WO1980000841A1 - Process for producing oxymorphone - Google Patents

Process for producing oxymorphone Download PDF

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Publication number
WO1980000841A1
WO1980000841A1 PCT/US1979/000862 US7900862W WO8000841A1 WO 1980000841 A1 WO1980000841 A1 WO 1980000841A1 US 7900862 W US7900862 W US 7900862W WO 8000841 A1 WO8000841 A1 WO 8000841A1
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Prior art keywords
demethylating
process according
boron
amount
boron compound
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Application number
PCT/US1979/000862
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French (fr)
Inventor
M Wilson
Original Assignee
Mallinckrodt Inc
M Wilson
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Publication date
Application filed by Mallinckrodt Inc, M Wilson filed Critical Mallinckrodt Inc
Priority to DE19792953230 priority Critical patent/DE2953230A1/en
Publication of WO1980000841A1 publication Critical patent/WO1980000841A1/en
Priority to DK258280A priority patent/DK258280A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom

Definitions

  • This invention relates to a process for producing oxymorphone.
  • Oxymorphone is- a narcotic substance. It is widely used as an analgetic. The most frequently used method for producing oxymorphone is described by Seki, Taka ine Kenkyisho Ne po , 12, 52 (1960): It involves reacting pyridine hydrochloride with oxycodone at high temperatures. It is disadvantageous on a commercial scale because the reaction is difficult to control, and high temperatures are needed. Further, this reaction produces only moderate yields along with the formation of substantial amounts of by-products.
  • a process for producing oxymorphone by selectively removing the methyl group from the methoxy group of oxycodone comprising reacting oxycodone with a demethylating amount of a demethylating agent under demethylating conditions in the presence of an attenuating amount of an attenuating agent to attenuate the activity of the demethylating agent, whereby oxymorphone is produced in good yields with substantially no by-products.
  • Suitable demethylating agents are boron compounds capable of demethylating the methoxy group but incapable of forming numerous by-products. Such boron compounds
  • OMPI include boron tribromide, boron trichloride or the reaction product of such halides with alcohols, e.g., those containing 1 to 10 carbon atoms, preferably lower alcohols such as those containing 1 to 6 carbon atoms, e.g., methanol, propanol, butanol, hexanol, etc.
  • alcohols e.g., those containing 1 to 10 carbon atoms, preferably lower alcohols such as those containing 1 to 6 carbon atoms, e.g., methanol, propanol, butanol, hexanol, etc.
  • the attenuating agent can be a weak Lewis base which does not chemically react with the demethylating agent.
  • Attenuating agents include normall liquid aromatic solvents that do not chemically react v/i the boron compound, e.g., benzene, toluene, xylene, ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ethe and mixtures thereof. Chlorobenzene is the preferred attenuating agent. Attenuating amounts include from 25% to 900% by weight based on the weight of the boron compound.
  • a demethylating composition which contains a boron compound in an amount sufficient to demethylate the methoxy group of oxycodone e.g. from about 5 to 20% preferably about 10% based on t total weight of the demethylating composition and an attenuating amount of an attenuating agent, e.g., 80 to 95% preferably about 90% by weight, based on the total weight of the demethylating composition.
  • Oxymorphone is reacted with the aforesaid demethylating agent under demethylating conditions.
  • Thi includes using a demethylating amount of the demethylati agent, e.g., in the case of boron trihalide, from about to 8 moles, advantageously 2.5 to 3.5 moles, preferably 2.5 to 7 moles, of the boron compound per mole of oxycodone. No significant advantage is achieved by usin more than 8 moles, although this is possible. Utilizing less than about 2 moles may result in an incomplete reaction.
  • Other demethylating conditions include suitable reaction times, e.g., 8 to 24 hours and reaction temperatures, e.g., from about 0 to 40°C.
  • the demethylating composition is sufficiently fluid that no further solvent is necessary to carry out the reaction.
  • a solvent e.g., an inert solvent that will not react with the boron compound, e.g., chlorobenzene.
  • a solvent is preferably the same as but can be different from the attenuating agent employed.
  • the demethylating agent can be added to the reaction medium separately, provided the attenuating agent is present in a sufficient amount to attenuate the activity of -the demethylating ' agent.
