WO2005100361A1

WO2005100361A1 - A METHOD OF PREPARATION OF 4,5α-EPOXY-6-OXOMORPHINAN DERIVATIVES

Info

Publication number: WO2005100361A1
Application number: PCT/SK2005/000008
Authority: WO
Inventors: Dusan Vandak; Dusan Berkes; Andrej Kolarovic; Milan Marko
Original assignee: Zentiva, A.S.
Priority date: 2004-04-13
Filing date: 2005-04-07
Publication date: 2005-10-27
Also published as: SK286047B6; CZ297571B6; SK1762004A3; CZ2005210A3

Abstract

A method of preparation of 4,5α-epoxy-6-oxomorphinan derivatives of formula (I), wherein R1 is hydrogen, methyl, or ethyl and R2 is hydrogen, methyl, cyclobutylmethyl or benzyl, in which compounds of formula (II), wherein R1 and R2 are as defined with respect to compounds (I), are isomerized into compounds of formula (I) in the presence of a mixed catalyst containing at least two elements from the group of platinum metals. The method provides the product in high yield and with low contents of impurities.

Description

A method of preparation of 4,5α-epoxy-6-oxomorphman derivatives

Technical Field

The invention relates to a new method of preparation of derivatives of 4,5α-epoxy-6- oxomorphinan of formula I, wherein R¹ is hydrogen, methyl or ethyl, R² is hydrogen, methyl, cyclobutylmethyl, or benzyl, from derivatives of 7,8-dehydro-4,5-epoxymorphinan of formula 1 -^

II, wherein R and R are as defined with respect to compounds I.

