EP0602151A1

EP0602151A1 - Method for synthesizing glucuronides of 4,5-epoxy morphinanes

Info

Publication number: EP0602151A1
Application number: EP92919332A
Authority: EP
Inventors: Alfred Adophe Henri Mertz
Original assignee: IREPA (INSTITUT REGIONAL DE PROMOTION de la RECHERCHE APPLIQUEE); ASSOCIATION ALSACE TECHNOLOGIE; IREPA INST REGIONAL DE PROMOTI
Current assignee: ASSOCIATION ALSACE TECHNOLOGIE
Priority date: 1991-09-04
Filing date: 1992-09-04
Publication date: 1994-06-22
Also published as: FR2680786B1; AU2555592A; FR2680786A1; WO1993005057A1

Abstract

Procédé de synthèse de glucuronides d'époxy-4,5 morphinanes représentés par la formule (I). Ce procédé comprend, après acétylation s'il y a lieu, dans une première étape, la réaction d'un composé de formule (I') avec un dérivé de formule (II) et dans une deuxième étape, l'hydrolyse du composé ainsi obtenu. Ce procédé est caractérisé par le fait que l'étape d'hydrolyse est effectuée par action d'au moins un métal alcalin, de préférence le lithium, ledit métal alcalin étant mis en oeuvre sous la forme métallique ou sous la forme d'au moins un sel.Process for the synthesis of 4,5-epoxymorphinan glucuronides represented by formula (I). This process comprises, after acetylation if necessary, in a first step, the reaction of a compound of formula (I ') with a derivative of formula (II) and in a second step, the hydrolysis of the compound as well got. This method is characterized in that the hydrolysis step is carried out by the action of at least one alkali metal, preferably lithium, said alkali metal being implemented in the metallic form or in the form of at least a salt.

Description

GLUCURONIDE SYNTHESIS PROCESS

EPOXY-4,5 MORPHINANES

The invention relates to a process for the synthesis of glucuronides of 4,5-epoxy morphinans.

By the expression "4,5-epoxy morphinan glucuronide", is meant the result of the reaction of glucuronic acid or one of its derivatives with an epoxy-4,5 morphinane, such as for example the morphine.

These glucuronides, which are formed in the body during the metabolism of epoxy-4,5 morphinans, are three in number in the case of morphine, namely 3-, 3,6- and 6-glucuronide. morphine; derivative 3- which mainly forms during said metabolism is an antagonist thereof, that is to say does not exhibit the analgesic activity of morphine on the central nervous system and on gastrointestinal motility, and would even have an important role in the phenomenon of tolerance to morphine; derivatives 3,6- and 6- (the first being formed linearly with respect to the second) are not only agonists of morphine but even have a greater analgesic activity than this, which makes these derivatives 3,6- and 6- particularly interesting, especially for the treatment of pain.

These 4,5-epoxy morphinan glucuronides were identified by High Performance Liquid Chromatography (HPLC) and by mass spectrometry; until this day. They could not be used as drugs _because of their cost of production.

Indeed, they have been obtained so far by extraction from urine, or by enzymetic synthesis on a very small scale.

In addition, two methods for synthesizing morphine glucuronides by chemical means have been published. nowadays. In their most general aspect, these methods essentially consist in the hydrolysis of an intermediate compound itself resulting from the fixation on its precursor of a protected derivative of glucuronic acid. Thus, the method of H. YOSHIMURA et al. Chem. Pharm. Bull, 1965, vol. 16, 2114-2119, provides, as hydrolysis reagents, successively sodium methylate and an aqueous solution of barium hydroxide; that of CW HAND et al., Ann. Clin. Biochem., 1987, vol. 24, 153-160, provides, as hydrolysis reagents, successively concentrated ammonia and an aqueous solution of barium hydroxide.

It turns out that these two processes only allow the formation of minute traces of the desired product (<1%).

The invention aims to remedy the drawbacks of the prior art and to develop a process for the synthesis of glucuronides of 4,5-epoxy morphinans of the genus in question, the yield of which is compatible with industrial exploitation.