  • oxycodone can be mixed with the attenuating agent to which is added the demethylating agent.
  • the demethylation reaction is quenched by adding to the reaction medium a quenching amount of water.
  • water is added in an amount equal to or greater than the volume of the anhydrous reaction medium.
  • the quenched reaction mixture is advantageously hydrolyzed for a period of time and under hydrolysis conditions sufficient to increase the amount of recoverable oxymorphone present in the reaction medium.
  • Hydrolysis serves to hydrolyze both excess reactants and reaction products present in the reaction medium after demethylation.
  • Suitable hydrolysis step reaction times include hydrolysis for from about 1/2 to 10 hours, preferably from 2 to 4 hours.
  • Suitable temperatures for the hydrolysis step range from about 60°C to 120°C, preferably from about 80°C to 100°C. It has been found that hydrolyzing the reaction mixture at higher temperatures, e.g. at the reflux temperature of the
  • _OMPI reaction mixture is especially advantageous, particular when the preferred chlorobenzene attenuating agent/solve is employed.
  • hydrolysis at higher temperatures promotes hydrolysis of those reaction products in the form of boron complexes such as complexe containing a boron-nitrogen bond, thereby converting mor of such complexes into recoverable oxymorphone.
  • Higher hydrolysis temperatures may also serve to convert other reaction by-products present into recoverable product.
  • the pH of the reaction mixture is adjusted to about 4.5 to about 6 with acid, e.g., hydrochloric or sulfuric, filtered and then adjusted wit a suitable base, e.g., sodium hydroxide, to a pH of abou 10 to 12 and extracted with one of the conventional iner organic extraction solvents, e.g. , toluene.
  • a suitable base e.g., sodium hydroxide
  • the aqueous layer is then adjusted to a pH of about 2 with acid and then to about 8.5 with base and extracted with an inert organic extraction solvent, e.g., methylene chloride, which is evaporated to give oxymorphone substantially fr of impurities.
  • the first organic extract is evaporated give oxycodone suitable for recycle.
  • a slurry of 25g of oxycodone base in 200ml of chlorobenzene is placed in a vessel equipped for efficie stirring and the contents are cooled to less than 10°C.
  • solution of 60g of boron, tribromide is prepared in 200ml ' of chlorobenzene and this solution is added over a span 5 minutes to the oxycodone slurry.
  • the cooling is removed and the mixture i stirred for 18 hours. At this point the mixture is pour into 250ml of water and the mixture is refluxed for 2 ' hours.
  • the aqueous and organic layers are separated and the aqueous layer is assayed for oxycodone and oxymorphone.
  • the aqueous layer is adjusted to a pH of 5.5 with sodium hydroxide or ammonia and filtered.
  • the filtrate is adjusted to a pH of 12 with sodium hydroxide and exhaustively extracted with methylene chloride.
  • the methylene chloride layer is separated and evaporated to give oxycodone which can be recycled.
  • the aqueous layer is acidified with hydrochloric acid to a pH of 2.0 and then adjusted to a pH of 8.5 with ammonia and exhaustively extracted with methylene chloride.
  • the organic layer is evaporated to give substantially pure oxymorphone.
  • oxycodone is demethylated to form oxymorphone using a boron tribromide demethylating agent. Variations in boron tribromide/oxycodone ratio, type of reaction medium organic solvent employed and hydrolysis conditions are se forth in Table III:
  • reaction vessel Upon completion of the boron tribromide addition, th contents of the reaction vessel are stirred for 6 hours a room temperature (25-28°C). At this point the reaction mixture is pumped with stirring to a 246 liter vessel containing 32.66kg of water which has been cooled to less than 10°C. The addition process is such that the vessel temperature remains below 30°C.
  • the resulting slurried mixture is pumped back into the 189 liter reaction vessel and is heated to reflux (96°C) with slow stirring so as to prevent emulsion formation. After two hours of refluxing, the reaction vessel contents are cooled to 60-80°C and the layers are allowed to separate. Upon separation the bottom aqueous layer is removed and the organic layer is rinsed with 5.67kg of de-ionized water and slowly stirred. As the mixture settles, the layers switch so that the aqueous layer becomes the top layer. The aqueous layer is remove and combined with the previous aqueous extraction.
