SK286047B6 - Method for the preparation of 4,5alpha-epoxy-6-oxomorphinane derivatives - Google Patents

Abstract

Method for the preparation of 4,5alpha-epoxy-6-oxomorphinane of the formula (I), wherein R1 is hydrogen, methyl or hydroxyl protective group, R2 is hydrogen, methyl, cyclobutylmethyl, benzyl or allyl and R3 is hydrogen or hydroxyl, consisting in the compounds of the formula (II), wherein R1, R2, R3 having the same meaning as at compounds (I), are isomerizated to compounds of the formula (I) by action of blending catalyst comprising at least two elements from the platinoids group.

Description

Technical field

The invention relates to a novel process for the preparation of 4,5α-epoxy-6-oxomorphinan derivatives of formula (I) wherein R ¹ is hydrogen, methyl, or a hydroxyl protecting group, R ² is hydrogen, methyl, cyclobutylmethyl, benzyl, or allyl and R ³ is hydrogen or hydroxyl from 7,8-dehydro-4,5-epoxymorphinan derivatives of formula (II) wherein R ¹ , R ² and R ³ are as defined for compounds I.

BACKGROUND OF THE INVENTION

Of the 4,5a-epoxy-6-oxomorphinan derivatives, hydrocodone (I, R ¹ R ² = methyl, R ³ = H) and hydromorphone (I, R ¹ , R ³ = H, R ² = methyl) are most commonly used in medical practice. ). Hydrocodone acts primarily as an antitussive, less than an analgesic agent; it works directly at the center of the cough reflex, and is 2 to 8 times more potent than codeine (AMA Drug Evaluations, 6th ed. American Medical Association, Chicago, 1986). It is 6-8 times more potent than codeine as an analgesic (Ar. Intem. Med. 77, 1984, 38; Curr. Ther. Res. 24, 1978, 503). Hydromorphone is a powerful analgesic agent 7 to 8 times more potent than seas (AMA Drug Evaluations, 5th ed. American Medical Association, Chicago, 1983).

Several processes for the preparation of hydrocodone and hydromorphone have been described. One of them utilizes catalytic hydrogenation of codeine / morphine and subsequent oxidation of dihydrocodeine / dihydromorphine to the desired product. The oxidation of dihydrocodeine to hydrocodone with chromium salts (VI) is the subject of DE 415097; the Oppenauer oxidation of dihydrocodeine / dihydromorphone to the corresponding oxo compounds in the presence of e.g. alkylaryl ketones with catalysis of aluminum t-butanolate in a maximum yield of 40% (US 2,628,962, US 2,654,756), aluminum phenolate in a yield of 60% (US 2,715,626) and in the presence of potassium t-butanolate in benzene with a yield of 71-83% (US 2,649,454). Hydrocodone was also prepared by oxidation of dihydrocodeine with silver carbonate (yield 75%; J. Heterocyclic Chem. 13, 1976, 525). The procedure with the altered sequence of the 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 the codeinone is hydrogenated to hydrocodone. Codeinone can also be prepared from codeine by Swem 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 processes used hitherto, hydrocodone / hydromorphone is prepared from codeine / morphine by a two-step synthesis with low selectivity and in relatively low yields.

Another method is the catalytic rearrangement of codeine / morphine to hydrocodone / hydromorphone. German patents DE 365 683 and DE 380 919 disclose a process for the preparation of hydrocodone / hydromorphone by catalytic treatment of free palladium or platinum in an acidic aqueous medium in the presence of hydrogen. DE 607 931 and DE 617 238 describe a similar process, but in the absence of hydrogen, with yields of 40 to 95%. Isomerization by means of palladium resp. Platinum black in ethanol is the subject of DE 623 821, with yields of alkaloid ketones of 60 to 70%. The disadvantage of these processes is low selectivity, e.g. in addition to hydromorphone 30-35% of O-demethyl-dihydrotebainone is also formed (J. Am. Pharm. Soc. 40, 1951, 580; Pharmazie 10, 1955, 180).

U.S. Pat. No. 2,544,291 discloses a process for preparing hydrocodone from codeine in aqueous sulfuric acid by isomerization to palladium on carbon. After completion of the reaction, the reaction mixture is basified, the product is extracted with benzene, from which it is purified by reextraction into an aqueous 10% sodium bisulfite solution. Adjusting the pH of this solution precipitates the crude hydrocodone. The crude base is further purified by chromatography on alumina. A similar principle is also used in US 2,577,947, wherein hydrocodone bisulfite is precipitated from a benzene extract of a reaction mixture containing hydrocodone by treatment with sodium sulfite. The separated hydrocodone bisulfite sodium salt is recrystallized from water and subsequent alkalization liberates the hydrocodone base. The yield is 40%.

