SK286233B6 - Isolation process of 14-hydroxycodeinone - Google Patents

Abstract

Process for the isolation of 14-hydroxycodeinone from a reaction mixture after completed conversion of thebaine or analogues thereof by oxidation with hydrogen peroxide or peroxy acids, wherein in the process the pH of the reaction mixture is adjusted by the addition of ammonium hydroxide to a value of from 9 to 10 at a temperature of from 0 to 10 °C, the released base of 14-hydroxycodeinone is extracted with an organic solvent, such as dichloromethane, toluene or their mixture with lower alcohols having 3 to 5 carbon atoms, the organic extract is separated and then optionally concentrated, so obtained 14-hydroxycodeinone is extracted with aqueous solution of an organic acid, such as formic acid or acetic acid, the acid aqueous layer containing 14-hydroxycodeinone is separated, the pH of the solution is adjusted by the addition of ammonium hydroxide to a value of from 9 to 10, so obtained 14-hydroxycodeinone is separated, washed with water and a mixture of acetone and water and dried.

Description

The invention relates to pharmaceutical production, isolation of 14-hydroxycodeinone of formula (I),

which is an intermediate for the preparation of potent analgesics (e.g. oxycodone) or morphine antagonists (Naltrexone) used in medical practice.

BACKGROUND OF THE INVENTION

14-Hydroxycodeinone (I) is prepared by transforming tebaine (II), a natural alkaloid isolated from Papaver somniferum L., or analogs (III) thereof, wherein R is an alkyl or benzyl residue. In this procedure (Scheme 1), thebaine (II), or an analogue thereof in an acidic environment, reacts with hydrogen peroxide, peracids, or other oxidizing agents to form 14 / S-hydroxycodeinone (I).

II R = CH 3

I

III R = (H2C5H5 or _Cn H2n + 1

Scheme 1

The 14-hydroxycodeinone prepared by transformation of codeenone dienolsilyl ether is purified from the reaction mixture according to US 6177567 by adding sodium bisulfite to the reaction mixture after transformation, concentrating to dryness, then adding water, toluene and ethyl acetate. The organic layer was separated, extracted with 25 aqueous hydrochloric acid solution, the acidic aqueous layer was separated, ammonium hydroxide and ethyl acetate were added, the mixture was heated to 65 ° C, the layers were separated, the ethyl acetate was concentrated to dryness, 2-propanol, the mixture is stirred at 5-10 ° C, the precipitated crystals are filtered off, washed with a 2-propanol-heptane mixture and dried.

According to Krassnig et al. (Ar. Pharm. Pharm.Med. Chem. 329, 325-6 (1996)), the reaction mixture was poured onto ice after trans30 formation of thebaine, ammonium hydroxide was added, the precipitated 14-hydroxycodeinone was extracted with dichloromethane, the extraxt dried, concentrated and crystallized from dichloromethane-ethanol (1: 1).

Seki I. (Takamine Kenmkyusho Nempo, 12, 52-5 (1960)) after oxidation of thebaine with hydrogen peroxide in formic acid, the reaction mixture was diluted with water, added acetone, sodium bisulfite, adjusted pH with ammonium hydroxide to 6.0, and subsequently precipitated at pH 14-hydroxycodeinone with ammonium hydroxide. The product was not further purified, but used directly for further processing.

Ijima I. et al. (Helv. Chim. Acta 60, 2135-7 (1977)) the crude 14-hydroxycodeinone was filtered off from the reaction mixture, washed with water, 95% ethanol and diethyl ether. For recrystallization they used a mixture of ethanol and chloroform. A similar purification procedure is also described in Hauser F. M., et al. J. Med. Chem. 17, 1117 (1974) and Lutz, R. E., Small L., J. Org. Chem. 9, 220-233 (1939) with the difference that the latter 40 dissolved the crude 14-hydroxycodeinone in chloroform and crystallized the product by adding ethanol.

According to Feldman and Liutenberg (J. Ex. Chim. 18, 716-717, (1945)), after the oxidation of thebaine, the reaction mixture was basified with ammonium hydroxide, the yellow 14-hydroxycodeinone precipitate was filtered off, washed with hot water and used for hydrogenation without further purification.

In WO9902529, the reaction mixture is basified with ammonia, extracted with chloroform, the phases are separated and the residue after distillation of the chloroform from the organic layer is concentrated and used for hydrogenation without further purification.