  • the pH of the organic layer is adjusted to 5.5-6.0 with ammonium hydroxide. About 0.45-0.9kg of darco (activated carbon; Darco G-60) are added and the resultin ixture is filtered and then washed with 3.8-7.6 liters of de-ionized water. The pH is readjusted to 8.8-8.9 with ammonium hydroxide. The resulting aqueous slurry is extracted with dichloromethane in a continuous Karr column extractor until the aqueous portion contains less than 1.5 mg of oxymorphone per ml.
  • the dichloromethane portion is backwashed with 2 3.8 liter portions of de-ionized water and' is returned to a 189 liter reaction vessel having a heating/cooling jacket which is maintained at 70-80°C.
  • the dichloromethane solution is stripped to dryness and the last of the dichloromethane and residual water is removed under vacuum.
  • About 30 liters of anhydrous ethanol are added to the reaction vessel whereupon the resulting mixture is warmed to 65-70°C.
  • the mixture is filtered if necessary and the ethanol mixture is then cooled with stirring to less than 10°C.
  • the resulting crystallization product is filtered and dried at 65-75°C for 2-4 hours to give 1.36-1.59kg of oxymorphone.
  • the filtrate is stripped to near dryness and is replaced with 7.57 liters of de-ionized ' water.
  • the pH is adjusted to less than 5.0 and is subsequently readjusted to 8.5-8.8 with ammonium hydroxide while maintaining the temperature of the mixture at less than 30°C.
  • the mixture is cooled to 10-15°C and the resulting precipitated solid is filtered and washed with two 0.95 liter portions of water at 10-15°C.
  • the solid is dried at 70-80°C for a minimum of 6 hours to give 0.36 to 0.5kg of residue as additional oxymorphone-containing product.
  • Oxycodone (50g) in 400ml of chlorobenzene is cooled to 8°C and treated with 120g of BBr 3 in 400ml of chlorobenzene, over 10 minutes.
  • the reaction medium is stirred for one hour at room temperature and is then ad to 500ml of ice water.
  • the mixture is heated to reflux
  • the aqueous layer is then cooled and separated, and adjusted to a pH of 5.5 with ammonia.
  • Activated charco is added, and the liquid is filtered with Celite.® The is then adjusted to 8.5 with ammonia.
  • the aqueous laye is then exhaustively extracted with methylene chloride.
  • the methylene chloride layer is extracted with diluted sodium hydroxide solution.
  • the aqueous layer i then adjusted to a pH of 4 and then 8.5, and the precipitated oxymorphone is collected by filtration.
  • T methylene chloride layer is extracted with IN. HCl.
  • Th resulting aqueous layer is treated with ammonia to give precipitate of oxycodone. Altogether, 27.2g of oxymorphone and 7.1g of oxycodone are recovered.

Abstract

A process for producing oxymorphone by converting oxycodone utilizing a suitable boron reagent in the presence of a weak Lewis base attenuating agent.

Description

PROCESS FOR PRODUCING OXYMORPHONE
This invention relates to a process for producing oxymorphone.
Oxymorphone is- a narcotic substance. It is widely used as an analgetic. The most frequently used method for producing oxymorphone is described by Seki, Taka ine Kenkyisho Ne po , 12, 52 (1960): It involves reacting pyridine hydrochloride with oxycodone at high temperatures. It is disadvantageous on a commercial scale because the reaction is difficult to control, and high temperatures are needed. Further, this reaction produces only moderate yields along with the formation of substantial amounts of by-products.
It is an object of this invention to provide a process for producing oxymorphone in good yields with substantially no by-products.
It is a further object of the present invention to selectively demethylate the oxycodone methoxy group without affecting the other sites in the oxycodone molecule where ether linkages can be cleaved.