However, the Applicant has had the merit of establishing that, surprisingly and unexpectedly, it was possible to synthesize with high purity and yields, using in particular a particular intermediate extraction step and, preferably, particular hydrolysis means which will be discussed below, 4,5-epoxy glucuronides morphinans of the genus in question which are represented by formula I:

in which :

R ₁ represents a hydrogen atom, a hydroxyl radical, a lower alkoxy radical, an acyloxy radical or an oxy-β-D-glucopyranosyl radical,

- R ₂ and R ₃ together represent the group "= 0", or

each represent or simultaneously a hydrogen atom, a hydroxyl radical, an amino radical, an azido radical or an arainoalkyl radical,

one of the two may also represent an oxy-β-D-glucopyranosyl radical,

it being understood that the vertices 7 and 8 can be joined by a single or a double bond,

- R ₄ represents a hydrogen atom or a hydroxyl radical,

R ₅ represents a hydrogen atom, a lower alkyl radical, a cycloalkyl radical substituted by a lower alkyl, an aryl radical substituted by a lower alkyl, a lower alkene or lower alkyne radical,

as well as their pharmaceutically acceptable addition salts, their anhydrous, solvated, hydrated, polymorphic forms and their optical antipodes.

By "lower alkyl" is meant linear or branched C ₁ to C ₇ and preferably C ₁ to C ₄ hydrocarbon groups such as for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. , preferably the methyl radical.

By "lower alkene" is meant linear or branched C ₂ -C ₇ hydrocarbon groups in which at least one carbon-carbon bond is unsaturated such as allyl, butenyl, dimethylallyl and the like.

By "lower alkyne" is meant radicals such as the propargyl radical and the like. By "cycloalkyl" is meant cyclic C ₃ -C ₇ hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and preferably the cyclopropyl radical.

By "lower alkoxy" is meant linear or branched C ₁ -C ₇ alkoxy radicals such as methoxy, ethoxy, propoxy, butoxy and the like, and preferably the methoxy radical.

By "aryl" is meant organic radicals derived from an aromatic ring by the elimination of a hydrogen atom such as, for example, phenyl, pyridyl, thienyl or furyl radicals substituted by a halogen atom, a radical nitro, an amino radical, an azido radical, a lower alkyl or lower alkoxy radical.

Consequently, the process according to the invention which comprises, in a first step, the reaction of a compound of formula I ', different from the compound of formula I in the sense that R ₁ , R ₂ and R ₃ cannot represent the oxy-β-D-glucopyranosyl radical, with a derivative of formula II:

in which :

- X represents a halogen atom, preferably bromine, and

Ac represents the acetyl radical,

after having protected by acetylation the position 3 of the derivative of formula I 'in the event that it is desired to fix the derivative of formula II only in position 6, and, in a second step, the hydrolysis of the compound thus obtained for transforming acetyl radicals into hydroxyl radicals, is characterized in that the compound resulting from the reaction is extracted using an acid, from the reaction medium obtained at the end of the first step reaction of a compound of formula I 'with a derivative of formula II, whereby said compound is obtained in the form of the salt of the acid in question.

It is this salt which is then subjected to the hydrolysis step.

Preferably, the extraction of the compound resulting from the reaction of a compound of formula I 'with a derivative of formula II is carried out using hydrochloric acid, consequently giving rise to the corresponding hydrochloride.

In an advantageous embodiment of the process according to the invention, the hydrolysis step subsequent to the above extraction is carried out by the action of at least one of the hydrolysis reagents from the group consisting of lithium carbonate, lithium methylate and lithium metal, lithium carbonate being preferred.

Indeed, it has been found that, unexpectedly and surprisingly, the yields of glucuronides of 4,5-epoxy morphinans were increased compared to those recorded with respect to the processes of the prior art by about 20% thanks to the 'intermediate extraction step and approximately 20% additional thanks to the hydrolysis reagents chosen in accordance with the invention.

According to another advantageous embodiment of the process according to the invention, the acetylation, if necessary, of the compound I ′ is carried out within a carbonate buffer, and preferably within the KHCO ₃ + buffer.

K ₂ CO ₃ .

The pharmaceutically acceptable addition salts of the compounds of formula I, as well as their anhydrous forms, solvated, hydrated, polymorphic and their optical antipodes are obtained in a manner known per se.

