Chemistry 150, Fall 2008

Synthetic Opium: The Occurrence, Bioactivity, Biosynthesis and Synthesis of Oxycodone

Andy Wong, Fall 2008
Introduction
Oxycodone is a derivative of the natural product morphine. Morphine was first discovered in the 1800s and was used for relief of pain after the invention of hypodermic needles in the 1850s. Oxycodone was discovered about half a century later in Germany and used more commonly thereafter because its effects did not last as long or did its onset occur as quickly. With the synthesis of this chemical, alternative for morphine is available without the side effects of morphine. The effectiveness of this drug itself and in combination with other drugs as an analgesic will be discussed in this paper.
H3 C O

Other sub-groups that have minimal amounts of these controlled chemicals have a wide variety of uses ranging from use as ornaments to use in food products.

II. Biological Activity

Oxycodone is an opioid analgesic that is a pure agonist in its hydrochloride salt form and directly affects the central nervous system through an unknown mechanism. While its main effect is analgesia, it does have other effects such as anxiolysis, respiratory depression, constipation, as well as cough suppression.4 Being a pure agonist, oxycodone's analgesic effect is limited only by the amount of the drug taken, increasing in effect with increase in dosage. In theory, this drug is able to control the most severe pain with an increase in dosage, however, with the increase in dosage, severity of side effects also increases. Unlike its precursor analgesic, morphine, this drug is eliminated from the body through the kidney instead of the liver. When metabolized, oxycodone undergoes Ndemethylation to form noroxycodone with CYP3A4 and Odemethylation to form oxymorphone with CYP2D. Oxycodone is often used in conjunction with acetaminophen and aids in fever reduction as well as analgesia. 5 This combination has been shown to be comparable to intramuscular morphine as well as a better pain management for osteoarthritis. Research has also shown that the combination is more effective than doubling the dose of either substituent alone.6 Oxycodone itself is not toxic nor is it toxic when metabolized. Over dosage amount of this chemical varies from person to person as a tolerance for the chemical can be built up. Death is caused only by the side effects this chemical has towards the body. Main cause of death would be its affect on the respiratory system causing the patient to breathe slowly 7 or not breath at all.

N OH CH 3

Figure 1. Oxycodone, narcotic alkaloid related to codeine.

I. Occurrence
Oxycodone does not occur naturally and is y synthesized from thebaine, morphine or codeine, all naturally occurring in the opium poppy, Papaver somniferum1. Papaver somniferum (Figure 2) is native to South-East Europe and Western Asia but has been cultivated and spread throughout the world because it can be easily grown, given the right amount of fertilizer and sufficient room.

III. Biosynthesis
Since oxycodone is not biosynthetically made, the biosynthesis of its precursor, morphine, a benzylisoquinoline alkaloid, will be discussed. The biosynthesis process is detailed in Figure 3. Starting from L-Tyrosine(1), an amino acid from the shikimate pathway, goes through decarboxylation, condensation, and methylation, all enzymes catalyzed to produce S-N-methylcoclaurine (5). The compound is then hydroxylated with NADPH and O 2 and methylated with SAM(S-adenosylmethionine) to form (S)reticuline(6) 8 which is later converted to (R)-reticuline(7) through oxidation and then reduction. (R)-reticuline marks the beginning of the pathway solely used for morphine biosynthesis as it is hydroxylated with NADPH and O2 followed by reduction, also with NADPH, to form salutaridinol(8). Salutaridinol is then acetylated with acetylCoA to form thebaine(9), which is the precursor of various opioids such as neopinone(10), codeinone(11), oripavine(13), and morphinone(14). The enzymes that catalyzed to create these less potent opioids are not yet known but demethylation occurs, there are theories that these demethylations are not

Figure 2. Papaver somniferum, source (www.poppies.org/gallery) With the varying growth conditions, many sub-groups of this species has been formed and range in content of morphine, thebaine and other chemicals. Those sub-groups of opium poppy cultivated for medicinal purposes generally contain about 0.3 percent to 1.5 percent2 of thebaine and 9 percent to 17 percent3 of morphine depending on their growth conditions.

