane[5] ) to write the phenanthrene nucleus in the steroids (Fig. 4) in a somewhat different manner from the classical formula for phenanthrene used by Graebe and Liebermann and also to use another system of numbering. If it is considered necessary to draw the graphic formula for morphine in a new way, it would be natural to base this on the relationship of morphine to the steroids, to accept the numbering used for the steroids, and to take the now fully established stereochemistry of morphine [6] into consideration. We must, however, bear in mind that this involves the drawback that the new numbering does not correspond to the classical numbering used in the numerous papers published over a period of more than sixty years, in which the structure of morphine is developed. The following is an attempt to introduce a new proposal of drawing the morphine formula and to submit a proposal for the nomenclature of compounds in the whole "morphine group ".

The Graphic Formula of Morphine

Morphine is regarded as a phenanthrene derivative and the phenanthrene part of the formula is drawn and numbered in the manner used in steroid chemistry. In order to connote the specific stereochemical configuration, solid lines are used as in steroid chemistry to indicate a position in front of the plane (the paper) and dotted lines to indicate a position behind the plane.

In Fig. 7 these directions are used and it is seen that the morphine molecule contains a morphinan nucleus consisting of the six-membered isocyclic rings A, B and C arranged angularly and a piperidine ring D, having three atoms in ring B. Ring A is a benzene ring; the fully hydrogenated morphinan, where the ring A is a cyclohexane ring is not known at the present time. Due to the benzene ring it would be natural to compare morphinan and morphine with estratrien.

Further, the figure shows that morphine is an epoxyderivative of morphinan and that the hydroxy group at C 12 and the oxygen bridge linked to C 11 are in cis-position. The heterocyclic ring D linked to C 9 is in trans-position to the two first mentioned groups and must be regarded as a bridge in ring B; the steric configuration for these two rings can be compared with tropane.

By comparison of morphine and estratrien it is seen that in the latter the rings B and C have trans-decalin structure while in morphine they have the cis-decalin structure.

In the following is given a survey of graphic formulae for morphinan and morphine with the new (" steroid ") and the classical numbering: Fig. 5: morphinan (" steroid " formula), Fig. 6: morphinan ( Grewe); Fig. 7: morphine (" steroid " formula) and Fig. 8: morphine ( Cahn- Robinson). It should be noted that the morphine formula ( Cahn- Robinson) often is turned through 90° in ring B.

The new "steroid" formula for morphine involves, as mentioned, a numbering which differs from the two old systems used by Cahn-Robinson and by The Ring Index, respectively. The following scheme shows the alterations:

"Steroid formula"

Cahn-Robinson

The Ring Index

1 4
-
2 3 3
3 2 2
4 1 1
5 11
-
6 10 9
7 9 8
8 14
-
9 13
9 c
10 12
-
11 5
4 a
12 6 5
13 7 6
14 8 7
15 15 12
16 16 11
(17)
N-(17)
10
Full size image: 9 kB

Nomenclature

If we compare the formula of morphine with that of morphinan it is seen that the nucleus in the morphine derivatives is epoxymorphinan, and we are now able to build up a rational nomenclature for the whole group of morphine derivatives, using the generally accepted prefixes and suffixes, and the alphabetical order of radicals [7] ; since epoxy-morphinan is considered as the nucleus the epoxy group is not arranged alphabetically among the other radicals.

In the following the proposal is exemplified by giving rational names based upon the " steroid " formula for some important compounds belonging to the morphinan or to the morphine group. If one wishes to base the rational names upon the Cahn-Robinson formula or upon the Ring Index formula it can easily be done only by changing the figures according to the scheme above.

Racemorphan = (±)-2-Hydroxy-N-methyl-morphinan.

Levallorphan = N-Allyl-2-hydroxy-morphinan.

Racemethorphan = (±)-2-Methoxy-N-methyl-morphinan.

Tetrahydrodesoxycodeine = 1-Hydroxy-2-methoxy-N-methyl-morphinan.

Desomorphine = 2-Hydroxy-N-methyl-1, 11-epoxy-morphinan. Dihydromorphine = 2, 12-Dihydroxy-N-methyl-1, 11-epoxy-morphinan.

Dihydrocodeine = 12-Hydroxy-2-methoxy-N-methyl-1, 11-epoxy-morphinan.

Acetyldihydrocodeine = 12-Acetoxy-2-methoxy-N-methyl-1, 11-epoxy-morphinan.

Diacetyldihydromorphine = 2, 12-Diacetoxy-N-methyl-1, 11-epoxy-morphinan.

Methyldihydromorphine = 2, 12-Dihydroxy-12, N-dimethyl-1, 11-epoxy-morphinan.

Dihydromorphinone = 2-Hydroxy-N-methyl-12-oxo-1, 11-epoxy-morphinan.

Dihydrocodeinone = 2-Methoxy-N-methyl-12-oxo-1, 11-epoxy-morphinan.

Metopon = 11, N-Dimethyl-2-hydroxy-12-oxo-1, 11-epoxy-morphinan.

Oxymorphone( Endo) = 2, 8-Dihydroxy-N-methyl-12-oxo-1, 11-epoxy-morphinan.

Dihydrohydroxycodeinone = 8-Hydroxy-2-methoxy-N-methyl-12- oxo-1, 11-epoxy-morphinan.

Methyldesoxymorphine = 12, N-Dimethyl-2-hydroxy-1, 11-epoxy-morphinene-12.

Normorphine = 2, 12-Dihydroxy-1, 11-epoxy-morphinene-13.

Morphine = 2, 12-Dihydroxy-N-methyl-1, 11-epoxy-morphi-nene-13.

Nalorphine( N-Allylnormorphine) = N-Allyl-2, 12-dihydroxy-1, 11-epoxy-morphinene-13.

Codeine = 12-Hydroxy-N-methyl-1, 11-epoxy-morphinene-13.

EthyImorphine = 2-Ethoxy-12-hydroxy-N-methyl-1, 11-epoxy-morphinene-13.

Pholcodin ( Morpholinyl-ethylmorphine) = 12-Hydroxy-N-methyl-2-(2-morpholinoethoxy)-1, 11-epoxy-morphinene-13.

Dihydrocodeinone enol acetate ( Acedicon) = 12-Acetoxy-2-methoxy-N-methyl-1, 11-epoxy-morphinene-12.

Diacetylmorphine = 2, 12-Diacetoxy-N-methyl-1, 11 epoxy-morphinene-13.

Thebaine = 2, 12-Dimethoxy-N-methyl-1, 11-epoxy-morphina-diene-12, 14.

REFERENCES

001

GATES, M. et al., J. Am. Chem. Soc ., 72, 228, 4839 (1950); 74,1109 (1952).

002

KNORR, L., and H. HÜRLEIN, Ber., 40, 3341 (1907).

003

Schaumann, O., Arch. exptl. Pathol. Pharmakol., 196 ,109,126 (1940).

004

GREWE, R. et al., Naturwissenschaften, 33 , 333 (1946); Chem. Ber., 81 , 279 (1948).

005

WIELAND, H. and E. DANE, Hoppe-Seyler's Z. PhysioI. Chem., 210 , 272 (1932).

006

GINSBURG, D., Bull Narcotics , U.N. Dep. Social Affairs, 5, No. 4, 32 (1953);J. M. LINDESY and W. H. BARNES, Acta Cryst . 8, 227 (1955).

007

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