HK1163096B

HK1163096B - Synthesis of morphine-6-glucuronide or of a derivative thereof

Info

Publication number: HK1163096B
Application number: HK12103827.9A
Authority: HK
Inventors: Alain Dlubala; Isabelle Ripoche; Claire Trecant
Original assignee: Sanofi
Priority date: 2008-12-10
Filing date: 2009-12-08
Publication date: 2014-10-17

Description

The field of invention

The present invention relates to a process for the preparation of morphine-6-glucuronide (M6G) or one of its derivatives.

The first two are the following:

Morphine is currently the most commonly used analgesic in the treatment of moderate to severe pain. This opioid is used in approximately 80% of acute post-operative pain cases. Despite its high efficacy, morphine use is associated with many opioid-specific adverse effects, such as respiratory depression, nausea, vomiting, intestinal transit inhibition, addiction and tolerance (Minoru Nariata et al. Pharmacol. Et Ther. 2001, 89, 1-15).

Morphine is known to undergo a major metabolism leading in particular to the formation of morphine-6-glucuronide (M6G). This metabolite penetrates weakly into the brain due to its hydrophilic nature. It has a more potent analgesic activity than that exhibited by centrally administered morphine with a decrease in respiratory depression, nausea and vomiting (Paul et al. J. Pharmacol. Exp. The 1989, 251, 477-483; Frances et al. J. Pharmacol. Exp. The 1992, 262, 25-31).

M6G was synthesized in 1968 by Yoshimurai et al. (Yoshimura, H.; Oguri, K.; Tsukamoto, H. Chem. Pharm. Bull. 1968, 16, 2114-2119). On an industrial scale, this process based on the Koenigs Knorr principle has low yields. It was modified in 1997 by Berrang et al. (Synthesis 1997, 1165-1168). The heavy metals present in trace form in the final product are difficult to remove. Finally, however, the silver salts must be recycled.

Other methods of O-glycosylation have been considered, including activation in the form of an imidat (WO 93/03051) or a thioaryl. These methods, which require implementation under special conditions of strict anhydricity, i.e. water content below 100 ppm, and low temperature, impose significant industrial constraints.

There is therefore a need for a process that can produce such derivatives on an industrial scale, not only with higher yields but also with a minimum of technical constraints.

The purpose of the present invention is to propose a method of preparation of M6G or one of its derivatives with an efficiency of at least 60%, the glycosylation step of which is carried out in a homogeneous medium, is moisture tolerant i.e. with a water content of up to 3000 ppm and can be carried out at a temperature of 20°C.

This is achieved by the process of the invention, which involves the combined use of a glycosylated derivative with trihalogen acetamide activation as a donor of glycosylated derivatives and dimorphic derivatives as an acceptor of glycosylated derivatives, resulting in very good stereoselectivity.

A process has now been found which allows a satisfactory yield with a minimum of industrial constraints.

The present invention is therefore, in the first place, a process for the preparation of M6G or one of its derivatives, comprising the following steps: (i) to react a compound having the following formula (I): - What? in which: R is a carbonyl group, COR5CO where R5 is a (C1-C4) alkane-diyl group, (C2-C4) alkene-diyl, (C2-C4) alcyne-diyl, hetero ((C1-C4) alkane-diyl, heterocyclo ((C3-C6) alkane-diyl, (C5-C14) arene-diyl, hetero ((C4-C10) arene-diyl, biC10-C16) arene-diyl, or biC10-C16) arene-diyl, SO2R6 where R6 is a (C1-C4) alkane-diyl group, (C2-C4) alcyne-diyl, (C2-C4) alkane-diyl, hetero ((C1-C4) calcene-diyl, hetero ((C3-C16) hetero ((C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C - What? in which: PG is an acetyl, isobutyryl, benzoyl or pivaloyl group,X is a trihalogen acetamide group, andR4 is a (C1-C4) alkylcarboxylate group,in the presence of: an aromatic solvent not substituted or substituted by one or more substituents chosen from the group consisting of a halogen atom, a (C1-C4) alkyl group and a (C1-C4) alkyloxy group, with a melting point of - 20°C or less, and trimethylsilane trifluoromethane sulphonyl (ii) to react the product obtained in step (i) with a strong basic agent and then (iii) to recover the product obtained in step (ii).

