NO793297L

NO793297L - PROCEDURE FOR THE MANUFACTURE OF OXYMORPHONE

Info

Publication number: NO793297L
Application number: NO793297A
Authority: NO
Inventors: Michael L Wilson
Original assignee: Mallinckrodt Inc
Priority date: 1978-10-19
Filing date: 1979-10-12
Publication date: 1980-04-22
Also published as: AU5189779A; GB2049680A; DK258280A; IT7969032A0; WO1980000841A1; NL7920126A; CS211364B2; ES485154A1; BE879494A; JPS55501025A; FR2439201A1; SE8004454L; IL58489A0; FI793235A; CA1108132A

Description

Fremgangsmåte for fremstilling av oksymorfon. Process for the production of oxymorphone.

Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av oksy morfon. The present invention relates to a method for the production of oxymorphone.

Oksymorfon er et narkotisk stoff og er meget anvendt som smertestillende middel. Den mest anvendte fremgangsmåten for fremstilling av oksymorfon er beskrevet av Seki, Takamine Kenkyisho Nempo, 12, 52 (1960). Den inbefatter at man omsetter pyridinhydroklorid med oksykodon ved høye temperaturer. Denne fremgangsmåten har ulemper når den skal anvendes på kommersiellskala, fordi reaksjonen er vanskelig å regulere, Oxymorphone is a narcotic drug and is widely used as a pain reliever. The most widely used method for the preparation of oxymorphone is described by Seki, Takamine Kenkyisho Nempo, 12, 52 (1960). It involves reacting pyridine hydrochloride with oxycodone at high temperatures. This method has disadvantages when it is to be used on a commercial scale, because the reaction is difficult to regulate,

og det trengs høye temperaturer. Videre vil man ved reaksjonen bare få moderate utbytter av det forønskede stoff, foruten at det dannes betydelige mengder av biprodukter. and high temperatures are needed. Furthermore, only moderate yields of the desired substance will be obtained in the reaction, in addition to the formation of significant amounts of by-products.

Det er en hensikt ved foreliggende oppfinnelseIt is a purpose of the present invention

å tilveiebringe en fremgangsmåte for fremstilling av oksymorfon i godt utbytte og hvor det i alt vesentlig ikke dannes noen biprodukter. to provide a method for producing oxymorphone in good yield and where essentially no by-products are formed.

Det er videre en hensikt ved foreliggende oppfinnelse å selektivt demetylere oksykodonmetoksygruppen uten at man påvirker andre posisjoner i oksykodonmolekylet hvor eterbindinger eventuelt kan spaltes. It is also a purpose of the present invention to selectively demethylate the oxycodone methoxy group without affecting other positions in the oxycodone molecule where ether bonds can possibly be cleaved.

Foreliggende oppfinnelse tilveiebringer så-ledes en fremgangsmåte for fremstilling av oksymorfon ved at man selektivt fjerner metylgruppen fra metoksygruppen i oksykodon, og hvor fremgangsmåten inbefatter at man reagerer sistnevnte forbindelse med en demetylert mengde av et demetyleringsmiddel under demetylerende betingelser i nærvær av en dempende mengde av et dempingsmiddel for å dempe aktiviteten på demetyleringsmidlet, hvorved oksymorfon fremstilles i godt utbytte og i alt vesentlig uten biprodukter. The present invention thus provides a method for the production of oxymorphone by selectively removing the methyl group from the methoxy group in oxycodone, and wherein the method includes reacting the latter compound with a demethylated amount of a demethylating agent under demethylating conditions in the presence of an attenuating amount of a dampening agent to dampen the activity of the demethylating agent, whereby oxymorphone is produced in good yield and essentially without by-products.

Egnede demetyleringsmidler er borforbindelser som er i stand til å demetylere metoksygruppen, men som ikke er istand til å danne tallrike biprodukter. Slike borforbindelser inbefatter bortribromid, bortriklorid eller reaksjonsproduktet av slike halogenider med alkoholer, f.eks. de som inneholder fra 1 til 10 karbonatomer, fortrinnsvis laverealkoholer, med fra 1 til 6 karbonatomer, f.eks. metanol, propanol, butanol, heksanol, etc. Suitable demethylating agents are boron compounds which are capable of demethylating the methoxy group, but which are not capable of forming numerous by-products. Such boron compounds include boron tribromide, boron trichloride or the reaction product of such halides with alcohols, e.g. those containing from 1 to 10 carbon atoms, preferably lower alcohols, with from 1 to 6 carbon atoms, e.g. methanol, propanol, butanol, hexanol, etc.

