WO2020188583A1 - An improved process for o-demethylating methoxy substituted morphinan-6-one derivatives using boron-based complexes - Google Patents

An improved process for o-demethylating methoxy substituted morphinan-6-one derivatives using boron-based complexes Download PDF

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WO2020188583A1
WO2020188583A1 PCT/IN2019/050421 IN2019050421W WO2020188583A1 WO 2020188583 A1 WO2020188583 A1 WO 2020188583A1 IN 2019050421 W IN2019050421 W IN 2019050421W WO 2020188583 A1 WO2020188583 A1 WO 2020188583A1
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Tejinder Kaur
Rupesh Chhaganbhai KHUNT
Aakarsh SAXENA
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Navin Saxena Research & Technology Pvt. Ltd.
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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

  • the present invention relates to an improved process for O-demethylation of methoxy-substituted morphinan-6-one derivatives using boron-based complex as a demethylating agent in a reaction-inert solvent.
  • the morphinan compounds are a group of structurally-related alkaloids that can act as opiate receptor agonists or opiate receptor antagonists.
  • Opiate receptor agonists such as e.g. morphine, hydromorphone, codeine, hydrocodone, dihydromorphine, dihydrocodeine, oxycodone, hydromorphone, oxymorphone, and nalbuphine are useful as analgesics for pain relief.
  • compounds such as naloxone, naltrexone, and nalmefene are opiate receptor antagonists useful for the treatment of substance abuse or to reverse the effects of opiate agonists.
  • O-demethylating agents for morphinane derivatives include hydrobromic acid, boron tribromide, aluminium chloride, and methanesulphonic acid/methionine system.
  • the yields of these demethylations range from 30% to 80%, depending on the position of O-methoxy group on the morphinane compound.
  • a common drawback involved in the use of the above reagents includes degradation of the starting substrate in varying extent during the period of O-demethylation, which results in a decrease in product yield and quality.
  • Zhang A. et. al. in Organic Letters 2005, 7, 3239-3242 describes another process for preparing 14-hydroxymorphinone by O-dem ethylating 14-hydroxycodeinone by treatment of 14-hydroxycodeinone with BBn in anhydrous dichlorom ethane. Although it is reported by Zhang that 14-hydroxymorphinone was obtained as a pure white solid with a 70% yield; however, according to the disclosures of WO2015/155181 Al by Ulrich Weigl, the results reported by Zhang A. et. al. could not be reproduced and 14-hydroxymorphinone could only be isolated in a yield of 15% to 25%, as shown below.
  • nitrobenzene as-of-yet has not received any regulatory classification (Class 1 / Class 2 / Class 3 solvent) according to accepted regulatory standards such as USFDA Q3C and/or ICH Q3C(R7) guidelines and its safety profile has not been clearly established.
  • the reaction work-up, purification, and product isolation procedure is tedious and difficult to perform, involving dilution with acetonitrile, filtration, washing with methylisobutylketone to isolate a crude product which is further diluted with methanol, filtered, and washed with acetone.
  • the obtained crude product is diluted with water, titrated with triethylamine to a pH of 8.8-9.2, followed by filtration, washing with water, and drying to yield the final product.
  • Patent CN103113378 describes the preparation of oxymorphone hydrochloride by O-demethylation of oxycodone using amino acids in an acidic environment.
  • a process for preparing oxymorphone by O-demethylating oxycodone is described originally by Jean Daniel Andre in Synthetic Communications 1992, 2313-2327 by treatment of oxycodone with methionine in methanesulfonic acid as a solvent.
  • Patent US5071985 describes the preparation of morphinane derivatives by O- demethylation of 3 -m ethoxy derivatives with methanesulfonic acid or trifluoromethanesulfonic acid in the presence of a sulphide (methionine).
  • novel demethylating reagents are air- and moisture-stable and easy-to- handle.
  • the reaction may also be performed in the presence of a catalyst, which can be an inorganic halide or be a quaternary iminium or phosphonium compound of formula (III), with no significant improvement to the isolated yield and/or purity of the O-demethylated product.
  • the present invention relates to a process for preparing a compound of formula (I), which is characterized by the steps of:
  • R 1 and R 2 independently are a hydrogen atom or a substituted or unsubstituted alkyl group with 1 to 20 carbon atoms, or an allyl group, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, or a substituted or unsubstituted carbonylalkyl group with 1 to 20 carbon atoms in the alkyl residue, or a substituted or unsubstituted carbonylaryl group, or a substituted or unsubstituted carbonylalkylaryl group with 1 to 20 carbon atoms in the alkyl reside, or a substituted or unsubstituted carbonyloxyalkyl group with 1 to 20 carbon atoms in the alkyl residue, or a substituted or unsubstituted carbonyloxyaryl group or a substituted or unsubstituted carbonyloxyalkylaryl group with 1 to 20 carbon
  • R 1 is substituted or unsubstituted alkyl group having 1 to 5 carbon atoms;
  • R 1 is methyl
  • R 2 is hydrogen
  • R 2 is acetyl
  • R 1 is methyl and R 2 is hydrogen; or g) R 1 is hydrogen and R 2 is hydrogen; or
  • R 1 is methyl and R 2 is acetyl
  • R 1 is CH2-cyclopropyl and R 2 is hydrogen
  • R 1 is CH2-cyclobutyl and R 2 is hydrogen
  • R 1 is CH2-cyclopropyl and R 2 is acetyl;
  • R 1 is CH2-cyclobutyl and R 2 is acetyl
  • R 1 is allyl and R 2 is hydrogen;
  • R 1 is allyl and R 2 is acetyl
  • the boron-based demethylating complex can be any complex of the general formula B(R 4 )3*xR 5 , wherein the groups R 4 can be the same or different and are each selected from fluoride, chloride, bromide, or iodide; and the group R 5 can be selected from a dialkyl sulphide, dialkenyl sulphide, diallyl sulphide, diaryl sulphide, arylalkyl sulphide of formula R 10 SR U wherein, R 10 and R 11 independently are a hydrogen atom or a substituted or unsubstituted alkyl group with 1 to 20 carbon atoms, or an allyl group, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, or the group R 5 can be dimethyl ether, diethyl ether, dipropyl ether, dibutyl ether, dipentyl
  • the boron-based demethylating complex of general formula B(R 4 )3*xR 5 can be preferably selected from the group consisting of BF3*2FbC) (Boron trifluoride dihydrate complex), BF3*H20 (Boron trifluoride monohydrate complex), BF3*MeOH (Boron trifluoride methanol complex), BF3*2PhOH (Boron trifluoride diphenol complex), BF3*OEt2 (Boron trifluoride diethyl etherate complex), BF3*OMe2 (Boron trifluoride dimethyl etherate complex), BF3*0(n-Bu)2 (Boron trifluoride dibutyl etherate complex), BF3*0(/-Bu)Me (Boron trifluoride tert- butylmethyl etherate complex), BF3*SMe2 (Boron trifluoride dimethyl sulphide complex), BF3*2CH3C02H
  • the boron-based demethylating complex is preferably BF 3* SMe2.