In accordance with this invention, there is provided a process for producing oxymorphone by selectively removing the methyl group from the methoxy group of oxycodone comprising reacting oxycodone with a demethylating amount of a demethylating agent under demethylating conditions in the presence of an attenuating amount of an attenuating agent to attenuate the activity of the demethylating agent, whereby oxymorphone is produced in good yields with substantially no by-products. Suitable demethylating agents are boron compounds capable of demethylating the methoxy group but incapable of forming numerous by-products. Such boron compounds
OMPI include boron tribromide, boron trichloride or the reaction product of such halides with alcohols, e.g., those containing 1 to 10 carbon atoms, preferably lower alcohols such as those containing 1 to 6 carbon atoms, e.g., methanol, propanol, butanol, hexanol, etc. Present in the reaction medium during the demethylating reaction is an attenuating agent to attenuate the activity of the boron compound such that when utilized in the process of this invention,, good yields of oxymorphone are produced with substantially n by-products. The attenuating agent can be a weak Lewis base which does not chemically react with the demethylating agent. Attenuating agents include normall liquid aromatic solvents that do not chemically react v/i the boron compound, e.g., benzene, toluene, xylene, ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ethe and mixtures thereof. Chlorobenzene is the preferred attenuating agent. Attenuating amounts include from 25% to 900% by weight based on the weight of the boron compound.
It is preferred to utilize a demethylating composition which contains a boron compound in an amount sufficient to demethylate the methoxy group of oxycodone e.g. from about 5 to 20% preferably about 10% based on t total weight of the demethylating composition and an attenuating amount of an attenuating agent, e.g., 80 to 95% preferably about 90% by weight, based on the total weight of the demethylating composition.
Oxymorphone is reacted with the aforesaid demethylating agent under demethylating conditions. Thi includes using a demethylating amount of the demethylati agent, e.g., in the case of boron trihalide, from about to 8 moles, advantageously 2.5 to 3.5 moles, preferably 2.5 to 7 moles, of the boron compound per mole of oxycodone. No significant advantage is achieved by usin more than 8 moles, although this is possible. Utilizing less than about 2 moles may result in an incomplete reaction. Other demethylating conditions include suitable reaction times, e.g., 8 to 24 hours and reaction temperatures, e.g., from about 0 to 40°C. As mentioned, it is preferred to react oxycodone with the aforesaid demethylating composition. Normally, the demethylating composition is sufficiently fluid that no further solvent is necessary to carry out the reaction. However, it may be advantageous to add a solvent, e.g., an inert solvent that will not react with the boron compound, e.g., chlorobenzene. Such a solvent is preferably the same as but can be different from the attenuating agent employed. Alternatively, the demethylating agent can be added to the reaction medium separately, provided the attenuating agent is present in a sufficient amount to attenuate the activity of -the demethylating' agent. For example, oxycodone can be mixed with the attenuating agent to which is added the demethylating agent.
After oxycodone demethylation has occurred to the extent desired, the demethylation reaction is quenched by adding to the reaction medium a quenching amount of water. Advantageously, water is added in an amount equal to or greater than the volume of the anhydrous reaction medium. To maximize yield of oxymorphone, the quenched reaction mixture is advantageously hydrolyzed for a period of time and under hydrolysis conditions sufficient to increase the amount of recoverable oxymorphone present in the reaction medium. Hydrolysis serves to hydrolyze both excess reactants and reaction products present in the reaction medium after demethylation. Suitable hydrolysis step reaction times, include hydrolysis for from about 1/2 to 10 hours, preferably from 2 to 4 hours. Suitable temperatures for the hydrolysis step range from about 60°C to 120°C, preferably from about 80°C to 100°C. It has been found that hydrolyzing the reaction mixture at higher temperatures, e.g. at the reflux temperature of the
_OMPI reaction mixture, is especially advantageous, particular when the preferred chlorobenzene attenuating agent/solve is employed. Without being bound by any particular theory, it is believed that hydrolysis at higher temperatures promotes hydrolysis of those reaction products in the form of boron complexes such as complexe containing a boron-nitrogen bond, thereby converting mor of such complexes into recoverable oxymorphone. Higher hydrolysis temperatures may also serve to convert other reaction by-products present into recoverable product.
After hydrolysis, the pH of the reaction mixture is adjusted to about 4.5 to about 6 with acid, e.g., hydrochloric or sulfuric, filtered and then adjusted wit a suitable base, e.g., sodium hydroxide, to a pH of abou 10 to 12 and extracted with one of the conventional iner organic extraction solvents, e.g. , toluene. The aqueous layer is then adjusted to a pH of about 2 with acid and then to about 8.5 with base and extracted with an inert organic extraction solvent, e.g., methylene chloride, which is evaporated to give oxymorphone substantially fr of impurities. The first organic extract is evaporated give oxycodone suitable for recycle.