The present invention also covers compounds having the following formula (III): - What? in which: R1 is as defined above,R2 and R3 independently represent a PG group as defined above or a group according to formula (IV): wherein: R4 and PG are as defined above, provided that at least one of R2 and R3 is a group of formula (IV).

The present invention also covers compounds of formula (I): - What? in which: R1 is as defined above.

The following definitions apply:

For the purposes of this invention, the following definitions shall apply: a PG group: a protective group which allows, on the one hand, to protect a reactive function such as a hydroxy or an amine during a synthesis and, on the other hand, to regenerate the intact reactive function at the end of synthesis; examples of protective groups as well as methods of protection and unprotection are given in Protective Groups in Organic Synthesis , Green et al., 2nd Edition (John Wiley & Sons, Inc., New York), 1991; in particular, the acetyl, isobutyryl, benzoyl and pivalyl groups; a halogen atom: a fluorine atom,A chlorine atom, a bromine atom or an iodine atom; a (C1-C4) alkyl group: a linear or branched saturated aliphatic group with substitution or unsubstitution, having 1 to 4 carbon atoms; examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, etc. a hydroxyl group: a -OH group (C1-C4); an alkyloxy group: a -O-(C1-C4) alkyl group where the (C1-C4) alkyl group is as previously defined; a carbonyl group, a C=O group; a (C1-C4) di-cyl group, a divalent saturated aliphatic group, having a linear or branched substitution; or a cyclic substitution group, with a carbon number of 1 to 4 atoms; an example of a cyclic substitution group,The methane-diyl (-CH2-), ethane-diyl (-CH2-CH2-), propane2,3-diyl (-CH(CH3) CH2-), propane1,3-diyl (-CH2-CH2-CH2-) groups may be mentioned; andan (C2-C4) alkene-diyl group, a linear or branched, mono- or polyunsaturated, aliphatic divalent group with 2 to 4 carbon atoms, including for example one or two ethylene insaturations; examples include ethylene-diyl groups (-CH=CH-), 1-propene 1,3-diyl (-CH2-CH=CH2-), etc.an (C2-C4) alkene-diyl group, a mono- or polyunsaturated, linear or branched aliphatic divalent group, containing two or four carbons; an acyl group, for example, an acyl-diyl group, containing one or two polyunsaturated, polyunsaturated or branched atoms (-C1-C3-C), or an acyl-diyl group, for example, a 1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-a divalent aromatic cyclic group with or without substitution , preferably between 5 and 14 carbon atoms; The following groups are examples: a hetero ((C1-C4) alkane-diyl group, an alkane-diyl group as defined above, whether or not substituted, preferably with 1 to 4 carbon atoms, including one or more heteroatoms, such as nitrogen, oxygen or sulphur; examples are the etheroxide-diyl group; a heterocyclo ((C3-C6) alkane-diyl group, a cyclo ((C3-C6) alkane-diyl group, as defined above, either substituted or not substituted, preferably with 3 to 6 carbon atoms, including one or more heteroatoms,The following are examples: oxirane-diyl, aziridine-diyl, thirane-diyl and pyrane-diyl; a hetero-O (((C4-C10) arene-diyl, a divalent cyclic aromatic group preferably between 4 and 10 carbon atoms and containing one or more hetero-atoms, such as nitrogen, oxygen or sulphur; a bi (C10-C16) -arene-diyl group, a divalent group comprising two aromatic rings each of which may or may not be independently substituted, preferably having 10 to 16 carbon atoms. a bi-C10-C16-arene-oxide-diyl group, a divalent group with two aromatic rings,each independently substituted or not, having 10 to 16 carbon atoms, as examples, the group - What? and a -C1-C4) alkylcarboxylate group, a -CO-O-C1-C4) alkyl group, the (C1-C4) alkyl group being as defined above.

The term strong basic agent , is well known to the professional as a basic agent which dissociates completely in neutral aqueous solution or has at least a high degree of dissociation in neutral aqueous solution. The term room temperature refers to a temperature between 20 and 25°C.