  • the boron-based demethylating complex is preferably BBn*SMe2.
  • the amount of boron-based demethylating agent of the formula B(R 4 )3*xR 5 ranges from about 1 molar equivalent to about 100 molar equivalent with respect to the compound of formula (II). If less boron-based demethylating complex is used the reaction takes longer and/or may not run to completion. If more boron-based demethylating complex is used, more side-products are formed.
  • the boron-based demethylating complex is preferably BF3*SMe2 and the amount of BF3*SMe2 used is preferably between about 1 molar equivalent to about 10 molar equivalent with respect to the compound of formula (II).
  • the catalyst used is an inorganic halide or a quaternary iminium or phosphonium compound of the following formula:
  • the catalyst used may be alkali halide such as lithium iodide, sodium iodide, potassium iodide or an iminium or phosphonium compound of the formula (III), wherein, A is tetravalent nitrogen or phosphorus, and R 6 , R 7 , R 8 , and R 9 independently are a hydrogen atom or a substituted or unsubstituted alkyl group with 1 to 20 carbon atoms, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, and B is an anion selected from fluoride, chloride, bromide, iodide, sulphate, sulphite, hydrogensulphate, hydrogensulphite, nitrate, nitrite, phosphate, hydrogenphosphate, or dihydrogenphosphate.
  • alkali halide such as lithium iodide, sodium iodide, potassium
  • the catalyst is used in an amount of 0.1 to 1 molar equivalent with respect to the morphinane compound of the formula (II), preferably 0.2 to 0.4 molar equivalent, wherein it is preferable to use an iminium or phosphonium compound of formula (III) selected from the group consisting of tetrabutylammonium chloride (TBAC), tetrabutyl ammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), benzyltriethylammonium chloride, benzyltriethylammonium bromide (TEBA), benzyltri ethyl ammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, cetyltriethylammonium chloride, cetyltriethylammonium bromide, cetyltrie
  • the inert reaction solvent can be any solvent that remains inert and do not interfere with the progress of the reaction that is selected from the group consisting of e.g. tetrahydrofuran, 2-methyl tetrahydrofuran, ieri-butylmethyl ether, cyclopentylmethyl ether, diethyl ether, dimethylsulfoxide, ethyl acetate, acetonitrile, cyclohexane, methylcyclohexane, A, A-di methyl acetamide, N,N- dimethylformamide, 1,4-dioxane, ethyleneglycol, formamide, pentane, hexane, heptane, toluene, xylene, trifluorotoluene, tetrachloromethane, trichloromethane, dichlorom ethane, 1,2-dichloroethane, 1, 1,1-trichloroethane,
  • the process of the present invention can be performed at any temperature above - 70 °C, requiring a reflux-condenser for any reaction temperature exceeding the boiling point of the inert reaction solvent.
  • dichloromethane is used as the inert reaction solvent
  • the process is performed at a temperature between about -50 °C and about 90 °C.
  • the temperature can range between about - 20 °C and about 70 °C, or between about -10 °C and 50 °C or between -10 °C to 40 °C.
  • toluene is used as the inert reaction solvent
  • the process is performed at a temperature between about -50 °C and about 110 °C.
  • the temperature can range between about -20 °C and about 70 °C, or between about - 10 °C and 50 °C or between -10 °C to 40 °C.
  • a 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer.
  • oxycodone 100 g, 317 mmol
  • dichloromethane 800 mL
  • the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0 °C - 5 °C.
  • 0.5 kg BBn*SMe2 was dissolved in 200 mL dichlormethane and the solution was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
  • the obtained oxymorphone could optionally be further purified by dissolving the solid in 300 mL isopropanol and stirring at 80 °C for 20 minutes. The mixture was slowly cooled to 15 °C at which point white solid was observed to precipitate out of the mixture. The temperature was maintained at 15 °C for 1 hour and the mixture was filtered and the precipitate was washed with 50 mL of cold isopropanol and then collected. The solid precipitate was dried in an oven at 65 °C - 70 °C for 5-6 hours, and oxymorphone was obtained in 86% isolated yield and having an HPLC purity of >95% using the method described under‘Analytical Method’.
  • reaction mixture 200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
  • the obtained oxymorphone could optionally be further purified by dissolving the solid in 300 mL isopropanol and stirring at 80 °C for 20 minutes. The mixture was slowly cooled to 15 °C at which point white solid was observed to precipitate out of the mixture. The temperature was maintained at 15 °C for 1 hour and the mixture was filtered and the precipitate was washed with 50 mL of cold isopropanol and then collected. The solid precipitate was dried in an oven at 65 °C - 70 °C for 5-6 hours, and oxymorphone was obtained in 91% isolated yield and having an HPLC purity of >99% using the method described under‘Analytical Method’.
  • Example 3 preparation of oxymorphone using BF3 «SMe2 in toluene as a solvent
  • thermometer pocket containing a thermometer.
  • oxycodone 100 g, 317 mmol was added to 1.0 L toluene and the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0
  • the obtained oxymorphone could optionally be further purified by dissolving the solid in 300 mL isopropanol and stirring at 80 °C for 20 minutes. The mixture was slowly cooled to 15 °C at which point white solid was observed to precipitate out of the mixture. The temperature was maintained at 15 °C for 1 hour and the mixture was filtered and the precipitate was washed with 50 mL of cold isopropanol and then collected.
  • Example 4 preparation of oxymorphone using BF 3 # SMe 2 and Nal as a catalyst
  • reaction mixture 200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
  • Example 5 preparation of oxymorphone using BF.i»SMe3 ⁇ 4 and TBAI as a catalyst
  • a 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer.
  • oxycodone 100 g, 317 mmol
  • tetrabutylammonium iodide 29 g, 79 mmol
  • reaction mixture 200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
  • a 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer. Under a nitrogen atmosphere 14-hydroxy codeinone (100 g, 317 mmol) was added to 1.0 L dichloromethane and the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0 °C - 5 °C.