The following examples illustrate the invention. A parts are by weight unless otherwise stated.
EXAMPLE 1
A slurry of 25g of oxycodone base in 200ml of chlorobenzene is placed in a vessel equipped for efficie stirring and the contents are cooled to less than 10°C. solution of 60g of boron, tribromide is prepared in 200ml' of chlorobenzene and this solution is added over a span 5 minutes to the oxycodone slurry. The temperature rise to about 35°C. The cooling is removed and the mixture i stirred for 18 hours. At this point the mixture is pour into 250ml of water and the mixture is refluxed for 2 ' hours. The aqueous and organic layers are separated and the aqueous layer is assayed for oxycodone and oxymorphone. The aqueous layer is adjusted to a pH of 5.5 with sodium hydroxide or ammonia and filtered. The filtrate is adjusted to a pH of 12 with sodium hydroxide and exhaustively extracted with methylene chloride. The methylene chloride layer is separated and evaporated to give oxycodone which can be recycled. The aqueous layer is acidified with hydrochloric acid to a pH of 2.0 and then adjusted to a pH of 8.5 with ammonia and exhaustively extracted with methylene chloride. The organic layer is evaporated to give substantially pure oxymorphone.
Data for this experiment are shown in the following Table I as well as that obtained for other solvents following substantially the same procedure.
. TABLE I
Run i Solvent Mole BBr3 Yield
1 Chlorobenzene 3 76%
2 Toluene 3 82% (9% oxycodone recovered)
3 CHC13 4 66%
4 CH2C12 ,4 51%
5 CHCl- 6 51%
6 Ethylene 4 29% Bichloride
7 S-tetrachloro. 4 65% ethane
EXAMPLE 2
slurry of 1.5 g of oxycodone in benzene is treated all at once with 2.3g of boron tribromide in benzene and the mixture stirred for 2 hours, the mixture was hydrolyzed with an equal volume of water at reflux for 2 hours. The aqueous layer was assayed to indicate an 85% yield of oxymorphone and a 15% yield of oxycodone.
By essentially following the procedure of Example 2 the data in Table II was obtained. TABLE II
Run # Solvent Moles BBr. Yield
1 CHCl_/Toluene 70%
1:1
2 Toluene 76% (15% oxycodon recovere )
3 Toluene 6 50%
4 . Toluene 3 85% (5% oxycodone recovered)
5 Toluene 2 62% (10% oxycodon recovered)
6 Toluene 1 . 23% (68% oxycodon recovered)
7 Xylene 3 81% (6% oxycodone recovered)
8 Chlorobenzene 3(BC13) 70%
EXAMPLE 3
Using the following general procedures, oxycodone is demethylated to form oxymorphone using a boron tribromide demethylating agent. Variations in boron tribromide/oxycodone ratio, type of reaction medium organic solvent employed and hydrolysis conditions are se forth in Table III:
Boron tribromide in solvent is added to a slurry of oxycodone in solvent for Runs 5-8 with the reaction mediu temperature being maintained below about 10°C. The order of addition is reversed for Runs 1-4. After reaction times varying from 1 to 20 hours, the reaction mixture is quenched by addition of water. Hydrolysis of the reactio mixture then takes place either at 40°C or at reflux temperature of the reaction medium. The pH of the reaction mixture is then adjusted to about 5.5, and the reaction mixture is analyzed for oxymorphone conversion using liquid chromatography techniques.
OM
" 1 . Table III
- Oxycodone to Oxymo;rphone Conversion
Hydrolysis Yield
Run No. BrBr3 (grns) Oxycodone (gms) BBr,, :Oxycιodone (Moles) Solvent Temp. Oxymor
1 -75 -15 6 CHC1- 40°C .66
2 71 15 6 CHC13 reflux 71
3 35 15 3 CHC13 40°C 51
4 35 15 3 CHC13 reflux 67
5 • 75 15 6 Cl-Benzene reflux 88
6 60 25 3 Cl-Benzene reflux 85
7 75 15 6 Cl-Benzene 40°C 70
8 78 15 3 Cl-Benzene 40°C 72
Figure imgf000009_0001
The above table III data illustrate that oxymorphone yield is improved by utilizing the chlorobenzene solvent/attenuating agent and by utilizing hot hydrolysis conditions.