All of the aforementioned methods of isolating 14-hydroxycodeinone have the drawback that by reacting peroxide / peracids with tebaine or analogs thereof, 14-hydroxycodeinone is contaminated with related substances such as e.g. 10-hydroxytebaine, 10,14-dihydroxycodeinone, hardly separable byproducts and the like, which are not removed by these processes but are carried forward to the next stages of the oxycodone preparation and thus reduce the product quality and / or the product quality. for further purification, in the final step, they reduce the overall yield of the process, and yield a low yield.

These drawbacks are overcome by the process of the present invention.

SUMMARY OF THE INVENTION

The present invention provides a process for the isolation of 14-hydroxycodeinone of formula (I) from a reaction mixture obtained by reacting thebaine (II) or analogues of formula (III) thereof, wherein R is an alkyl having 2 to 5 carbon atoms, alkylaryl preferably benzyl, or methoxybenzyl,

III R = CH 2 C 6 H 5 or C _n H 2n + 1

Even with hydrogen peroxide or peracids, in which the reaction mixture is alkalinized to pH 9-10 at 0-10 ° C by addition of ammonia at the end of the conversion of thebaine or analogs of formula III, the precipitated 14-hydroxycodeinone base is extracted with an organic solvent, preferably dichloromethane , toluene, or a mixture thereof with lower alcohols having a carbon number of 3 to 5, wherein the ratio of dichloromethane or toluene to the lower alcohol is preferably 99: 1 to 9: 1, the organic extract is separated and concentrated. 14-Hydroxycodeinone is extracted with an aqueous solution of an organic acid, e.g. form or vinegar. The acidic 14-hydroxycodeinone-containing aqueous layer is separated, the pH of the solution is adjusted to 9.0-10 by the addition of a base, preferably ammonium hydroxide, and the precipitated 14-hydroxycodeinone is separated, washed with water, acetone-water and dried.

The advantage of this process is that it makes it possible to obtain a product of high purity.

The following examples describe the process of the patent in more detail, but do not in any way limit its scope.

Examples of the invention

Example 1

Dissolve 10.0 g of thebaine (31.6 mmol) in an aqueous solution of oxalic acid (2.2 g of oxalic acid (17.53 mmol) and 14.0 mL of water) at 15 ° C. After dissolution of thebaine, a mixture of 4.6 g of 88% formic acid (101.3 mmol) and 4.4 ml of 30% hydrogen peroxide (43.14 mmol) was added. The reaction mixture was stirred at 25 ° C to to complete conversion of tebaine (assessed by capillary electrophoresis; capillary 50 cm x 0.05 mm, electrolyte 100 mM TRIS / phosphate, pH 2.7, 5 mM dimethoxy-O-cyclodextrin, temperature 25 ° C 30 kV; migration time tebain 5 , 6 min.). After completion of the reaction, the reaction mixture was cooled to 5 ° C, horses, ammonium hydroxide added to pH 9.2. The resulting suspension is extracted with dichloromethane (100 mL), the organic phase is separated, washed with water and saturated NaCl solution. The dichloromethane solution was extracted with an aqueous formic acid solution (5 g formic acid in 60 mL water), the aqueous acidic extract was separated, mixed with charcoal, the suspension was filtered, the clear filtrate was cooled to 5 ° C and stirred with the addition of The ammonium hydroxide was adjusted to pH 9.2, the precipitated 14-hydroxycodeinone crystals were filtered off, washed with water, acetone-water (1: 1) and dried. This gives 9.0 g of 14-hydroxycodeinone, content (99.5%), water content: 0.0648%, solids: 99.97%, melting point: 271.6-273.1 ° C, amount of thebaine : 0.0%.

Example 2

The reaction mixture prepared as in Example 1 was cooled to 5 ° C, adjusted to pH 9.3 by addition of 25% ammonium hydroxide, extracted with toluene (100 mL), washed with water, saturated NaCl solution. , and extracted with aqueous acetic acid (5 g in 100 mL water). The acidic aqueous phase was separated, washed with carboraffin and filtered. After cooling to 10 ° C, 100 ml of acetone are added to the purified acidic aqueous phase and 14-hydroxycodeinone is precipitated by addition of concentrated ammonium hydroxide to pH 9.5. The precipitated 14-hydroxycodeinone crystals are filtered off, washed with water, acetone-water (1: 1) and dried. This gave 9.1 g of 14-hydroxycodeinone (99.9% content), water: 0.06%, solids: mp: 274.2 ° C; tebaine: 0.0%.