Thus, the salts can be obtained by adding compounds of the genus in question with an equimolar amount of an alkali metal, for example sodium, potassium or lithium, or of an amino acid such as for example lysine, or d 'an organic or mineral acid such as hydrochloric acid, tallow acid, tartaric acid and its esters, fumaric acid or salicylic acid.

The anhydrous forms can be obtained by drying the compounds of the genus in question, for example at 70 ° C for about 3 hours or under a high vacuum using a vane or membrane pump.

The solvated and polymorphic forms can be obtained by crystallization of the compounds of the genus in question with a solvent such as, for example, ether or ethyl acetate.

Among the hydrated forms, the dihydrate forms can be obtained by drying at room temperature the compounds of the genus in question and the hemihydrate forms can be obtained by drying the compounds of the genus in question under vacuum using a water pump.

In addition, the process in accordance with the invention applies equally to the synthesis of glucuronides of epoxy4,5 dextrorotatory or levorotatory morphines depending on whether the starting product is in the dextrorotatory or levorotatory form.

Thanks to the process according to the invention, it is possible to obtain quantities of the desired product sufficient to easily determine its pharmacological and toxicological properties.

As indicated above, the process according to the invention essentially uses two raw materials, namely an epoxy-4,5 morphine, such as for example morphine, and a protected derivative of glucuronic acid.

The 4,5-epoxy morphinans are stable compounds whose conservation does not pose any particular problem; it is not the same for the protected derivative of glucuronic acid.

However, the Applicant has found that, surprisingly and unexpectedly, it was possible to make the latter product capable of being stored for a period of more than one year, as soon as it is prepared in crystallized form by crystallization in strict absence of alcohol, for example in the presence of ether; this conservation being preferably ensured at a temperature of -20 to -80 ° C.

Advantageously, the shelf life can be further increased to reach approximately 2 years, by addition to the protected derivative of glucuronic acid, after its crystallization in strict absence of alcohol, barium carbonate (BaCO ₃ ) or calcium carbonate ( CaCO ₃ ) at a rate of 1 to 10% by weight relative to the weight of the total mixture.

The following examples will better understand the invention; they are not limiting and relate to advantageous embodiments of the invention. EXAMPLE 1

Preparation of methyl tetra-O-acetyl-β-Dglucopyranuronate.

200 g of D-glucurono-3, 6 lactone are added to a solution of 1.5 g of sodium hydroxide in 1500 ml of methanol. The mixture is stirred for 1 hour and the methanol is then removed in vacuo. The residue is dissolved in 460 ml of pyridine and 850 ml of acetic anhydride are added at 0 ° C. After 24 hours at 0ºC, the precipitate is filtered and recrystallized from ethanol. 43 g of methyl tetra-O-acetyl-β-Dglucopyranuronate are obtained.

The analytical data are as follows: mp = 177-178 ° C; α _D (c = 2, CH ₂ Cl ₂ ) = + 8º; NMR (CDCI ₃ , 200 MHz): 5.76 (d, 1H, H ₁ , J _1-2 - 10.0 Hz); 5.23 (m, 3H, H ₂ + H ₃ + H ₄ ); 4.18 (d, 1H, H ₅ , J _4-5 = 10.0 Hz); 3.75 (s, CO ₂ CH ₃ , 3H); 2.12 (s, 1 O-COCH ₃ , 3H); 2.04 (s, 2-4 O-COCH ₃ , 9H).

Elementary analysis for C ₁₅ H ₂₀ O ₁₁ .

Theory (%): C = 47.88; H = 5.36; O = 46.76.

Found (%): C = 47.92; H = 5.33; O = 46.75.

EXAMPLE 2

Preparation of bromo-1α deoxy-1 tri-O-acetyl-2,3,4 Methyl dglucopyranuronate.

