Process for the preparation of opiates

Abstract: A novel process for the preparation of codeinone and analogues thereof comprising the oxidation of a compound of formula, or a salt thereof, wherein R 1 is lower alkyl or a group wherein R 4 is lower alkyl, lower alkyl substituted by halogen or phenyl, phenyl or substituted phenyl; and R 2 is lower alkyl, allyl or lower alkyl substituted by cycloalkyl, characterised in that the oxidation is carried out in an acidic environment is disclosed.

Description: The present invention relates to a novel process for the preparation of codeinone and analogues thereof. Codeinone is a key intermediate for the synthesis of many morphinoid compounds. It is therefore desirable for a simple, straightforward and cost effective process for its preparation. In earlier works, codeinone was obtained from thebaine by treating it with dry HBr in CH 2 Cl 2 at -25°, followed by hydrolysis with water and dehydrobrominating with cold NaOH (Vesely, Z., Hodkova, J. and Trojanek J., Cesk. Farm. 1986, 35 , 222-6). In another method, thebaine was converted to a mixture of codeinone and neopinone in aqueous HCO 2 H containing Hg(OAc) 2 (US 4,277,604). However, thebaine is very expensive and does not occur naturally in a high yield; therefore the preparation of codeinone from thebaine is not an attractive method. An alternative process for the preparation of codeinone is the direct oxidation of codeine using variety of reagents, such as silver carbonate (Rapoport, H. and Reist, N.H., J. Am. Chem. Soc. 1955, 77 , 490-491) and Jones' reagent (Findlay, J.W.A., Butz, R.F. and Jones, E.C., Clin. Chem. 1981, 27 , 1524-1535); however, these reagents only gave codeinone in poor yield. Only Oppenauer oxidation (US 2,654,756) has given codeinone in reasonably good yield and high purity. All these methods have their drawbacks, however. Oxidation with silver carbonate is not preferred due to its cost and incomplete reaction, whereas in the case of Jones' oxidation and Oppenauer oxidation the isolation of the product is difficult and complex. The direct oxidation of codeine with active manganese dioxide (Ninan, A. and Sainsbury, M., Tetrahedron, 1992, 48 , 6709) and γ-manganese dioxide (Highet, R.J. and Wildman, W.C., J. Am. Chem. Soc., 1955, 77 , 4399) has also been reported. However, in both cases pure codeinone was obtained in only low yield due to the formation of 14β-hydroxycodeinone and low conversion. The direct oxidation of codeine with chromate reagents in acidic conditions has also been reported (Knorr, Chem. Ber. 1903, 36 , 3070 and DE 408870). Codeinone was obtained in low or very low yields. The object of the present invention is to provide a simple process for the preparation of codeinone and analogues thereof, and which provides the desired product in high yield and purity. The present inventors have found that if oxidation of codeine or a salt thereof, for example the phosphate salt, is carried out at a pH greater than 0.1 and less than 4.5, and the oxidation reagent is manganese dioxide, a high yield of codeinone is obtained which is not obtainable by any of the methods heretofore disclosed. Accordingly, the present invention provides a novel process for the preparation of a compound of formula (I) wherein R 1 is C 1-6 alkyl or a group wherein R 4 is C 1-6 alkyl, C 1-6 alkyl substituted by halogen or phenyl, or phenyl; and R 2 is C 1-6 alkyl, allyl