Review:
Codeine to Morphine Conversion

Experimental

Using Pyridine HCl^1,2

A mixture of 1.00 g. of codeine and 3 g. of pyridine hydrochloride was placed in a bath at 220°C and heated for six minutes in a nitrogen atmosphere, after which the reaction mixture was immediately cooled and dissolved in 20 ml. of water, basified with 10 ml. of 4 N sodium hydroxide, and the non-phenolic material was removed by extraction with four 15-ml. portions of chloroform. The combined chloroform extracts were washed with 10 ml. of 0.5 N sodium hydroxide and 10 ml. of water, and the aqueous phase, after adding the washings, was adjusted to pH 9 and cooled thoroughly to precipitate phenolic material. After filtering and drying, this phenolic material was digested with 75 ml of methanol, the mixture was filtered hot and the filtrate was chromatographed on an alumina (Merck) column (120x11 mm) using 700 ml of methanol as eluent. The residue after evaporation of the methanol was dissolved in 10 ml. of 0.2 N sodium hydroxide, filtered, and the filtrate was adjusted to pH 9, precipitating the crude morphine. After drying, this crude morphine was sublimed (180-190°C (0.1 mm)), and the sublimate was crystallized from absolute ethanol. There was thus obtained a total of 210 mg. (22%) of morphine, mp 254-255°C.

The "Homebake" Method³

This is excerpted from a report dealing with clandestine manufacture of morphine and heroin from OTC codeine remedies, in so-called "homebake" laboratories in New Zealand. The method used is the same as the one introduced by Rapoport in 1951¹, using pyridine hydrochloride. The authors report some perp's claims of 50% conversion from the codeine, but say they obtained 30% typically, and further state that this is about what one would expect from Rapoport's paper . Purity of up to 92% with a more typical purity in the 80% range was reported by the forensic chemists evaluating the method.

The following is the procedure reportedly used in the clandestine labs, with some elaboration:

1. Crush sufficient pills to yield 2 g of codeine and mix with distilled water. Filter with a vacuum funnel to remove insolubles and add to a separatory funnel. Add NaOH solution to make the solution pH 12. Extract twice with chloroform (2x25 mL). This will be the bottom layer. Discard the water layer, which contains the aspirin or acetominophen) and evaporate the chloroform layer to dryness under gentle heat. The result is codeine base, a white crystalline powder.
2. Combine 20 mL pyridine and 25 mL conc. HCl in a beaker and heat strongly to 190°C to drive off any water. Cover and cool rapidly to obtain a white waxy material. This should be stored in a sealed container in the freezer if not to be used immediately.
3. The reaction is carried out in a glass boiling tube (here one could use a large ignition type test tube) which is sealed on one end. This should be oven dried before use. Then 3.5 g of the pyridine salt is added to the tube and this is then heated until it melts and for a few minutes more to drive off any moisture. Add 1.5 g of the base and seal the tube with a rubber stopper covered with a filter paper. Heat until the mixture begins to fume and continue until the mixture develops a reddish-orange color and becomes noticeably more viscous, typically 6-12 minutes.
4. Pour this into a 500 mL sep funnel and make the volume up to 100 mL with distilled water. Add 10% NaOH until strongly basic. The contents will become milky brown and then clear brown as the solution is made basic. When this point is reached, extract with 20 mL chloroform. This will contain any unreacted codeine (up to 70%) and may be saved for recovery if desired. The morphine is in the water layer.
5. Put the water layer in a beaker and carefully adjust the pH with HCl to pH 9 using a narrow range pHydronium paper. This is critical. Rapidly filter using two layers of paper (here one could use a paper designed for very fine crystals) and a vacuum flask/funnel as in step 1. A very fine brown powder will collect on the paper. This is unwanted byproducts and should be discarded.
6. Pour the filtrate into a clean beaker and, while carefully adjusting the pH to 8.5, vigorously rubbing the inside of the beaker with a "seeding stick" (here the authors mention that a split wooden peg is sometimes used in the home labs in NZ; a glass stirring rod would be preferable). Crystals should begin to form. These are allowed to settle for at least 5 minutes and then are recovered by vacuum filtering to recover the morphine as a beige to dark brown product.

