Synthetic Communications

ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20

A Rapid, Nearly Quantitative Conversion of

Codeine to Hydrocodone

T. Howard Black , Jennifer C. Forsee & Donald A. Probst

To cite this article: T. Howard Black , Jennifer C. Forsee & Donald A. Probst (2000) A Rapid,
Nearly Quantitative Conversion of Codeine to Hydrocodone, Synthetic Communications, 30:17,
3195-3201, DOI: 10.1080/00397910008086930

To link to this article: http://dx.doi.org/10.1080/00397910008086930

Published online: 04 Dec 2007.

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SYNTHETICCOMMUNICATIONS,30(17), 3 195-3201 (2000)

A RAPID, NEARLY QUANTITATIVE CONVERSION OF

CODEINE TO HYDROCODONE

T. Howard Black*, Jennifer C. Forsee, Donald A. Probst

Department of Chemistry, Eastern Illinois University, Charleston, [L 6 1920

Ahsiruct: A very rapid, two-step, virtually quantitative synthesis of

hydrocodone from codeine, via the intermediacy of dihydrocodeine,
has been developed.

In the course of a project involving the synthesis of potentially very

specific opiate antagonists, we recently required multi-gram quantities of

hydrocodone (1, see Figure) as the free base. This material is commercially

available only as the bitartrate salt, and the price is prohibitively expensive for a

synthetic starting material (cu. $450ig' ), especially considering that the tartaric

* To whom correspondence should be addressed

3195

Copyright Q 2000 by Marcel Dekker, Inc. www.dekker.com

3196 BLACK, FORSEE, AND PROBST

acid would immediately be removed in the planned sequence.

Consultation of the literature revealed several syntheses of hydrocodone,

usually beginning with either codeine (2) or thebaine (3). The most promising of

these appeared to be a method published by Rapoport et ul. in 1950; which

entailed the catalytic hydrogenation of codeine in dilute acetic acid followed by

an Oppenauer oxidation that, although rather operationally complex and possibly

dangerous, provided a reported 83% yield of the desired product. Using this

sequence as a starting point, we expended considerable effort toward the

development of an inexpensive, scaleable, high-yield process, and we now report

a very facile, operationally straightforward sequence that provides pure

Ia = H2, 10% PdK, EtOAc: b = t-BuOK, PhZCO, b c u n c .

hydrocodone in neur1.v yuuntitutive overull yield front codeine, which can be

obtained for about $17/g.' The procedure, which is depicted below, has run

smoothly on scales greater than 10 grams and the overall conversion, which

requires no discrete purification steps, can be completed in a single day.

In our hands, the catalytic hydrogenation ofcodeine in dilute acetic acid to

dihydrocodeine (4). as called for in the original paper, gave material that was

rather gummy and not suitable for carrying on to the oxidation step. After
CODEINE TO HYDROCODONE 3197

considerable experimentation, we determined that ethyl acetate constituted an

idcal solvent. Hydrogenation of codeine at room temperature in a Pam apparatus

at 35psi of hydrogen for two to three hours afforded a quantitative yield of pure,

snowy-white dihydrocodeine, the melting point of which was higher than any

reported value.’

Considerable time was invested in optimization of the oxidation step,

including the examination of a variety of oxidation methods (PCC,

hypochlorite/TEMPO, DMSO-based oxidants, etc.) that were unavailable fifty

years ago. However, the notorious acid-lability of the morphinan skeleton

precluded the utilization of any of the alternative methods tested, as in each case

only R complex mixture of polar material was recovered. Therefore, we focused

our attention on streamlining or refining the reported Oppenauer method in an

attempt to maximize the yield, shorten the operation, and render the

transformation less dangerous. In Rapoport’s paper, potassium r-butoxide was

prepared from potassium and 1-butyl alcohol, after which time the excess alcohol

was removed via co-distillation with benzene, which served as the reaction

solvent. We utilized instead a commercially available 1M solution of potassium

/-butoside in tetrahydrofuran,’ which worked very well as long as the

tetrahydrofuran was removed prior to the addition of the oxidation reagents.

lieactions in which the small amount of THF was left in the reaction mixture

failed to provide any oxidized material, returning mostly impure starting matenal

Also, the attempted substitution of toluene for benzene (due to its notorious

carcinogenicity) proved unsatisfactory, regardless of whether the reaction was

3198 BLACK, FORSEE. AND PROBST

carried out at 80 "C (the boiling point of benzene) or at reflux (1 10 "C). In all

experiments, only unreacted starting material was recovered.

Once the solution of potassium r-butoxide in benzene was prepared, it was

cooled slightly and a solution of codeine and benzophenone in benzene was added

in one portion, causing a sudden but mild exotherm and the precipitation of a

small amount of white material. The resulting mixture was refluxed for a short

time under dry nitrogen, whereupon a standard extraction sequence provided pure

hydrocodone in nearly quantitative (990/,) yield.