The manufacturer shall provide the manufacturer with a detailed description of the device. Compound of formula (I)

- What? in which: R is a carbonyl group, COR5CO where R5 is a (C1-C4) alkane-diyl group, (C2-C4) alkene-diyl, (C2-C4) alcyne-diyl, hetero ((Cx1-Cy1) alkane-diyl, heterocyclo ((C3-C6) alkane-diyl, (C5-C14) arene-diyl, hetero ((C4-C10) arene-diyl biC10-C16) arene-oxydiyl or biC10-C16) arene-diyl, SO2R6 where R6 is a (C1-C4) alkane-diyl group, (C2-C4) alcyne-diyl, (C2-C4) alcyne-diyl, hetero ((C1-C1-C4) alkene-diyl, hetero ((C1-C1-C4) arene-diyl, hetero ((C3-C1-C6-C1-C1-C1-C1-C4-C1-C6-C1-C1-C1-C1-C1-C1-C1-C1-C1-C6-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C6-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-

The compounds of formula (I) include: The Commission shall adopt implementing acts laying down detailed rules for the application of this Regulation in respect of the following substances: dimorphin-3-yl terephthalate, dimorphin-3-yl isophthalate, dimorphin-3-yl phthalate, dimorphin-3-yl fumarate, dimorphin-3-yl benzene-1,2-disulfonate, dimorphin-3-yl benzene-1,3-disulfonate, dimorphin-3-yl thiophene-2,5-dicarboxylate, dimorphin-3-yl naphthalene-2,7-dicarboxylate, dimorphin-3-yl 4,4'-oxybenzoate, dimorphin-3-yl biphenyl-4,4'-dicarboxylate, dimorphin-3-yl dimer carbonate.

The compound of formula (I) as defined above may be prepared by various processes, including esterification of the morphine phenol group by dicarboxylic acid and removal of water by azeotropic distillation.

It can also be prepared by the process described below.

According to a particular embodiment of the process of the present invention, the process comprises, prior to step (i), the steps of reacting a compound of formula R1Cl2 in which R1 is as defined above with morphine in a diphasic medium containing at least water, a strong base agent and an aromatic solvent not substituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a (C1-C4) alkyl group and a (C1-C4) alkyloxy group, the said solvent having a melting point of -20°C or less.

In this method of preparation of formula (I), morphine is preferably introduced in excess of the formula R1Cl2, e.g. in a molar ratio of 2,2 moles of morphine to 1 mole of R1Cl2.

The strong base agent used may be soda.

Solvents that can be used in the process as defined above include chlorobenzene, toluene, 1,2-dichlorobenzene, 1,3,5-trifluorobenzene and mesetylen, and chlorobenzene is preferred for the best solubilization of the reagents.

It is preferable to prepare the mixture of morphine and water and to add the strong basic agent in a quantity to obtain a pH of 10 or more. The mixture is agitated until a homogeneous solution is obtained.

The present invention also covers compounds according to formula (I).

These compounds are useful as intermediates for the synthesis of M6G or its derivatives.

Compound of formula (II)

Glucuronic acid derivative with the formula (II): - What? in which: PG is an acetyl, isobutyryl, benzoyl or pivaloyl group,X is a trihalogenanoacetamide group, andR4 is a (Cx1-Cy1) alkylcarboxylate group.

Glucuronic acid derivatives of formula (II) include in particular those with one or more of the following characteristics: PG is an acetyl group,X is an -OCNHCl3 or -OCNPhCF3 group, andR4 is a methylcarboxylate group.

According to a particular embodiment of the process of the invention, the glucuronic acid derivative of formula (II) is 2,3,4-tri-O-acetyl-α-D-glucopyranosyluronate methyl trichloroacetimidate. The compound of formula (II) can be prepared by various processes well known to the professional. For example, trichloroacetimidate 2,3,4-tri-O-acetyl-α-D-glucopyranosyluronate methyl can be synthesized by the process described in the following Figure 1: - What?

Such synthesis processes are described in particular in Chem.Pharm. Bull. 53 (6) 684-687 (2005) for trichloroacetimidate 2,3,4-tri-O-acetyl-α-D-glucopyranosyluronate in J.Chem. Soc. Perkin trans. 1 1995, for the tri-O pivaloyl derivative and in Liebigs Ann. Chem. 1983, 570-574 for the tri-O-benzoate derivative.

The following information shall be provided for each step:

As indicated above, in the process of the invention, a compound of formula (I) is reacted in step (i) with a derivative of glucuronic acid of formula (II) in the presence of an aromatic solvent and trimethylsilane trifluoromethanesulfonyl.