  • reaction mixture 200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
  • the obtained 14-hydroxymorphinone could optionally be further purified by dissolving the solid in 300 mL isopropanol and stirring at 80 °C for 20 minutes. The mixture was slowly cooled to 15 °C at which point white solid was observed to precipitate out of the mixture. The temperature was maintained at 15 °C for 1 hour and the mixture was filtered and the precipitate was washed with 50 mL of cold isopropanol and then collected. The solid precipitate was dried in an oven at 65 °C - 70 °C for 5-6 hours, and 14-hydroxymorphinone was obtained in 83% isolated yield and having an HPLC purity of >95% using the method described under ‘Analytical Method’.
  • Example 7 preparation of 14-acetylmorphinone using BF3 # SMe2
  • a 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer. Under a nitrogen atmosphere 14-acetylcodeinone (100 g, 317 mmol) was added to 1.0 L dichloromethane and the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0 °C - 5 °C.
  • reaction mixture 200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
  • the obtained 14-acetylmorphinone could optionally be further purified by dissolving the solid in 300 mL isopropanol and stirring at 80 °C for 20 minutes. The mixture was slowly cooled to 15 °C at which point white solid was observed to precipitate out of the mixture. The temperature was maintained at 15 °C for 1 hour and the mixture was filtered and the precipitate was washed with 50 mL of cold isopropanol and then collected. The solid precipitate was dried in an oven at 65 °C - 70 °C for 5-6 hours, and 14-acetylmorphinone was obtained in 92% isolated yield and having an HPLC purity of >99% using the method described under‘Analytical Method’ .
  • Sample solvent 10 g H3PO4 (85wt%) in 800 mL water and 200 mL acetonitrile (1/80/20; W/V/V).
  • the use of the boron-based complex as demethylating agent avoids the problem of degradation of the demethylating agent such as BBn and production of hazardous fumes during the reaction. Therefore, the claimed process is highly safe to carry out on industrial scale.
  • the process of the present invention can be carried out preferably at ambient temperature to reflux temperature of the solvent used, thereby making the process easier for industrial scale up.
  • the process of the present invention facilitates easy isolation of the product with high purity by simple work up, i.e., by extracting into organic layer.
  • the boron- based demethylation complex and its by-products will remain in the aqueous layer, thereby making the process cost-effective.
  • the boron-based demethylating complex facilitates the reaction to completion with a higher yield whereby little or no unreacted starting material is found after work up procedure.
  • the solvents employed in the process are cheaper, safer and commercially available which makes the process easier to carry out on industrial scale.

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Abstract

The present invention discloses an improved process for O-demethylation of methoxy-substituted morphinan-6-one derivatives using boron-based complex as a demethylating boron complex in an inert reaction solvent.

Description

“An improved process for O-demethylating Methoxy Substituted Morphinan-6-One Derivatives Using Boron-Based Complexes”
Field of the Invention:
The present invention relates to an improved process for O-demethylation of methoxy-substituted morphinan-6-one derivatives using boron-based complex as a demethylating agent in a reaction-inert solvent.
Background of the Invention:
The morphinan compounds are a group of structurally-related alkaloids that can act as opiate receptor agonists or opiate receptor antagonists. Opiate receptor agonists such as e.g. morphine, hydromorphone, codeine, hydrocodone, dihydromorphine, dihydrocodeine, oxycodone, hydromorphone, oxymorphone, and nalbuphine are useful as analgesics for pain relief. However, compounds such as naloxone, naltrexone, and nalmefene are opiate receptor antagonists useful for the treatment of substance abuse or to reverse the effects of opiate agonists.
The commonly used O-demethylating agents for morphinane derivatives include hydrobromic acid, boron tribromide, aluminium chloride, and methanesulphonic acid/methionine system. The yields of these demethylations range from 30% to 80%, depending on the position of O-methoxy group on the morphinane compound.
A common drawback involved in the use of the above reagents includes degradation of the starting substrate in varying extent during the period of O-demethylation, which results in a decrease in product yield and quality.
Ulrich Weiss in the Journal of Organic Chemistry 1957, 1505-1508 discloses a process for preparing 14-hydroxymorphinone by O-demethylating 14- hydroxycodeinone by treatment of 14-hydroxy codeinone with a concentrated aqueous solution of hydrobromic acid at 120 °C, followed by removal of non- phenolic material by extraction with chloroform from alkaline medium, and extraction of the phenolic reaction products with chloroform or chloroform-ethanol at pH range of 8-9. The reported yields are very low and variable ranging between 35% and 52%. Also, undesired hydration of the double bond in 14- hydroxymorphinone was observed with the formation of 8, 14- dihydroxy dihydromorphinone as a by-product.
Figure imgf000003_0001
Zhang A. et. al. in Organic Letters 2005, 7, 3239-3242 describes another process for preparing 14-hydroxymorphinone by O-dem ethylating 14-hydroxycodeinone by treatment of 14-hydroxycodeinone with BBn in anhydrous dichlorom ethane. Although it is reported by Zhang that 14-hydroxymorphinone was obtained as a pure white solid with a 70% yield; however, according to the disclosures of WO2015/155181 Al by Ulrich Weigl, the results reported by Zhang A. et. al. could not be reproduced and 14-hydroxymorphinone could only be isolated in a yield of 15% to 25%, as shown below.
Figure imgf000003_0002
Hence there is a need for a more efficient process with a higher yield whereby little or no unreacted starting material is found after work-up procedures. Another process for preparing 14-hydroxymorphinone by O-demethylating 14- hydroxycodeinone is described by Ulrich Weigl in the patent WO2015/155181 A1 by treatment of 14-hydroxy codeinone with AlCb in a reaction-inert solvent having water content from 0.1% wt. to 0.8% wt. The solvent used by Weigl is nitrobenzene, which is a relatively expensive choice of solvent. More importantly, nitrobenzene as-of-yet has not received any regulatory classification (Class 1 / Class 2 / Class 3 solvent) according to accepted regulatory standards such as USFDA Q3C and/or ICH Q3C(R7) guidelines and its safety profile has not been clearly established. Additionally, the reaction work-up, purification, and product isolation procedure is tedious and difficult to perform, involving dilution with acetonitrile, filtration, washing with methylisobutylketone to isolate a crude product which is further diluted with methanol, filtered, and washed with acetone. The obtained crude product is diluted with water, titrated with triethylamine to a pH of 8.8-9.2, followed by filtration, washing with water, and drying to yield the final product.
Figure imgf000004_0001
Hence there is a need for a more efficient process that utilizes an efficient demethylating agent and a solvent with a well-established safety profile found in the USFDA and ICH regulatory guidelines. Furthermore, a process with a simple reaction work-up, purification, and product isolation procedure would be highly- desirable.
