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United States Patent Office Patented Aug 3,830,819 United States Patent Office Patented Aug. 20, 1974 2 The invention provides a process for the purification of l-dihydrocodeine containing as impurities 1-dihydrothebai 3,830,819 MANUFACTURE OF l-DHYDROCODENE none and or 1-dihydrothebainol, which comprises treating Edward Leon Grew and David Jackson Powles, Edin the impure 1-dihydrocodeine to remove said impurities burgh, Scotland, assignors to MacFarlan Smith Limited, therefrom by either extraction with an aqueous alkali or Edinburgh, Scotland 5 by passage of the material through an anion exchange No Drawing. Fied Feb. 22, 1972, Ser. No. 228,367 resin of a quaternary ammonium type in the hydroxide Claims priority, application Great Britain, Feb. 22, 1971, form whereby the proportion of said impurities is reduced. 5,081/71 The crude 1-dihydrocodeine may be one prepared by Int, C. C07d 43/28 the catalytic hydrogenation of 1-dihydrocodeinone and ac U.S. C. 260-285 3 Claims 0. cording to a feature of the invention, there is therefore provided a process for the preparation of a purified 1-di ABSTRACT OF THE DESCLOSURE hydrocodeine which comprises the steps of A process for the preparation of a purified 1-dihydro (a) catalytically hydrogenating 1-dihydrocodeinone in a codeine which comprises the steps of: 5 liquid medium using a platinum oxide or supported (a) catalytically hydrogenating 1-dihydrocodeinone in a platinum metal catalyst to produce a solution of crude liquid medium using a catalyst selected from the group l-dihydrocodeine, consisting of platinum oxide and supported platinum (b) removing the catalyst from the solution, and metal to produce a solution of crude 1-dihydrocodeine, (c) treating the solution for the recovery of a purified (b) removing the catalyst from the solution, and 20 1-dihydrocodeine having a reduced content of l-dihy (c) treating the solution for recovery of a purified 1-di drothebainone and/or 1-dihydrothebainol. The purified hydrocodeine having a reduced content of 1-dihydro 1-dihydrocodeine may be recovered in salt form, if thebainone and/or 1-dihydrothebainol. desired. 25 The solution in step (c) may be treated by isolating the This invention relates to an improved process for the crude 1-dihydrocodeine therefrom, dissolving the crude manufacture of 1-dihydrocodeine (l=laevorotary) and to 1-dihydrocodeine in a water-immiscible solvent and ex the purification thereof. tracting the solution with an aqueous alkali. l-Dihydrocodeine is an important analgesic which is The solution in step (c) may alternatively be passed used extensively in the relief of pain. It is normally manu 30 through an anion exchange resin of a quaternary ammo factured by the catalytic hydrogenation of codeine, which nium type in the hydroxide form. is an alkaloid obtained from the opium poppy. By the term “liquid medium' as used herein, we mean l-Dihydrocodeine may also be prepared by the catalytic a liquid in which l-dihydrocodeinone has an appreciable hydrogenation of 1-dihydrocodeinone, which in turn may solubility. Typical of such liquid media are the lower al be obtained from thebaine. kanols (having from one to five carbon atoms per mol In U.S. Application No. 204,298 of one of us and ecule) and, in particular, ethyl alcohol, especially in its Alastir A. Robertson filed 2nd December 1971 and entitled commercially available form of industrial methylated Reduction of Thebaine there is disclosed a method for the spirit. In the latter case it is convenient to employ a sus conversion of thebaine into dihydrothebaine, which may pension of the 1-dihydrocodeinone in the solvent whereby be hydrolysed to 1-dihydrocodeinone. Thebaine is also an 40 the alkaloid dissolves as the hydrogenation proceeds. alkaloid obtained from the opium poppy. However it The catalytic hydrogenation may be carried out at am finds considerably less commercial utility than codeine bient or higher temperatures and at atmospheric or greater and hence is economically more attractive for use in the than atmospheric pressure of hydrogen. manufacture of 1-dihydrocodeine. In carrying out the alkaline extraction method of puri It is an object of the present invention to provide an 45 fication according to the invention, 1-dihydrocodeine is improved process for the preparation of 1-dihydroco isolated from solution by well known techniques, for ex deinone from 1-dihydrocodeine which is commercially at ample evaporation under low pressure, and dissolved in a tractive because it is based on thebaine rather than co water-immiscible solvent, for example a liquid aromatic deine as starting material for the synthesis. It is also an hydrocarbon such as benzene. The solution is then ex object of the invention to provide a process for the purifi 50 tracted at least once with aqueous alkali, which is prefer cation of 1-dihydrocodeine by reducing the content of l-di ably an