Among the aromatic solvents as defined above that may be used are in particular chlorobenzene, toluene, 1,2-dichlorobenzene, 1,3,5-trifluorobenzene and mesythylene.

Depending on the particular manufacturing method, the molar ratio of this derivative of formula (II) to this compound of formula (I) is between 2 and 5 and is in particular 4.

The reaction is carried out in the presence of a weak Lewis acid, trimethylsilane trifluoromethane sulphonyl (TMSOTf).

The molar ratio of TMSOTf to the compound of formula (I) is between 2,2 and 20 and is in particular 3,1.

According to a particular method of manufacture, TMSOTf is introduced in two steps: a first part is introduced into the solution of the product of formula (I) in the aromatic solvent prior to the addition of the glucuronic acid derivative, in order to salivate the two nitrates of the compound of formula (I), and then the remaining part is introduced after the addition of the glucuronic acid derivative in order to ensure O-glycosylation.

The implementation of step (i) leads to the formation of a compound meeting the following formula (III): - What? in which: R1 is as defined above,R2 and R3 independently represent a PG group as defined above or a group according to formula (IV): - What? wherein: R4 and PG are as defined above, provided that at least one of R2 and R3 is a group of formula (IV).

The present invention also covers compounds of formula (III) which are useful as intermediates for the synthesis of M6G or its derivatives.

Preferably, R2 and R3 both represent a group of formula (IV).

Among the compounds of formula (III) covered by the invention, a first group of compounds exhibits one or more of the following characteristics: R1 represents a terephtaloyl group,at least one of R2 and R3 represents a group of formula (IV) in which R4 is a 2,3,4-tri-O-acetyl-β-D-glucuropryranosyluronate methyl group and PG is an acetyl group.

These include: the 6-O-acetylmorphine-3-yl and 6-O- ((2,3,4-tri-O-acetyl-β-D-glucopyranosyluronate methyl) morphine-3-yl terphenate, and the di6-O- ((2,3,4-tri-O-acetyl-β-D-glucopyranosyluronate methyl) morphine-3-yl terphenate.

The following parameters are used for the calculation of the CO2 savings:

As indicated above, the product obtained in step (i), namely the compound of formula (III), is reacted with a strong basic agent.

According to a particular method of manufacture, before the addition of the strong basic agent, the aromatic solvent is removed by methods known to the trade, e.g. by extraction of the organic phase, possibly completed by evaporation at reduced pressure.

Generally the compound of formula (III) is then dissolved in a hydro-alcoholic mixture e.g. in a methanol/water mixture, in a ratio of 20/80 to 80/20, stirred until a homogeneous mixture is obtained.

This mixture is usually cooled to a temperature of 5°C or less.

The strong basic agent is then introduced into the mixture usually in quantities to obtain a pH of 10 or more and in particular of 12.5 or more, preferably maintaining the temperature at 5°C or less.

According to a particular method of manufacture, the basic strong agent is soda.

The resulting mixture may then be heated, for example, to 20°C for a sufficient time to complete the reaction, for example, for one hour.

When M6G or one of its derivatives is to be obtained in the basic form, the mixture, after having been previously cooled, for example to a temperature of 5°C or less, is acidified to a pH lower than the pKa of the product to be synthesized, for example at a pH of 5.6.

The resulting mixture may then be heated, for example, to 20°C for a sufficient time to complete the reaction, for example, for 30 minutes.

The following parameters are used for the calculation of the CO2 savings:

The product obtained at the end of step (ii) can be recovered as is, i.e. in raw form, e.g. by filtration and then vacuum concentration of the filtrate.

It is preferable to recover it in purified form, which can be achieved by any purification method known to the professional, in particular by desalination, if necessary followed by one or more steps of adsorption and desorption on ion exchange resins and possibly by one or more cycles of dissolution/evaporation/crystallization.

In order to reduce the salt content in order to remove residual sodium acetate and sodium terephthalate, for example, the filtrate can be resuspended in alcohol, especially in methanol, under conditions which allow the dissolution of M6G or its derivatives, for example at 50 °C for 3 hours, and then the resulting mixture can be filtered to remove solid particles and the resulting residue dried, for example by evaporation under reduced pressure.