Tilstede i reaksjonsmediet under den nevnte demetyleringsreaksjon er et dempende middel for å dempe aktiviteten på borforbindelsen slik at når denne brukes i foreliggende fremgangsmåte, så får man godt utbytte av oksymorfon og i alt vesentlig ingen biprodukter. Det dempende middel kan være en svak Lewis-base som ikke kjemisk reagerer med demetyleringsmidlet. Dempningsmidlet inbefatter normalt flytende, aromatisk oppløsningsmiddel som ikke kjemisk reagerer med borforbindelsen, man kan f.eks. bruke benzen, toluen, xylen, etylbenzen, nitrobenzen, klorbenzen, difenyleter og blandinger av disse. Klorbenzen er det foretrukne dempningsmiddel. Dempende mengder inbefatter fra 25 til 900 vektsprosent basert .på vekten av borforbindelsen. Present in the reaction medium during the aforementioned demethylation reaction is a dampening agent to dampen the activity of the boron compound so that when this is used in the present method, a good yield of oxymorphone is obtained and essentially no by-products. The quenching agent may be a weak Lewis base that does not chemically react with the demethylating agent. The dampening agent normally includes a liquid, aromatic solvent which does not chemically react with the boron compound, one can e.g. use benzene, toluene, xylene, ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ether and mixtures of these. Chlorobenzene is the dampening agent of choice. Attenuating amounts include from 25 to 900 weight percent based on the weight of the boron compound.

Det er foretrukket å bruke en demetylerende sammensetning som inneholder en borforbindelse i en mengde som er tilstrekkelig til å demetylere metoksygruppen i oksykodon, f.eks. fra 5 til 20%, fortrinnsvis ca. 10% basert på It is preferred to use a demethylating composition containing a boron compound in an amount sufficient to demethylate the methoxy group in oxycodone, e.g. from 5 to 20%, preferably approx. 10% based on

den totale vekt av den nevnte demetylerende sammensetningen,the total weight of said demethylating composition,

samt en dempende mengde av et dempningsmiddel, f.eks. fra 80 til 95%, fortrinnsvis ca. 90 vektsprosent, basert på den totale vekt av den demetylerende sammensetningen. as well as a dampening amount of a dampening agent, e.g. from 80 to 95%, preferably approx. 90% by weight, based on the total weight of the demethylating composition.

Oksymorfon reageres med forannevnte demetyleringsmiddel under demetylerende betingelser. Dette inbefatter at man bruker en demetylerende mengde av et demetyleringsmiddel, f.eks. Oxymorphone is reacted with the aforementioned demethylating agent under demethylating conditions. This includes using a demethylating amount of a demethylating agent, e.g.

i form av bortrihalogenid, hvor man anvender fra 2 til 8 mol, fortrinnsvis 2,5 til 3,5 mol, mere foretrukket fra 2,5 til 7 in the form of boron trihalide, using from 2 to 8 mol, preferably 2.5 to 3.5 mol, more preferably from 2.5 to 7

mol, av borforbindelsen pr. mol av oksykodon. Man oppnår ingen betydelig fordel ved å bruke mere enn 8 mol, skjønt dette er mulig. Bruker man mindre enn ca. 2 mol, så får man en ufullstendig reaksjon. Andre demetylerende betingelser inbefatter egnede reaksjonstider, d.v.s. fra 8 til 24 timer og temperaturer fra 0 til 40°C. Som nevnt foran er det foretrukket å reagere oksykodon med forannevnte demetylerende sammensetning. Normalt mol, of the boron compound per moles of oxycodone. No significant advantage is gained by using more than 8 moles, although this is possible. If you use less than approx. 2 mol, then you get an incomplete reaction. Other demethylating conditions include suitable reaction times, i.e. from 8 to 24 hours and temperatures from 0 to 40°C. As mentioned above, it is preferred to react oxycodone with the aforementioned demethylating composition. Normally

vil denne sammensetningen være tilstrekkelig flytende til at det ikke er nødvendig å bruke ytterligere oppløsningsmiddel for å få gjennomført reaksjonen. Det kan imidlertid være fordelaktig å tilsette et oppløsningsmiddel, f.eks. et inert oppløsningsmiddel, som ikke vil reagere med borforbindelsen, f.eks. klorbenzen. Et slikt oppløsningsmiddel er fortrinnsvis det samme, men kan være forskjellig fra det anvendte dempningsmiddel . this composition will be sufficiently liquid that it is not necessary to use additional solvent to carry out the reaction. However, it may be advantageous to add a solvent, e.g. an inert solvent, which will not react with the boron compound, e.g. chlorobenzene. Such a solvent is preferably the same, but may be different from the dampening agent used.