Patent CN103113378 describes the preparation of oxymorphone hydrochloride by O-demethylation of oxycodone using amino acids in an acidic environment. A process for preparing oxymorphone by O-demethylating oxycodone is described originally by Jean Daniel Andre in Synthetic Communications 1992, 2313-2327 by treatment of oxycodone with methionine in methanesulfonic acid as a solvent. Patent US5071985 describes the preparation of morphinane derivatives by O- demethylation of 3 -m ethoxy derivatives with methanesulfonic acid or trifluoromethanesulfonic acid in the presence of a sulphide (methionine). Depending on the starting morphinane, the authors obtained product in yields of 60% - 90%. These methods are not ideal due to their laborious work-up and purification procedure. During aqueous extraction of the crude reaction mixture, a thick and unavoidable emulsion forms between the organic and aqueous layers, which does not settle even when left to settle for several days. This inadvertently leads to isolation of the desired product with diminished yields and containing high levels of various other impurities.
Figure imgf000005_0001
Hence there is a need for a more efficient process with simpler reaction work-up, purification, and product isolation procedures so as to be scalable for industrial production.
Another process for preparing oxymorphone by O-demethylating oxycodone is described by Ole Heine Kvemenes in the patent US20100022774A1, by treatment of oxycodone with BBn in a halogenated solvent. International application WO 9902529A1 describes preparation of naltrexone by O-demethylation of 3-methoxy derivative using BBn in dichloromethane. The authors obtained product in a yield of 98%, however the purity of the obtained product is not stated. International application WO 2007/137785A2 describes preparation of morphinane derivatives by O -demethyl ati on using BBn in aprotic solvents. The authors obtained product in yields of 60% - 90%, with the O-demethylated product showing a purity of not more than 90%. International application WO 2009/111162 describes preparation of oxymorphone by O-demethylation of oxycodone with BBn in dichloromethane. The authors isolated the product in the form of a crude base in a yield of 78%. International application WO 2019/009820 describes the O-demethylation of methoxy-substituted morphinan-6-one derivatives by using BBn in a non- halogenated eco-friendly solvent with the addition of a catalyst. In all the examples of this application, the in-process HPLC analysis results are presented showing the percentage of product formed and the percentage of un-reacted starting material in situ ; however, the yield and purity of the isolated product has not been mentioned in any single case.
Figure imgf000006_0001
A cursory review of prior art reveals that while BBn has been employed extensively for the O-demethylation of methoxy-substituted morphinan-6-one derivatives, the reported yield and purity seems to be highly variable and inconsistent. This inconsistency can be attributed to the highly reactive and highly unstable nature of BBn (and other pure boron trihalides), making these reagents extremely difficult to use in large-scale industrial operations as they degrade spontaneously upon exposure to air and moisture releasing toxic fumes of HBr. This further poses serious health and safety concerns. Due to their instability, boron trihalide reagents require special handling procedures so as to ensure that exposure to air is minimized as this can lead to rapid degradation of the reagent leading to inconsistent reaction outcome. Hence there is a need for a more efficient process utilizing safer and easy- to-use reagents. The hazardous nature of BBn and other boron-based Lewis acids is well-known and well-reported in literature. Complexation is a technique commonly-employed in order to stabilize these highly air- and moisture-unstable boron reagents, making the resulting boron trihalide complexes easy-to-handle and air- and moisture-stable over a long duration of time as is documented in the paper Tetrahedron Letters 1980, 21, 3731. To the best of our knowledge, these boron trihalide complexes, while routinely used for O-demethylation of simple aryl alkyl ethers, have yet not been employed for the selective O-demethylation of more complex methoxy- substituted morphinan-6-one derivatives.
Summary of the Invention:
It has now been found that O-demethylation of methoxy-substituted morphinan-6- one derivatives of formula (II), for example, oxycodone and 14-hydroxy codeinone, can be performed with a higher yield, and higher purity in an inert reaction solvent using boron-based demethylating complex of formula B(R4)3*xR5, as a demethylating reagent, wherein the groups R4 can be the same or different and are each selected from fluoride, chloride, bromide, or iodide; and the group R5 can be a dialkyl sulphide, dialkenyl sulphide, diallyl sulphide, diaryl sulphide, arylalkyl sulphide of formula R10SRU wherein, R10 and R11 independently are a hydrogen atom or a substituted or unsubstituted alkyl group with 1 to 20 carbon atoms, or an allyl group, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, or the group R5 can be dimethyl ether, diethyl ether, dipropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, cyclopentylmethyl ether, ieri-butylmethyl ether, tetrahydrofuran, acetonitrile, phenol, methanol, ethanol, propanol, butanol, water, acetic acid; and x, representing the number of complexing molecules, can be between 1 to 3.
These novel demethylating reagents are air- and moisture-stable and easy-to- handle. The reaction may also be performed in the presence of a catalyst, which can be an inorganic halide or be a quaternary iminium or phosphonium compound of formula (III), with no significant improvement to the isolated yield and/or purity of the O-demethylated product.
Description of the Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term“about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein in meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.
To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that where a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein.
Accordingly, in one aspect, the present invention relates to a process for preparing a compound of formula (I), which is characterized by the steps of:
O-demethylating a compound of formula (II) in an inert reaction solvent using a boron-based complex as demethylating agent in the presence or absence of a catalyst which can be an inorganic halide or be a quaternary iminium or phosphonium compound of formula (III),
Figure imgf000009_0001
wherein
R1 and R2 independently are a hydrogen atom or a substituted or unsubstituted alkyl group with 1 to 20 carbon atoms, or an allyl group, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, or a substituted or unsubstituted carbonylalkyl group with 1 to 20 carbon atoms in the alkyl residue, or a substituted or unsubstituted carbonylaryl group, or a substituted or unsubstituted carbonylalkylaryl group with 1 to 20 carbon atoms in the alkyl reside, or a substituted or unsubstituted carbonyloxyalkyl group with 1 to 20 carbon atoms in the alkyl residue, or a substituted or unsubstituted carbonyloxyaryl group or a substituted or unsubstituted carbonyloxyalkylaryl group with 1 to 20 carbon atoms in the alkyl reside, or a cyanide group, or a silyl group of formula Si(R3)3, wherein the groups R3 can be the same or different and are each selected from substituted or unsubstituted alkyl groups having 1 to 6 carbon atoms and substituted or unsubstituted phenyl groups, respectively; and represents a saturated C-C single bond or an unsaturated C-C double bond.