The purification can be continued using ion exchange resins. According to a particular method, the residue obtained is resuspended in demineralized water, then the suspension is acidified to a pH between 2 and 4 and above or equal to 3, for example by addition of sulfuric acid, filtered and the filtrate is brought into contact with a cationic resin under conditions allowing adsorption of M6G or its derivative e.g. by agitation at 20°C for 30 minutes, and then filtered. These operations are repeated until the filtrate is exhausted into M6G or its derivative. The desorbed residues are then reduced to a basic solution e.g. by using ammonia.

Finally, this residue is resuspended in a hydro-alcoholic mixture e.g. in a methanol/water mixture, in a ratio of 20/80 to 80/20, heated under conditions allowing its total dissolution e.g. at ebb for 30 minutes and then the homogeneous mixture is cooled slowly e.g. to 0°C in 2 hours, the first crystals appearing at 35°C.

The crystals are isolated, for example, on sintered glass, washed, for example, with methanol, and finally dried, for example, by heating and evaporation under vacuum.

The invention is illustrated by the following examples, but not limited to:

Examples The Commission has

Figure 2 describes the synthesis of compounds from intermediate compounds of formula (I) and (III) and M6G and its derivatives.

In Figure 2 the starting compounds and reagents, when their method of preparation is not described, are commercially available or described in the literature, or may be prepared by methods described therein or known to the professional. - What?

The following examples describe the preparation of certain compounds in accordance with the invention, and are not exhaustive and are merely illustrative of the present invention.

Preparation of compounds of formula (I) The test chemical is a dimorphine-3-yle terephthalate.

At room temperature, to a solution of morphine monohydrate (40.0 g, 0.132 mol) in 0.66N (300 mL, 0.198 mol) soda and chlorobenzene (300 mL) add terephtaloyl chloride (12.0 g, 0.0594 mol) in small portions for 2.5 h. Agitate the reaction medium for 15 min after completion of addition.

The precipitate formed is filtered and re-mixed in a 0,66N chlorobenzene/sodium mixture (300 mL/300 mL) and then washed with water (3 x 250 mL) to obtain dimorphin-3-yle terephthalate in the form of white crystals (38,2 g, 92%).

The mean of the measurements performed was approximately 0,05 (m, 2H, H-6), 0,05 (m, 2H, H-6), 0,01 (m, 2H, H-10a), 0,01 (m, 2H, H-14), 0,01 (m, 2H, H-16a), 0,01 (m, 2H, H-16a), 0,01 (m, 2H, H-16b), 0,01 (m, 2H-16b), 0,01 (m, 2H-15a), 0,01 (m, 2H, H-15b), 0,01 (m, 2H, H-16a), 0,01 (m, 2H, H-1), 0,01 (m, 2H, H-1), 0,01 (m, 2H, H-1), 0,01 (m, 2H, H-1), 0,01 (m, 2H, J-1), 0,01 (m, 2H, J-1), 0,01 (m, 2H, H-1), 0,01 (m, 2H, H-1), 0,01 (m, 2H, H-1), 0,01 (m, 2H-1), 0,01 (m, 2H-1), 0,01 (m, 2H-1), 0,01 (m, 2H-1), 0,01 (m, 2H-1), 0,01 (m, 2H-1), 0,01 (m, 2H-1), 0,01 (m, 2H-1), 0,01 (m, 2H-1), 0,01 (m, 2H-1), 2,01 (m, 2H-1), 2,01 (m, 2H-1), 2,01 (m, 2H-1), 2,01 (m, 2H-1), 2,01 (m, 2H-1), 2,01, 2H-1), 2,01, 2H-1, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2

The total number of samples of the product concerned shall be calculated by adding the total number of samples of the product concerned to the total number of samples of the product concerned.

Mass High resolution (ES)

Calculated for C42H42N2O8 [M+H2]2+: m/z = 351.1471Finds: m/z = 351.1467

In the same way, the compounds of the following examples 2 to 11 were prepared.

Example 2- Dimorphin-3-yl isophthalate

The following substances are to be classified in the additive: acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, ac The following is the total mass of the product:

The following is the list of active substances:

The following substances are to be classified in the additive: - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, - the active substance, the active substance - active substance, the active substance - active substance, the active substance - active substance, the active substance - active substance, the active substance - active substance - active substance, the active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance - active substance The mass (chemical ionization) is [M+H]+= 701.6

Example 4- Dimorphin-3-yle fumarate

The mean of the measurements performed was approximately 0.01% (see section 4.5) and the mean of the measurements performed was approximately 0.01% (see section 4.8). The mass (chemical ionization) is given by:

The test chemical is a dimorphine-3-yl benzene-1,2-disulfonate.

