NL7920126A - METHOD FOR PREPARING OXYMORPHON. - Google Patents

Description

7 9 2 0 1 2 6 VO 526

Title: Method for the preparation of oxymorphone.

This oxymorphone is a narcotic and is widely used as an analgesic. The most commonly used method for preparing oxymorphone is described by Seki in Takamine Kerikyiskho Nempo, 12, 52 (1960); pyridine hydrochloride is reacted with oxycodone at high temperatures. This method has disadvantages on a technical scale, because the reaction is difficult to control and high temperatures are required. Furthermore, only moderate yields are thus obtained, while relatively large amounts of by-products are formed.

The invention now relates to a process for preparing oxymorphone in good yields with virtually no by-products.

Thereby, the oxycodone-methoxy group is selectively demethylated without affecting other sites of the oxycodone molecule.

According to the invention, the methyl group of the methoxy group of oxycodone is selectively removed by reacting this oxycodone with a demethylating amount of a demethylating agent under demethylation conditions in the presence of a softening amount of a control agent to mitigate the activity of the demethylating agent, thereby oxymorphone in good yields and without by-products.

Appropriate demethylating agents are boron compounds which can demethylate the methoxy group but do not form by-products. Such boron compounds are e.g. boron trichloride, boron trichloride or the reaction products of these halides with alcohols, preferably with 1-10 carbon atoms. Preferably, alcohols with up to 6 carbon atoms, such as methanol, propanol, butanol and hexanol, are used.

Control agents are present in the reaction medium during the reaction to mitigate the activity of the boron compounds to produce good yields of oxymorphone without clearly producing by-product. As control agent, weak Lewis bases are preferably used, which do not react chemically with the demethylating agent. Beneficial regulators are e.g. liquid aromatics that do not chemically react with the boron compound, such as benzene, toluene, xylene, ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ether and mixtures thereof. Chlorobenzene is 7920126-2- the preferred regulating agent. A controlling amount of charvan is 25-900% by weight, based on the weight of the boron compound.

Preferably, a demethylation combination containing a boron compound in an amount sufficient to demethylate the methoxy group of oxycodone is used, e.g. 5-20%, most preferably about 10%, based on the total weight of the demethylating composition, as well as a controlling amount of a mitigating agent, e.g. 80-95, most preferably about 90% by weight, based on the total weight of the demethylating composition.

Oxymorphone is reacted with this demethylating preparation under demethylating conditions. This includes the use of a demethylating amount of the demethylating agent, e.g. in the case of a boron trihalide about 2-8 moles, preferably 2.5-3.5 moles of the boron compound per mole of oxycodone. If more than 8 moles are used, it is true that no disadvantages but also no advantages are achieved. When using less than 2 moles, the reaction may proceed incompletely. Under demethylation conditions, reaction times of e.g. 8-2 hours and reaction temperatures of 0-Ho ° C. As mentioned, the oxycodone is preferably reacted with said demethylation preparation. Usually the demethylation preparation is sufficiently liquid that no further solvent is required to carry out the reaction. However, it may sometimes be beneficial to use a solvent, e.g. adding an inert solvent that does not react with the boron compound, such as chlorobenzene.

Such a solvent is preferably the same, but may also be different from the controlling agent used.

The demethylating agent can also be added separately to the reaction medium provided the controlling agent is already present in an amount sufficient to soften the activity of the demethylating agent. E.g. oxycodone can be mixed with a controlling agent and the demethylating agent added.

After the oxycodone has been demethylated to the desired degree, the demethylation reaction is terminated by adding a sufficient amount of water. Preferably, an amount of water equal to or greater than the volume of the anhydrous reaction medium is added.

7920126 -3-

To maximize the yield of oxymorphone, the reaction mixture thus obtained is preferably hydrolyzed for a period of time and under conditions sufficient to increase the amount of recoverable oxymorphone in the reaction medium. In this hydrolysis, both the excess reactants and the reaction products present in the medium after demethylation are hydrolyzed. Appropriate hydrolysis takes 1 to 10 hours, preferably 2-b hours. Suitable temperatures for this hydrolysis range from 1 (-0-120, most preferably from 60-100 ° C. It has been found that hydrolysis at elevated temperatures, eg the boiling temperature of the reaction mixture, is particularly favorable, especially when the preferred Chlorhenzene is used as the controlling agent / solvent It is believed that hydrolysis at higher temperatures promotes the hydrolysis of those reaction products in the form of boron complexes, which complexes contain a boron-nitrogen bond, thereby converting more of these types of complexes into recoverable oxymorphone Higher by-drolysis temperatures can also convert other by-products into recoverable desired product.

