Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 Sep 27.
Published in final edited form as: J Pharm Sci Pharmacol. 2014 Mar;1(1):54–56.

A One-Step Synthesis of β-Bromocodide from Codeine

Christopher W Cunningham 1,*, Jeffrey R Deschamps 2, Andrew Coop 3
PMCID: PMC8474124  NIHMSID: NIHMS1741550  PMID: 34584903

Abstract

Opioid analgesics are the treatment of choice for chronic, severe pain. During the course of developing new derivatives of morphine and codeine, we observed an unanticipated SN2′ substitution reaction product during an attempted 3-O-demethylation of codeine using BBr3. NMR spectroscopy and X-ray crystallographic data indicate that a significant product is β-bromocodide, a useful intermediate for the production of C-6-demethoxythebaine derivatives. Herein we report the first, single-step synthesis of β-bromocodide.

Keywords: Boron Tribromide (BBr3), β-Bromocodide, Codeine, Morphine, X-Ray Crystallography

INTRODUCTION

Codeine (1), a secondary metabolite produced by the opioid poppy, Papaver somniferum, is a non-selective, opioid receptor agonist with reduced potency compared to morphine (2) (Casy, 1986). Clinically, codeine is employed for the treatment of moderate pain, often co-administered with non-steroidal anti-inflammatory drugs (NSAIDs), and is a standard treatment for short-term and chronic cough due to its antitussive actions (Bolser, 2007).

Codeine is a common starting material in the synthesis of 4,5-epoxymorphinan-based opioid receptor probes. The aromatic methyl ether at C-3 can be cleaved using a number of methods (Rapoport, 1951; Gates, 1956; Lawson, 1976), with the conditions reported by Rice in 1977 (BBr3, CHCl3, 0 °C) (Rice, 1977) offering improved yield, simplicity, and practicality for scale-up over less efficient methods. The reaction of 1 with HBr in refluxing HOAc, for example, results predominantly in the substitution product β-bromomorphide (4) (Przybyl, 2003). Under these conditions, the 3-O-methyl analogue, β-bromocodide (3), was not identified as a by-product, likely due to the ease in removal of methyl ethers using refluxing HBr.

The use of CHCl3 as the solvent for 3-O-demethylation of 1 has not been rationalized in the literature. Methyl ethers have been cleaved from various substances using alternate solvent conditions, however an interesting cationic rearrangement resulting in a bromo substitution product was once reported using CH2Cl2 as the solvent (Grieco, 1977). During the course of synthesizing derivatives of 2 (Cunningham, 2008a), we noticed the presence of competing side products as a result of 3-O-demethylation of 1 when using BBr3 in CH2Cl2 that were not observed when demethylation was carried out in CHCl3. This study details the isolation and structure elucidation of a competing side product formed under these alternate reaction conditions.

MATERIALS AND METHODS

Codeine (4.00 g, 10.1 mmol) dissolved in CH2Cl2 (20 mL) was added dropwise to a solution of BBr3 (15 g, 59.9 mmol, 6 equiv.) in CH2Cl2 (175 mL) at 0–5 °C over 5 minutes. The solution was stirred under nitrogen for 30 minutes, and the reaction mixture was then added with stirring to NH4OH (conc.) in an ice bath. After stirring for 20 minutes, the two-pharse mixture was filtered, and the organic layer separated. Drying (Na2SO4) and evaporation under reduced pressure afforded a complex mixture. The first product (3) to elute from column chromatography (CHCl3:MeOH 95:5) was isolated as a brown foam, and was subsequently crystallized from MeOH to give a fine white solid. m/z (H+): 363, 365. 1H NMR: δ 6.72 (d, 1 H, J = 8.0 Hz), 6.65 (d, 1 H, J = 8.0 Hz), 6.04 (dt, 1 H, J = 1.0, 10.5 Hz), 5.70 (dt, 1 H, J = 2.5, 10.5 Hz), 5.04 (m, 1 H), 4.11 (dd, 1 H, J = 2.0, 10.5 Hz), 3.84 (s, 3 H), 3.61 (dd, 1 H, J = 2.5, 6.5 Hz), 3.09 (d, 1 H, J =18.75 Hz), 2.79 (dd, 1 H, J =2.5, 10.0 Hz), 2.58 (dd, 1 H, J = 4.5, 12.5 Hz), 2.45–2.55 (m, 1 H), 2.48 (s, 3 H), 2.33 (td, 1 H, J = 3.5, 12.5 Hz), 2.00 (td, 1 H, J = 5.0, 12.5 Hz), 1.79 (td, 1 H, J = 2.0, 12.5 Hz).