II

Background Art

Hydrocodone (I, R¹ R² = methyl) and hydromorphone (I, R¹ = H, R² = methyl) are the most frequently used derivatives of 4,5α-epoxy-6-oxomorphinan in general medical practice. Hydrocodone acts especially as an antitussive agent, less as an analgesic agent; it acts directly in the center of the coughing reflex and it is 2 — 8 times more effective than codeine (AMA Drug Evaluations, 6th ed. American Medical Association, Chicago, 1986). As an analgesic, it is 6 - 8 times more effective than codeine (Arch. Intern. Med. 77, 1984, 38; Curr. Ther. Res. 24, 1978, 503). Hydromorphone is a strong analgesic agent, 7 - 8 times more effective than morphine (AMA Drug Evaluations, 5th ed. American Medical Association, Chicago, 1983). Several methods of preparation of hydrocodone and hydromorphone have been described so far. One of them uses catalytic hydrogenation of codeine/morphine and subsequent oxidation of dihydrocodeine/dihydromorphine to the desired product. Oxidation of dihydroco- deine to hydrocodone with chromium (VI) salts is the subject of DE 415097; Oppenauer oxidation of dihydrocodeine/dihydromorphone to the respective oxo compounds in the presence of, for example, alkyl aryl ketones catalyzed with aluminium t-butanolate with the yield of max. 40 % (US 2,628,962, US 2,654,756), aluminium phenolate with the 60 % yield (US 2,715,626) and in the presence of potassium t-butanolate in benzene with the yield of 71 to 83 % (US 2,649,454) has been known. Hydrocodone was prepared also by oxidation of dihydro- codeine with silver carbonate (75% yield; J. Heterocyclic Chem. 13, 1976, 525). A process with changed sequence of reaction steps is described in US 2,654,756. In the first step, codeinone is obtained by Oppenauer oxidation of codeine, in the second step, codeinone is hydro- genated to hydrocodone. Codeinone can be prepared from codeine also by Swern oxidation in the presence of dimethylsulfoxide and oxalyl chloride at -78 °C (US 6,008,355), or by oxidation with silver carbonate (J. Am. Chem. Soc. 77, 1955, 490). In all the so-far described methods, hydrocodone/hydromorphone is prepared from codeine/morphine by a two-step synthesis with low selectivity and in relatively low yields. Another method involves catalytic rearrangement of codeine/morphine to hydrocodone/hydromorphone. German patents DE 365 683 and DE 380 919 describe a method of preparation of hydrocodone/hydromorphone by catalytic action of free palladium or platinum in an acidic aqueous environment in the presence of hydrogen. Documents DE 607 931 and DE 617238 describe a similar method, but without the presence of hydrogen, with yields 40 to 95 %. Isomerization by means of palladium or platinum black in an ethanol environment is described in patent DE 623 821, with yields of alkaloid ketones 60 to 70 %. These methods have a disadvantage of low selectivity, for example 30-35% of O-desmethyldihydrothebainone is formed in addition to hydromorphone (J. Am. Pharm. Soc. 40, 1951, 580; Pharmazie 10, 1955, 180). Patent US 2,544,291 describes a method of preparation of hydrocodone from codeine in aqueous sulfuric acid by isomerization on palladium anchored on charcoal. After the reaction is complete, the reaction mixture is alkalized, the product is extracted with benzene, from which it is refined by re-extraction with an aqueous 10% solution of sodium hydrogen sulfite. Crude hydrocodone is precipitated by adjustment of pH of the solution. The crude base is further purified chromatographically on aluminium oxide. US 2,577,947 uses a similar principle wherein hydrocodone bisulfite is precipitated from the benzene extract of the reaction mixture, which contains hydrocodone, with sodium sulfite. The separated sodium salt of hydrocodone bisulfite is re-crystallized from water and the hydrocodone base is released by subsequent al- kalization. The yield of the process is 40 %. US 6,512,117 describes a method of preparation of hydrocodone/ hydromorphone that is again based on the principle of the previous methods. Codeine/morphine is stirred in an acidic aqueous environment in the presence of metallic palladium and the resulting product is purified via the bisulfite adduct. Yields of hydromorphone hydrochloride in the mentioned examples range from 23 to 30 %. Patent US 6,589,960 describes a similar method, while claiming a defined profile of impurities in hydromorphone obtained in this way. In all the mentioned patents, isomerization of opium alkaloids is catalyzed with metallic free or anchored palladium, or platinum. A newer method is described in EP 0 915 884, in which hydrocodone/hydromorphone is prepared by isomerization in the presence of or- ganometallic complexes in a single-phase homogenous system. The reaction takes place in an anhydrous environment in the presence of phosphane complexes of Rh(I). Crude hydrocodone was obtained in the yield of 83 %; that of hydromorphone was only 35 %. Isomerizations of allyl alcohols to ketones were studied in various types of compounds, whereas the reactions were catalyzed with complexes of rhodium (C. R. Hebd. Seances Acad. Sci. Ser. C 282, 1976, 65; J. Chem. Soc. Dalton Trans., 1984, 219; Tetrahedron Lett. 25, 1984,769), ruthenium (C. R. Hebd. Seances Acad. Sci. Ser. C 278, 1974, 9; Tetrahedron Lett. 34, 1993, 5459; J. Org. Chem. 10, 2001, 3141; Chem. Commun., 2004, 232.), molybdenum (J. Organomet. Chem. 251, 1983, 321), or iron carbonyls (Synth. Commun. 19, 1989, 2955; Tetrahedron 57, 2001, 2379).

Disclosure of Invention

This patent provides a method of preparing derivatives of 4,5α-epoxy-6-oxomorphinan of formula I, wherein R¹ is hydrogen, methyl or ethyl and R² is hydrogen, methyl, cyclobutylmethyl or benzyl, from derivatives of 7,8-dehydro-4,5-epoxymorphinan of formula II, wherein R and R are as defined with respect to compounds I, in the presence of a mixed catalyst from the group of platinum metals.