Experimental Section

All reactions were carried out under dry nitrogen, unless otherwise

specified. Glassware was routinely oven-dned at 120 "C for a minimum of 4 h

and was then assembled under a nitrogen stream. Anhydrous solvents were

obtained by distillation, immediately PT;Gi ta .&e, h r n salilim k n z c ~ m n e

ketyl (tetrahydrofuran, diethyl ether), barium oxide (diisopropylamine,

dimethylfonnamide), or sodium (benzene, toluene). 'H N M R spectra were

recorded at 60 or 360 MHz. Thin layer chromatographic analyses were carried

out on Analtech silica gel G (250 um)plates using the specified solvent as eluent;

visualization was effected by either ultraviolet light or by charring with

phosphomolybdic acid Codeine sulfate was obtained from Research

Biochemicals International, Natick, MA or Sigma Chemical Co., St. Louis, MO;

it was converted to the free base before use.

Dihydrocodeioe (4). In a Pam hydrogenator jar, codeine (2.0g, 6.7mmol) and 10

percent palladium-on-carbon catalyst (200mg) were combined in ethyl acetate

CODEINE TO HYDROCODONE 3199

(75mL). This mixture was hydrogenated at room temperature at 37 psi for 2

hours. During this time, the hydrogen pressure decreased to 34 psi within 30 min.,

was increased back to 37 psi, and thereafter remained constant for the duration of

the reaction. The mixture was filtered through Celite, the filter cake was washed

with two lOmL portions of ethyl acetate, and the resulting solution was stripped

of solvent using a rotary evaporator followed by high vacuum. The product

foamed considerably upon initial application of high vacuum, so care was taken

not to lose any product. Leaving the product on high vacuum overnight afforded a

white, crunchy, crystalline solid (2.Og (99.3 96) mp 1 13-4 "C [lit.21 12-3 "C]).

Dihydrocodeinone (Hydrocodone, I). A 100 mL round bottom flask was

weighed and equipped with a Vigreaux column and distillation head along with

benzene (20mL). Using a syringe, potassium mi-butoxide (5mL of a 1.OM

solution in tetrahydrofuran, Smmol) was added to the reaction tlask and the

resulting yellow misture was distilled under a dry nitrogen atmosphere. Fresh

benzene was added periodically until the head temperature reached 80 "C and

remained constant. When about 20 mL of benzene had been distilled, the

apparatus was allowed to cool and the reaction flask was set up for reflux. In a 25

ml, round bottom flask was prepared a solution of dihydrocodeine (SOOmg,

1.66mmol). benzophenone (3g, 16.5mmol), and benzene (15 mL), which was

added i n a single portion via syringe to the reaction flask, accompanied by a slight

exotherin. The reaction was flushed with nitrogen and then was gently refluxed

li,r 7.5 hours. During the retlus, the formation of a greenish-brown precipitate
3200 BLACK, FORSEE, AND PROBST

was observed. The reaction mixture turned a deep green color by the end of the

reaction time and contained large quantities of a white solid

At this time, the reaction flask was cooled in an ice bath and hydrochloric

acid (1 5 mL of a 3M solution, 45mmol) was added to the flask. The resulting

mixture was transferred to a separatory funnel and the layers were separated. The

organic (benzene) layer was extracted twice with hydrochloric acid (15 mL of a

3M solution, 45mmol). The first aqueous layer and the combined aqueous

extracts from the two organic layer extractions were then combined and extracted

twice with 15 mL of diethyl ether. The ether layers were discarded.

The aqueous layers were then basified with 20 percent aqueous sod~um

hydroxide solution, causing the separation of a white clumpy precipitate. This

mixture was extracted three times with 100 mL of ethyl acetate. The combined

organic extracts were dried with magnesium sulfate, stripped of solvent on a

rotary evaporator, and then placed on high vacuum to remove residual traces of

solvent. This protocol afforded 492mg (99Yo) of a snowy-white solid, mp 195-6

“C (lit.* 194-5 “C).

Acknowledgments

We gratefully thank the National Institutes of Health ( R I 5-GM52677-01)

and the Petroleum Research Fund, administered by the American Chemical

Society (26935-B1), for their generous support of this work.

References

1. Research Biochemicals International, Natick, MA; catalog no. H-114.

7. Rapoport, H.; Naumann, R.: Bissell, E.R.; Bonner, R.M. .I. Org. ( ‘ / m i . 1950,
 I
CODEINE TO HYDROCODONE 3201

15, 1 103 and references cited therein.

3. Research Biochemicals International, Natick, MA; catalog no.C-!22.

4. Skita, F.; Franck, D. Chem. Rer. 1911,44,2862.

5. Aldnch Chemical Company, Milwaukee, WI; catalog no. 32,865-0.

Received in the USA 11/26/99