Alternativt kan demetyleringsmidlet tilsettes reaksjonsmediet separat forutsatt at det dempende middel er tilstede i tilstrekkelig mengde til å dempe aktiviteten på demetyleringsmidlet. F. eks. kan oksykodon blandes med dempningsmidlet som så tilsettes demetyleringsmidlet. Alternatively, the demethylating agent may be added to the reaction medium separately provided that the dampening agent is present in sufficient quantity to dampen the activity of the demethylating agent. For example oxycodone can be mixed with the suppressant to which the demethylating agent is added.

Etterat oksykodon dem etyleringen er utførtAfter the oxycodone dem ethylation is done

i så høy grad som ønskelig, kan demetyleringsreaksjonen stanses ved at reaksjonsmediet tilsettes vann. Fortrinnsvis bør vann tilsettes i en mengde som er lik eller større enn volumet på det vannfrie reaksjonsmediet. to the extent desired, the demethylation reaction can be stopped by adding water to the reaction medium. Preferably, water should be added in an amount equal to or greater than the volume of the anhydrous reaction medium.

For å få maksimalt utbytte av oksymorfonTo get the maximum benefit from oxymorphone

kan reaksjonsblandingen deretter med fordel hydrolyseres i et visst tidsrom.og under slike hydrolysebetingelser at man kan øke den mengde av innvinnbart oksymorfon som er til- the reaction mixture can then advantageously be hydrolysed for a certain period of time and under such hydrolysis conditions that the amount of recoverable oxymorphone that is available can be increased

stede i reaksjonsmediet. Hydrolysen tjener til å hydrolysere både overskudd av reaktanter og reaksjonsprodukter som måtte være tilstede i reaksjonsmediet etter demetyleringen. Egnede hydrolysereaksjonstider inbefatter fra en 1/2 til present in the reaction medium. The hydrolysis serves to hydrolyze both excess reactants and reaction products that may be present in the reaction medium after the demethylation. Suitable hydrolysis reaction times include from a 1/2 to

10 timer, fortrinnsvis 2 til 4 timer. Egnede temperaturer for denne hydrolysen varierer fra 60 til 120°C, fortrinnsvis 80 - 100°C. Man har funnet at en hydrolyse av reaksjonsblandingen ved høyere temperaturer, f.eks. ved koking med tilbakeløp er spesielt fordelaktig, spesielt når man bruker klorbenzen som dempende middel og oppløsningsmiddel. Uten å være bundet av en eller flere spesielle teorier, så antar man at hydrolysen ved høyere temperaturer fremmer hydrolyse av de reaksjonsprodukter som er i form av borkomplekset, f. eks. komplekser som inneholder en bor- nitrogenbinding, hvorved man omdanner mer av slike komplekser til innvinnbart oksomorfon. Høyere hydrolysetemperaturer tjener også til omdannelse av andre biprodukter som måtte være tilstede i blandingen til et innvinnbart produkt. . ^ , . EttSr h^drolysen ble pH på reaksjonsblandingen istert txl ca. 4,5 til 6 med syre, f.eks. saltsyre eller svovelsyre, ble så filtrert og justert med en egnet baée, 10 hours, preferably 2 to 4 hours. Suitable temperatures for this hydrolysis range from 60 to 120°C, preferably 80 to 100°C. It has been found that a hydrolysis of the reaction mixture at higher temperatures, e.g. under reflux is particularly advantageous, especially when using chlorobenzene as a quencher and solvent. Without being bound by one or more particular theories, it is assumed that the hydrolysis at higher temperatures promotes hydrolysis of the reaction products that are in the form of the boron complex, e.g. complexes containing a boron-nitrogen bond, whereby more of such complexes are converted into recoverable oxomorphone. Higher hydrolysis temperatures also serve to convert other by-products that may be present in the mixture into a recoverable product. . ^ , . After the hydrolysis, the pH of the reaction mixture was adjusted to approx. 4.5 to 6 with acid, e.g. hydrochloric or sulfuric acid, was then filtered and adjusted with a suitable baée,

