SK3952004A3 - 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

Technical field

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

HjCO.

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 process (Scheme 1), thebaine (II), or an analogue thereof in an acidic environment, reacts with hydrogen peroxide, peracids, or other oxidizing agents to form 14β-hydroxycodeinone (I).

IU R = CH 2 C 6 H 5 or C 11 H 11 + 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 aqueous hydrochloric acid, 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 mixture of 2-propanol and heptane and dried.

According to Krassnig et al. (Arch.Pharm.Pharm.Med.Chem. 329, 325-6 (1996)) the reaction mixture was poured onto ice after transformation 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).

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And. * 3

- ,, ·> ··· 1 m

X 1 í _Λ X. , « ₃ -» »»

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 from the reaction mixture after precipitation, 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), except that the latter authors dissolved crude 14-hydroxycodeinone in chloroform and crystallized the product by adding ethanol.

According to Feldman and Liutenberg (Ch. Ex.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 stebaine or analogs thereof, 14hydroxycodeinone is contaminated with related substances, such as e.g. 10-hydroxytebaine, 10,14-dihydroxycodeinone, difficult to separate byproducts and the like, which are not removed by these processes but are carried forward to the next stages of the preparation of Oxycodone and thus reduce the quality of the product and / or the product. for further purification, in the final step, they reduce the overall yield of the process, and provide 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 thereof of formula (II) wherein R is C ₂ -C 5 alkyl, preferably alkylaryl benzyl, or methoxybenzyl, allyl,

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 C-3 to C-5, the organic extract is separated and concentrated. The 14-hydroxycodeinone is extracted with an aqueous solution of an organic acid, e.g. form or vinegar. The acidic aqueous layer containing 14-hydroxycodeinone is separated, the pH of the solution is adjusted to 9.0 to 9.5 by 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.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Dissolve 10.0 g of tebaine (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. mixture of 4.6 g of formic acid 88% (101.3 mmol) and 4.4 ml of 30% hydrogen peroxide (43.14 mmol) The reaction mixture was stirred at 25 ° C until complete conversion of the thebaine (evaluated capillary 50 cm x 0.05 mm, electrolyte 100 mM TRIS / phosphate, pH 2.7, 5 mM dimethoxy-β-cyclodextrin, 25 ° C 30 kV; tebain migration time 5.6 min). After completion of the reaction, the reaction mixture was cooled to 5 ° C and horses were added. ammonium hydroxide to pH 9.2. The resulting suspension was extracted with dichloromethane (100 mL), the organic phase was 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 with 25% ammonium hydroxide, extracted with toluene (100 mL), washed with water, saturated NaCl, and extract with aqueous acetic acid solution (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 is 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 procedure 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 (evaluated

capillary electrophoresis). The reaction mixture was cooled to 10 ° C and the addition of horse. The pH of the ammonium hydroxide was adjusted to 9.2, and the suspension was extracted with toluene 2-propanol (94: 6) 2 x 250 ml. The combined organic phases were washed with water and a saturated aqueous NaCl solution. The organic layer was extracted with aqueous formic acid solution (100 mL in 1500 mL of water), the acidic aqueous extract was treated with charcoal, filtered through diatomaceous earth, the filtrate was cooled to 5 ° C, precipitated by addition of concentrated ammonium hydroxide to pH 9.5. -Hydroxykodeinon. The precipitated crystals are filtered off, washed with cold water and finally with acetone-water (1: 1) and dried under vacuum at 50 ° C. This gives 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. Then, 23.0 g (0.44 mol) of 88% formic acid are added, at a temperature of about 15 ° C. mol) of 30% hydrogen peroxide. 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 9.2, 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, 99.86% solids content - 98.8%, thebaine 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 (5)

PATENT CLAIMS Process for isolating 14-hydroxycodeinone from the reaction mixture after the conversion of thebaine or its analogs is complete, characterized in that the pH of the reaction mixture is adjusted to 9-10 by addition of a base, the precipitated 14-hydroxycodeinone base is extracted with an organic solvent, the organic extract is separated. optionally concentrate, the 14-hydroxycodeinone is extracted with an aqueous organic acid solution, the acidic aqueous layer containing 14-hydroxycodeinone is separated, the pH of the solution is adjusted to 9.0-10 by addition of a base, and the precipitated 14-hydroxycodeinone is separated, washed with water and acetone- water and dried. A process for the isolation of 14-hydroxycodeinone according to claim 1, characterized in that ammonium hydroxide is used as the base. Process for the isolation of 14-hydroxycodeinone according to claim 1, characterized in that dichloromethane, toluene or a mixture thereof with lower alcohols having carbon numbers of C-3 to C-5 is used as the organic solvent in the extraction. A 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 aqueous solution of the organic acid for the extraction of 14-hydroxycodeinone. A process for the isolation of 14-hydroxycodeinone according to claims 1 and 3, characterized in that the ratio of dichloromethane or toluene to the lower alcohol having a carbon number of C-3 to C-5 is 99: 1 to 9: 1.