Morphine extraction, Structure elucidation, structure activity relationship

1. MORPHINE CHEMISTRY
Prepared By:
Dr. Ram Babu Tripathi
Associate Prof
Ram Eesh Institute of Voc. & Tech
Edu.
Greater Noida, UP

2. WHAT IS MORPHINE?
1. Morphine is a natural opium alkaloid
2. Opium is the air-dried milky exudates, or latex, obtained by incising the unripe
capsules of the opium poppy Papaver somniferum (Papaveraceae)
3. Opium is a combination of chemicals, not actually a chemical compound of its
own it contains up to 25 alkaloids

3. CLASSIFICATION OF OPIUM
ALKALOID
1. According to ring structure
- Morphine
- Thebaine
-Codeine
Phenanthrene derivatives
- Papaverine
- Noscapine
Benzo-isoquinoline
derivatives

4. 2. According to synthesis
- Morphine
- Codeine
A. Natural opium
alkaloids
B. Semi synthetic
opium alkaloids
- Heroine
- Pholcodeine
- Pethidine
- Methadine
C. Synthetic opiods

5. Opium Alkaloid of the Benzylisoquinoline gruop

6. Opium Alkaloid of the Phenanthrene Group
Opium alkaloids usually occur naturally combined with a specific acid: (Meconic acid).
■ Meconic acid present only in Opium with morphine.
■ Meconic acid gives a deep purplish red-colored complex with FeCl3
Meconic acid

7. ISOLATION OF OPIUM ALKALOIDS

8. WHAT IS STRUCTURE ELUCIDATION?
Structure elucidation involves identification of various parts of structure
like its functional groups, double/triple bonds, cyclic groups, molecular
weight, etc. Methods available for structure elucidation are
 Classical organic chemistry methods
 Spectroscopic methods

9. STRUCTURE ELUCIDATION OF MORPHINE
1.A rigid pentacyclic structure consisting of a benzene ring (A), two
partially unsaturated cyclohexane rings (B and C), a piperidine ring
(D) and a tetra hydro furan ring (E). Rings A, B and C are the
phenanthrene ring system. This ring system has little
conformational flexibility...
2. Two hydroxyl functional groups: a C3-phenolic [hydroxyl group]
and a C6-allylic [hydroxyl group],
3. An ether linkage between C4 and C5
4. Unsaturation between C7 and C8,
5. A basic, [tertiary]-amine function at position 17
6. [Five] centers of chirality (C5, C6, C9, C13 and C14) with
morphine exhibiting a high degree of stereoselectivity of
analgesic action

10. CHEMICAL CONSTITUTION:
1. Molecular formula of morphine is: C17H19NO3
When applied above formula in morphine the degree of unsaturation was found to be= 09
Means several double bonds present in structure including benzene
2. Nature of the N atom As morphine adds on one mole of methyl iodide to form a
quaternary salt, this shows that it contains tertiary nitrogen atom
Morphine + CH3 I→ quart. Salt
The tertiary nature of the N atom is further conformed by Hofmann degradation of codeine
derivatives-reveals the presence of nitrogen in the ring.

11. 3.Morphine on acetylation gives the diacetyl (HEROIN)morphine it indicate that morphine containing
two hydroxyl groups
4.With ferric chloride morphine give characteristic violet color which indicates the presence of
phenolic hydroxyl group but when Morphine is methylated with methyl chloride gives monomethyl
product which does not give any color with FeCl3 indicating that phenolic hydroxyl group is
methylated

12. 5.Presence of phenanthrene nucleus Morphine on distillation with zinc dust gives
phenanthrene and a number of bases, suggesting that morphine may contain phenanthrene
nucleus
6.From the unreactivity of third oxygen atom and degradation product of morphine concluded
that third oxygen atoms present as ether linkage.

13. STRUCTURE ACTIVITY RELATIONSHIP
OF MORPHINE (SAR)
 The structure–activity relationship is the relationship between the chemical structure of a
molecule and its biological activity
 The study of SAR helps the determination of the chemical groups responsible for
biological effect in the organism.
 Medicinal chemists use the techniques of chemical synthesis to insert new chemical
groups into the biomedical compound and test the modifications for their biological
effects.

14. ANALGESIC ACTIVITY OF MORPHINE
CAN INCREASE BY
1. Catalytic Reduction, methylation, oxidation or even elimination of the C-6-OH (alcoholic OH
group). Introduction of an OH group at C-14.
2. Introduction of a CH3 group at C-5
3. Replacement of N-CH3 group by other groups e.g. phenylethyl "N-CH2-CH2-ph" group.
4. Acetylation diacetylmorphine (heroin), that is more potent than morphine.

15. ANALGESIC ACTIVITY OF MORPHINE
CAN INCREASE BY
1. Catalytic Reduction, methylation, oxidation or even elimination of the C-6-OH (alcoholic OH
group). Introduction of an OH group at C-14.
2. Introduction of a CH3 group at C-5
3. Replacement of N-CH3 group by other groups e.g. phenylethyl "N-CH2-CH2-ph" group.
4. Acetylation diacetylmorphine (heroin), that is more potent than morphine.

16. ANALGESIC ACTIVITY OF MORPHINE
CAN DECREASE BY
1. Methylation of the phenolic OH group e.g.codeine.
2. Opening of the N-containing ring.
3. Opening of 4,5-oxygen bridge.
4. Dehydration by heating with HCl apomorphine.
5. Demethylation, N-CH3 N-H (Nor-morphine).

17. USES
1. It is an analgesic for the relief of severe pain e.g. morphine
2. Used as pre-anesthetic medication
3. For producing sleep and sedation
4. Used as anti-tussive e.g. codeine and Noscapine
(Narcotine)
5. For the treatment of diarrhea e.g. Papaverine
NOTE: Its original name ‘narcotine’ was changed to Noscapine reflect this lack of
narcotic action.

18. REFERENCES:
1. Chemistry of Natural products vol I & II by O.P.Agrawal
2. Natural Products : Chemistry and Biological Significance, J. Mann, R.S. Davidson,
J.B. Hobbs, D.V. Banthropeadn J.B. Harbome, Longman, Esses.