Single-crystal X-ray diffraction data on 3 was collected using MoKα radiation and a Bruker APEX 2 CCD area detector. A 0.44 × 0.39 × 0.10 mm3 crystal was prepared for data collection by coating with high viscosity microscope oil. The oil-coated crystal was mounted on a micro-mesh mount (Mitergen, Inc.) and transferred to the diffractometer and data was collected at 113 °K. 3 crystallized with two molecules in the asymmetric unit and was triclinic in space group P1, with unit cell dimensions α = 8.015(4) Å, b = 8.361(4) Å, c = 13.330(6) Å, α = 88.397(9)°, β = 73.056(7), and γ = 65.732(7)°. Data was 96.9% complete to 26.50°θ (approximately 0.80 Å), with an average redundancy of 1.99 (see Fig. 1). The structure was solved by direct methods and refined by full-matrix least squares on F2 values using the programs found in the SHELXTL suite (Bruker, 2000). Corrections were applied for Lorentz, polarization, and absorption effects. Parameters refined included atomic coordinates and anisotropic thermal parameters for all non-hydrogen atoms. Hydrogen atoms on carbons were included using a riding model [coordinate shifts of C applied to H atoms] with C–H distance set at 0.96 Å. The final anisotropic full matrix least-squares refinement on F2 with 401 variables and 267 restraints converged at R1 = 4.68%, for the observed data and wR2 = 13.38% for all data. Complete information on data collection and refinement is available upon request.

Figure 1.

Figure 1.

Open in a new tab

Structure of 3 as determined by X-ray diffraction. Displacement ellipsoids are at the 50% level, only one of the two molecules in the asymmetric unit is shown for clarity.

RESULTS

The effect of solvent on the reaction of 1 with BBr3 was determined by repeating the published procedure using CH2Cl2 in place of CHCl3 (Scheme 1) (Rice, 1977). Although 2 was still produced in high quantities, thin layer chromotography (TLC) showed the presence of three additional products not encountered when using CHCl3. These products were isolated by flash chromotography (95:5 CHCl3:MeOH) and identified by mass spectroscopy (MS) and NMR analysis. Crude MS analysis of the most significant product (4) exhibited peak m/z ratios of 348 and 350 of similar intensity, indicating a product modified by a single Br group. This corresponds to addition of Br and loss of OH from 2. The second significant product showed m/z peaks of 362 and 364, indicating the presence of 3 obtained by the addition of a CH3group to 4. Compound 3 was readily purified by crystallization from MeOH and was analyzed by 1H NMR and X-ray crystallography.

Scheme 1.

Scheme 1.

Open in a new tab

Synthesis of 2–4. Reagents and conditions: (a) BBr3, CH2Cl2, 0 °C, 30 min; NH4OH, H2O, 0 °C, 20 min.

A third product seen by MS analysis (m/z = 268) correlates with a loss of HBr from 4. Significant quantities could not be collected for extensive structural analysis, however it is conveived that this could correspond to 6-demethoxyoripavine, a product that has only been reported previously as a product of a multi-step synthesis and in moderate yields (Beyerman, 1984). Such a product would be a valuable intermediate in synthesizing aporphine derivatives, as well as a useful diene for producing 6-demethoxyorvinols.

DISCUSSION

The conversion of 1 to 2 relies upon a two-step mechanism originating from nucleophilic attack by the O3 electron pair on BBr3, which leads to loss of bromide anion and formation of an oxonium intermediate as shown in Scheme 2. Because codeine contains three oxygen substituents, an excess (6 equiv.) of BBr3 is used during this procedure. Under standard solvent conditions (CHCl3), bromide anion attacks the C3 methyl ether, cleaving the C—O bond in an SN2 type fashion (path a). Any coordinated 6-OBBr2 is hydrolyzed back to 6-OH during the subsequent NH4OH workup. Under the experimental solvent conditions reported here (CH2Cl2), bromide anion is also capable of attacking the allylic C8 position, resulting in π-bond migration and loss of HOBBr2 through an SN2′ mechanism (path b). The presence of both compounds 4 (β-bromomorphide) and 3 (β-bromocodide) raises questions concerning the kinetics of these competing processes. The fact that compound 3 is isolated in the presence of both 2 and 4 suggests the rate of 8-substitution is similar to the rate of 3-O-demethylation. Though exact amounts of all products were not calculated, the approximate ratio of 2:3:4 is estimated to be 90:5:5.

Scheme 2.

Scheme 2.

Open in a new tab

Competing mechanisms resulting in products 2 (path a) and 3 (path b). Compound 4 is produced as a result of both synthetic routes.