US 6 512 117 discloses a process for the preparation of hydrocodone / hydromorphone which is again based on the principle of the foregoing procedures. The codeine / morphine is stirred in an acidic aqueous medium in the presence of palladium metal and the resulting product is purified through a bisulfite adduct. The yields of hydromorphone hydrochloride in the present examples range from 23 to 30%. U.S. Patent No. 6,589,960 describes a similar process, claiming a defined impurity profile in the hydromorphone thus obtained.

In all of the aforementioned patents, the isomerization of opium alkaloids is catalyzed by metallic free or grounded palladium or platinum. A more recent process is described in EP 0 915 884, in which hydrocodone / hydromorphone is prepared by isomerization in the presence of organometallic complexes in a single-phase homogeneous system. The reaction is carried out in an anhydrous environment in the presence of Rh (I) phosphane complexes. Crude hydrocodone was obtained in 83% yield, hydromorphone only 35%.

Isomerizations of allylic alcohols to ketones have been studied on various types of compounds using the parent complexes as catalysts (CR Hebd. Seances Acad. Sci. Ser. C 282, 1976, 65; J. Chem. Soc. Dalton Trans., 1984, 219). Tetrahedron Lett. 25, 1984, 769), ruthenium (CR 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).

SUMMARY OF THE INVENTION

The subject of the patent is a process for the preparation of 4,5α-epoxy-6-oxomorphinan derivatives of formula (I) wherein R ¹ is hydrogen, methyl, or hydroxyl protecting group, R ² is hydrogen, methyl, cyclobutylmethyl, benzyl, or allyl and R ³ is hydrogen or hydroxyl from 7,8-dehydro-4,5-epoxymorphinan derivatives of formula (II) wherein R ¹ , R ² and R ³ are as defined for compounds I in the presence of a mixed platinum group catalyst.

(I)

By hydroxyl protecting group is meant a group commonly used to protect the hydroxyl group of phenols such as t-butyl, benzyl, methoxymethyl, methoxythiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, benzoyl, mesitoyl, methyloxycarbonyl.

The compounds of formula (I) are reacted in the form of a base or in the form of salts with mineral or organic acids. The process takes place in an aqueous medium or a mixture of water and a water miscible solvent such as methanol, ethanol, tetrahydrofuran, acetonitrile and in the presence of acids such as sulfuric, hydrochloric, phosphoric, formic, acetic and the like, at a temperature ranging from ambient 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 under an inert atmosphere.

The catalyst used in the process comprises a mixture of at least two elements from the group of platinum metals (palladium, platinum ruthenium, rhodium, iridium), preferably palladium and ruthenium. Said elements are present in the form of metals (oxidation number 0), which is free or bound to a carrier, in the form of salts, preferably in the form of halides, or in a combination of these forms.

Upon completion of the isomerization, the soluble forms of the catalyst are removed from the reaction mixture by reduction with hydrogen or another reducing 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 worked up to the product by methods known in the art.

The advantage of this procedure is that it uses low concentrations of catalyst, the reaction being carried out with high selectivity. This method makes it possible to obtain a product with a low content of impurities in low yields well above those described in the prior art by simple isolation procedures.

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Dissolve the codeine base (20 g, 66.8 mmol) in aqueous sulfuric acid (4.5%, 130 mL) in the flask. After dissolving the codeine at elevated temperature, add 10% Pd / C (1.42) to the flask. g) and 5% Ru / C (2.21 g). The mixture was heated to reflux under a nitrogen atmosphere for 3 h. After the isomerization is complete, the flask is purged with hydrogen and the reaction mixture is subsequently stirred under a hydrogen atmosphere at 50 ° C for 1 h. The cooled reaction mixture is filtered, the pH of the filtrate is adjusted to 10-10.5, the precipitate is collected and dried. The crude hydrocodone base (16.1 g; 74% yield) was obtained as a light brown powder.

The hydrocodone base is dissolved hot in ethanol, the solution is decolorized with charcoal and the pure hydrocodone base is crystallized by gradual cooling to 10 ° C, which is collected by filtration, then dissolved in ethanol and 50% aqueous hot is added thereto. tartaric acid solution. After cooling, the mixture was filtered and the obtained crystal was dried. Hydrocodone bitartrate hemipentahydrate (18.9 g; yield 58%) was obtained as a white crystalline solid (HPLC content 99.82 area%).