EXAMPLE 4
'Approximately 2.68kg of oxycodone are added to a 189 liter reaction vessel furnished with a heating/cooling jacket, said vessel containing 48kg of chlorobenzene. Th contents of the reaction vessel are rapidly stirred and the system is purged with nitrogen. About 7.8kg of boron tribromide are added to the mixture over a period of 20-3 minutes during which time the temperature of the reaction mixture is kept below 25°C.
Upon completion of the boron tribromide addition, th contents of the reaction vessel are stirred for 6 hours a room temperature (25-28°C). At this point the reaction mixture is pumped with stirring to a 246 liter vessel containing 32.66kg of water which has been cooled to less than 10°C. The addition process is such that the vessel temperature remains below 30°C.
The resulting slurried mixture is pumped back into the 189 liter reaction vessel and is heated to reflux (96°C) with slow stirring so as to prevent emulsion formation. After two hours of refluxing, the reaction vessel contents are cooled to 60-80°C and the layers are allowed to separate. Upon separation the bottom aqueous layer is removed and the organic layer is rinsed with 5.67kg of de-ionized water and slowly stirred. As the mixture settles, the layers switch so that the aqueous layer becomes the top layer. The aqueous layer is remove and combined with the previous aqueous extraction.
The pH of the organic layer is adjusted to 5.5-6.0 with ammonium hydroxide. About 0.45-0.9kg of darco (activated carbon; Darco G-60) are added and the resultin ixture is filtered and then washed with 3.8-7.6 liters of de-ionized water. The pH is readjusted to 8.8-8.9 with ammonium hydroxide. The resulting aqueous slurry is extracted with dichloromethane in a continuous Karr column extractor until the aqueous portion contains less than 1.5 mg of oxymorphone per ml. The dichloromethane portion is backwashed with 2 3.8 liter portions of de-ionized water and' is returned to a 189 liter reaction vessel having a heating/cooling jacket which is maintained at 70-80°C. The dichloromethane solution is stripped to dryness and the last of the dichloromethane and residual water is removed under vacuum. About 30 liters of anhydrous ethanol are added to the reaction vessel whereupon the resulting mixture is warmed to 65-70°C. The mixture is filtered if necessary and the ethanol mixture is then cooled with stirring to less than 10°C. The resulting crystallization product is filtered and dried at 65-75°C for 2-4 hours to give 1.36-1.59kg of oxymorphone.
The filtrate is stripped to near dryness and is replaced with 7.57 liters of de-ionized'water. The pH is adjusted to less than 5.0 and is subsequently readjusted to 8.5-8.8 with ammonium hydroxide while maintaining the temperature of the mixture at less than 30°C. The mixture is cooled to 10-15°C and the resulting precipitated solid is filtered and washed with two 0.95 liter portions of water at 10-15°C. The solid is dried at 70-80°C for a minimum of 6 hours to give 0.36 to 0.5kg of residue as additional oxymorphone-containing product.
EXAMPLE 5
Preparation with Oxymorphone with
Recovery of Unreacted Oxycodone Oxycodone (50g) in 400ml of chlorobenzene is cooled to 8°C and treated with 120g of BBr3 in 400ml of chlorobenzene, over 10 minutes. The reaction medium is stirred for one hour at room temperature and is then ad to 500ml of ice water. The mixture is heated to reflux The aqueous layer is then cooled and separated, and adjusted to a pH of 5.5 with ammonia. Activated charco is added, and the liquid is filtered with Celite.® The is then adjusted to 8.5 with ammonia. The aqueous laye is then exhaustively extracted with methylene chloride.
The methylene chloride layer is extracted with diluted sodium hydroxide solution. The aqueous layer i then adjusted to a pH of 4 and then 8.5, and the precipitated oxymorphone is collected by filtration. T methylene chloride layer is extracted with IN. HCl. Th resulting aqueous layer is treated with ammonia to give precipitate of oxycodone. Altogether, 27.2g of oxymorphone and 7.1g of oxycodone are recovered.