Similar SN2′ allylic rearrangements have been described elsewhere using the Lewis acid PBr3 (Corey, 1970) or Brønsted acid HBr (Przybyl, 2003). The use of PBr3 in such instances produces predominantly the SN2′ substitution product and loss of O=PBr2. Neumeyer and colleagues reported in 2005 the PBr3-mediated rearrangement and deoxygenation of a 14-hydroxy analogue of thebaine (Zhang, 2005). Although desired conversion of 1 to 2 remains the principle product of this reaction, it should be noted that side products 3 and 4 have not been observed in our hands under standard solvent conditions, and also have not been reported previously in the literature using BBr3. This study indicates competing chemical reactions are possible during the converstion of 1 to 2, and raises questions as to the role of solvent in this process and the kinetics of such transformations.

CONCLUSION

We have found that the choice of solvent plays a role in the efficiency of the 3-O-demethylation of 1 to produce 2. Specifically, the use of CH2Cl2 promotes a competing SN2′ substitution reaction, resulting in 8β-bromo derivatives 3 and 4 that are not observed in an analogous reaction in CHCl3. X-ray crystallographic studies confirmed the identity of 3.

Acknowledgments:

The authors wish to thank the National Institute on Drug Abuse (NIDA) for financial support of this work (Andrew Coop, DA 13583). Christopher W. Cunningham was the recipient of a pre-doctoral Ruth L. Kirschstein National Research Service Award (NRSA, DA 021049). This work was included in part in the doctoral disseratation of Christopher W. Cunningham (Cunningham, 2008b). This research was supported in part by the Naval Research Laboratory and the National Institute on Drug Abuse (NIDA) under contract Y1-DA-1101 (Jeffrey R. Deschamps).

Footnotes

Conflict of Interest

There is no conflict of interest.

REFERENCES

  1. Beyerman HC, Crabbendam PR, Lie TS, and Maat L (1984). Convenient conversions of codeine to 6-demethoxythebaine. Recl. Trav. Chim. Pay-B 103, 112–114. [Google Scholar]
  2. Bolser DC and Davenport PW (2007). Codeine and cough: An ineffective gold standard. Curr. Opin. Allergy Clin. Immunol 7, 32–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bruker (2000). SHELXTL v6.10, Bruker AXS Inc., Madison, WI. [Google Scholar]
  4. Casy AF and Parfitt RT (1986). Opioid Analgesics, Plenum Press, New York and London. [Google Scholar]
  5. Corey EJ, Kirst HA, and Katzenellenbogen JA (1970). A stereospecific total synthesis of α-santalol. J. Am. Chem. Soc 92, 6314–6320. [Google Scholar]
  6. Cunningham CW, Mercer SL, Hassan HE, Traynor JR, Eddington ND, and Coop A (2008a). Opioids and efflux transporters. Part 2: P-glycoprotein substrate activity of 3- and 6-substituted morphine analogs. J. Med. Chem 51, 2316–2320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cunningham CW (2008b). Opioid analgesics with reduced tolerance [dissertation]. University of Maryland School of Pharmacy, Baltimore, USA. [Google Scholar]
  8. Gates M and Tschudi G (1956). The synthesis of morphine. J. Am. Chem. Soc 78, 1390–1393. [Google Scholar]
  9. Grieco PA, Noguez JA, and Masaki Y (1977). (±)-Deoxyvernolepin. A cytotoxic vernolepin prototype. J. Org. Chem 42, 495–501. [DOI] [PubMed] [Google Scholar]
  10. Lawson JA and DeGraw JI (1976). An improved method for O-demethylation of codeine. J. Med. Chem 20, 165–166. [DOI] [PubMed] [Google Scholar]
  11. Przybyl AK, Flippen-Anderson JL, Jacobson AE, and Rice KC (2003). Practical and high-yield syntheses of dihydromorphine from tetrahydrothebaine and efficient syntheses of (8S)-8-bromomorphide. J. Org. Chem 68, 2010–2013. [DOI] [PubMed] [Google Scholar]
  12. Rapoport H, Lovell CH, and Tolbert BM (1951). The preparation of morphine-N-methyl-C14. J. Am. Chem. Soc 73, 5900. [Google Scholar]
  13. Rice KC (1977). A rapid, high-yield conversion of codeine to morphine. J. Med. Chem 2016, 4–5. [DOI] [PubMed] [Google Scholar]
  14. Zhang A, Csutoras C, Zong R, and Neumeyer JL (2005). Synthesis of 2-Fluoro-11-hydroxy-N-propylnoraporphine: A potential dopamine D2 agonist. Org. Lett 7, 3239–3242. [DOI] [PubMed] [Google Scholar]

RESOURCES