Interesting processes of the present invention are those wherein one or more of the following restrictions apply to the compounds of formula (I) as well as formula (II): a) R1 is hydrogen; or
b) R1 is substituted or unsubstituted alkyl group having 1 to 5 carbon atoms; or
c) R1 is methyl; or
d) R2 is hydrogen; or
e) R2 is acetyl; or
f) R1 is methyl and R2 is hydrogen; or g) R1 is hydrogen and R2 is hydrogen; or
h) R1 is methyl and R2 is acetyl; or
i) R1 is CH2-cyclopropyl and R2 is hydrogen; or
j) R1 is CH2-cyclobutyl and R2 is hydrogen; or
k) R1 is CH2-cyclopropyl and R2 is acetyl; or
l) R1 is CH2-cyclobutyl and R2 is acetyl; or
m) R1 is allyl and R2 is hydrogen; or
n) R1 is allyl and R2 is acetyl
The boron-based demethylating complex can be any complex of the general formula B(R4)3*xR5, wherein the groups R4 can be the same or different and are each selected from fluoride, chloride, bromide, or iodide; and the group R5 can be selected from a dialkyl sulphide, dialkenyl sulphide, diallyl sulphide, diaryl sulphide, arylalkyl sulphide of formula R10SRU wherein, R10 and R11 independently are a hydrogen atom or a substituted or unsubstituted alkyl group with 1 to 20 carbon atoms, or an allyl group, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, or the group R5 can be dimethyl ether, diethyl ether, dipropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, cyclopentylmethyl ether, ieri-butylmethyl ether, tetrahydrofuran, acetonitrile, phenol, methanol, ethanol, propanol, butanol, water, acetic acid; and x, representing the number of complexing molecules, can be between 1 to 3.
The boron-based demethylating complex of general formula B(R4)3*xR5 can be preferably selected from the group consisting of BF3*2FbC) (Boron trifluoride dihydrate complex), BF3*H20 (Boron trifluoride monohydrate complex), BF3*MeOH (Boron trifluoride methanol complex), BF3*2PhOH (Boron trifluoride diphenol complex), BF3*OEt2 (Boron trifluoride diethyl etherate complex), BF3*OMe2 (Boron trifluoride dimethyl etherate complex), BF3*0(n-Bu)2 (Boron trifluoride dibutyl etherate complex), BF3*0(/-Bu)Me (Boron trifluoride tert- butylmethyl etherate complex), BF3*SMe2 (Boron trifluoride dimethyl sulphide complex), BF3*2CH3C02H (Boron trifluoride acetic acid complex), BF3*CH3CN (Boron trifluoride acetonitrile complex), BF3*n-PrOH (Boron trifluoride n- propanol complex), BF3*n-BuOH (Boron trifluoride n-butanol complex), BF3*THF (Boron trifluoride tetrahydrofuran complex), BCl3*SMe2 (Boron trichloride dimethyl sulphide complex), BCb*MeOH (Boron trichloride methanol complex), and BBr3*SMe2 (Boron tribromide dimethyl sulphide complex).
In one preferred embodiment, the boron-based demethylating complex is preferably BF3*SMe2.
In another preferred embodiment, the boron-based demethylating complex is preferably BBn*SMe2.
The amount of boron-based demethylating agent of the formula B(R4)3*xR5 ranges from about 1 molar equivalent to about 100 molar equivalent with respect to the compound of formula (II). If less boron-based demethylating complex is used the reaction takes longer and/or may not run to completion. If more boron-based demethylating complex is used, more side-products are formed. In an embodiment, the boron-based demethylating complex is preferably BF3*SMe2 and the amount of BF3*SMe2 used is preferably between about 1 molar equivalent to about 10 molar equivalent with respect to the compound of formula (II).
The catalyst used is an inorganic halide or a quaternary iminium or phosphonium compound of the following formula:
Figure imgf000011_0001
Formula (III) The catalyst used may be alkali halide such as lithium iodide, sodium iodide, potassium iodide or an iminium or phosphonium compound of the formula (III), wherein, A is tetravalent nitrogen or phosphorus, and R6, R7 , R8, and R9 independently are a hydrogen atom or a substituted or unsubstituted alkyl group with 1 to 20 carbon atoms, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, and B is an anion selected from fluoride, chloride, bromide, iodide, sulphate, sulphite, hydrogensulphate, hydrogensulphite, nitrate, nitrite, phosphate, hydrogenphosphate, or dihydrogenphosphate.
The catalyst is used in an amount of 0.1 to 1 molar equivalent with respect to the morphinane compound of the formula (II), preferably 0.2 to 0.4 molar equivalent, wherein it is preferable to use an iminium or phosphonium compound of formula (III) selected from the group consisting of tetrabutylammonium chloride (TBAC), tetrabutyl ammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), benzyltriethylammonium chloride, benzyltriethylammonium bromide (TEBA), benzyltri ethyl ammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, cetyltriethylammonium chloride, cetyltriethylammonium bromide, cetyltriethylammonium iodide, optionally in association with alkali halide.
The inert reaction solvent can be any solvent that remains inert and do not interfere with the progress of the reaction that is selected from the group consisting of e.g. tetrahydrofuran, 2-methyl tetrahydrofuran, ieri-butylmethyl ether, cyclopentylmethyl ether, diethyl ether, dimethylsulfoxide, ethyl acetate, acetonitrile, cyclohexane, methylcyclohexane, A, A-di methyl acetamide, N,N- dimethylformamide, 1,4-dioxane, ethyleneglycol, formamide, pentane, hexane, heptane, toluene, xylene, trifluorotoluene, tetrachloromethane, trichloromethane, dichlorom ethane, 1,2-dichloroethane, 1, 1,1-trichloroethane, fluorobenzene, chlorobenzene, 1,2-di chlorobenzene, 1,3-dichlorobenzene, 1,4-di chlorobenzene, 1, 2, 4-tri chlorobenzene, benzene, or a mixture thereof. In one embodiment, the reaction-inert solvent is preferably dichloromethane. In another preferred embodiment, the reaction-inert solvent is toluene.
The process of the present invention can be performed at any temperature above - 70 °C, requiring a reflux-condenser for any reaction temperature exceeding the boiling point of the inert reaction solvent. When dichloromethane is used as the inert reaction solvent, the process is performed at a temperature between about -50 °C and about 90 °C. In an embodiment, the temperature can range between about - 20 °C and about 70 °C, or between about -10 °C and 50 °C or between -10 °C to 40 °C. When toluene is used as the inert reaction solvent, the process is performed at a temperature between about -50 °C and about 110 °C. In an embodiment, the temperature can range between about -20 °C and about 70 °C, or between about - 10 °C and 50 °C or between -10 °C to 40 °C.