Claims

-11-WHAT IS CLAIMED:
1. A process for producing oxymorphone by reacting oxycodone with a demethylating amount of a boron compound selected from the group consisting of boron tribromide, boron trichloride and the reaction product of any such halide with a lower alcohol, in an organic solvent- containing reaction medium under demethylating conditions, characterized in that said reaction medium contains an attenuating amount of an attenuating agent to attenuate the activity of the boron compound, said attenuating agent being a weak Lewis base which is non-reactive with said demethylating agent, whereby oxymorphone is produced in good yields with substantially no by-products.
2. A process according to Claim 1 characterized in that the boron compound is used in an amount to provide - from about 2 to 8 moles of the boron compound per mole of oxycodone and the attenuating agent is selected from the group consisting of benzene, toluene, xylene, ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ether and mixtures of said attenuating agents.
3. A process according to Claims 1 or 2 characterized in that the boron compound is used in an amount to provide from about 2.5 to about 3.5 moles of the boron compound per mole of oxycodone.
4. A process according to Claim 2 characterized in that the boron compound is boron tribromide or boron trichloride.
5. A process according to Claim 4 characterized in that the attenuating agent is diphenyl ether, chlorobenzene or toluene.
6. A process according to Claim 1 characterized in that the oxycodone is reacted with a demethylating amount of a demethylating composition containing said boron compound and said attenuating agent.
7. A process according to Claim 6 characterized i that the boron compound is boron tribromide or boron trichloride and the attenuating agent is selected from benzene, toluene, xylene, ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ether and mixtures of said attenuating agents.
8. A process according to Claim 7 characterized i that the attenuating agent is diphenyl ether, chlorobenzene or toluene.
9. A process according to Claim 8 characterized i that the attenuating agent is present in the demethylat composition in an amount of about 90% by weight, based the total weight of the demethylating composition and t boron compound is present in an amount of 10% by weight, based on the total weight of the. demethylating composition.
10. A process according to Claim 9 characterized i that the demethylating conditions include temperatures from about 0° to about 40°C.
11. A process according to Claim 10 characterized that the demethylating conditions include a reaction ti of from about 3 to about 8 hours.
12. A process for producing oxymorphone in good yields and with substantially no by-products by
A) reacting oxycodone under demethylating conditio with a demethylating amount of a boron compound selected from the group consisting of boron tribromide, boron trichloride and the reaction product of any such trihalide with a lower alcohol, in an organic solvent-containing reac¬ tion medium; B) adding water to said reaction medium in an amount sufficient to quench the demethylation reaction; C) hydrolyzing the reactants and reaction products formed in said reaction medium; and D) separating from the reaction medium the oxymorphone produced; characterized in that said reaction medium contains from about 25% to 900% by weight based on said boron demethylating agent of an attenuating agent selected from the group consisting of benzene, toluene, xylene, ethylbenzene, chlorobenzene, diphenyl ether and mixtures of said attenuating agents; and further characterized in that the hydrolysis step is conducted for a period of time and under hydrolysis conditions sufficient to increase the amount of recoverable oxymorphone present in the reaction medium.
13. A process according to Claim 12 characterized in that hydrolysis of reactants and reaction products in the reaction medium occurs for a period of time of from about 1/2 to 10 hours and at hydrolysis temperatures of from about 60°C to 120°C.
14. A process according to Claim 13 characterized in that the boron compound is boron tribromide or boron trichloride.
15. A process according to Claims 13 or 14 characterized in that the attenuating agent is diphenyl ether, chlorobenzene or toluene.
16. A process according to Claim 15 characterized in that hydrolysis occurs for from about 2 to 4 hours at the reflux temperature of the reaction medium.
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 attenuating agent.
18. A process according to Claim 17 characterized .in that the boron compound is boron tribromide or boron trichloride.
19. A process according to Claims 17 or 18 characterized in that the attenuating agent is diphenyl ether, chlorobenzene or toluene.
^ EA'ΪT OMH_ O 20. A process according to Claim 19 characterized that the attenuating agent is present in the demethylat composition in an amount of about 90% by weight, based the total weight of the demethylating composition and t boron compound is present in an amount of 10% by weight, based on the total weight of the demethylating composition.
" 21. A process according to Claim 20 characterized that the demethylating conditions include temperatures o from about 0° to about 40°C.
