FR2680786A1 - Process for the synthesis of glucuronides of 4,5-epoxymorphinans - Google Patents

Abstract

A method for synthesizing glucuronides of 4,5-epoxy morphinanes having formula (I). The method comprises, optionally after acetylation, a first step of reacting a compound of formula (I') with a derivative of formula (II), and a second step of hydrolyzing the resulting compound. The method is characterized in that the hydrolysis step is performed by means of at least one alkali metal, preferably lithium, which is provided in the form of a metal or of at least one salt.

Description

GLUCURONIDE SYNTHESIS PROCESS
EPOXY-4,5 MORPHINANES
The subject of the invention is 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 4,5-epoxy 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 in a minority compared to the second) are not only agonists of morphine but even exhibit an analgesic activity greater than this, which makes these derivatives 3,6- and 6- particularly interesting, especially for the treatment of pain.

 These epoxy-4,5 morphinans glucuronides were identified by High Performance Liquid Chromatography (HPLC) and by mass spectrometry; to date, they have not been able to be used as medicines due to their manufacturing cost.

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

 In addition, two methods for synthesizing morphine glucuronides by chemical means have been published to date. 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 object of the invention is 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.

dans laquelle
- R1 représente un atome d'hydrogène, un radical hydroxyle, un radical alcoxy inférieur, un radical acyloxy ou un radical oxy-p-D-glucopyranosyle,
- R2 et R3 représentent ensemble le groupe "=0", ou
représentent chacun ou simultanément un atome d'hydrogène, un radical hydroxyle, un radical amino, un radical azido ou un radical aminoalkyle,
l'un des deux pouvant également représenter un radical oxy-B-D-glucopyranosyle, étant entendu que les sommets 7 et 8 peuvent être réunis par une simple ou une double liaison,
- R4 représente un atome d'hydrogène ou un radical hydroxyle,
- R5 représente un atome d'hydrogène, un radical alkyle inférieur, un radical cycloalkyle substitué par un alkyle inférieur, un radical aryle substitué par un alkyle inférieur, un radical alcène inférieur ou alcyne inférieur, ainsi que leurs sels d'addition pharmaceutiquement acceptables, leurs formes anhydres, solvatées, hydratées, polymorphes et leurs antipodes optiques.Now, 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 particular hydrolysis conditions which will be discussed below, 4,5-epoxy morphinan glucuronides of the genus in question which are represented by formula I

in which
R1 represents a hydrogen atom, a hydroxyl radical, a lower alkoxy radical, an acyloxy radical or an oxy-pD-glucopyranosyl radical,
- R2 and R3 together represent the group "= 0", 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-BD-glucopyranosyl radical, it being understood that the vertices 7 and 8 can be joined by a single or a double bond,
- R4 represents a hydrogen atom or a hydroxyl radical,
R5 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 hydrocarbon groups in C1 to C7 and preferably in C1 to C4 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 C2 to C7 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 C3 to C7 cyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and preferably the cyclopropyl radical.

 By "lower alkoxy" is meant linear or branched C1 to C7 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.

dans laquelle
- X représente un atome d'halogène, de préféren
ce le brome, et
- Ac représente le radical acétyle, après avoir protégé par acétylation la position 3 du dérivé de formule I' dans l'éventualité où l'on souhaite fixer le dérivé de formule II uniquement en position 6, et, dans une deuxième étape, l'hydrolyse du composé ainsi obtenu pour transformer les radicaux acétyle en radicaux hydroxyle, 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.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 R1, R2 and R3 cannot represent the radical oxy -PD-glucopyranosyle, with a derivative of formula II

in which
- X represents a halogen atom, preferably
this 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 acetyl radicals into hydroxyl radicals, 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 used in metallic form or in the form of at least one salt.

 It has in fact been found that the result obtained by using the alkali metal in metallic form is the same as that obtained by using said alkali metal in the form of a salt.

 In an advantageous embodiment of the process according to the invention, the lithium salt used in the hydrolysis step consists of lithium methylate, lithium hydroxide or lithium carbonate or their mixtures, lithium carbonate being preferred.

 According to another advantageous embodiment, and when the alkali metal consists of sodium and / or potassium, the salt used in the hydrolysis step consists of hydroxide, carbonate or bicarbonate or their mixtures, carbonate being preferred.

 In an advantageous embodiment of the process according to the invention, the compound obtained in the form of the base at the end of the step preceding the hydrolysis step, that is to say the compound resulting from the reaction of a compound of formula I 'with a derivative of formula II as indicated above, is used, in the hydrolysis step in the form of a salt, and preferably in the form of a hydrochloride.

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 buffer
KHC03 + K2C03.

 The pharmaceutically acceptable addition salts of the compounds of formula I, as well as their anhydrous, solvated, hydrated, polymorphic forms 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, sulfuric 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 approximately 3 hours or under a high vacuum using a vane or membrane pump.

 The solvated and polymorphic forms can be obtained by the 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 according to the invention applies equally to the synthesis of glucuronides of 4,5-epoxy dextrorotatory or levorotatory morphinans depending on whether the starting product is in the dextrorotatory or levorotatory form.

 A particular advantage of the process according to the invention lies in the fact that the yield of the hydrolysis step can exceed 30% in the case of the use of lithium hydroxide and 70% in the case of the use of lithium carbonate.

 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 morphinane, 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 (BaC03-) or calcium carbonate ( CaCO3) 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-p-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 0 C, the precipitate is filtered and recrystallized from ethanol.

43 g of methyl tetra-O-acetyl-ss-Dglucopyranuronate are obtained.