The present invention is exemplified by the following examples which are provided for illustration only and, should not be construed to limit the scope of the invention.
Examples:
Example 1: preparation of oxymorphone using BBr3«SMe2
Figure imgf000013_0001
A 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer. Under a nitrogen atmosphere oxycodone (100 g, 317 mmol) was added to 800 mL dichloromethane and the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0 °C - 5 °C.
0.5 kg BBn*SMe2 was dissolved in 200 mL dichlormethane and the solution was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
1.35 L demineralised water was slowly added into the reaction mixture and stirred for 15 minutes. Aqueous ammonia was added into the reaction mixture until a pH of 8.5 - 9.0 was obtained at ambient temperature (25 °C - 30 °C) at which point stirring of the reaction mixture was halted and the layers were allowed to separate. The organic dichloromethane layer was collected, whereas the aqueous layer was subjected to 4 further extractions using 1.5 L of dichloromethane in each extraction. The combined organic dichloromethane layers was dried using anhydrous sodium sulphate (100 g), filtered, and rinsed with additional 200 mL dichloromethane. The filtrate was concentrated via distillation. Solid oxymorphone was obtained with an isolated yield of 92% and HPLC purity of 90.4% using the method described under ‘Analytical Method’.
Purification of oxymorphone:
The obtained oxymorphone could optionally be further purified by dissolving the solid in 300 mL isopropanol and stirring at 80 °C for 20 minutes. The mixture was slowly cooled to 15 °C at which point white solid was observed to precipitate out of the mixture. The temperature was maintained at 15 °C for 1 hour and the mixture was filtered and the precipitate was washed with 50 mL of cold isopropanol and then collected. The solid precipitate was dried in an oven at 65 °C - 70 °C for 5-6 hours, and oxymorphone was obtained in 86% isolated yield and having an HPLC purity of >95% using the method described under‘Analytical Method’.
Example 2: preparation of oxymorphone using BF3 #SMe2
Figure imgf000015_0001
A 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer. Under a nitrogen atmosphere oxycodone (100 g, 317 mmol) was added to 1.0 L dichloromethane and the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0 °C - 5 °C.
200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
1.35 L demineralised water was slowly added into the reaction mixture and stirred for 15 minutes. Aqueous ammonia was added into the reaction mixture until a pH of 8.5 - 9.0 was obtained at ambient temperature (25 °C - 30 °C) at which point stirring of the reaction mixture was halted and the layers were allowed to separate. The organic dichloromethane layer was collected, whereas the aqueous layer was subjected to 4 further extractions using 1.5 L of dichloromethane in each extraction. The combined organic dichloromethane layers was dried using anhydrous sodium sulphate (100 g), filtered, and rinsed with additional 200 mL dichloromethane. The filtrate was concentrated via distillation. Solid oxymorphone was obtained with an isolated yield of 96% and HPLC purity of 95.5% using the method described under ‘Analytical Method’.
Purification of oxymorphone:
The obtained oxymorphone could optionally be further purified by dissolving the solid in 300 mL isopropanol and stirring at 80 °C for 20 minutes. The mixture was slowly cooled to 15 °C at which point white solid was observed to precipitate out of the mixture. The temperature was maintained at 15 °C for 1 hour and the mixture was filtered and the precipitate was washed with 50 mL of cold isopropanol and then collected. The solid precipitate was dried in an oven at 65 °C - 70 °C for 5-6 hours, and oxymorphone was obtained in 91% isolated yield and having an HPLC purity of >99% using the method described under‘Analytical Method’.
Example 3: preparation of oxymorphone using BF3«SMe2 in toluene as a solvent
Figure imgf000016_0001
A 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer. Under a nitrogen atmosphere oxycodone (100 g, 317 mmol) was added to 1.0 L toluene and the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0
C - 5 °C. 200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
1.35 L demineralised water was slowly added into the reaction mixture and stirred for 15 minutes. Aqueous ammonia was added into the reaction mixture until a pH of 8.5 - 9.0 was obtained at ambient temperature (25 °C - 30 °C) at which point stirring of the reaction mixture was halted and the layers were allowed to separate. The organic toluene layer was collected, whereas the aqueous layer was subjected to 4 further extractions using 1.5 L of di chi orom ethane in each extraction. The combined organic dichloromethane and toluene layers was dried using anhydrous sodium sulphate (100 g), filtered, and rinsed with additional 200 mL dichloromethane. The filtrate was concentrated via distillation. Crude oxymorphone was obtained with an isolated yield of 98% and HPLC purity of 70.8% using the method described under‘Analytical Method’.
Purification of oxymorphone:
The obtained oxymorphone could optionally be further purified by dissolving the solid in 300 mL isopropanol and stirring at 80 °C for 20 minutes. The mixture was slowly cooled to 15 °C at which point white solid was observed to precipitate out of the mixture. The temperature was maintained at 15 °C for 1 hour and the mixture was filtered and the precipitate was washed with 50 mL of cold isopropanol and then collected.
The above purification of oxymorphone procedure was repeated two additional times. The solid precipitate obtained was dried in an oven at 65 °C - 70 °C for 5-6 hours, and oxymorphone was obtained in 77% isolated yield and having an HPLC purity of >95% using the method described under‘Analytical Method’. Example 4: preparation of oxymorphone using BF3 #SMe2 and Nal as a catalyst
Figure imgf000018_0001
A 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer. Under a nitrogen atmosphere oxycodone (100 g, 317 mmol) and sodium iodide (12 g, 79 mmol) was added to 1.0 L dichloromethane and the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0 °C - 5 °C.
200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
1.35 L demineralised water was slowly added into the reaction mixture and stirred for 15 minutes. Aqueous ammonia was added into the reaction mixture until a pH of 8.5 - 9.0 was obtained at ambient temperature (25 °C - 30 °C) at which point stirring of the reaction mixture was halted and the layers were allowed to separate. The organic dichloromethane layer was collected, whereas the aqueous layer was subjected to 4 further extractions using 1.5 L of dichloromethane in each extraction. The combined organic dichloromethane layers was dried using anhydrous sodium sulphate (100 g), filtered, and rinsed with additional 200 mL dichloromethane. The filtrate was concentrated via distillation. Solid oxymorphone was obtained with an isolated yield of >95% and HPLC purity of >95% using the method described under ‘Analytical Method’.
Since the product is obtained in a HPLC purity of more than 95%; no further purification of oxymorphone is required to carry out unlike purification process demonstrated in the examples 1 and 2
Example 5: preparation of oxymorphone using BF.i»SMe¾ and TBAI as a catalyst
Figure imgf000019_0001
A 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer. Under a nitrogen atmosphere oxycodone (100 g, 317 mmol) and tetrabutylammonium iodide (29 g, 79 mmol) were added to 1.0 L dichloromethane and the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0 °C - 5 °C.