f.eks. natriumhydroksyd, til en pH mellom 10 og 12 og så ekstrahert med ett av de vanlige kjente inerte organiske ekstraksjonsmidler, f.eks. toluen. Det vandige lag ble sa justert til en pH ca. 2 med syre og så til ca. 8,5 med base, og igjen ekstrahertover i inert organisk oppløsninga--ddel, f.eks. metylenklorid, som så ble fordampet hvorved man far oksymorfon i alt vesentlig fritt for urenheter. Det første organiske ekstrakt blir fordampet, hvorved man får oksykodon som egnet kan brukes for resirkulering. e.g. sodium hydroxide, to a pH between 10 and 12 and then extracted with one of the usual known inert organic extractants, e.g. toluene. The aqueous layer was thus adjusted to a pH of approx. 2 with acid and then until approx. 8.5 with base, and again extracted into inert organic solution part, e.g. methylene chloride, which was then evaporated, thereby obtaining oxymorphone essentially free of impurities. The first organic extract is evaporated, whereby oxycodone is obtained which can be used for recycling.

_De følgende eksempler illustrerer oppfinnelsen. Alle deler er pr. vekt hvis intet annet er angitt. _The following examples illustrate the invention. All parts are per weight unless otherwise stated.

Eksempel 1Example 1

En suspensjon av 25 g oksykodonbase i 200 ml klorbenzen ble tilsatt i et kar med tilstrekkelig røreutstyr og innholdet ble avkjølt til mindre enn 10°C. En oppløsning på 60 g bortribromid ble fremstillet i 200 ml klorbenzen og denne oppløsningen ble i løpet av 5 minutter tilsatt oksykodon-suspensjonen. Temperaturen stiger til ca. 35°C. Kjølingen ble fjernet, og blandingen ble rørt i 18 timer. Blandingen ble så helt over i 250 ml vann og deretter kokt under tilbakeløp i 2 timer. De vandige og organiske lag ble adskilt og det vandige lag ble undersøkt for oksykodon og oksymorfon. Det vandige lag ble justert til pH 5,5 med natriumhydroksyd eller ammoniakk og så filtrert. Filtratet ble justert til en pH 12 med natriumhydroksyd og så ekstrahert med metylenklorid. Metylenkloridlaget ble utskilt og fordampet, hvorved man fikk oksykodon som kan recykleres. Det vandige lag ble surgjort med saltsyre til en pH på 2,0 og så justert til pH 8,5 med ammoniakk og så igjen ekstrahert med metylenklorid. Det organiske lag ble fordampet og man fikk i alt vesentlig ren oksymorfon. A suspension of 25 g of oxycodone base in 200 ml of chlorobenzene was added to a vessel with adequate stirring equipment and the contents were cooled to less than 10°C. A solution of 60 g of boron tribromide was prepared in 200 ml of chlorobenzene and this solution was added to the oxycodone suspension within 5 minutes. The temperature rises to approx. 35°C. The cooling was removed and the mixture was stirred for 18 hours. The mixture was then poured into 250 ml of water and then boiled under reflux for 2 hours. The aqueous and organic layers were separated and the aqueous layer was examined for oxycodone and oxymorphone. The aqueous layer was adjusted to pH 5.5 with sodium hydroxide or ammonia and then filtered. The filtrate was adjusted to a pH of 12 with sodium hydroxide and then extracted with methylene chloride. The methylene chloride layer was separated and evaporated, yielding oxycodone which can be recycled. The aqueous layer was acidified with hydrochloric acid to a pH of 2.0 and then adjusted to pH 8.5 with ammonia and then again extracted with methylene chloride. The organic layer was evaporated and essentially pure oxymorphone was obtained.

Data for dette eksperiment er vist i den følg-ende tabell I, såvel som det man fikk for andre oppløsningsmidler idet man brukte i alt vesentlig den samme fremgangsmåten. Data for this experiment are shown in the following Table I, as well as that obtained for other solvents using essentially the same procedure.