II

The compounds of formula I enter the reaction in the form of a base, or in the form of salts with mineral or organic acids. The process takes place in an aqueous environment, or in an environment of a mixture of water with a water-miscible solvent such as methanol, ethanol, tetrahydrofuran, acetonitrile, and in the presence of acids such as sulfuric acid, hydrochloric acid, phosphoric acid, formic acid, acetic acid, and the like, at temperatures ranging from room temperature to the boiling point of the solvent, preferably at the boiling point of the solvent, for 0.25 h to 10 h, preferably for 0.5 h to 3 h, preferably in an inert atmosphere. A hydroxyl protecting group may be used. i.e. a group commonly used to protect the hydroxyl group of phenols, such as for example t-butyl, benzyl, methoxymethyl, meth- oxythiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, benzoyl, mesitoyl, methyloxycar- bonyl. The catalyst used in the process contains a mixture of at least two elements from the group of platinum metals (palladium, platinum, ruthenium, rhodium, iridium), preferably palladium and ruthenium. The mentioned elements are present in the form of metals (oxidation number 0), which are free or bound onto a carrier, in the form of salts, preferably halides, or of a combination of these forms. After completion of the isomerization, the soluble forms of the catalyst are removed from the reaction mixture by reduction with hydrogen, or another reduction agent, or by precipitation of metals in the form of an insoluble salt, for example sulfide, sulfite or iodide. After separation of the catalyst, the reaction mixture is processed to the product using methods known in the art. The method as described herein has the advantage of using low concentrations of the catalyst, while the reaction proceeds with high selectivity. The method allows to obtain the product having low content of impurities in yields highly exceeding those described in the art by low-demanding isolation procedures. The following examples describe in more detail the method of executing the invention; however, they do not limit the extent of the invention in any respect.

Examples

Example 1

In a flask, codeine base (20 g, 66.8 mmol) is dissolved in aqueous sulfuric acid (4.5 %, 130 ml); after codeine has dissolved, 10 % Pd/C (1.42 g) and 5 % Ru/C (2.21 g) axe further added to the flask at increased temperature. The mixture is heated until reflux under nitrogen atmosphere for 3 hours. After completion of isomerization, the flask is flushed with hydrogen and the reaction mixture is subsequently stirred in hydrogen atmosphere at 50 °C for 1 h. The cooled reaction mixture is filtered, pH of the filtrate is adjusted to 10 - 10.5, the precipitated substance is separated and dried. Crude hydrocodone base is obtained (16.1 g; yield 74 %) in the form of a light brown powder.

The hydrocodone base is dissolved in hot ethanol, the solution is decoloured with active carbon, and by gradual cooling down to 10 °C pure hydrocodone base is crystallized, which is separated by filtration, then dissolved in ethanol and a 50% aqueous solution of tartaric acid is added when hot. After cooling down, the mixture is filtered and the obtained crystals are dried. Hydrocodone bitartrate hemipentahydrate is obtained (18.9 g; yield 58 %) in the form of a white crystalline substance (HPLC content 99.82 area %). Example 2

In a flask, codeine base (20 g, 66.8 mmol) is dissolved in diluted sulfuric acid (5.5 %, 100 ml) at 30 - 40 °C, a solution of PdCl₂ (0.1 M, 3.35 ml) and a solution of RuCl₃ (0.1 M, 2.5 ml) are added to the solution. The mixture is heated until reflux under nitrogen atmosphere for 3 hours, after completion of the reaction, the flask is flushed with hydrogen and the reaction mixture is subsequently stirred in hydrogen atmosphere at 50 °C for 1 h, the mixture is cooled down, filtered, and sodium pyrosulfite (1.6 g) is added to the filtrate and pH of the solution is adjusted to 6.0, a solution of sodium disulfide (0.25 M, 9.4 ml) is added and the mixture is heated until reflux for 1 hour. The suspension is filtered and pH of the filtrate is adjusted to 10.0 - 10.5. The precipitate is filtered off, washed with water and dried. Crude hydrocodone base is obtained (18.8 g; yield 92 %). The crude hydrocodone base is dissolved in hot ethanol, the solution is decoloured with active carbon, and by gradual cooling down to 10 °C pure hydrocodone base is crystallized, which is separated by filtration. The pure hydrocodone base is dissolved in hot ethanol, hot 50% aqueous solution of tartaric acid is added, the mixture is cooled down, and the precipitated crystals are filtered off and dried. Hydrocodone bitartrate hemipentahydrate is obtained (23.0 g; yield 70 %) in the form of a white crystalline substance (HPLC content 99.91 area %).