200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
1.35 L demineralised water was slowly added into the reaction mixture and stirred for 15 minutes. Aqueous ammonia was added into the reaction mixture until a pH of 8.5 - 9.0 was obtained at ambient temperature (25 °C - 30 °C) at which point stirring of the reaction mixture was halted and the layers were allowed to separate. The organic dichloromethane layer was collected, whereas the aqueous layer was subjected to 4 further extractions using 1.5 L of dichloromethane in each extraction. The combined organic dichloromethane layers was dried using anhydrous sodium sulphate (100 g), filtered, and rinsed with additional 200 mL dichloromethane. The filtrate was concentrated via distillation. Solid oxymorphone was obtained with an isolated yield of >95% and HPLC purity of >95% using the method described under ‘Analytical Method’.
Since the product is obtained in a HPLC purity of more than 95%; no further purification of oxymorphone is required to carry out unlike purification process demonstrated in the examples 1 and 2
Example 6: preparation of 14-hydroxymorphinone using BF3«SMe2
Figure imgf000020_0001
A 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer. Under a nitrogen atmosphere 14-hydroxy codeinone (100 g, 317 mmol) was added to 1.0 L dichloromethane and the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0 °C - 5 °C.
200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
1.35 L demineralised water was slowly added into the reaction mixture and stirred for 15 minutes. Aqueous ammonia was added into the reaction mixture until a pH of 8.5 - 9.0 was obtained at ambient temperature (25 °C - 30 °C) at which point stirring of the reaction mixture was halted and the layers were allowed to separate. The organic dichloromethane layer was collected, whereas the aqueous layer was subjected to 4 further extractions using 1.5 L of dichloromethane in each extraction. The combined organic dichloromethane layers was dried using anhydrous sodium sulphate (100 g), filtered, and rinsed with additional 200 mL dichloromethane. The filtrate was concentrated via distillation. Solid 14-hydroxymorphinone was obtained with an isolated yield of 89% and HPLC purity of 93.7% using the method described under‘Analytical Method’.
Purification of 14-hydroxymorphinone:
The obtained 14-hydroxymorphinone could optionally be further purified by dissolving the solid in 300 mL isopropanol and stirring at 80 °C for 20 minutes. The mixture was slowly cooled to 15 °C at which point white solid was observed to precipitate out of the mixture. The temperature was maintained at 15 °C for 1 hour and the mixture was filtered and the precipitate was washed with 50 mL of cold isopropanol and then collected. The solid precipitate was dried in an oven at 65 °C - 70 °C for 5-6 hours, and 14-hydroxymorphinone was obtained in 83% isolated yield and having an HPLC purity of >95% using the method described under ‘Analytical Method’.
Example 7: preparation of 14-acetylmorphinone using BF3#SMe2
Figure imgf000022_0001
A 5.0 L 4-neck flask was equipped with a stirrer, reflux condenser, nitrogen inlet, dropping funnel and thermometer pocket containing a thermometer. Under a nitrogen atmosphere 14-acetylcodeinone (100 g, 317 mmol) was added to 1.0 L dichloromethane and the resulting mixture was stirred at ambient temperature (25 °C - 30 °C) until a clear solution was obtained (15 minutes) and was then cooled to a temperature of 0 °C - 5 °C.
200 mL BF3*SMe2 was added into the dropping funnel under an atmosphere of nitrogen and was allowed to drip into the reaction flask at a rate sufficient to ensure that the reaction temperature did not exceed 10 °C. After the addition was complete, the reaction mixture was stirred at 5 °C - 10 °C for 3 hours and then at ambient temperature (25 °C - 30 °C) for a further 13 hours, at which point the reaction was deemed to be complete.
1.35 L demineralised water was slowly added into the reaction mixture and stirred for 15 minutes. Aqueous ammonia was added into the reaction mixture until a pH of 8.5 - 9.0 was obtained at ambient temperature (25 °C - 30 °C) at which point stirring of the reaction mixture was halted and the layers were allowed to separate. The organic dichloromethane layer was collected, whereas the aqueous layer was subjected to 4 further extractions using 1.5 L of dichloromethane in each extraction. The combined organic dichloromethane layers was dried using anhydrous sodium sulphate (100 g), filtered, and rinsed with additional 200 mL dichloromethane. The filtrate was concentrated via distillation. Solid 14-acetylmorphinone was obtained with an isolated yield of 97% and HPLC purity of 96.2% using the method described under‘Analytical Method’. Purification of 14-acetylmorphinone:
The obtained 14-acetylmorphinone could optionally be further purified by dissolving the solid in 300 mL isopropanol and stirring at 80 °C for 20 minutes. The mixture was slowly cooled to 15 °C at which point white solid was observed to precipitate out of the mixture. The temperature was maintained at 15 °C for 1 hour and the mixture was filtered and the precipitate was washed with 50 mL of cold isopropanol and then collected. The solid precipitate was dried in an oven at 65 °C - 70 °C for 5-6 hours, and 14-acetylmorphinone was obtained in 92% isolated yield and having an HPLC purity of >99% using the method described under‘Analytical Method’ .
Analytical method:
Instalment: Agilent 1260 series HPLC with UV detector
Sample solvent: 10 g H3PO4 (85wt%) in 800 mL water and 200 mL acetonitrile (1/80/20; W/V/V).
Column: Phenomenox, 3pm, 250 x 4.6 mm, Octadecylsilane (Cl 8),
100 A
Cycle time: 65.0 minutes
Injection Volume: 5pL, with needle wash, wash solution: acetonitrile/water (1/1)
Mobile Phases: A: 1.0% H3PO4 in water (W/V)
B: acetonitrile
Figure imgf000024_0001
Flow Rate: 0.600 mL/minute
Column temperature: 45 °C
Detection: UV (205 nm)
Industrial advantages:
The use of the boron-based complex as demethylating agent avoids the problem of degradation of the demethylating agent such as BBn and production of hazardous fumes during the reaction. Therefore, the claimed process is highly safe to carry out on industrial scale. The process of the present invention can be carried out preferably at ambient temperature to reflux temperature of the solvent used, thereby making the process easier for industrial scale up. The process of the present invention facilitates easy isolation of the product with high purity by simple work up, i.e., by extracting into organic layer. The boron- based demethylation complex and its by-products will remain in the aqueous layer, thereby making the process cost-effective. The boron-based demethylating complex facilitates the reaction to completion with a higher yield whereby little or no unreacted starting material is found after work up procedure. The solvents employed in the process are cheaper, safer and commercially available which makes the process easier to carry out on industrial scale.