aqueous solution of an alkali metal hydroxide, hydrothebainone and/or 1-dihydrothebainol which we such as sodium hydroxide. Following the alkali extrac have found may be associated with the synthesis. tion process, the organic solvent is removed, for example We have found that 1-dihydrocodeinone may be readily by evaporation under reduced pressure, and if recovery converted to 1-dihydrocodeine by hydrogenation in a liquid 55 of the purified 1-dihydrocodeine is required in salt form, a medium (as hereinafter defined) using a supported plati water-miscible solvent such as ethyl alcohol or acetone and num metal or a platinum oxide catalyst, and further that an acid, such as tartaric acid, are added. the resulting 1-dihydrocodeine is contaminated with small In the other method of purification, the solution of amounts of 1-dihydrothebainone and 1-dihydrothebainol. crude dihydrocodeine obtained after completion of the hy These impurities are, like morphine, phenols and have 60 drogenation and removal of the catalyst is passed through been found to give a positive reaction in the test in the a column of the hydroxide form of a quaternary ammoni 1968 British Pharmacopoeia (1969 addendum) and simi um type anion exchange resin. A satisfactorily purified lar official specifications for the presence of morphine in product may be obtained after a single passage of the solu 1-dihydrocodeine tartrate, in spite of the absence of mor phine itself as an impurity. As a result, dihydrocodeine tion through the column. However, several passages may tartrate prepared by the catalytic hydrogenation of 1-di 65 be effected if desired. The purified 1-dihydrocodeine may hydrocodeinone may fail to comply with the specification be recovered or converted to the salt form by usual tech of the British and other pharmacopoeias. We have found niques. that such contaminants can be removed either by alkaline The 1-dihydrocodeine prepared or purified by the proc extraction or by an ion exchange process and that follow esses of the invention can be converted to 1-dihydro ing such treatment the product obtained complies with 70 codeine tartrate which complies with the specification of the official specifications. the 1968 British Pharmacopoeia (1969 Addendum) for 1 3,830,819 3. 4. dihydrocodeine tartrate, in particular with regard to the values in the morphine test of the four samples of dihy figure for the morphine test which is below the maximum drocodeine tartrate obtained are shown in the table below: allowed. O Colour values of The following Examples illustrate the invention: dilhydrocodeine tartrate in B.P. EXAMPLE sample Resin used for treating solution of crude morphine.est No. dihydrocodeine (limit 0.16) lull-l-H-r-H 48.0 g of 1-dihydrocodeinone, 1.2 g of platinum oxide l--------- None------------------------------ 0.41 2--------- Grade SRA 69 (7-9% crosslinking). 0.08 and 400 ml. of 95% industrial methylated spirit were 8--------- Grade SRA 65 (3-5% crosslinking)-------- 0.012 placed in a 1 litre glass flask provided with a sealed stirrer, 4--------- Grade SRA 61 (2-3% crosslinking)-------- 0.010 glass baffle and gas inlet tube. The air in the flask was 10 replaced by hydrogen and the mixture vigorously stirred EXAMPLE 3 at room temperature under hydrogen at atmospheric pres" sure. After a short induction period, rapid uptake of hy 12 g of 1-dihydrocodeinone suspended in 400 ml. of drogen commenced and was complete after about 5-6 95% industrial methylated spirit was hydrogenated at at hours. After removal of the catalyst by filtration, the Solu mospheric pressure with 0.3 g of platinum oxide catalyst tion was analysed by gas-liquid chromatography and the as described in Example 1. After removal of the catalyst, reaction product found to consist of 97.4% l-dihydro dihydrocodeine tartrate was isolated from one-half of the codeine, 1.6%. 1-dihydrothebainol, 0.5% l-dihydrothe solution without resin treatment and from the other half bainone and 0.5%. 1-dihydrocodeinone. after treatment on a column of Deacidite FF resin, grade The solution was divided into three equal portions A, 20 SRA 69, in the hydroxide form. The colour values in the B and C which were treated separately as described below. B.P. morphine test of the untreated and resin treated (A) The solution was concentrated under reduced pres samples were 0.72 and 0.02 respectively. sure to about 100 ml. final volume and treated, with EXAMPLE 4 stirring, with rather more than one molar ratio of tartaric 25 6 g. of dihydrocodeinone was stirred with 50 ml. of acid referred to the total weight of alkaloid present in the 95% industrial methylated spirit and 0.15 g. of platinum solution. After cooling to room-temperature the dihydro oxide catalyst at room temperature under hydrogen at codeine tartrate was filtered off, washed with spirit and 30 lbs. per sq. inch pressure until absorption of the gas dried.
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