Example 2

Dissolve codeine base (20 g, 66.8 mmol) in dilute sulfuric acid (5.5%, 100 mL) at 30-40 ° C in a flask and add PdCl ₂ (0.1 M, 3) to the solution. , 35 mL) and a solution of RuCl ₃ (0.1 M, 2.5 mL). The mixture was heated to reflux under a nitrogen atmosphere for 3 h, after completion of the reaction, the flask was flushed with hydrogen and the reaction mixture was subsequently stirred under a hydrogen atmosphere at 50 ° C for 1 h, cooled, filtered, , 6 g) and the pH of the solution was adjusted to 6.0, sodium disulfide solution (0.25 M, 9.4 mL) was added and the mixture was heated to reflux for 1 h. The suspension is filtered and the pH of the filtrate is adjusted to 10.0-10.5. The precipitate was filtered off, washed with water and dried. The crude hydrocodone base was obtained (18.8 g; yield 92%). The crude hydrocodone base is dissolved hot in ethanol, the solution is decolorized with charcoal and, by gradual cooling to 10 ° C, the pure hydrocodone base crystallizes and is filtered off. The pure hydrocodone base is dissolved hot in ethanol, hot 50% tartaric acid in water is added, the mixture is cooled, the precipitated crystal is filtered off and dried. Hydrocodone bitartrate hemipentahydrate (23.0 g; yield 70%) was obtained as a white crystalline solid (HPLC content 99.91 area%).

Example 3

Dissolve morphine sulfate pentahydrate (10 g, 26.36 mmol) in dilute sulfuric acid (2%, 50 mL), add a solution of PdCl ₂ (0.1 M, 2.6 mL) and 5% Ru / L at elevated temperature. C (0.49 g). The mixture was heated to reflux under a nitrogen atmosphere for 3 h. The flask was purged with hydrogen and the reaction mixture was subsequently stirred under a hydrogen atmosphere at 50 ° C for 3 h. The cooled reaction mixture was filtered, ethanol (10 mL) was added to the filtrate, and the pH of the filtrate was adjusted to 10-10.5. The precipitated substance was filtered off and dried. The hydromorphone base (6.65 g; yield 84%) was dissolved in hot ethanol (90%), the solution was decolourised with charcoal, filtered and concentrated hydrochloric acid (2.3 ml) was added to the filtrate. The mixture is cooled to 10 ° C, the precipitated crystal is filtered off and the product is dried. Hydromorphone hydrochloride (5.6 g; yield 75%; HPLC content 99.75% area) was obtained.

Example 4

A 250 mL round bottom flask equipped with a magnetic stirrer and nitrogen inlet was charged with water (200 mL) and sulfuric acid (4.5 mL of 96% H ₂ SO ₄ ). Codeine (25 g; 83.6 mmol) was added gradually with stirring and stirred under N ₂ atmosphere for 15 min. To this solution was added a solution of RuCl ₃ in methanol (9 mL; 0.046 M) and 10% Pd / C (0.8 g). The flask is closed and immersed in an oil bath heated to 100-105 ° C. The reaction mixture was stirred slowly for 3 h. After completion of the reaction (HPLC), the contents of the flask were cooled, purged with hydrogen and stirred for 30 min under a hydrogen atmosphere. Then the catalyst is filtered off, the filtrate is cooled to 6-10 ° C and the pH is adjusted to 9.0-9.1 with concentrated aqueous ammonia solution. The crude product is filtered off and washed with 2 x 50 ml of ice water, dried at 30-40 ° C under reduced pressure. Dissolve the crude base in hot in 300 mL of ethyl acetate, purify with activated charcoal (2 g), filter the suspension, concentrate the filtrate under reduced pressure to about 100 mL and allow to crystallize. Separation and drying of the crystal yielded 18.5-19 g (74-76%) of white crystalline dihydrocodeinone with m.p. Mp 198-199 ° C.

Industrial applicability of the invention

The production of the compounds of formula (I) according to the present invention represents a substantial advantage in terms of cost and environmental burden over known processes. The compounds of formula (I) are suitable for the manufacture of pharmaceutical preparations with analgesic and antitussive effects.

Claims (8)

A process for the preparation of 4,5α-epoxy-6-oxomorphinan derivatives of formula (I) wherein R ¹ is hydrogen, methyl, or hydroxyl protecting group, R ² is hydrogen, methyl, cyclobutylmethyl, benzyl, or allyl and R ³ is hydrogen or hydroxyl, characterized in that the compounds of formula (II), wherein R ¹ , R ² , Ŕ ³ have the same meaning as for the compounds I, are isomerized in the presence of a mixed catalyst containing at least two platinum group elements. Process according to claim 1, characterized in that the mixed catalyst used comprises at least two elements from the group of palladium, platinum ruthenium, rhodium, iridium. 3. A process according to claim 1, wherein the individual components of the mixed catalyst are present in free form, anchored on a carrier, in the form of salts, or in a combination thereof. Process according to claim 1, characterized in that the mixed catalyst used contains palladium and ruthenium. A process according to claim 4, characterized in that the palladium is present in the form of a halide or carbon-bound. The process of claim 4, wherein the ruthenium is present in the form of a halide or carbon-bound. The process according to claim 5, characterized in that the palladium is present in the form of palladium chloride or carbon-bound. The process according to claim 6, wherein the ruthenium is present in the form of ruthenium chloride or bound to carbon.