Eksempel 2 Example 2

En suspensjon av 1,5 g oksykodon i benzen ble på en gang behandlet med 2,3 g bortribromid i benzen og blandingen ble rørt i 2 timer og deretter hydrolysert med et tilsvarende volum vann med koking under tilbakeløp i 2 timer. Det vandige lag ble undersøkt og man fant at det inneholdt 85% utbytte av oksymorfon og 15 % utbytte av oksykodon. A suspension of 1.5 g of oxycodone in benzene was treated at once with 2.3 g of boron tribromide in benzene and the mixture was stirred for 2 hours and then hydrolyzed with an equal volume of water at reflux for 2 hours. The aqueous layer was examined and found to contain 85% yield of oxymorphone and 15% yield of oxycodone.

Ved i det alt vesentlige å bruke samme fremgangsmåte som i eksempel 1 oppnådde man de data som er angitt i tabell II. By essentially using the same method as in example 1, the data set out in table II was obtained.

Eksempel 3 Example 3

Ved å bruke følgende generelle fremgangsmåte ble oksykodon demetylert til oksymorfon ved å bruke bortribromid som demetyleringsmiddel. Variasjoner med hensyn til forholdet mellom bortribromid og oksykodon, type av reaksjonsmediet anvendt organisk oppløsningsmiddel og hydrolysebetingelser er angitt i tabell III. Bortribromid i oppløsningsmiddel ble tilsatt en suspensjon av oksykodon i oppløsningsmiddel i forsøk 5-8, mens reaksjonsmediums temperaturen ble holdt under 10°C. Rekkefølgen med hensyn til tilsetning ble snudd opp ned Using the following general procedure, oxycodone was demethylated to oxymorphone using boron tribromide as the demethylating agent. Variations with regard to the ratio between boron tribromide and oxycodone, type of reaction medium used organic solvent and hydrolysis conditions are indicated in Table III. Boron tribromide in solvent was added to a suspension of oxycodone in solvent in experiments 5-8, while the temperature of the reaction medium was kept below 10°C. The order of addition was reversed

i forsøkene 1 til 4. Etter reaksjonstider fra 1 til 20 timer ble reaksjonen stoppet ved tilsetning av vann. Hydrolyse av reaksjonsblandingen finner enten sted ved 40°C eller ved koking ved tilbakeløp. pH i blanding ble så justert til ca. in experiments 1 to 4. After reaction times of 1 to 20 hours, the reaction was stopped by the addition of water. Hydrolysis of the reaction mixture takes place either at 40°C or by boiling at reflux. The pH in the mixture was then adjusted to approx.

5,5, og reaksjonsblandingen ble analysert for oksymorfon-omdannelse ved å bruke væskekromatografi teknikk. 5.5, and the reaction mixture was analyzed for oxymorphone conversion using a liquid chromatography technique.

Den ovennevnte tabell III viser klart at The above Table III clearly shows that

utbyttet av oksymorfon økes ved å bruke klorbenzen som et oppløsningsmiddel og dempningsmiddel, og ved å bruke varme hydrolysebetingelser. the yield of oxymorphone is increased by using chlorobenzene as a solvent and quencher, and by using hot hydrolysis conditions.

Eksempel 4Example 4

Ca 2,68 kg oksykodon ble tilsatt et reaksjons-?kar på 189 liter utstyrt med en varme/ kjølekappe, og nevnte kar inneholdt også 48 kg klorbenzen. Innholdet i karet ble raskt rørt og systemet renset med nitrogen. Ca. 7,8 kg bortribromid ble tilsatt blandingen i løpet av 20 til 30 About 2.68 kg of oxycodone was added to a reaction vessel of 189 liters equipped with a heating/cooling jacket, and said vessel also contained 48 kg of chlorobenzene. The contents of the vessel were quickly stirred and the system purged with nitrogen. About. 7.8 kg of boron tribromide was added to the mixture over 20 to 30

minutter og temperaturen på mediet ble holdt under 25°C.minutes and the temperature of the medium was kept below 25°C.

Etter bortribromidtilsetningen ble innholdetAfter the boron tribromide addition, the content became

rørt i 6 timer ved 25 til 28°C. På dette punkt ble reaksjonsblandingen pumpet til et kar på 246 liter og som inneholdt 32,66 kg vann som var avkjølt til mindre enn 10°C. Tilsetningen skjer slik at kartemperaturen holder seg under 30°C. stirred for 6 hours at 25 to 28°C. At this point the reaction mixture was pumped into a 246 liter vessel containing 32.66 kg of water which had been cooled to less than 10°C. The addition takes place so that the vessel temperature remains below 30°C.

