morphine synthesis

1. Morphine Synthesis
Presented by:
Rabia Rashid
Roll no: 245956831
Presented to:
Dr. Muhammad Abbas

2. Outline
• Source
• History
• Classification
• Introduction
• Natural and Synthetic Morphine
• SAR (Structural Activity Relationship)
• Morphine Synthesis
• Uses
• Conclusion
• References

3. Source
• Plants were the first source for medications and continue to play an
important role in modern medicine.
• For instance, Morphine, an alkaloid derived from the poppy, is one of
the best known examples of a plant-derived medicine.
• Poppy plant has a long history of medicinal use, with morphine being
a more recent variant.

4. Poppy Plant
• The word for opium comes from ancient Greek ὀπός, meaning
vegetable juice, and refers to the dried latex derived from the Opium
Poppy (Papaver somniferum, Latin papāver poppy; somni sleep +
ferre to bring).
• Opium produces, a powerful narcotic whose derivatives include
morphine, codeine, heroin, and oxycodone.

5. Morphine
• First alkaloid to be isolated from serturner Plants.
• Morphin is highly potent analgesic used to treat moderate to severe
chronic pain.
• Morphin act as monoacid base & forms well defined salt with acids.
• In medicine morphine is used as powerful pain reliever and also used
as the diacetyl derivatives under the trade name heroin.

6. The German apothecary Friedrich Wilhelm Adam
Sertürner (1783-1841) isolated a crystalline
powder from opium in 1805 and named it
‘morphium.’
British organic chemist Sir Robert Robinson (1886-
1975) discovered the molecular structure of morphine
in 1925. He was awarded the Nobel Prize in Chemistry
in 1947.
History

7. A timeline highlighting important periods in the history of opium and morphine

9. Classification
According to ring structure
a. Phenanthrene derivatives
• Morphine
• Codeine
• Thebaine
b. Benzo-isoquinolinederivatives
• Papaverine
• Noscapine
According to synthesis
a. Natural Opium Alkaloids
• Morphine
• Codeine
b. Semi-synthetic Opium Alkaloids
• Heroine
• Pholcodeine
c. Synthetic Opiods
• Pethidine
• Methadine

10. Introduction (Morphine)
• Morphine is the principal alkaloid of the pharmacologically active
substance has significant effectiveness as structure of morphine has a
strained pentacyclic core (morphine skeleton) with five contiguous
chiral centers including a benzylic quaternary carbon.

11. Chiral centers

13. Properties
• Odorless
• White crystalline alkaloid
• Bitter in Taste
• Boiling Point: 190℃
• Melting Point: 255℃
• Levorotatory
• Insoluble in Water and soluble in alcohol or alkali

14. Derivatives of Morphine

15. Natural morphine
• Natural (-)-morphine is a complex stereostructure alkaloid extracted from poppy
opium plant.
• Levorotatory isomer is active.
• Includes benzene ring (A), two unsaturated cyclohexane rings (B and C), a
piperdine ring (E) and a tetrahydrofuran ring (D). In addition, there are five
contiguous stereocentre, one of which is the benzylic quaternary carbon (C13).

16. Synthetic Morphine
• Retrosynthesis
Retrosynthesis is designing a reverse synthesis of the organic
compound. This helps us to find the way of synthesis for that
compound. Retrosynthesis give us an idea about the synthetic steps of
a complex compound as well.
Mannich reaction approach

17. Total Synthesis
• Total synthesis (the construction of a compound from simple
compounds that are available commercially) of morphine would allow
scientists, in very simplified terms, to create morphine from
scratch,rather than extract it from the poppy plant.

18. • In 1950, Otto Diels (1876-1954) and Kurt Alder (1902-1958)
discovered the eponymous chemical reaction that was critical in the
synthesis of morphine.[35]
• For this accomplishment they were awarded the 1950 Nobel Prize in
Chemistry.
• Gate Synthesis
• Rice Synthesis
• Fukuyama, Guillou, Stork, and Magnus

19. SAR (Structural Activity Relationship)
1. The Phenol Moiety
 R=H Morphine
 R=Me Coedine
 An aromatic phenyl ring is essential
for activity. Any other substitution
on phenyl ring diminishes activity.
 Esterification at C3 decreases the
analgesic activity but increase the
anti-tussive activity.

20. 2. The 6-Alcohol
• The alcoholic group of C-6 when methylated, esterified and oxidized
removed analgesic activity as well as toxicity of the compound
increase.
• The saturation of double bond at C-7 position gives more potent
compound.
• Bridging of C-6 and C-14 through ethylene linkage gives potent
derivatives.

21. 3. Modification of 3 Nitrogen
• Nitrogen is essential for the activity, removal of nitrogen results in
decrease in analgesic activity.
• Double bond at 7 and 8 positions is not important to binding.

22. Summary

23. Morphine Synthesis

27. Uses of Morphine Adverse Effect of Morphine

28. Conclusions
• Morphine structure has phenanthrene nucleus
• Removal of 3-OH group reduce analgesic activity
• Acetylation of 3-OH and 6-OH group produces very potent lipophilic
compound
• N-methyl group substitution with large alkyl group reduces the
activity, elimination enhances the activity.
• N-methyl group replacement with alkyl methyl cyclopropyl group
antagonist the activity.

29. References
1. Taber, Douglass F. (2004). [Strategies and Tactics in Organic
Synthesis] Volume 5 || Chapter 11 The enantioselective synthesis of
morphine., (), 353–389.
2. Nagase, Hiroshi (2011). [Topics in Current Chemistry] Chemistry of
Opioids Volume 299 || Recent Advances in the Synthesis of Morphine
and Related Alkaloids. , 10.1007/978-3-642-18107-8(Chapter 73), 1–28.
3. Brook, Karolina; Bennett, Jessica; Desai, Sukumar P. (2017). The
Chemical History of Morphine: An 8000-year journey, from resin to de-
novo synthesis. Journal of Anesthesia History, (), S2352452916301293–
.

30. 4. Gao, H. (2021, February). Advances of the total synthesis of
morphine in the last decade. In IOP Conference Series: Earth and
Environmental Science (Vol. 657, No. 1, p. 012073). IOP Publishing.
5. Vardanyan, R., Hruby, V. (2006). Synthesis of Essential
Drugs. Netherlands: Elsevier Science.