153 g of methyl tetra-O-acetyl-β-Dglucopyranuronate are dissolved in 600 ml of hydrobromic acid at 30% in acetic acid and stored overnight at 0 ° C. The solvent is then removed in vacuo and the residue is dissolved in 400 ml of methylene chloride. This solution is extracted with aqueous potassium bicarbonate and water, dried over sodium sulfate and the solvent is removed in vacuo. The residual syrup is crystallized from ether and 135 g of bromo-lα deoxy-1 tri-O-acetyl-2,3,4 methylglucopyranuronate are obtained. The analytical data are as follows = PF =

104-107ºC; α _D (c = 2, CH ₂ Cl ₂ ) = + 196º; NMR (CDCl ₃ ,

200 MHz): 6.64 (s, 1H, J _{1 - 2} = 4.0 Hz); 5.76 (d, 1H,

H ₁ , J _1-2 = 10.0 Hz); 5.62 (t, 1H, H ₄ ); 5.26 (t, 1H, H ₃ ); 4.86 (q, 1H, H ₂ ); 4.58 (d, 1H, H ₅ , J _4-5 = 10.0 Hz); 3.75 (s, 3H, CO ₂ CH ₃ ); 2.10 (s, 3-O-COCH ₃ , 3H); 2.04 (s, 6H, 2 and 4-O-COCH ₃ ).

Elementary analysis for C ₁₃ H ₁₇ O ₉ Br

Theory (%): C = 39.31; H = 4.31; O = 36.25; Br = 20.13. Found (%): C = 39.34; H = 4.33; O = 36.19; Br = 20.14. EXAMPLE 3

Preparation of acetyl-3 morphine.

In a 3 liter Erlenmeyer flask, 38.0 g of morphine C1H trihydrate (0.101 M) are dissolved in 400 ml of distilled water and then basified with carbonate buffer (100 mM KHCO ₃ / liter + K ₂ CO ₃ qs pH 9.0) to pH 9.0. The pH is checked with the pH meter, then stirred at room temperature for 1 hour. 115 ml of acetic anhydride (1.217 M) and 1.013 liters of KHCO ₃ at 20% w / V (2.024 M) are then added in two batches. The mixture is stirred after the addition has ended for 2 hours at room temperature. The pH of the solution is adjusted to 9.50 on the pH meter, then extracted 5 times with 100 ml of CH ₂ Cl ₂ . The organic phases are combined, washed with 300 ml of water, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. To 26.0 g of orange-yellow oily residue (0.079 M) dissolved in 200 ml of absolute alcohol heated to 60ºC, 7.77 g of sulfamic acid (0.080 M) dissolved in 20.0 ml of distilled water are added heated to 60ºC and allowed to crystallize for 15 hours. It is filtered and dried in an oven. We recrystallize from alcohol. It is filtered and dried. Yield: 27.0 g.

The analytical data are as follows: PF = 207-208ºC. IR (KBr): (OH) = 3305 cm ^-1 , (NH ⁺ ) = 2670 cm ^-1 , (OCOCH ₃ ) = 1740 cm ^-1 , (CH = CH) = 1620 cm ^-1 , M (CH = CH arom.) = 1575 cm ^-1 .

α _D (c - 2, H ₂ O) = - 67 °.

UV (H ₂ O): maximum at 280 nm (specific absorbance = 46). NMR (DMSO d ₆ , 200 MHz): 6.86 (d, 1H, H ₂ , J _1-2 = 7.5 Hz); 6.70 (d, 1H, H ₁ ); 5.65 (d, 1H, H _7, J _7-8 = 10.0 Hz); 5.39 (d, 1H, H ₈ ); 4.92 (d, 1H, H ₈ , J _5-6 = 6.0 Hz); 4.24 (m, 1H, H ₆ ); 2.70 (s, 3H, N-CH ₃ ); 2.31 (s, 3H, COCH ₃ ).

Elementary analysis for C ₁₉ H ₂₁ NO ₄ , NH ₂ SO ₃ H

Theory (%): C = 53.76; H = 5.70; 0 = 26.38; N = 6.60

S = 7.56.

Found (%): C = 53.70; H = 5.73; 0 = 26.52; N = 6.49. EXAMPLE 4

Preparation of hydrochloride hemihydrate of [acetyl-3 (triacetyl-2,3,4 βDglucopyranoside) -6 yl-6 morphine] methyl uronate.