The following substances are to be classified in the additive: acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, ac The mass (chemical ionization) is given by:

The test chemical is a chemical that is used to test the concentration of a substance in a solution.

The mean free path of the two samples is approximately the same for all samples, but the mean free path is approximately the same for all samples. The mass (chemical ionization) is given by: [M+H]+=773,6

The test chemical is a dimorphin-3-yl thiophen-2,5-dicarboxylate.

The mean of the measurements performed was approximately 0.01% for the two samples, and the mean of the measurements was approximately 0.01% for the two samples. The mass (chemical ionization) is [M+H]+= 708,6

The test chemical is a dimorphin-3-yl 2-dicarboxylate.

The following substances are to be classified in the additive: acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, ac The mass (chemical ionization) is given by: [M+H]+=751,6

Example 9 - 4,4'-oxybenzoate of dimorphin-3-yle

The mean value of the measurement of the effects of the test chemical on the human body is calculated by dividing the mean value of the measurement of the effects of the test chemical by the mean value of the measurement of the effects of the measurement of the test chemical on the human body. The mass (chemical ionization) is [M+H]+= 793,5

The test chemical is a dimorphin-3-yl biphenyl-4,4'-dicarboxylate.

The mean value of the measurement of the effects of the test chemical on the human body is calculated by dividing the mean value of the measurement of the effects of the test chemical by the mean value of the measurement of the effects of the measurement of the test chemical on the human body. The mass (chemical ionization) is [M+H]+= 777,5

The following is the list of active substances:

The frequency range of the measurement is defined as the frequency range of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measur The mass (chemical ionization) is [M+H]+= 597.5

Glycosylation

At room temperature, add TMSOTf (27 μL, 0,15 mmol) to a solution of dimorphin-3-yl terephthalate (50 mg, 0,071 mmol) in chlorobenzene (4 mL) and stir the reaction mixture for 3 min. Then add 2,3,4-tri-O-acetyl-α-D-glucopyranosyluronate methyl trichloroacetimidate (171 mg, 0,36 mmol) and then TMSOTf (13 μL, 0,071 mmol).

The reaction medium is agitated for 0,5 h at room temperature.

NaHCO3 (100 mg) is added and then CH2Cl2 (5 mL) and water (5 mL) are added.

The solvent is removed at reduced pressure. A mixture of three products: di-6-O-acetylmorphine-3-yl terephthalate, 6-O-acetylmorphine-3-yl terephthalate and 6-O- ((2,3,4-tri-O-acetyl-β-D-glucopyranosyluronate methyl) morphine-3-yl and di-6-O- ((2,3,4-tri-acetyl-β-D-glucopyranosyluronate methyl) morphine-3-yl terephthalate in the ratio 7:30:63 is obtained.

A purification by reverse phase preparatory chromatography (gradient (H2O+0.1% TFA) -CH3CN from 95:5 to 20:80) allows the isolation of the three species.

The test chemical is a di-O-acetylmorphine-3-yl terephthalate.

The mean value of the measurement of the effects of the test chemical on the human body is calculated by dividing the mean value of the measurement of the effects of the test chemical by the mean value of the measurement of the effects of the measurement of the test chemical on the human body.

The following substances are to be classified as 'methanol' and 'methanol' in the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council:

Mass High resolution (ES)

Calculated for C46H46N2O10 [M+H2]2+: m/z = 393.1576Finds: m/z = 393.1560

The test chemical is a 3-methyl-morphine 3-yl and 6-O- ((2,3,4-tri-O-acetyl-β-D-glucopyranosyluronate methyl) morphine 3-yl terephthalate.

Err1:Expecting property name enclosed in double quotes: line 1 column 250 (char 249)

Err1:Expecting ',' delimiter: line 1 column 317 (char 316)

Mass High resolution (ES)

Calculated for C57H60N2O18 [M+H2]2+: m/z = 530.1921Finds: m/z = 530.1918

The following is the list of active substances which are to be classified in the additive:

The following substances are to be classified in the additive: acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, ac

Mass High resolution (ES)

Calculated for C68H74N2O26 [M+H2]2+: m/z = 667.2265Finds: m/z = 667.2253

Saponification of intermediates from O-glycosidic coupling

After treatment and extraction of the organic phase (chlorobenzene) from the coupling, the chlorobenzene is evaporated at reduced pressure (15 mbar) to obtain a brownish oil (m= 47.4 g). To this oil a mixture of methanol (140 ml) and demineralised water (35 ml) is added at 30 °C, stirred until a homogeneous mixture is obtained. The mixture is then cooled to -5 °C.