22. A process according to Claim 21 characterized that the demethylating conditions include a reaction tim of from about 3 to about 8 hours.
OM
PCT/US1979/000862 1978-10-19 1979-10-18 Process for producing oxymorphone WO1980000841A1 (en)

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US4795813A (en) * 1981-08-17 1989-01-03 The Florida Board Of Regents On Behalf Of The Florida State University Synthesis of derivatives of codeine and other 3-O-alkylmorphines
FR2636330A1 (en) * 1988-09-13 1990-03-16 Sanofi Sa PROCESS FOR THE PREPARATION OF MORPHINANE DERIVATIVES
WO1991005768A1 (en) * 1989-10-16 1991-05-02 The United States Of America, Represented By The Secretary, United States Department Of Commerce Total synthesis of northebaine, normorphine, noroxymorphone enantiomers and derivatives via n-nor intermediates
US5668285A (en) * 1986-10-31 1997-09-16 The United States Of America As Represented By The Department Of Health And Human Services Total synthesis of northebaine, normophine, noroxymorphone enantiomers and derivatives via N-Nor intermediates
US8309122B2 (en) 2001-07-06 2012-11-13 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8871779B2 (en) 2006-03-02 2014-10-28 Mallinckrodt Llc Process for preparing morphinan-6-one products with low levels of α,β-unsaturated ketone compounds
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
EP3252055A1 (en) 2016-05-31 2017-12-06 Alcaliber Investigacion Desarrollo e Innovacion, S.L. Process for obtaining 3,14-diacetyloxymorphone from oripavine
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
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US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form

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Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4795813A (en) * 1981-08-17 1989-01-03 The Florida Board Of Regents On Behalf Of The Florida State University Synthesis of derivatives of codeine and other 3-O-alkylmorphines
US5668285A (en) * 1986-10-31 1997-09-16 The United States Of America As Represented By The Department Of Health And Human Services Total synthesis of northebaine, normophine, noroxymorphone enantiomers and derivatives via N-Nor intermediates
FR2636330A1 (en) * 1988-09-13 1990-03-16 Sanofi Sa PROCESS FOR THE PREPARATION OF MORPHINANE DERIVATIVES
EP0359647A1 (en) * 1988-09-13 1990-03-21 Elf Sanofi Process for the preparation of morphinane derivatives
WO1991005768A1 (en) * 1989-10-16 1991-05-02 The United States Of America, Represented By The Secretary, United States Department Of Commerce Total synthesis of northebaine, normorphine, noroxymorphone enantiomers and derivatives via n-nor intermediates
US8309122B2 (en) 2001-07-06 2012-11-13 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US9820982B2 (en) 2001-07-06 2017-11-21 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US10369109B2 (en) 2002-06-17 2019-08-06 Grünenthal GmbH Abuse-proofed dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US10675278B2 (en) 2005-02-04 2020-06-09 Grünenthal GmbH Crush resistant delayed-release dosage forms
US8871779B2 (en) 2006-03-02 2014-10-28 Mallinckrodt Llc Process for preparing morphinan-6-one products with low levels of α,β-unsaturated ketone compounds
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10493033B2 (en) 2009-07-22 2019-12-03 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10864164B2 (en) 2011-07-29 2020-12-15 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
EP3252055A1 (en) 2016-05-31 2017-12-06 Alcaliber Investigacion Desarrollo e Innovacion, S.L. Process for obtaining 3,14-diacetyloxymorphone from oripavine
WO2017207519A1 (en) 2016-05-31 2017-12-07 Alcaliber Investigación Desarrollo E Innovación, S.L. Process for obtaining 3,14-diacetyloxymorphone from oripavine

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GB2049680A (en) 1980-12-31
IL58489A0 (en) 1980-01-31
NO793297L (en) 1980-04-22
IT7969032A0 (en) 1979-10-18
CS211364B2 (en) 1982-02-26
NL7920126A (en) 1980-08-29
AU5189779A (en) 1980-04-24
ES485154A1 (en) 1980-06-16
FR2439201A1 (en) 1980-05-16
JPS55501025A (en) 1980-11-27
BE879494A (en) 1980-02-15
DK258280A (en) 1980-06-17
CA1108132A (en) 1981-09-01
SE8004454L (en) 1980-06-16

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