A solution of 140 g of bromo-1α deoxy-1 tri-O-acetyl-2,3,4 methyl dglucopyranuronate in 400 ml of benzene is added dropwise to a mixture of 33 g of acetyl-3 morphine and 70 g of silver carbonate in 500 ml of benzene. The reaction mixture is then heated at reflux for 5 hours. After cooling the mineral salts are removed from the benzene solution containing the base obtained by the above reaction; this benzene solution is concentrated under vacuum to 200 ml and the above-mentioned base is extracted from this solution in 3 times with dilute hydrochloric acid, which gives rise to the formation of the corresponding hydrochloride. The combined acid extracts are in turn extracted 4 times with methylene chloride. The organic layer based on methylene chloride which contains the acid extracts is washed with water, dried over sodium sulfate and evaporated to dryness under vacuum. The resulting viscous residue is crystallized with a mixture of ethyl acetate / ether (1/6), filtered and recrystallized with a mixture of ethanol / ethyl acetate (5/95) to obtain pale yellow crystals. 52 g of hydrochloride hemihydrate are thus obtained [3-acetyl (2,3,4-triacetyl βDglucopyranoside) -6 yl-6 morphine] methyl uronate, ie a yield of 75%. The analytical data are as follows:

Mp = 172-174 ° C (decomposition); α _D (c = 2, CH ₃ OH) = - 124 °; NMR (CDCl ₃ , 200 MHz): 6.83 (d, 1H, H ₂ , J _1-2 = 7.5 Hz); 6.70 (d, 1H, H ₁ ); 5.72 (d, 1H, H ₇ , J _7-8 = _10.0 Hz); 5.32 (d, 1H, H ₈ ); 5.10 (d, 1H, H ₅ , J _5-6 = 6.0 Hz); 3.64 (s, 3H, CO ₂ CH ₃ ); 2.91 (s, 3H, N-CH ₃ ); 2.26 (s, 3H, 3-O-COCH ₃ ); 2.11 (s, 3H, 2'-O- COCH ₃ ); 1.99 (s, 3H, 3'-O-COCH ₃ ); 1.97 (s, 3H, 4'-O-COCH ₃ ). Elementary analysis calculated for: C ₃₂ H ₃₇ NO _{1 3} , ClH, 0.5

H ₂ O.

Theory (%): C = 55.78; H = 5.70; 0 = 31.34;

N = 2.03; Cl = 5.15.

Found (%): C = 55.64; H - 5.70; 0 = 31.50;

N = 2.01; Cl = 5.15.

EXAMPLE 5 Preparation of 6βDglucuronide of morphine.

To a solution of 27.6 g of the compound obtained in Example 4 in 300 ml of methanol, 29.6 g of Li ₂ CO ₃ and 300 ml of water are added. The reaction mixture is stirred for 24 hours at room temperature. The mineral salts are separated by filtration and the solvents are removed under vacuum. The residue is dissolved in 200 ml of water, the reaction mixture is brought to pH 6 and the solvents are removed in vacuo. The residue is chromatographed on a silica gel column with a methylene chloride / methanol mixture (3/1) as eluent. The residue is then purified on an H ion exchange resin with aqueous methanol as the eluent. 13.4 g of 6βDglucuronide of morphine are obtained, ie a yield of 72%. The analytical data are as follows: mp = 245-250 ° C (decomposition); α _D (c = 2, H ₂ O) = 148 °; NMR (D ₂ O, 200 MHz): 6.64 (d, 1H, H ₂ , J _1-2 = 8.0 Hz); 6.57 (d, 1H, H ₁ ); 5.77 (d, 1H, H ₇ , J _7-8 = 10.0 Hz); 5.39 (d, 1H, H ₈ ); 5.12 (d, 1H, H ₅ , J _5-6 = 6.0 Hz); 2.74 (s,

3H, N-CH ₃ ).

Elementary analysis calculated for: C ₂₃ H ₂₇ NO ₉ .

Theory (%): C = 59.86; H = 5.90; N = 3.04.

Found (%): C = 59.90; H = 5.88; N = 3.04.

EXAMPLE 6

Preparation of morphine 6βDglucuronide.

1.10 g Li ₂ CO ₃ and 50 ml of water are added to a solution of 1.03 g of the compound obtained in Example 4 in 50 ml of methanol. The reaction mixture is stirred for 24 hours at room temperature. The mineral salts are separated by filtration and the solvents are removed under vacuum. The residue is dissolved in 100 ml of water, the reaction mixture is brought to pH 6 and the solvents are removed in vacuo. The residue is dissolved in 50 ml of water and purified by HPLC on a column loaded with octadecyl silica particles (ODS-silica) with a particle size of 1-10 μm and eluted with 25% methanol or acetonitrile in 10 mM sodium dihydrogen phosphate buffer at pH 2.1, (adjusted with phosphoric acid) containing 1 mM dodecylsulphate as a counterion. 0.49 g of 6βDglucuronide of morphine is obtained, ie a yield of 71%.