Chemistry 150, Fall 2008

enzyme catalyzed. After codeinone and morphinone are produced, reduction with NADPH forms codeine(12) and morphine(15) respectively, while codeine is further demethylated to form morphine.9
O

CH3 O HO N H 3C H O H OH 8, salutaridinol CH3

HO CO 2 OH NH 2 1, L-Tyrosine

OH CO 2

acetyl-CoA
OH H 2N 3, Tyramine H 2O

NH 2

OH 2, Dopamine

coenzyme A CH3 O

O
OH

HO H HO NH 4, (S)-norcoclaurine S-adenosyl-L-methionine S-adenosyl-L-homocysteine HO H3 C O S-adenosyl-L-methionine S-adenosyl-L-homocysteine

H 3C

H O 9, thebaine

N CH3

CH3 O

HO

O
H N CH 3 OH

N H CH3

O H 3C H O 13, oripavine

N CH3

5, S-N-methylcoclaurine S-adenosyl-L-methionine S-adenosyl-L-homocysteine H 3C O HO H3 C N 6, (S)-reticuline NADPH H+ NADP+ HO H 3C O H N CH3 7, (R)-reticuline O CH3 OH NADPH O2 NADP+ H2O OH H CH3 O

O 10, neopinone H 3C O O

HO

N H CH3

O H

N CH3

O 11, codeinone NADPH NADP+ H 3C O O

O 14, morphinone NADPH NADP+ HO

N H CH3 12, codeine

O H HO

N CH3

HO

15, morphine

NADPH O2 NADP+ 2H2 O CH3 O HO

NADPH NADP+

Figure 3. Biosynthesis of morphine

IV. Synthesis
The semi-synthesis of oxycodone requires thebaine or a derivative of it. Since the amount of thebaine in nature is very scarce, methods of synthesizing oxycodone from codeine or morphine have been developed as it is much more abundant naturally. Various methods of synthetically producing morphine have been developed and the complete synthesis of oxycodone is possible using synthesized morphine. The various methods of morphine synthesis includes the Gates Synthesis, the Rice Synthesis, Evan's synthesis, Overman Synthesis, White Synthesis and the Parker Synthesis.

N H 3C H O H OH 8, salutaridinol CH3

Chemistry 150, Fall 2008

Among these various methods, Gates synthesis is one of the first methods of morphine synthesis discovered in 1953 and the Parker synthesis is one of the latest methods discovered in 2006. However, one of the highest yield of morphine would be through the Rice synthesis with a good 12% yield. Rice synthesis is summarized in Figure 4. 10
1. a) NaHSO3 OH b)KCN, H2 SO4 O O H 3C O 2. SnCl2, HCL HO 17 H 2N HOAc 1. 2. a)POCl3 b)NaCNBH4