Den resulterende blandingen blir pumpet tilbake til reaksjonskaret på 189 liter og oppvarmet med koking tilbakeløp (96°C) under langsom røring for å hindre en emulsjonsdannelse. Etter to timers koking med tilbakeløp ble innholdet i reaksjonskaret avkjølt til 60 til 80°C og lagene ble hensatt for adskillelse. Etter separasjonen ble bunnlaget som var det vandige lag fjernet, og det organiske lag ble renset med 5,67 kg de-ionisert vann under langsom røring. Ved hensetting av blandingen bytter lagene plass slik at det vandige lag nå blir topplaget. Dette ble fjernet og slått sammen med den tidligere vandige ekstraksjons-blandingen . The resulting mixture is pumped back to the 189 liter reaction vessel and heated at reflux (96°C) with slow stirring to prevent emulsion formation. After two hours of reflux, the contents of the reaction vessel were cooled to 60 to 80°C and the layers were set aside for separation. After the separation, the bottom layer which was the aqueous layer was removed, and the organic layer was cleaned with 5.67 kg of de-ionized water under slow stirring. When the mixture is set aside, the layers switch places so that the aqueous layer now becomes the top layer. This was removed and combined with the previous aqueous extraction mixture.

pH i det organiske lag ble justert til 5,5-6,0 med ammoniumhydroksyd. Ca 0,45-0,9 kg darko (aktivert karbon, Darco G-60) ble tilsatt, og blandingen ble filtrert og vasket med fra 3,8-7,6 liter de-ionisert vann. pH ble igjen justert til 8,8-8,9 med ammoniumhydroksyd. Den vandige suspensjonen ble ekstrahert med diklormetan i en kontinuerlig karr kolonne ekstraktor inntil den vandige delen inneholdt mindre enn 1,5 mg oksymorfon pr. ml. Diklormetandelen ble vasket tilbake med 2 3,8 liters porsjoner av de-ionisert vann og returnert til nevnte reaksjonskar på 189 liter og temperaturen ble holdt på 70-80°C. Diklormetanoppløsningen ble destillert til tørrhet, og den siste delen av diklormetanen og gjenværende vann ble fjernet The pH in the organic layer was adjusted to 5.5-6.0 with ammonium hydroxide. About 0.45-0.9 kg of darko (activated carbon, Darco G-60) was added, and the mixture was filtered and washed with from 3.8-7.6 liters of de-ionized water. The pH was again adjusted to 8.8-8.9 with ammonium hydroxide. The aqueous suspension was extracted with dichloromethane in a continuous vessel column extractor until the aqueous portion contained less than 1.5 mg of oxymorphone per ml. The dichloromethane portion was washed back with 2 3.8 liter portions of de-ionized water and returned to said reaction vessel of 189 liters and the temperature was maintained at 70-80°C. The dichloromethane solution was distilled to dryness and the last portion of the dichloromethane and remaining water was removed

under vakuum. Ca.30 liter vannfri etanol ble tilsatt reaksjonskaret og blandingen ble holdt på 65-70°C. Blandingen ble så filtrert hvis dette var nødvendig, og etanolblandingen ble så avkjølt under røring til under 10°C. Det resulterende krystalli-sasjonsproduktet ble frafiltrert og tørket ved 65-70°C fra 2-4 timer, og man fikk fra 1,36 - 1,59 kg oksymorfon. under vacuum. About 30 liters of anhydrous ethanol were added to the reaction vessel and the mixture was kept at 65-70°C. The mixture was then filtered if necessary and the ethanol mixture was then cooled with stirring to below 10°C. The resulting crystallization product was filtered off and dried at 65-70°C from 2-4 hours, and 1.36-1.59 kg of oxymorphone was obtained.

Filtratet ble fordampet til nesten tørrhet og er-stattet med 7,57 liter de-ionisert vann. pH ble justert til mindre enn 5,0 og så igjen justert til 8,5 til 8,8 med ammoniumhydroksyd, mens temperaturen ble holdt på under 30°C. Blandingen ble avkjølt til 10-15°C og det utfelte faste stoff The filtrate was evaporated to near dryness and replaced with 7.57 liters of deionized water. The pH was adjusted to less than 5.0 and then again adjusted to 8.5 to 8.8 with ammonium hydroxide while maintaining the temperature below 30°C. The mixture was cooled to 10-15°C and a solid precipitated

ble filtrert og vasket med to 0,95 liters porsjoner av vann ved 10-15°C. Det stoffet ble så tørket ved 70-80°C i minimum 6 timer, og man fikk 0,36 til 0,5 kg residuum av ytterligere oksymorfon-holdig produkt. was filtered and washed with two 0.95 liter portions of water at 10-15°C. That substance was then dried at 70-80°C for a minimum of 6 hours, and 0.36 to 0.5 kg residue of further oxymorphone-containing product was obtained.