The analytical data are the same as those mentioned in Example 5.

EXAMPLE 7

Preparation of morphine 6βDglucuronide.

To a solution of 3.44 g of the compound obtained in Example 4 in 100 ml of methanol, 3.69 g of Li ₂ CO ₃ and 100 ml of water are added. The reaction mixture is stirred for 24 hours at room temperature. The salts minerals are separated by filtration and the solvents are removed under vacuum. The residue is then dissolved in 100 ml of water, the reaction mixture is brought to pH 6 and the solvents are removed in vacuo. The residue is dissolved in 50 ml of water and purified by HPLC on a column loaded with styrene-divinylbenzene copolymers with a particle size of 100-200 μm (Amberlite XAD-2) and eluted with methanol in water (1 / 1, v / v). 1.69 g of 6βDglucuronide of morphine are obtained, ie a yield of 73%.

The analytical data are the same as those mentioned in Example 5.

EXAMPLE 8

Preparation of morphine 6βPglucuronide.

To a solution of 1.0 g of the compound obtained in Example 4 in 50 ml of methanol, 0.46 g of LiOH, H ₂ O is added. The reaction mixture is stirred for 2 hours at room temperature then the methanol is evaporated. The residue is dissolved in 50 ml of water and 0.55 g of LiOH, H ₂ O are added. After 1 hour, the reaction mixture is brought to pH 6 and the solvents are removed under vacuum. The residual product is purified as in Examples 5, 6 or 7. 0.32 g of 6βD-glucuronide of morphine is obtained, ie a yield of 48%.

The analytical data are the same as those mentioned in Example 5.

EXAMPLE 9

Preparation of 3,6-diglucuronide of morphine.

To a solution of 4.5 g of morphine hydrochloride in 100 ml of methanol, 1.26 g of LiOH, H ₂ O and 16.65 g of bromo-lα deoxy-1 tri-O-acetyl Dglucopyranuronate are added. . After 5 hours of stirring at room temperature, the residue obtained after evaporation of the solvent is purified as indicated in examples 5, 6 or 7. 3.50 g of [(2,3,4-triacetyl βD glucopyranoside) are obtained - 3 yl-3 morphine] methyl uronate. In a 2-liter three-necked flask, methyl uronate is added to a solution of 3.0 g of [2,3,4-triacetyl-2,3,4 βDglucopyranoside) -3 yl-3 morphine] in 100 ml of benzene redistilled over sodium, 3, 18 g of silver carbonate then 6.42 g of bromo-lα deoxy-1-2,3-triacetyl-2,3,4 methyl Oglucopyranuronate in 150 ml of benzene redistilled over sodium. The mixture is heated at reflux for 5 hours. After cooling, the silver salts are removed by filtration and then the benzene is concentrated to 50 ml by evaporation under vacuum. Extraction is carried out 5 times with 30 ml of 0.5N hydrochloric acid. The acid solutions are combined and they are extracted 4 times with 50 ml of CH ₂ Cl ₂ . The organic phases are combined, washed with 300 ml of distilled water, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue is dissolved in 100 ml of ethyl acetate. 600 ml of dried ether on sodium and benzophenone are added, then crystallization is carried out with magnetic stirring for 15 hours. It is filtered away from humidity and dried in an oven at 70ºC for 1 night. Yield: 3.0 g.

1.70 g of Li ₂ CO ₃ and 50 ml of water are added to a solution of 2.5 g of the above derivative in 50 ml of methanol. After 24 hours of stirring at ordinary temperature, the inorganic salts are separated by filtration and the solvents are evaporated in vacuo. The residue obtained is dissolved in 100 ml of water, acidified to pH 6 and the solvents are evaporated in vacuo. The residual product is purified according to Examples 5, 6 or 7 and 0.52 g of morphine-3, 6 βD morphine glucuronide is obtained, ie a yield during the hydrolysis step of 35%.

Elementary analysis for: C ₂₉ H ₃₅ NO ₁₅

Theory (%): C = 54.63; H = 5.53; O = 37.64;

N = 2.20.