HO

H 3C O trimethylphenylammoniumethoxide O H HO 12, codeine DMSO/ acid halide

N CH 3 15, morphine

N CH3

HO

O H 3C HO 16

H 3C O H 2O2 /CH 2 O2 O N OH CH3

H 3C O O

H HN

1. Li/NH3 2. PhOCHO, EtOAc

O CH3 H HN

N CH3

O 23, 14-hydroxycodeinone H 2/Pd

O 11, codeinone

H3 C O

OH 19

O CH3 1. a) MeSO3H b) (CH 2OH) 2 c) NBS d) HCO 2H

H3 C O

OH 18

O CH3
H 3C O

O N Br

O H N Br NH 4F/HF TfOH

N OH CH3 24, oxycodone

Figure 5. Synthesis of oxycodone from morphine

H 3C O OH O 21 1. Br 2, AcOH 2. CHCl3, NaOh 3. H 2, PD, CH 2O, NaOAc CH 3 N O O 22

H 3C O

OH 20

Conclusion
Oxycodone is an opioid analgesic that is not biosynthetically produced. The precursor for this drug can be thebaine, morphine or codeine but these compounds are only available in small quantities in opium poppy. The complete synthesis of oxycodone is possible but to date, its synthesis is complicated and with low yield. Development in the synthesis of morphine, its most abundant precursor, is needed because of the effectiveness of opioid analgesics. Despite the high regulation of these drugs, since they are Schedule II in accordance to DEA standards, they are still widely prescribed to patients. In the future, they are likely to be able to develop a synthetic opioid that isn't and can't be abused with none habit forming side-effects as they have been working on this since they first realized opioids are addictive.

HO O HO 15

1. ClCO 2Et H 3C CH3 2. PhSeCl O N 3. NaIO4 4. NaBH 4 5. BBr 3, CHCl3

Figure 4. Synthesis of morphine Starting from isovanillin(16), carboxylation occurs forming 3-hydroxy-4-methoxybenzoic acid(17) which reacts with 3methoxyphenethylamine which yields 18. Reduction and formylation occurs and after ketalizatoin and regioselective bromination, 20 is formed. The bromine acts as a blocking group to prevent para-coupling as cyclization occurs forming 21. The compound then has the bromine cleaved and methylation of the amine occurs forming dihydrocodeinone (22). From this, through demethylation and hydrogenation, morphine (15) is finally formed. From here, selective methylation of the 3-hydroxy group on the morphine ring is carried out by trimethyphenylammonium ethoxide forming codeine (12). 11 Oxidation occurs with codeine (12) to form codeinone (11) which is then hydroxylated to form 14hydroxycodeinone (23). Oxycodone (24) is finally produced once 14-hydroxycodeinone is hydrogenated. This synthesis is described in Figure 5.12

References ________________
1 Wikipedia, the free encyclopedia: Opium poppy

http://en.wikipedia.org/wiki/Opium_poppy (accessed December 1, 2008)

2

PubChem Public Chemical Database: Thebaine http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid= 408120&loc=ec_rcs (accessed December 1, 2008) Ma, J.;Corcoran, R.C. Process for extracting and purifying morphine from opium. U.S. Patent 6,054,584, April 25, 2000

Chemistry 150, Fall 2008

National Library of Medicine. Current Medication Information: Daily Med. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6743 (accessed December 1, 2008) National Library of Medicine. Current Medication Information: Daily Med. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=961 (accessed December 1, 2008) Zhukovsky, D. S.; Walsh, D.; Doona, M., The relative potency between high dose oral oxycodone and intravenous morphine: a case illustration. J Pain Symptom Manage 1999, 18, (1), 53-55. National Library of Medicine.. MedlinePlus. http://www.nlm.nih.gov/medlineplus/ency/article/007285.htm (accessed December 1, 2008) Plant Metabolic Network.. PlantCyc Pathway: (S)-reticuline biosynthesis. http://www.plantcyc.org:1555/PLANT/NEWIMAGE?type=PATHWAY&object=PWY-3581&detaillevel=3&detail-level=2 (accessed December 1, 2008) Plant Metabolic Network.. PlantCyc Pathway: morphine biosynthesis. http://www.plantcyc.org:1555/PLANT/NEWIMAGE?type=PATHWAY&object=PWY-5270&detaillevel=3 (accessed December 1, 2008) organic molecules. Chemical Communications 2002, (11), 1159-1168.

10 Blakemore, P. R.; White, J. D., Morphine, the Proteus of

11 Vardanyan, R.S.; Hruby, V.J. Synthesis of Essential Drugs;

Elsevier, B.V.; Amsterdam, 2006; Vol. 1; p 21-26

12 Huang, B.S.; Yansong, L.; Ji, B.Y.; Christodoulou, A.P.

Preparation of 14-hydroxynormorphinones from normorphinone dienol. U.S. Patent 5,869,669, February 9, 1999