Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B63/00—Purification; Separation; Stabilisation; Use of additives
  • C07B63/02—Purification; Separation; Stabilisation; Use of additives by treatment giving rise to a chemical modification
• • 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:

Definitions

• the present invention relates to a process for the preparation of morphine compounds, especially naloxone, with a low content of unsaturated ⁇ - ⁇ compounds. It also relates to the compositions thus obtained.
• Morphine and related compounds such as codeine, hydrocodone, hydromorphone, naloxone, naltrexone, oxycodone and oxymorphone are used as active ingredients in analgesics.
• Naloxone base (CAS No. 465-65-5) is a morphine derivative used as a pharmaceutical active ingredient, particularly for the treatment of overdose: naloxone is administered to move the morphine receptors to stop its action.
• This compound is accessible by total synthesis, but given the complexity of the molecule, the synthesis generally begins with plant extracts, especially poppy, either from the capsule or from the resin (opium ). These extracts usually comprise different structurally close compounds which give rise during the synthesis to the formation of species that are sometimes difficult to separate.
• the morphine compounds it is sought to limit in the morphine compounds the presence of ⁇ - ⁇ unsaturated ketone compounds because of the supposed toxicity of some of them.
• the morphine compounds have a content of ⁇ - ⁇ unsaturated compounds below 100 ppm.
• WO 2006/084389 proposes to reduce the content of unsaturated ⁇ - ⁇ compounds by selective hydrogenation.
• document WO 2006/084412 recommends that the ⁇ -ketonic hydroxyl group be preliminarily converted into a leaving group with acetic anhydride and then hydrogenated selectively.
• the document US 2006/0111383 proposes to acidify the mixture to a pH of less than 6 and to possibly heat it above 55 ° C. before the hydrogenation.
• hydrogenation most often involves the use of catalysts whose total absence in the final product is then very difficult to ensure.
• WO2007 / 062184 proposes the elimination of ⁇ - ⁇ unsaturated electrophilic compounds of oxycodone by reaction with a thiol.
• WO2007 / 103105 also uses a reaction with a thiol to remove unsaturated ⁇ - ⁇ compounds.
• thiol is accompanied by significant odors, and toxicity for most of them. In addition, it must also ensure the absence of thiol in the active product.
• the object of the present invention is to provide a process for the preparation of morphine compounds of high purity, and in particular comprising a low content of unsaturated ⁇ - ⁇ compounds.
• the invention relates to a process for the preparation of morphine compounds with a low content of unsaturated ⁇ - ⁇ compounds comprising the steps of:
• the invention provides a composition comprising at least 99%, preferably at least 99.5% by dry weight of morphine compound or a pharmaceutically acceptable salt thereof and an ⁇ - ⁇ -unsaturated compound in a lower content. at 100 ppm and preferably less than 50 ppm.
• morphine compounds is understood to mean compounds of structure close to morphine, and in particular comprising a phenolic ring. These compounds may differ from morphine in particular by the nature of their substituents or the nature of the bonds. More specifically, these are 3-hydroxymorphinone derivatives corresponding to the following formula (I):
• R1 represents a hydrogen atom or a hydroxyl group
• R 2 represents a hydrogen atom or a (C 1 -C 6 ) alkyl, cyclo (C 3 -C 6 ) alkyl or (C 2 -C 6 ) alkenyl group.
• a (C 1 -C 8) alkyl group a linear or branched saturated aliphatic group containing between 1 and 6 carbon atoms, for example methyl or ethyl groups may be mentioned; propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, etc .;
• a cyclo (C 3 -C 6 ) alkyl group a cyclic alkyl group comprising between 3 and 6 carbon atoms.
• cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;
• a (C 2 -C 6 ) alkenyl group a linear or branched, mono- or poly-unsaturated aliphatic group comprising, for example, one or two ethylenic unsaturations and containing between 2 and 6 carbon atoms.
• the vinyl group Particularly targeted are hydromorphone, naloxone, naltrexone, noroxymorphone, oxymorphone and nalbuphone.
• ⁇ - ⁇ -unsaturated compounds is intended to mean compounds comprising a double bond at position 7 and 8 of the morphine ring conjugated with a ketone at position 6. More precisely, these are 3-hydroxy-derivatives. 7,8-Didehydromorphinone corresponding to the following formula (II):
• R1 and R2 have the same meanings as previously indicated.