To this mixture 62.5 ml of concentrated soda solution (30% m/m) are added at a temperature not exceeding 5°C in the reactor, this mixture (pH=12.72) is then heated to 20°C for 1 hour under nitrogen and then cooled to -3°C.

To the resulting mixture, 37 ml of a solution of hydrochloric acid (HCl 37%) is added (pH = 5.6). The mixture is heated to 20°C and maintained at this temperature for 30 min (pH stable at 5.6). The mixture is then filtered and the resulting filtrate is concentrated under vacuum (15 mbar) to obtain a dry extract of 67,0 g.

Purification of saponification and acidification residues

This residue is suspended in 500 ml of methanol at 50°C for 3 h (descaling) to obtain after filtration and evaporation at reduced pressure (15 mbar) a residue of 30.8 g comprising a mixture of morphine analysed in H.P.L.C. (approximately 30%) and M6G (approximately 70%).

The resulting residue is suspended in 100 ml of demineralized water and the resulting suspension is acidified at pH 3,58 with H2SO4 98 % (2 ml) and then filtered.

6 g of the resin marketed under the name IRP 69 by Rohm and Hass is added to the filtrate (in a weight ratio of 3 to the weight of M6G contained according to the HPLC estimate).

The operation is repeated until the M6G contained is exhausted.

The resulting resins are desorbed with diluted ammonia (3% NH4OH) and the resulting basic solution (pH = 10,9) is neutralized at a pH of 5-6 with diluted HCl.

The resulting acidic aqueous solution is evaporated at reduced pressure (15mbar) to obtain a dry residue of 5,6 g.

It is identified as H.P.L.C. (M6G content of 80%).

Recrystallization of the M6G

The previous dry residue (5.55 g) is suspended in a mixture of water (166.5 ml) and methanol (277.5 ml) and heated at 90°C for 30 min. The mixture is then cooled to 0°C in 2 h. The first crystals are formed at 35°C.

The crystals are isolated on frying glass and then washed with 5 ml of methanol. The following information is provided for the purpose of the calculation of the M6G content: The mass (chemical ionization) is equal to [M+H] += 462,2 The following are the values of the emission levels of the products, expressed as a percentage of the total emission levels of the product concerned:

Claims

Process for preparing morphine-6-glucuronide or a derivative thereof, comprising the steps consisting in:
(i) reacting a compound corresponding to formula (I) below: in which:
R₁ represents a carbonyl group, COR₅CO in which R₅ represents a group (C₁-C₄)alkane-diyl, (C₂-C₄)alkene-diyl, (C₂-C₄)alkyne-diyl, hetero(C₁-C₄)alkane-diyl, heterocyclo(C₃-C₆)alkane-diyl, (C₅-C₁₄)arene-diyl, bi(C₁₀-C₁₆)arene-oxide-diyl, bi(C₁₀-C₁₆)arene-diyl, or hetero(C₄-C₁₀)arene-diyl, SO₂R₆SO₂ in which R₆ represents a group (C₁-C₄)alkane-diyl, (C₂-C₄)alkene-diyl, (C₂-C₄)alkyne-diyl, hetero(C₁-C₄)alkane-diyl, heterocyclo(C₃-C₆)alkane-diyl, (C₅-C₁₄)arene-diyl, hetero(C₄-C₁₀)arene-diyl, bi(C₁₀-C₁₆)arene-oxide-diyl or bi(C₁₀-C₁₆)arene-diyl,

with a glucuronic acid derivative corresponding to formula (II) below:
in which:
PG represents an acetyl, isobutyryl, benzoyl or pivaloyl group,

X represents a trihaloacetimidate group, and

R₄ represents a group (C₁-C₄)alkylcarboxylate,

in the presence:
- of an aromatic solvent that is unsubstituted or substituted with one or more substituents chosen from the group formed by a halogen atom, a group (C₁-C₄)alkyl and a group (C₁-C₄)alkyloxy, said solvent having a melting point of less than or equal to - 20°C, and