Claims

1. Process for the production of 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 halides with a lower alcohol, in an organic solvent-containing reaction medium under demethylating conditions, characterized in that said reaction medium contains a dampening amount of a dampening agent to dampen the activity of the boron compound, and wherein said dampening agent is a weak Lewis base which is non-reactive with respect to the demethylating agent, whereby oxymorphone is produced in good yield without everything essential gets formed by-products.

2. Method according to claim 1, characterized in that the boron compound is used in an amount such that one obtains from 2 to 8 mol of the boron compound per mol of oxycodone, and the dampening agent is selected from the group consisting of benzene, toluene, xylene, ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ether and mixtures of said dampening agent.

3. Method according to claims 1 to 2, characterized in that the boron compound is used in an amount such that one gets from 2.5 to 3.5 mol of the boron compound per moles of oxycodone.

4. Method according to claim 2, characterized in that the boron compound is boron tribromide or boron trichloride.

5. Method according to claim 4, characterized in that the dampening agent is diphenyl ether, chlorobenzene or toluene.

6. Method 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 dampening agent.

7. Method according to claim 6, characterized in that the boron compound is boron tribromide or boron trichloride and the dampening agent is selected from the group consisting of benzene, toluene, xylene, ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ether and mixtures of these dampening agents.

8. Method according to claim 7, characterized in that the dampening agent is diphenyl ether, chlorobenzene or toluene.

9. Method according to claim 8, characterized in that the dampening agent is present in the demethylating composition in an amount of approx. 90% by weight, based on the total weight of the demethylating composition, and the boron compound is present in an amount of approx. 10% by weight, based on the total weight of the demethylating composition.

10. Method according to claim 9, characterized in that the demethylating conditions include temperatures from approx. 0° to approx. 40°C.

11. Method according to claim 10, characterized in that the demethylating conditions include a reaction time from approx. 3 to approx. 8 hours.

12. Process for producing oxymorphone in good yield and without significant formation of by-products by A) reacting oxycodone under demethylating conditions 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 reaction medium; B) adding water to said reaction medium in an amount sufficient to stop the demethylation reaction; C) hydrolyzes the reactants and reaction products that were formed in said reaction medium; and D) separates the reaction medium and the product oxymorphone; characterized in that said reaction medium contains from approx. 25 to approx. 900 percent by weight based on the weight of said bordemethylating agent of a dampening agent selected from the group consisting of benzene, toluene, xylene, ethylbenzene, chlorobenzene, diphenyl ether and mixtures thereof, and further characterized in that the hydrolysis step is carried out for a sufficiently long time and under such hydrolysis conditions that increases the amount of recoverable oxymorphone present in the reaction medium.

13. Method according to claim 12, characterized in that the hydrolysis of the reactants and reaction products in the reaction medium takes place over a period of 1/2 to 10 hours and the hydrolysis temperature varies from 60 to 120°C.

14. Method according to claim 13, characterized in that the boron compound is boron tribromide or boron trichloride.

15. Method according to claim 13 or 14, characterized in that the dampening agent is diphenyl ether, chlorobenzene or toluene.

16. Method according to claim 15, characterized in that the hydrolysis takes place over a period of 2 to 4 hours, while the reaction medium is boiled under reflux.

17. Method 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 dampening agent.

18. Method according to claim 17, characterized in that the boron compound is boron tribromide or boron trichloride.

19. Method according to claim 17 or 18, characterized in that the dampening agent is diphenyl ether, chlorobenzene or toluene.

20. Method according to claim 19, characterized in that the dampening agent is present in the demethylating composition in an amount of approx. 90% by weight, based on the total weight of the composition, and the boron compound is present in an amount of approx. 10% by weight based on the total weight of the demethylating composition.

21. Method according to claim 20, characterized in that the demethylating conditions include temperatures from 0 to 40°C.

22. Method according to claim 21, characterized in that the demethylating conditions include a reaction time from approx. 3 to approx. 8 hours.