• R1 and R2 have the same meanings as previously indicated.
• crude morphine compound is intended to mean a mixture of compounds essentially comprising a morphine compound or a derivative of 3-hydroxymorphinone as defined above and generally an ⁇ , ⁇ -unsaturated compound or 3-hydroxy derivative. , 8 didehydromorphinone as defined above in a smaller amount.
• the ⁇ , ⁇ -unsaturated compound content is generally less than 1% and most often between 0.1% and 0.2% by weight.
• product resulting from the aldolisation reaction is meant the dimer resulting from the reaction of the enolate with the ketone. More specifically, these are bis hydroxy morphinol-morphinone derivatives having the following formula (IV):
• R1 and R2 have the same meanings as previously indicated.
• product resulting from the crotonization reaction is meant the mother resulting from the dehydration reaction of aldol. More specifically, these are bis hydroxy morphinene-morphinone derivatives having the following formula (V):
• R1 and R2 have the same meanings as previously indicated.
• the invention is based on the surprising finding that the content of the morphine compounds can be reduced to ⁇ - ⁇ -unsaturated compounds, especially those having a double bond in position 7 and 8 of the ketone conjugated morphine ring at the 6-position. Michael addition of the hydroxide ion on the double bond.
• the invention relates to a process for the preparation of morphine compounds with a low content of unsaturated ⁇ - ⁇ compounds comprising the steps of:
• the method further comprises the subsequent step of:
• step (i) of the described process is carried out:
• the step (N) is carried out by precipitation, which is advantageously obtained by adding a neutralization agent, in particular an acid.
• Step (iii) is preferably performed at the same time as step (iv).
• the morphine compound is naloxone.
• the unsaturated ⁇ - ⁇ compound is 7,8-didehydronaloxone.
• the process according to the invention makes it possible, by a simple and rapid treatment, involving current and non-toxic reagents, to obtain a morphine compound of very high purity.
• the process makes it possible to lower the presence of unsaturated ⁇ - ⁇ compounds below the regulatory thresholds, and most often below the detection threshold.
• the addition compounds formed are hydrophilic and can therefore be easily removed.
• this elimination takes place during the usual purification, and in particular during the transformation into a pharmaceutically acceptable salt, for example during the hydrochlorination.
• the purification may comprise in particular a filtration step, for example on alumina.
• the method described can therefore be implemented without major modifications of the procedures in place and recorded.
• the process described makes it possible to transform the unsaturated ⁇ - ⁇ unsaturated compounds by a nucleophilic addition reaction called Michael type addition.
• Michael type addition This reaction is well known as such, and is described for example in "Advanced Organic Chemistry” by Smith and March, 5 th Edition, (Chapter 15, p.976, 1022 to 1024).
• the addition takes place on the double bond conjugated to the ketone function.
• the adduct formed is therefore the corresponding hydroxylated saturated compound. These compounds are most often less toxic than ⁇ - ⁇ unsaturated compounds.
• Reaction Scheme 1 illustrates the reaction to the base of the process for the particular example of naloxone.
• Naloxone may contain as ⁇ - ⁇ -unsaturated impurity especially 7.8 didehydronaloxone. This compound is converted by basic treatment to 8-hydroxy naloxone.
• Basic treatment
• the compound formed by the reaction is more hydrophilic and may optionally be readily separated from the morphine compound.
• the compounds formed by the Michael addition reaction are separated during the usual subsequent isolation and purification steps.
• the Michael-type addition reaction proceeds in competition with secondary reactions, in particular the aldolization and crotonization reaction.
• Reaction Scheme 2 illustrates the aldol reaction for the example of naloxone.
• the dimeric product formed is relatively hydrophilic. It is therefore easily separable during subsequent isolation and purification steps.
• naloxone Crotonization of naloxone leads to the corresponding dehydrated compound.
• the reaction is illustrated in Reaction Scheme 3 above for the example of naloxone. It has been established by structural NMR analysis that only the compound with endocyclic unsaturation is formed.
• Crotonization is an irreversible reaction, unlike the aldol reaction, which is in equilibrium with the reverse reaction called retroaldolisation. Furthermore, the compound resulting from the crotonization of the aldol product is not very water-soluble and therefore more difficult to separate from the reaction product.