After the hydrolysis, the pH of the reaction mixture is adjusted to about b.5-5 with acid, e.g. with hydrochloric or sulfuric acid; then it is filtered and then the pH with an appropriate base, e.g. caustic soda, adjusted to 10-12 and extracted with a conventional inert organic solvent, such as toluene. The water layer is then brought to a pH of 2 with an acid and then again to about 8.5 with a base, after which it is extracted again with an inert organic solvent, such as methylene chloride. When the latter is distilled off, an oxymorphone is formed, which is practically free from impurities. The first organic extract, upon evaporation, yields an oxycodone, which is suitable for recycling.

The following examples further illustrate the invention.

Example I: 3

A suspension of 25 g of oxycodone base with 200 cm of chlorobenzene was placed in a container equipped with a stirrer, after which the contents were cooled below 10 ° C. A solution of 60 g of boron tribromide 3 was prepared in 200 cm of chlorobenzene and this solution was added to the oxycodone suspension over the course of 35 minutes. The temperature rose 7920126 -1 + - to about 35 ° C. The cooling vessel was removed and the mixture was stirred for 18 hours. . . 3 stir. The mixture was then poured into 250 cm of water and the mixture was boiled for 2 hours. The water layer and the organic layer were separated and the water layer analyzed for oxycodone and oxymorphone. This water layer 5 was then brought to pH 5> 5 with sodium hydroxide or ammonia and filtered. The filtrate was adjusted to pH 12 with sodium hydroxide and extracted completely with methylene chloride. This methylene chloride layer was separated and evaporated to dryness to recycle oxy-codon. The water layer was acidified to pH 2.0 with hydrochloric acid and then brought back to pH 8.5 with ammonia, after which it was completely extracted with methylene chloride. The organic layer was evaporated to dryness to obtain substantially pure oxymorphone. Figures for this experiment are shown in the following Table A as well as the results obtained with other solvents using substantially the same procedure.

Table A

Exp, φ / solvent Mol BBR ^ Op.

1 chlorobenzene 3 76 $ 2 toluene 3 8? $ (9 $ oxocodone recovered) 3 chci3 1+ 66% J + ch2ci2 U '51% 5 CHC13 6 51% 6 ethylene- k 29% 2 <-chloride T S- tetrachloro-U 65% ethane

Example II:

A suspension of 1.5 g of oxocodone in benzene was poisoned in one time with 2.3 g of boron tribramide in benzene and this mixture was stirred for 2 hours. The mixture was then hydrolyzed with an equal volume of water, boiling for 2 hours. The water layer was analyzed to find it contains 65% oxymorphone and 15% oxycodone.

If the same procedure of this example II is followed, the figures of table B are obtained.

7920126 -5-

Table B

Exp. W sol. mole BBr ^ opbr.

1 CHCl 3 / toluene b 10% 1: 1 2 toluene ^ 16% (15 $ oxycodone recovered) 3 toluene 6 50%! + Toluene 3 85 $ {5% oxycodone recovered) 5 toluene 2 62 $ (10 $ oxycodone tea * '10 backg.) 6 toluene 1 23 $ (68 $ oxocodone reg.) 7 xylene 3 8l $ (6 $ oxycodone back:) 15 8 chlorobenzene 3. (601 ^) 70 $

Example III:

According to the following general procedure, oxycodone was demethylated to oxymorphone using boron tribrcanide as demethylating agent. Variations in the boron tribramide / oxycodone ratio, the type of the reaction medium, the organic solvent and the hydrolysis conditions are shown in Table C.

