Introduction
In this topic, you can learn the easiest way to synthesize Oxycodone from Codeine. There are several paths of its synthesis with more stages, but I describe here the simplest one. This procedure is that it is effortless and fast and uses only very available reagents. You can find Codeine extraction method in following topics: "Cold Water Extraction of codeine from over-the-counter analgesics" or this "Morphine synthesis from codeine".
Equipment and glassware:
- 250 mL Round bottom flask;
- 250 mL Three necked round bottom flask;
- Oil and Ice water baths;
- Magnetic stirrer with heating surface;
- Laboratory scale (0.1 — 100 g is suitable);
- Nitrogen or Argon balloon 10-20 L is enough;
- Glass rod;
- Laboratory grade thermometer (0 °C to 200 °C) with flask adapter;;
- 0.5 or 1L Separatory funnel;
- Addition funnel;
- Nitrogen-inlet adapter;
- Beakers 500 ml x2; 200 ml x4; 100 ml x2;
- Rotary evaporator (optional);
- pH indicator paper;
- Buchner funnel and flask 500 mL.
Reagents:
- 30 g Codeine;
- ~500 mL Distilled water;
- 192 g Acetic acid;
- 20 g Sodium dichromate;
- Ammonia solution (NH4OHaq);
- 75 mL Chloroform (CHCl3);
- Sodium chloride (NaCl) (optional);
- 5% Pd/C (50% water wet, 3.0 g);
- 6.0 g Sodium hypophosphite (NaPO2H2);
- 540 mL Ethyl acetate;
Boiling Point: 454.92 °C at 760 mm Hg;
Melting Point: 218 - 220 °C;
Molecular Weight: 315.36 g/mole;
Density: 1.2164 g/ml (20 °C);
CAS Number: 76-42-6.
14-Hydroxycodeinone from Codeine
1. Dissolve 30 g of codeine in the 80 mL water with 25 g acetic acid in a 250 mL round bottom flask and set it in an ice water bath with stirring.
2. Now that it's cool, slowly pipette in the 20 g sodium dichromate in 25 mL water. The solution immediately turns a milky orange/yellow.
3. Now remove the ice and set it in your oil bath on a hotplate and install your water cooled condenser on top. I used a temperature controlled hotplate, so I just dialed the temp in to ~83 °C and made sure it stayed there for ~20 min. If you stick a thermometer in your oil bath, you should be able to do about the same. Heat is bad for opiates, but I have not found that letting it cook at 80-90 °C for 30 min to be terribly detrimental. Anyway, you can tell that the reaction is complete when there is no more color change. The new color should be a dark brown/red.
2. Now that it's cool, slowly pipette in the 20 g sodium dichromate in 25 mL water. The solution immediately turns a milky orange/yellow.
3. Now remove the ice and set it in your oil bath on a hotplate and install your water cooled condenser on top. I used a temperature controlled hotplate, so I just dialed the temp in to ~83 °C and made sure it stayed there for ~20 min. If you stick a thermometer in your oil bath, you should be able to do about the same. Heat is bad for opiates, but I have not found that letting it cook at 80-90 °C for 30 min to be terribly detrimental. Anyway, you can tell that the reaction is complete when there is no more color change. The new color should be a dark brown/red.
4. Pipette pour your solution into a Separatory funnel, wash your flask with a bit of water and pour that in too. There will be some black, insoluble sediment left in the flask. Don't worry about that sediment.
5. Now basify with ammonia (NH4OHaq). You don't have to be exact, just make sure the pH is taken to above 10.
6. Then extract three times x25 ml with chloroform. If you get an emulsion, just deal with it by adding a buttload of chloroform or NaCl (it will rice density of water solution and divides layers) and only taking the unemulsified chloroform with each separation.
7. Take your chloroform solutions and back extract with water twice to make sure you didn't bring nasty Cr with your product. The product is yellow when dissolved in a large amount of solvent and dark brown/red when concentrated. You just converted codeine's hydroxy group to a ketone and put a hydroxy group under the nitrogen bridge.
8. Evaporate off your solvent.
5. Now basify with ammonia (NH4OHaq). You don't have to be exact, just make sure the pH is taken to above 10.
6. Then extract three times x25 ml with chloroform. If you get an emulsion, just deal with it by adding a buttload of chloroform or NaCl (it will rice density of water solution and divides layers) and only taking the unemulsified chloroform with each separation.