Found (%): C = 54.60; H = 5.62; O = 37.59;

N = 2.19. EXAMPLE 10

Preparation of morphine 3βDglucuronide.

1.1 g of LiOH, H ₂ O and 14.62 g of bromo-1α deoxy-1 tri-O-acetyl-2,3 are added to a solution of 3.0 g of morphine base in 50 ml of methanol. , 4 Methyl dglucopyranuronate. After stirring for 5 hours at room temperature, 3.11 g of Li ₂ CO ₃ and 50 ml of water are added. The reaction mixture is stirred for 15 hours at room temperature and then the solvents are evaporated. The residue is dissolved in 50 ml of water, the reaction mixture is brought to pH 9 and extracted four times with a mixture of methylene chloride / methanol (3/1) to remove the unprocessed morphine. The aqueous layer is removed under vacuum. The residual product is purified as in Example 5 and 2.18 g of 3βDglucuronide of morphine are obtained, ie a yield during the hydrolysis step of 45%.

The analytical data are as follows: mp = 243-248 ° C (decomposition); αD (c = 2, H ₂ O) = -132º; NMR (D ₂ O, 200 MHz): 6.56 (d, 1H, H ₂ , J _1-2 = 8.0 Hz); 6.42 (d, 1H, H ₁ ); 5.83 (d, 1H, H ₇ , J _7-8 = 10.0 Hz); 5.47 (d, 1H, H ₈ ); 5.25 (d, 1H, H ₅ , J _5-6 = 6.0 Hz); 2.66 (s, 3H, N-CH ₃ ).

Elementary analysis for: C ₂₃ H ₂₇ NO ₉ .

Theory (%): C = 59.86; H = 5.90; N = 3.04.

Found (%): C = 559.93; H = 5.86; N = 3.02.

Claims

1. Process for the synthesis of glucuronides of epoxy-4,5 morphinans represented by formula I:

in which :

- R ₂ and R ₃ together represent the group

"= O", or

each represent or simultaneously a hydrogen atom, a hydroxyl radical, an amino radical, an azido radical or an aminoalkyl radical,

one of the two may also represent an oxy-β-D-glucopyranosyl radical,

- R ₄ represents a hydrogen atom or a hydroxyl radical,

- R ₅ represents a hydrogen atom, a lower alkyl radical, a cycloalkyl radical substituted by a lower alkyl, an aryl radical substituted by lower alkyl, lower alkene or lower alkyne radical,

as well as pharmaceutically acceptable addition salts, anhydrous, solvated, hydrated, polymorphic forms and optical antipodes of the compounds of formula I, a process which comprises in a first step the reaction of a compound of formula I ', different from the compound of formula I in the sense that R ₁ , R ₂ and R ₃ cannot represent the oxy-β-D-glucopyranosyl radical, with a derivative of formula II:

in which :

- X represents a halogen atom, preferably bromine, and

Ac represents the acetyl radical,

after having protected by acetylation the position 3 of the derivative of formula I 'in the event that it is desired to fix the derivative of formula II only in position 6, and in a second step the hydrolysis of the compound thus obtained to transform the radicals acetyl in hydroxyl radicals, and which is characterized in that the compound resulting from the reaction of a compound of is extracted with the aid of an acid from the reaction medium obtained at the end of the first step formula I 'with a derivative of formula II, whereby said compound is obtained in the form of the salt of the acid in question.

2. Method according to claim 1, characterized in that the acid is hydrochloric acid.

3. Method according to claim 1 or 2, characterized in that the hydrolysis step is carried out by action of at least one of the hydrolysis reagents of the group consisting of lithium carbonate, lithium methylate and lithium metal, lithium carbonate being preferred.

4. Method according to claims 1 to 3, characterized in that the acetylation, if necessary, of the compound I 'is carried out in a carbonate buffer.

5. Method according to claim 4, characterized in that the carbonate buffer is the KHCO ₃ + K ₂ CO ₃ buffer.

6. Method according to claims 1 to 5, characterized in that the derivative of formula II is prepared in crystallized form, by crystallization in strict absence of alcohol.

7. Method according to claims 1 to 6, characterized in that the 4,5-epoxy morphinan used consists of morphine.