or C 1-6 alkyl substituted by cycloalkyl; comprising the oxidation of a compound of formula (II), or a salt thereof, wherein R 1 and R 2 are as hereinbefore defined; and wherein and the oxidation reagent is manganese dioxide, characterised in that the oxidation is carried out in an acidic environment, at a pH or greater than 0.1 and less than 4.5. Preferably, each of R 1 and R 2 may be the same or different and each is C 1-6 alkyl, such as C 1-4 alkyl, for example methyl or ethyl and preferably ethyl. When the compound of formula (II) is present as a salt, preferably the salt is the phosphate salt (H 3 PO 4 ). The oxidation is carried out at a pH of from 0.1 < pH > 4.5; most preferably the oxidation is carried out at a pH of from 0.8 to 1.2. The solvent may be any solvent suitable for use in such an oxidation reaction. Acetone was found to be the most suitable solvent for giving the desired product in high yield and high purity. Other solvents were also found to be particularly useful and were preferred in the order: acetone > THF > IPA > CH 3 CN > NMP. Preferably, the solvent is used as a 50:50 (v/v) solvent/water mixture. The oxidation reagent is manganese dioxide, such as activated manganese dioxide or γ-manganese dioxide, preferably γ-manganese dioxide. Suitably, the oxidation reagent is present in an amount of at least 3 equivalents or more with respect to the compound of formula (I). The invention will now be further described by way of example only. General Procedure for the Preparation of Codeinone from Codeine Phosphate or Codeine A solution of codeine or codeine phosphate was dissolved in the appropriate solvent system and a specified volume of hydrochloric acid of varying concentration was added. Manganese dioxide (either freshly prepared γ-manganese dioxide or activated manganese dioxide from Aldrich) was added and the reaction mixture was stirred at ambient temperature for 1.5 to 4 hours. The progress of the reaction was monitored by HPLC. The reaction mixture was filtered through a celite pad, washed with additional solvent or water, and neutralised with ammonium hydroxide. The product was extracted with methylene chloride (3 x 150ml) and the combined extracts washed with water and dried over anhydrous sodium sulphate. The organic layer was then evaporated to yield codeinone. In all the experiments the reaction was followed by HPLC and the retention time of the product was compared with that of the standard. In some cases the crude product was quantitated to obtain the purity. The HPLC analysis was done on a Shimadzu system. The column used was Phenomenex's Prodigy 5µ ODS (3) 100°A, 250 x 4.6mm. The method was isocratic. The mobile phase was: water (1450ml) + acetonitrile (550ml) + Et 3 N (2ml) + 1.73g of 1-octanesulphonate, sodium salt + pH 3.5 (adjusted with 85% phosphoric acid). In the cases where the product was isolated, it was also characterised by comparing its 1 H NMR with that of the standard: 1 H NMR (CDCl 3 ) δ 1.85-1.92(1H, m, 15 α ), 2.05-2.15(1H, m, 16 α ), 2.27-2.4(2H, m, 15 β , 10 α ), 2.45(3H, s, N-CH 3 ), 2.58-2.62(1H, m, H 16β ), 3.07-3.14(1H, d, H 10β ), 3.19-3.21(1H, d, H 9α ), 3.39-3.44(1H, m, H 14 ), 3.84(3H, s, OCH 3 ), 4.70(1H, s, H 5β ), 6.05-6.11(1H, dd, H 8 ), 659-6.70(3H, m, H 1 , H 2 , H 7 ). The following examples were carried out using the starting material and reagents indicated. Starting Material (g) Solvent System (ml) Acid (ml) Oxidant (g) pH Yield (%) Purity (HPLC area %) Example 1 Codeine IPA (14) 6N HCl γ-MnO 2 1.62 94 ∼95 (05) H 2 O(14) (0.5) (1.6) Comparative Example 2 Codeine IPA (22) - γ-MnO 2 4.5 NA ∼34 phosphate (1) H 2 O (22) (3.2) Example 3 Codeine IPA (14) 6N HCl γ-MnO 2 1.6 80 91.8 phosphate (0.5) H 2 O(14) (0.5) (1.6) Example 4 Codeine IPA(40) 6N HCl γ-MnO 2 1.44 NA 60.3 (2) H 2 O (40) (2) (4) Example 5 Codeine IPA (40) 6N HCl γ-MnO 2 1.3 86 ∼91.8 (2) H 2 O (40) (3) (7) Example 6 Codeine IPA(10) 6N HCl γ-MnO 2 0.73 75 82 (0.5) H 2 O(10) (2) (15) Example 7 Codeine IPA(10) 6N HCl γ-MnO 2 1.16 92 ∼97 (0.5) H 2 O(10) (1) (1.5) Example 8 Codeine IPA (10) 6N HCl γ-MnO 2 1.41 95 ∼95 (0.5) H 2 O(10) (0.75) (1.5) Example 9 Codeine CH 3 CN (10) 6N HCl γ-MnO 2 0.9 89.7 ∼93 (0.5) H 2 O(10) (0.75) (1.5) Comparative Example 10 Codeine IPA(10) 6N HCl γ-MnO 2 <0.1 50.4 ∼71 (0.5) H 2 O(10) (4) (1.5) Example 11 Codeine Acetone (10) 6N HCl γ-MnO 2 0.92 95.2 94 (0.5) H 2 O(10) (0.75) (1.5) Example 12 Codeine THF (10) 6N HCl γ-MnO 2 1.21 89 93 (0.5) H 2 O(10) (0.75) (15) Comparative Example 13 Codeine NMP - γ-MnO 2 - NA ∼21.6 (0.5) (20) Example 14 Codeine NMP (10) 6N HCl γ-MnO 2 1.45 NA ∼90 (0.5) H 2 O(10) (1) Example 15 Codeine Acetone (200) 6N HCl γ-MnO 2 1.02 83.5 95.5 (11.45) H 2 O(200) (16) (36) Example 16 Codeine Acetone (10) 6N HCl Activated 0.87 NA ∼45 (0.5) H 2 O(10) (0.75) 85% MnO 2 (Aldrich) Comparative Example 17 Codeine IPA (25) - γ-MnO 2 (3) - NA ∼41 (1) CH 2 Cl 2 (25) NA = Not Available (the product was not isolated) Preparation of γ-Manganese Dioxide Manganese (II) sulphate monohydrate (140g) was dissolved in 2.66 litres of water and heated to 60°C. Potassium permanganate (97.3g) in 1.85 litre of water was added over a period of 15 minutes and stirred at 60°C for 1 hour, until manganese dioxide precipitated out. The reaction mixture was filtered and the residue was washed with deionised water until no sulphate ion was present. The solid was dried under suction for 2 hours followed by drying at 70°C under vacuum to a constant weight (∼8 days) to give 115 g of a dark brown powder.

Claims: A process for the preparation of a compound of formula (I) wherein R 1 is C 1-6 alkyl or a group wherein R 4 is C 1-6 alkyl, C 1-6 alkyl substituted by halogen or phenyl, or phenyl; and R 2 is C 1-6 alkyl, allyl or C 1-6 alkyl substituted by cycloalkyl; comprising the oxidation of a compound of formula (II), or a salt thereof, wherein R 1 and R 2 are as hereinbefore defined, and wherein the oxidation reagent is manganese dioxide, characterised in that the oxidation is carried out in an acidic environment, at a pH of greater than 0.1 and less than 4.5. A process according to claim 1 wherein each of R 1 and R 2 may be the same or different and each is C 1-6 alkyl. A process according to claim 2 wherein each of R 1 and R 2 may be the same or different and is methyl or ethyl. A process according to claim 3 wherein R 1 and R 2 are both ethyl. A process according to any one of claims 1 to 4 wherein when the compound of formula (II) is present as a salt, the salt is the phosphate salt. A process according to any one of claims 1 to 5 wherein the oxidation is carried out at a pH of from 0.8 to 1.2.

Inventors: SEBASTIAN ALICE, SEBASTIAN, ALICE
Applicants: JOHNSON MATTHEY PLC, JOHNSON MATTHEY PUBLIC LIMITED COMPANY
Application year: 1999
Main classification: C07D489
IPC codes: C07D489, C07D307