Report from someone using the above method

Using Boron Tribromide⁴

A solution of 2.99g (10 mmol) of anhydrous codeine in 25 ml of CHCl3 was added during 2 min to a well-stirred solution of 15g (59.9 mmol) of BBr3 in 175 ml of CHCl3 maintained in the range 23-26°C. A 10 ml portion of CHCl3, which was used to rinse the addition funnel, was added to the reaction mixture and stirring was continued for 15 min at 23-26°C. The reaction mixture was then poured into a well-stirred mixture of 80g ice and 20 ml of concentrated (28-30%) ammonia. The two-phase system was kept at -5°C to 0°C for 0.5h (continous stirring) and filtered. The resulting crystalline material was washed thorougly with small portions of cold CHCl3 and H2O and dried to give 2.67g (88.1%) of slightly off-white morphine hydrate, mp 252.5-254°C.

Report from a chemist trying out the above method:

I extracted the codeine using the NaOH/chloroform method. I then went through the synthesis - the BBr3 is really nasty - fuming toxic shit! I had a high power exhaust fan in front of my work area and it took care of the fumes (all the insects outside the window died!). I dissolved the BBr3 in chloroform and then added the codeine/chloroform mixture - lots of HBr gas evolved - stoppered the flask and lead the fumes into water, which dissolved the HBr gas. The codeine made this funky pink precipitate. Continued to follow the steps, added mix to ammonia/ice (I had this in a alcohol/ice bath at -5°C). Once again fumes evolved (not as much). Stirred 30 min. Filtered out a pale white-yellow gelatinous material, washed with cold chloroform and water and dried. It seemed to have a bromine odor and was very acidic (I probably used a bit too much BBr3) so I washed with cold water again (morphine hydrate isn't water soluble) and the pH normalized. I then dissolved it in dilute HCl, and neutralized to pH 6 with NaOH.

I'm going to be more precise with amounts etc. next time, and hopefully this will improve the yield (now it was only 50%!).

Using Sodium Propylmercaptide⁵

A solution of 3.00 grams (10 mmol) of codeine in 60 ml of dry dimethylformamide was degassed under nitrogen by repeatedly stirring under vacuum, followed by inletting nitrogen. Following the addition of 3.00 grams (26.7 mmol) of potassium tert-butoxide, the degassing process was repeated, and 3.0 ml (32.7 mmol) of n-propanethiol was injected by syringe. The mixture was stirred at 125°C under nitrogen for 45 min (similar results at 110°C for 3h), cooled, and quenched with 3.0 ml of acetic acid. The solvent was removed under high vacuum, and the residue dissolved in 30 ml of 1N hydrochloric acid. The acid solution was washed with several portions of ether, treated with 5ml of 20% sodium bisulfite, and alkalized to pH 9 with ammonium hydroxide. The precipitated solid was collected, washed with water, and dried in vacuo (100°C) to leave 2.30g (80%) of morphine as tan crystals.

Using L-Selectride (Lithium tri-sec-butyl Hydride)^6,7

482 mg (1.6 mmol) of codeine was dissolved in 4 ml of an 1 M solution of L-selectride in THF (4.0 mmol) and was refluxed for 3.5h. The reaction was quenched with water (5ml), followed by 2ml of 15% NaOH solution and removal of the THF. The resulting mixture was washed twice with CH₂Cl₂, cooled to 0-5°C and acidified to pH 1 with 10% HCl. After basification with ammonium hydroxide to pH 9, the mixture was extracted into CHCl₃, the organic phase was washed with brine and dried over Na₂SO₄. Removal of the solvent, followed by recrystallization from water gave 355mg (73%) of morphine hydrate. Unreacted codeine was recovered from the non-phenolic extracts, and after purification by recrystallization from water, it amounted to 71mg (14%).