• an effective means for limiting the crotonization reaction is to limit the formation of aldol, which is the starting material of crotonization.
• the crude morphine compound obtained by these processes generally has a content of ⁇ - ⁇ unsaturated compounds of less than 1%, most often between 0.1% and 0.2% by weight.
• the process according to the invention allows the Michael-type addition reaction on the unsaturated ⁇ - ⁇ compounds present in the crude morphine compound.
• the crude morphine compound is generally dissolved in a suitable solvent, advantageously in aqueous solution. It is preferable that the solution has a concentration between 5 and 25% by weight of crude morphine compound.
• the base used is preferably a strong mineral base, such as alkali and alkaline earth metal hydroxides and in particular sodium or potassium hydroxide.
• the amount of base is preferably in excess relative to the morphine compound employed. Generally, it represents at least 3, or even at least 5 equivalents calculated with respect to the morphine compound.
• the reaction mixture has a pH greater than 13 or even greater than 14.
• a base in concentrated solution will be used. Indeed, the retro-aldolization reaction is favored in a strongly basic medium, which limits the amount of aldol available for crotonization.
• the morphine compound solution is introduced into the base and not vice versa.
• This variant called reverse casting, provides a strongly basic reaction medium at any time.
• the process according to the invention can be carried out in a simple manner and on conventional equipment.
• the morphine compound is brought into contact with a basic medium, preferably with stirring.
• the reaction medium is preferably maintained at a temperature of 20 to 25 ° C.
• the contact time of the reaction mixture is preferably short in order to disadvantage the aldolization. This is not a problem in terms of conversion since the addition reaction of Michael is usually complete in 10 to 40 minutes, and most often in 20 to 30 minutes.
• the reaction medium is neutralized.
• the neutralizing agent will most often be a usual acid, strong or weak, organic or mineral. Particularly preferred are hydrochloric acid, sulfuric acid or acetic acid.
• the morphine compound is neutralized until precipitation. Generally, the morphine product precipitates at neutral to moderately basic pH, for example between pH 8 and 10.
• the solid product is then separated from the reaction mixture by conventional methods, for example by filtration.
• Filtration on a polar medium such as alumina is particularly interesting because it allows affinity retention of the more hydroxylated compounds, especially the aldol products.
• the morphine compound obtained, in the form of a solvent base is then converted into a pharmaceutically acceptable salt, especially hydrochloride, mucate, hydrobromide, stearate, pamoate, napsylate, 2-hydroxy (1, 1, 3, 3-tetramethylbutyl) benzoate, or else 3,5-bis (1,1-dimethylethyl) -2,6-dihydrobenzoate.
• a pharmaceutically acceptable salt especially hydrochloride, mucate, hydrobromide, stearate, pamoate, napsylate, 2-hydroxy (1, 1, 3, 3-tetramethylbutyl) benzoate, or else 3,5-bis (1,1-dimethylethyl) -2,6-dihydrobenzoate.
• This step can be carried out by reaction of the morphine compound obtained with the corresponding acid.
• the base is poorly water soluble, and so a solution of the morphine compound is prepared in a suitable solvent, for example acetone.
• the salt formed is separated, for example by precipitation.
• the salts of the dimeric compounds from the aldolization and crustalization reactions are better soluble in water than the salt of the morphine compound. Their content can therefore be reduced during this step.
• the morphine compound or its salt thus obtained can, if necessary, be further purified according to known methods, for example by recrystallization.
• anhydrous morphine compound by removal of the solvent, especially by drying in an oven.
• the compounds resulting from the reaction and the secondary reactions are thus separated by the subsequent purification steps, without the need for a step specifically provided for this purpose.
• the invention relates to a composition comprising at least 99% by dry weight of morphine compound and an ⁇ - ⁇ -unsaturated compound content of less than 100 ppm.
• the invention provides a composition comprising at least 99%, preferably at least 99.5% by dry weight of morphine compound or a pharmaceutically acceptable salt thereof and an ⁇ - ⁇ -unsaturated compound in a content of less than 100.
• ppm preferably less than 50 ppm and more preferably less than 25 ppm.