Oxycodone was added in the solvent to a solution of boron tribromide in the solvent keeping the reaction temperature below about 10 ° C. After 1-20 hours of reaction, the reaction was quenched by the addition of water. Hydrolysis of the reaction mixture took place at 10 ° C or the boiling temperature of the medium. The pH of the mixture was then adjusted to 5.5 and the reaction mixture analyzed for its oxymorphonane set-up using liquid chromatography techniques.

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7920126 -7-

This Table C shows that the ceymorphone yield is improved by using chlorobenzene as the solvent / control agent and by using hot hydrolysis.

Example IV: 5 Ca. 2.68 kg of oxycodone was added to a 189 L container equipped with a heating / cooling jacket containing container U8 kg of chlorobenzene. The contents of this container were stirred well and the system was purged with nitrogen. Approx. 7 kg of boron trichloride was added to this mixture over 20-30 min, during which time the temperature of the reaction mixture was kept below 25 ° C.

After all of the boron tribromide was added, the contents of the container were stirred for an additional 6 hours at room temperature, after which the reaction mixture was pumped under stirring into a container of 2k1 containing I 32.66 kg of water, which was cooled below 10 ° C. The rate of pumping over was such that the temperature remained below 30 ° C.

The resulting suspension-like mixture was pumped back to the 189 L container and boiled at 96 ° C with gentle stirring to prevent emulsion formation. After 2 hours of boiling, the contents were cooled to 60-80 ° C and the layers separated. After separating the bottom water layer, the organic layer was washed well with 5.67 kg of demineralized water and stirred gently. As the mixture separated, the layers turned over so that the water layer became the top layer. This water layer was removed and combined with the previous aqueous extract.

The pH of the organic layer was then adjusted to 5.5-6.0 with ammonia, after which Ο.ί + 5-0.9 kg of activated carbon was added, the mixture formed was filtered and then washed with 3.8-7, 6 liters of demineralized water. The pH was then adjusted to 8.8-8.9 with ammonia and the resulting aqueous suspension was extracted with dichloromethane in a continuous Karr column extractor until the water layer 3 contained less than 1.5 mg oxymorphone per cm. The dichloromethane phase was backwashed with 2 portions of 3.8 L of demineralized water and returned to a 1889 L container with a heating / cooling jacket maintained at 70-80 ° C. The dichloromethane solution 7920126 -8- was then evaporated to dryness and the last residues of dichloromethane and residual water were removed in vacuo. Approx. 30 L of anhydrous ethanol were added to the reaction container and the resulting mixture was heated to 65-70 ° C. This mixture was filtered if necessary and cooled with stirring below 10 ° C. The crystallized product was filtered off and dried for 2-1 + hours at 65-75 ° C to 1.36-1.59 kg oxymorphone.

The filtrate was evaporated to almost dryness and then endowed with 7.57 L of demineralized water. The pH was then adjusted to below 10 50 and then again adjusted to 8.5-8.8 with ammonia, while keeping the temperature of the mixture below 30 ° C. This mixture was cooled to 10-15 ° C and the resulting precipitate filtered off and washed with 2 portions of 0.95 l of water at 10-15 ° C.

The solid material was dried for at least 6 hours at 70-80 ° C to 0.36-0.5 kg of further oxymorphone-containing product.

Example V:

Preparation of oxymorphone recovering unreacted oxycodone 50 g of oxycodone in 1 + 00 cm 2 of chlorobenzene was cooled to 8 ° C

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and treated with 120 g BBr ^ in 1 + 00 cm chlorobenzene for 10 min.

The reaction medium was stirred at room temperature for 1 hour and then 3 added to 500 cm of ice water. Then this mixture was heated to boiling. The water layer was then cooled and separated and adjusted to pH 5.5 with ammonia. Activated carbon was added and the liquid filtered with Celite. The pH was then adjusted to 8.5 with ammonia and the aqueous layer extracted completely with methylene chloride.

The methylene chloride layer was then extracted with dilute sodium hydroxide solution and the water layer first adjusted to pH 1+ and then 8.5, after which the precipitated oxymorphone was filtered off. The methylene chloride layer was extracted on this with 1 N hydrochloric acid, after which the resulting water layer was treated with ammonia until further oxycodone precipitated.

A total of 27.2 g of oxymorphone was thus recovered and 7.1 g of oxycodone were recovered.