Example 3

Morphine sulfate pentahydrate (10 g; 26.36 mmol) is dissolved in diluted sulfuric acid (2 %, 50 ml), at increased temperature a solution of PdCl₂ (0.1 M, 2.6 ml) and a solution of 5 % Ru/C (0.49 g) are added. The mixture is heated until reflux under nitrogen atmosphere for 3 hours. The flask is flushed with hydrogen and the reaction mixture is subsequently stirred in hydrogen atmosphere at 50 °C for 3 h. The cooled reaction mixture is filtered, ethanol (10 ml) is added to the filtrate, pH of the filtrate is adjusted to 10 - 10.5. The precipitated substance is separated and dried. The hydrocodone base is obtained (6.65 g; yield 84 %), which is dissolved in hot 90% ethanol, the solution is decoloured with active carbon, filtered, and concentrated hydrochloric acid (2.3 ml) is added to the filtrate. The mixture is cooled down to 10 °C, the precipitated crystals are filtered out and dried. Hydromorphone hydrochloride is obtained (5.6 g; yield 75 %, HPLC content 99.75 area %). Example 4

Water (200 ml) and sulfuric acid (4.5 ml 96 % H₂SO₄) are placed in a 250-ml flask with round bottom equipped with a magnetic stirrer and nitrogen inlet. Codeine (25 g; 83.6 mmol) is gradually added with stirring and the mixture is stirred under N₂ atmosphere for 15 min. A solution of RuCl₃ in methanol (9 ml; 0.046 M) and 10% Pd/C (0.8 g) are added to thus prepared solution. The flask is sealed and immersed in an oil bath heated to 100-105 °C. The reaction mixture is slowly stirred for 3 hours. After the reaction is complete (HPLC), the content of the flask is cooled down, the flask is flushed with hydrogen and the reaction mixture is stirred under hydrogen atmosphere for another 30 min. Then the catalyst is filtered off, the filtrate is cooled down to 6-10 °C, and pH is adjusted with a concentrated aqueous solution of ammonia to 9.0-9.1. The crude product is filtered off and washed with 2 x 50 ml of ice-cold water, dried at 30 - 40 °C under reduced pressure. The crude base is dissolved in 300 ml of hot ethyl acetate, purified with active carbon (2 g), the suspension is filtered, and the filtrate is concentrated under reduced pressure to a volume of about 100 ml and let to crystallize. After the crystals are separated and dried, 18.5 to 19 g (74 to 76 %) of white crystalline dihydrocodeinone having b.p. 198-199 °C are obtained.

Industrial applicability

Manufacture of compounds of formula I according to the present invention represents a significant advantage with respect to economic demand factor and environmental burden compared to known methods. Compounds of formula I are useful for the production of pharmaceuticals having analgesic and antitussive effects.

Claims

C L A I M S

1. A method of preparation of 4,5α-epoxy-6-oxomorphinan derivatives of formula I, • 1 1 wherein R is hydrogen, methyl, or ethyl and R is hydrogen, methyl, cyclobutylmethyl or benzyl, characterized in that compounds of formula II, wherein R¹ and R are as defined with respect to compounds I, are isomerized in the presence of a mixed catalyst containing at least two elements from the group of platinum metals.

II

2. The method according to claim 1, characterized in that isomerization is carried out in an aqueous environment, or in an environment of a mixture of water with a water- miscible solvent, in the presence of an acid, at temperatures ranging from room temperature to the boiling point of the solvent, for 0.25 h to 10 h.

3. The method according to claim 1, characterized in that the mixed catalyst used contains at least two elements from the group including palladium, platinum, ruthenium, rhodium and iridium.

4. The method according to claim 1, characterized in that individual components of the mixed catalyst are present in the free form, bound to a carrier, in the form of salt, or in a combination of these forms.

5. The method according to claim 1, characterized in that the mixed catalyst used contains palladium and ruthenium.

6. The method according to claim 5, characterized in that palladium is present in the form of a halide, or bound to charcoal.

7. The method according to claim 5, characterized in that ruthenium is present in the form of a halide, or bound to charcoal.

8. The method according to claim 6, characterized in that palladium is present in the form of palladium (II) chloride, or bound to charcoal.

9. The method according to claim 7, characterized in that ruthenium is present in the form of ruthenium (III) chloride, or bound to charcoal.