• the morphine compounds and their salts easily form solvates, and especially in the form of mono-, di- or trihydrates.
• the contents of these compounds are therefore generally expressed relative to the dry compound, without taking into account the water content or solvents.
• the contents indicated in the following, unless otherwise indicated, are therefore always in relation to the dry compound.
• compositions when the morphine compound is naloxone, its hydrochloride or hydrochloride dihydrate are particularly targeted.
• the unsaturated ⁇ - ⁇ compound is preferably 7,8-didehydronaloxone.
• the composition also contains, in a small amount, compounds resulting from the aldolisation and crotonization reaction.
• the subject of the present invention is in particular a composition comprising at least 99% by dry weight, preferably at least 99.5% by dry weight, of morphine compound or of a pharmaceutically acceptable salt thereof, an unsaturated ⁇ - ⁇ compound. in a content of less than 100 ppm and preferably less than 50 ppm, and further comprising at least one compound derived from the aldolization and crotonization reactions.
• the compounds resulting from the aldolisation reaction and the crotonization reaction are generally present in a content of less than 1000 ppm and in particular less than or equal to 500 ppm in the compositions according to the invention
• the compound resulting from the aldolization reaction is generally present in a content ranging from 20 to 200 ppm and in particular from 50 to 150 ppm.
• the morphine compound when in the composition according to the invention the morphine compound is in salt form, the compound resulting from the crotonization reaction is generally present in a content ranging from 150 to 500 ppm and in particular from 200 to 350 ppm.
• naloxone it is 6'-7-naloxol-naloxone and
• compositions according to the invention comprising a pharmaceutically acceptable salt of morphine compound; in particular a naloxone hydrochloride.
• morphine compounds or their salts are most often solvates, and in particular hydrates.
• Particularly targeted is a composition comprising naloxone hydrochloride dihydrate.
• the present invention relates to a composition
• a composition comprising naloxone hydrochloride dihydrate, 7-8 didehydronaloxone, especially at a content of less than 90 ppm, 6'-7 naloxol naloxone especially in a content ranging from 50 to 150 ppm and 6'-7 'olefin of 6'-7-naloxol-naloxone especially in a content ranging from 200 to 350 ppm.
• the composition will further contain solvent in a corresponding amount.
• the composition may further contain up to 10% by weight of water relative to the total weight of the composition.
• Fig. 1 HPLC analysis result of naloxone base with low content of ⁇ - ⁇ unsaturated compounds obtained in the example
• 2 HPLC analysis result of naloxone hydrochloride with low content of ⁇ - ⁇ unsaturated compounds obtained in the example.
• the medium is then loaded into a dropping funnel and then added dropwise into a three-necked flask containing 36 ml (0.27 mol; 8 eq) of concentrated sodium hydroxide (30%).
• the initial ambient temperature of 21.6 ° C. of the reaction medium reaches, at the end of the casting, 21.5 ° C., the pH of the reaction medium then being 14.4.
• the reaction medium has a temperature of 41.7 ° C. and a pH of 9.
• the medium is cooled to 10.degree. C. and the precipitate is separated by filtration on sintered glass.
• the separated solid product is dried in a ventilated oven at 60 ° C.
• the treated crude base naloxone is isolated with a mass of 15.64 g dry.
• the product obtained at the end of these operations is called "naloxone base treated" in Tables 1 to 4 below.
• the naloxone base obtained is dissolved in acetone and then chlorhydrated by addition of concentrated hydrochloric acid.
• the hydrochloride is precipitated by cooling, filtered and dried.
• the product obtained after these operations is called "pure naloxone HCl" in Tables 1 to 4 below.
• the product obtained is analyzed according to the HPLC method described by the European Pharmacopoeia after the basic treatment, and after hydrochlorination.
• the process according to the invention makes it possible to obtain, by the basic treatment, naloxone with a low content of 7,8-didehydronaloxone.
• the treatment makes it possible to lower the content of 7,8-didehydronaloxone from 0.8% by weight initially to less than 0.03% by weight, and therefore below the detection threshold.
• a more specific HPLC method shows that the content of 7,8-didehydronaloxone, to be less than 100 ppm, has a usual value of 60 to 90 ppm.
• Naloxone thus obtained at this stage meets the regulatory requirements for the content of 7,8-didehydronaloxone.

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