35 7920126

Claims (19)

1. Process for preparing oxymorphone by reaction of oxycodone with a demethylating amount of a boron compound in the form of boron tribromide, boron tri chloride or a reaction product of such halide with an alcohol, in an organic solvent-containing reaction medium under demethylating conditions, with. characterized in that this reaction medium also contains a controlling amount of a controlling agent to mitigate the activity of the boron compound, which. controlling agent is in the form of a weak Lewis base, which does not react with said demethylating agent, thereby obtaining a good yield of oxymorphone, which is substantially free of by-products. 2. Process according to claim 1, characterized in that the boron compound is used in an amount of 2-8 moles of boron compound per mole of oxycodone and the controlling agent is selected from benzene, toluene, xylene, ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ether, or mixtures of these types of liquids. Process according to claim 1 or 2, characterized in that the boron compound is used in an amount of 2.5-3.5 mol boron compound per mol oxycodone. U. A method according to claim 2, characterized in that the boron compound is boron tribramide or boron trichloride. Process according to claim, characterized in that diphenyl ether, chlorobenzene or toluene are used as the regulating agent. 6. A method according to claim 1, characterized in that the oxy-codon is reacted with a demethylating amount of a demethylating composition containing said boron compound and a regulating agent. 7. Process according to claim 6, characterized in that the boron compound is boron tribromide or boron trichloride and the controlling agent is selected from benzene, toluene, xylene, ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ether or mixtures of these liquids. Process according to claim 75, characterized in that the regulating agent is phenyl ether, chlorobenzene or toluene. 9. Process according to claim 8, characterized in that the controlling agent is present in an amount of 90%, based on the total 7920126 a -10% of demethylating agent and boron compound, while the boron compound is present therein. in an amount of 10% by weight. 10. Process according to claim 9, characterized in that the demethylating conditions comprise temperatures between 0 and 0 ° C. 11. Process according to claim 10, characterized in that the demethylating conditions comprise a reaction time of 3-8 hours. 12. Process for preparing oxymorphone in good yields and substantially without by-products by reacting A) oxycodone under demethylating conditions with a demethylating amount of a boron compound in the form of boron trichloride, boron trichloride or a reaction product of such trihalide with an alcohol in an organic solvent-containing reaction medium; B) adding water to this reaction medium in an amount sufficient to terminate the demethylation reaction; C) hydrolyzing the reactants and the reaction products formed in this reaction; and D) separating the formed oxymorphone from the reaction medium, characterized in that the reaction medium contains 25-900% by weight, based on the boron demethylating agent, to a control agent selected from benzene, toluene, xylene, ethylbenzene, chlorine. earbenzene, diphenyl ether or mixtures of these agents; and further characterized by the fact that the hydrolysis step is carried out for a period of time and under conditions sufficient to increase the amount of recoverable oxymorphone in the reaction medium. 13. A process according to claim 12, characterized in that the hydrolysis of the reactants and the reaction products takes up to 10 hours and a hydrolysis temperature of between 60 and 120 ° C is used. 30 il +. Process according to claim 13, characterized in that the boron compound used is boron trichloride or boron trichloride. 15. Process according to claim 13 or 1, characterized in that diphenyl ether, chlorobenzene or toluene are used as the regulating agent. 35 16. Process according to claim 15, characterized in that the hydrolysis lasts 2-hours and the boiling temperature of the reaction medium 7920126 * 11 is used. 17. A process according to claim 13, characterized in that the oxycodone is reacted with a demethylating amount of a demethylating composition containing said boron compound and said controlling agent. Process according to claim 17, characterized in that boron tribromide or boron trichloride is used as the boron compound. 19. Process according to claim 17 or 18, characterized in that diphenyl ether, chlorobenzene or toluene are used as the regulating agent. 20. A method according to claim 19, characterized in that the controlling agent in the demethylating preparation is present therein in an amount of 90% by weight, based on the total weight of this demethylating preparation and the boron compound is present therein in an amount of 10 wt. $. 21. A method according to claim 20, characterized in that the demethylating conditions comprise temperatures between 0 and f ° C. Process according to claim 21, characterized in that the demethylating conditions comprise a reaction time of 3-8 hours. 7920126