Claims

We claim.
1. A process for preparing compound of formula (I)
Figure imgf000026_0001
wherein
R1 and R2 independently are a hydrogen atom or a substituted or unsubstituted alkyl group with 1 to 20 carbon atoms, or an allyl group, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, or a substituted or unsubstituted carbonylalkyl group with 1 to 20 carbon atoms in the alkyl residue, or a substituted or unsubstituted carbonylaryl group, or a substituted or unsubstituted carbonylalkylaryl group with 1 to 20 carbon atoms in the alkyl reside, or a substituted or unsubstituted carbonyloxyalkyl group with 1 to 20 carbon atoms in the alkyl residue, or a substituted or unsubstituted carbonyloxyaryl group or a substituted or unsubstituted carbonyloxyalkylaryl group with 1 to 20 carbon atoms in the alkyl reside, or a cyanide group, or a silyl group of formula Si(R3)3, wherein the groups R3 can be the same or different and are each selected from substituted or unsubstituted alkyl groups having 1 to 6 carbon atoms and substituted or unsubstituted phenyl groups, respectively; and
•y represents a saturated C-C single bond or an unsaturated C-C double bond; by O-demethylating compound (II) in an inert reaction solvent using a boron-based demethylating complex in the presence or absence of a catalyst.
2. The process according to claim 1, wherein the R1 is hydrogen, allyl, C1-5 alkyl, CH2- cyclopropyl, or CTb-cyclobutyl.
3. The process according to claim 2 wherein R1 is hydrogen.
4. The process according to claim 3, wherein the R2 is hydrogen.
5. The process according to claim 2 wherein R1 is C1-5 alkyl.
6. The process according to claim 5 wherein R1 is methyl.
7. The process according to claim 6, wherein the R2 is hydrogen or acetyl.
8. The process according to any one of the claims 1 to 7 wherein the boron-based demethylating complex is of the general formula B(R4)3*xR5, wherein the groups R4 can be the same or different and are each selected from fluoride, chloride, bromide, or iodide; and the group R5 can be selected from a group consisting of dialkyl sulphide, diallyl sulphide, dialkenyl sulphide, diaryl sulphide, arylalkyl sulphide, dimethyl ether, diethyl ether, dipropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, cyclopentylmethyl ether, ieri-butylmethyl ether, tetrahydrofuran, acetonitrile, phenol, methanol, ethanol, propanol, butanol, water, acetic acid; and x, representing the number of complexing molecules, can be between 1 to 3.
9. The process according to claim 8 wherein the dialkyl sulphide, dialkenyl sulphide, diallyl sulphide, diaryl sulphide, or arylalkyl sulphide can be of the formula R10SRU wherein
R10 and R11 independently are a hydrogen atom or a substituted or unsubstituted alkyl group with 1 to 20 carbon atoms, or an allyl group, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms.
10. The process according to claim 9 wherein the boron-based demethylating complex is BF3*SMe2.
11. The process according to claim 9 wherein the boron-based demethylating complex is BBn*SMe2.
12. The process according to claim 10 or 11 wherein BF3*SMe2 or BBn*SMe2 is used in greater than 1.0 molar equivalent with respect to the morphinane compound of the formula (II), preferably between 2 to 10 molar equivalents with respect to the morphinane compound of the formula (II).
13. The process according to any one of claims 1 to 12 wherein the inert reaction solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, tert- butylmethyl ether, cyclopentylmethyl ether, diethyl ether, dimethylsulfoxide, ethyl acetate, acetonitrile, cyclohexane, methylcyclohexane, V-di methyl acetamide, V. V-dimethylformamide, 1,4-dioxane, ethyleneglycol, formamide, pentane, hexane, heptane, toluene, xylene, trifluorotoluene, tetrachloromethane, trichloromethane, di chi orom ethane, 1,2-dichloroethane, 1,1,1-trichloroethane, fluorobenzene, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4- dichlorobenzene, 1, 2, 4-tri chlorobenzene, benzene, or a mixture thereof.
14. The process according to claim 13, wherein the inert reaction solvent is dichloromethane.
15. The process according to any one of the claims 1 to 14 wherein the catalyst is an inorganic halide or a quaternary iminium or phosphonium compound of the following formula (III):
Figure imgf000028_0001
Formula (III)
16. The process according to claim 15, wherein the catalyst is lithium iodide, sodium iodide, potassium iodide or an iminium or phosphonium compound of formula (III), where A is a tetravalent nitrogen or phosphorus atom, and R6, R7 , R8, and R9 independently are a hydrogen atom or a substituted or unsubstituted alkyl group with 1 to 20 carbon atoms, or a substituted or unsubstituted aryl group, or a substituted or unsubstituted alkenyl group having 2 to 20 carbon atoms, and B is an anion selected from fluoride, chloride, bromide, iodide, sulphate, sulphite, hydrogensulphate, hydrogensulphite, nitrate, nitrite, phosphate, hydrogenphosphate, or dihydrogenphosphate; and selected from the group consisting of tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), benzyltriethylammonium chloride, benzyltriethylammonium bromide (TEBA), benzyltriethylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, cetyltri ethyl ammonium chloride, cetyltriethylammonium bromide, cetyltriethylammonium iodide.
17. The process according to claim 16, wherein the catalyst is used in an amount of 0.1 to 1 molar equivalent with respect to the morphinane compound of the formula (II), preferably between 0.2 to 0.4 molar equivalents.
18. The process according to any one of the claims 1 to 17 wherein the process is performed at a temperature between about -80 °C to the refluxing temperature of the solvent, preferably at a temperature between -10 °C to +40 °C.
19. The process according to any one of the claims 1 to 18 wherein the process is performed in a batch reactor, or a continuous flow reactor, or a microwave reactor, or a combination thereof.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2015155181A1 (en) * 2014-04-10 2015-10-15 Cilag Ag O-demethylating process of methoxy substituted morphinan-6-one derivatives
WO2019009820A1 (en) * 2017-07-04 2019-01-10 Saneca Pharmaceuticals A.S. Process for the preparation of morphinane compounds

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WO2015155181A1 (en) * 2014-04-10 2015-10-15 Cilag Ag O-demethylating process of methoxy substituted morphinan-6-one derivatives
WO2019009820A1 (en) * 2017-07-04 2019-01-10 Saneca Pharmaceuticals A.S. Process for the preparation of morphinane compounds

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