- of trimethylsilyl trifluoromethanesulfonate

(ii) in reacting the product obtained in step (i) with a strong basic agent, and then

(iii) in recovering the product obtained in step (ii).
Process according to Claim 1, in which, prior to step (i), a compound of formula R₁Cl₂ in which R₁ is as defined in Claim 1 is reacted with morphine in a two-phase medium comprising at least water, a strong basic agent and an aromatic solvent that is unsubstituted or substituted with one or more solvents chosen from the group formed by a halogen atom, a group (C₁-C₄)alkyl and a group (C₁-C₄)alkyloxy, said solvent having a melting point of less than or equal to -20°C.
Process according to Claim 1 or 2, characterized in that said compound of formula (I) is chosen from the group formed by:
- dimorphin-3-yl terephthalate,

- dimorphin-3-yl isophthalate,

- dimorphin-3-yl phthalate,

- dimorphin-3-yl fumarate,

- dimorphin-3-yl benzene-1,2-disulfonate,

- dimorphin-3-yl benzene-1,3-disulfonate,

- dimorphin-3-yl thiophene-2,5-dicarboxylate,

- dimorphin-3-yl naphthalene-2,7-dicarboxylate,

- dimorphin-3-yl 4,4'-oxybenzoate,

- dimorphin-3-yl biphenyl-4,4'-dicarboxylate, and

- dimorphin-3-yl carbonate.
Process according to any one of the preceding claims, characterized in that said compound of formula (II) has one or more of the following characteristics:
- PG represents an acetyl group,

- X represents a group -OCNHCl₃ or a group -OCNPhCF₃, and

- R₄ represents a methylcarboxylate group.
Process according to any one of the preceding claims, characterized in that said compound of formula (II) is methyl 2,3,4-tri-O-acetyl-α-D-glucopyranosyluronate trichloroacetimidate.
Process according to any one of the preceding claims, characterized in that said aromatic solvent is chosen from chlorobenzene, toluene, 1,2-dichlorobenzene, 1,3,5-trifluorobenzene and mesitylene.
Process according to any one of the preceding claims, characterized in that said strong basic agent is sodium hydroxide.
Process according to any one of the preceding claims, characterized in that the mole ratio of said glucuronic acid derivative of formula (II) to said compound of formula (I) is between 2 and 5.
Process according to any one of the preceding claims, characterized in that the mole ratio of the trimethylsilyl trifluoromethanesulfonate to said compound of formula (I) is between 2.2 and 20.
Compound of formula in which:
R₁ is as defined in Claim 1,

R₂ and R₃ independently represent a group PG as defined in Claim 1 or a group of formula (IV) below:
in which:
R₄ and PG are as defined in Claim 1,

with the proviso that at least one from among R₂ and R₃ represents a group of formula (IV).
Compound according to Claim 10, characterized in that it has one or more of the following characteristics:
- R₁ represents a terephthaloyl group,

- at least one from among R₂ and R₃ represents a group of formula (IV) in which R4 is a methyl 2,3,4-tri-O-acetyl-β-D-glucuropryranosyluronate group and PG is an acetyl group.
Compound according to Claim 10 or 11, characterized in that it is chosen from the group formed by:
- 6-O-acetylmorphin-3-yl 6-O-(methyl 2,3,4-tri-O-acetyl-β-D-glucopyranosyluronate)morphin-3-yl terephthalate, and

- bis[6-O-(methyl 2,3,4-tri-O-acetyl-β-D-glucopyranosyluronate)-morphin-3-yl] terephthalate.
Compound of formula in which:
R₁ is as defined in Claim 1.
Compound according to Claim 13, chosen from the group formed by:
- dimorphin-3-yl terephtalate,

- dimorphin-3-yl isophthalate,

- dimorphin-3-yl phthalate,

- dimorphin-3-yl fumarate,

- dimorphin-3-yl benzene-1,2-disulfonate,

- dimorphin-3-yl benzene-1,3-disulfonate,

- dimorphin-3-yl thiophene-2,5-dicarboxylate,

- dimorphin-3-yl naphthalene-2,7-dicarboxylate,

- dimorphin-3-yl 4,4'-oxybenzoate,

- dimorphin-3-yl biphenyl-4,4'-dicarboxylate, and

- dimorphin-3-yl carbonate.