Example 3

Dissolve 500.0 g of tebaine (1.58 mol) in aqueous oxalic acid (110.0 g of oxalic acid (867.5 mmol) and 700.0 ml of water at 15 ° C, add 120 g of formic acid with stirring. (2.20 mol) and 220 ml of 30% hydrogen peroxide (2.16 mol) The reaction mixture was stirred at 25 ° C until complete conversion of thebaine (assessed by capillary electrophoresis) was cooled to 10 °. The pH of the solution was adjusted to 9.2 with the addition of horse ammonium hydroxide, the suspension was extracted with toluene-2-propanol (94: 6) 2 x 250 mL each, and the combined organic phases were washed with water and saturated aqueous NaCl. extract with aqueous formic acid solution (100 ml in 1500 ml of water), treat the acidic aqueous extract with charcoal, filter through diatomaceous earth, cool the filtrate to 5 ° C, precipitate 14-Hydroxycodeinone by adding concentrated ammonium hydroxide to pH 9.6 The precipitated crystals were filtered off Wash with cold water and finally with acetone-water (1: 1) and dry under vacuum at 50 ° C. This gave 430 g of 14-hydroxycodeinone, content (99.3%), thebaine content 0.021%, water content 0.14%.

Example 4

100.0 g (0.26 mol) of 6-O-benzyltebaine are added with cooling and stirring to a solution prepared from 22.0 g (0.174 mol) of oxalic acid dissolved in 140 ml of water. 23.0 g (0.44 mol) of 88% formic acid are then added at a temperature of about 15 ° C. After dissolution of thebaine, the reaction mixture was warmed to 20 ° C, and 44.0 mL (0.17 mol) of 30% hydrogen peroxide was added. And the reaction mixture was stirred at 25 ° C (conversion of thebaine was monitored by capillary electrophoresis, conditions set forth in Example 1). The reaction mixture is cooled to 5 ° C by addition of ammonium hydroxide, the pH is adjusted to 9.5, the resulting suspension is extracted with toluene-n-butanol 97: 3 (2 x 120 ml), the combined extracts are washed with water, organic concentrate to 100 ml, extract the residue with aqueous formic acid solution (250 ml, 15%), treat the acidic aqueous phase with carboraffin and, after stirring for 30 minutes, filter through diatomaceous earth, cool the filtrate to 5 ° C by adding of concentrated ammonium hydroxide is adjusted to pH 9.1, the precipitated 14-hydroxycodeinone is filtered off, washed with cold water, acetone-water (1: 1) and dried under reduced pressure. This procedure yielded 78.2 g of 14-hydroxycodeinone, dry matter 99.86% content - 98.8%, tebaine 0.19%.

Industrial usability

The present invention is useful in the preparation of an intermediate in the manufacture of a pharmaceutical substance oxycodone or morphine antagonists used in medical practice.

Claims (4)

PATENT CLAIMS A process for the isolation of 14-hydroxycodeinone from a reaction mixture after the conversion of thebaine or its analogs by oxidation with hydrogen peroxide or peracids, characterized in that the pH of the reaction mixture is adjusted to 9-10 by addition of ammonium hydroxide at 0-10 ° C. the precipitated 14-hydroxycodeinone base is extracted with an organic solvent, the organic extract is separated or concentrated, the 14-hydroxycodeinone is extracted with an aqueous solution of organic acid, the acidic aqueous layer containing 14-hydroxycodeinone is separated, the pH of the solution is adjusted to 9 by addition of ammonium hydroxide. 0-10 and the precipitated 14-hydroxycodeinone is separated, washed with water and acetone-water and dried. Process for the isolation of 14-hydroxycodeinone according to claim 1, characterized in that dichloromethane, toluene or a mixture thereof with lower alcohols having a carbon number of 3 to 5 is used as the organic solvent in the extraction. The process for the isolation of 14-hydroxycodeinone according to claim 1, characterized in that an aqueous solution of formic or acetic acid is used as the 5 aqueous solution of the organic acid for the extraction of 14-hydroxycodeinone. A process for the isolation of 14-hydroxycodeinone according to claim 2, characterized in that the volume ratio of dichloromethane or toluene to a lower alcohol having a carbon number of 3 to 5 is 99: 1 to 9: 1.