7. Take your chloroform solutions and back extract with water twice to make sure you didn't bring nasty Cr with your product. The product is yellow when dissolved in a large amount of solvent and dark brown/red when concentrated. You just converted codeine's hydroxy group to a ketone and put a hydroxy group under the nitrogen bridge.
8. Evaporate off your solvent.
Oxycodone from 14-Hydroxycodeinone
9. 14-Hydroxycodeinone (4.98 g) and acetic acid (137 g) were added to a reaction flask (3-neck, 250 mL) equipped with mechanical/magnetic stirrer, addition funnel, thermocouple/thermometer and nitrogen-inlet adapter. The system was evacuated, and the flask filled with nitrogen.
10. Subsequently, 5% Pd/C (50% water wet, 3.0 g) in one portion was added under the nitrogen atmosphere.
11. While the mixture was stirred for about 5 minutes at ambient temperature (22 ± 5 °C), a solution of sodium hypophosphite (6.0 g) in de-ionized water (25 g) was prepared.
12. The aqueous sodium hypophosphite solution was transferred into the addition funnel, and added to the reaction mixture over a period of about 30 minutes with maintenance of content temperature at about 22 ± 5 °C The mixture was then warmed to about 45 °C and stirred for about 1 hour.
To determine the completeness of the reaction, a small sample was withdrawn from the batch and the sample was filtered through a syringe filter into a mixture of ethyl acetate and saturated sodium bicarbonate solution. After extraction, the organic layer was concentrated to dryness and the residue dissolved with HPLC mobile phase. The disappearance of 14-hydroxycodeinone was determined. If the reaction was discerned to be incomplete, the batch was stirred for an additional 2 h period at 45 °C, and the HPLC check performed once more.
10. Subsequently, 5% Pd/C (50% water wet, 3.0 g) in one portion was added under the nitrogen atmosphere.
11. While the mixture was stirred for about 5 minutes at ambient temperature (22 ± 5 °C), a solution of sodium hypophosphite (6.0 g) in de-ionized water (25 g) was prepared.
12. The aqueous sodium hypophosphite solution was transferred into the addition funnel, and added to the reaction mixture over a period of about 30 minutes with maintenance of content temperature at about 22 ± 5 °C The mixture was then warmed to about 45 °C and stirred for about 1 hour.
To determine the completeness of the reaction, a small sample was withdrawn from the batch and the sample was filtered through a syringe filter into a mixture of ethyl acetate and saturated sodium bicarbonate solution. After extraction, the organic layer was concentrated to dryness and the residue dissolved with HPLC mobile phase. The disappearance of 14-hydroxycodeinone was determined. If the reaction was discerned to be incomplete, the batch was stirred for an additional 2 h period at 45 °C, and the HPLC check performed once more.
13. Upon determination that the reaction was complete, the batch was cooled to ambient temperature (22 ± 5 °C) under the nitrogen atmosphere, and the contents filtered over a Hyflo-Supercel filtering pad (3.0 g, wetted with water).
14. The flask and wet cake were rinsed with acetic acid (20 g). The filtrate was concentrated in vacuo in rotavap machine to near dryness at temperature < 50 °C.
15. The residue was dissolved with de-ionized water (50 g) and the pH adjusted to 11.0 to 12.0 with 20% aqueous KOH solution and concentrated ammonium hydroxide (about 4 g).
16. The mixture was then extracted with ethyl acetate (4 x 135 mL) and the combined organic layers concentrated to dryness in vacuo. Crude oxycodone with an HPLC purity of over 85% was obtained in a yield of 70.0 to 85.0% (3.51 to 4.26 g).
14. The flask and wet cake were rinsed with acetic acid (20 g). The filtrate was concentrated in vacuo in rotavap machine to near dryness at temperature < 50 °C.
15. The residue was dissolved with de-ionized water (50 g) and the pH adjusted to 11.0 to 12.0 with 20% aqueous KOH solution and concentrated ammonium hydroxide (about 4 g).
16. The mixture was then extracted with ethyl acetate (4 x 135 mL) and the combined organic layers concentrated to dryness in vacuo. Crude oxycodone with an HPLC purity of over 85% was obtained in a yield of 70.0 to 85.0% (3.51 to 4.26 g).
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