The analytical data are as follows: PF = 177-178 "C; aD (c = 2, CH2C12) = + 80; NMR (CDC13, 200
MHz): 5.76 (d, 1H, H1, J1-2 = 10.0 Hz); 5.23 (m, 3H,
H2 + H3 + H4); 4.18 (d, 1H, H5, Jq-5 = 10.0 Hz); 3.75 (s, C02CH3, 3H); 2.12 (s, 10-COCH3, 3H); 2.04 (s, 2-4
O-COCH3, 9H).

Elementary analysis for C15H20011.

Theory (%): C = 47.88; H = 5.36; 0 = 46.76.

Found (%): C = 47.92; H = 5.33; 0 = 46.75.

EXAMPLE 2
Preparation of bromo-deoxy-1 tri-0-acetyl-2,3,4 methyl dglucopyranuronate.

 153 g of methyl tetra-O-acetyl-ss-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 under vacuum 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-deoxy1 tri-0-acetyl-2,3,4 methylglucopyranuronate are obtained.

The analytical data are as follows = PF = 104-107 "C; aD (c = 2, CH2C12) = + 1960; NMR (CDC13, 200 MHz): 6.64 (s, 1H, J1-2 = 4.0 Hz); 5.76 (d, 1H,
H1, J1-2 = 10.0 Hz); 5.62 (t, 1H, H4); 5.26 (t, 1H,
H3); 4.86 (q, 1H, H2); 4.58 (d, 1H, H5, J45 = 10.0
Hz); 3.75 (s, 3H, CO2CH3); 2.10 (s, 3-O-COCH3, 3H); 2.04 (s, 6H, 2 and 4-O-COCH3).

Elementary analysis for C13H1709Br Theory (*): C = 39.31; H = 4.31; O = 36.25; Br = 20.13.

Found (t): 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 ClH trihydrate (0.101 M) are dissolved in 400 ml of distilled water and then basified with carbonate buffer (100 mM KHCO3 / liter + K2CO3 qs pH 9.0) up 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 20% w / v KHCO3 (2.024 M) are then added in two batches. After stirring the addition, the mixture is stirred 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 CH2Cl2. The organic phases are combined, washed with 300 ml of water, dried over anhydrous Na2SO4, 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 60 "C, 7.77 g of sulfamic acid (0.080 M) dissolved in 20.0 ml of distilled water heated to 60 "C 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: P.F. = 207-208 "C.

IR (KBr): 8 (OH) = 3305 cm-1, a (NH +) = 2670 cm ~ l, a (OCOCH3) = 1740 cm-1, a (CH = CH) = 1620 cm-l
M (CH = CH arom.) = 1575 cm'l.

 QD (c = 2, H2O) = -670.

UV (H2O): maximum at 280 nm (specific absorbance = 46).

NMR (DMSO d6, 200 MHz): 6.86 (d, 1H, H2, J12 = 7.5 Hz); 6.70 (d, 1H, H1); 5.65 (d, 1H, H7, J7-8 = 10.0 Hz); 5.39 (d, 1H, H8) 4.92 (d, 1H H5, J5-6 H 6.0 Hz); 4.24 (m, 1H, H6); 2.70 (s, 3H, N-CH3); 2.31 (s, 3H, COCH3).

Elementary analysis for ClgH21N04, NH2SO3H
Theory (%): C = 53.76; H = 5.70; O = 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 tacetyl-3 (triacetyl-2,3,4 ss Glucopyranoside) -6 yl-6 morphine] methyl uronate.

A solution of 140 g of 1-bromo-1 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 3-acetyl 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 eliminated and the benzene is concentrated under vacuum to 200 ml and extracted in 3 times with dilute hydrochloric acid. The combined acid extracts are then extracted 4 times with methylene chloride. The organic layer is washed with water, dried over sodium sulfate and evaporated in vacuo until it is dry. 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 of (acetyl-3 (2,3-triacetyl, 2,3 ss Glucopyranoside) -6 yl-6 morphine] methyl uronate are obtained with a yield of 75%. The analytical data are the following: PF = 172 -174 "C (decomposition); aD (c = 2, CH30H) = -124"; NMR (CDC13, 200 MHz): 6.83 (d, 1H, H2, J12 = 7.5 Hz); 6.70 (d, 1H, H1); 5.72 (d, 1H, H7, J7-8 = 10.0 Hz); 5.32 (d, 1H, H8); 5.10 (d, 1H, H5tJ5 ~ 6 = 6.0 Hz); 3.64 (s, 3H, CO2CH3); 2.91 (s, 3H,
N-CH3); 2.26 (s, 3H, 3-O-COCH3); 2.11 (s, 3H, 2'-O
COCH3); 1.99 (s, 3H, 3'-O-COCH3); 1.97 (s, 3H, 4'-0- COCH3).

Elemental analysis calculated for: C32H37N013, ClH, 0.5
H20.

Theory (*): C = 55.78; H = 5.70; 0 = 31.34;
N = 2.03; C1 = 5.15.

Found (): C = 55.64; H = 5.70; O = 31.50
N = 2.01; Cl = 5.15.

EXAMPLE 5
Preparation of morphine glucuronide 6ssD.

 To a solution of 27.6 g of the compound obtained in Example 4 in 300 ml of methanol, 29.6 g of Li2CO3 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 6ssD glucuronide of morphine are obtained, ie a yield of 72%.

The analytical data are as follows: P.F. = 245 2500C (decomposition); D (c = 2, H2O) = 1480; NMR (D20, 200 MHz): 6.64 (d, 1H, H2, J1-2 = 8.0 Hz); 6.57 (d, 1H, H1); 5.77 (d, 1H, H7, J7-8 = 10.0 Hz); 5.39 (d, 1H, H8); 5.12 (d, 1H, H5, J5-6 = 6.0 Hz); 2.74 (s, 3H, N-CH3).

Elemental analysis calculated for: C23H27NOg.

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 6ssDglucuronide.

1.10 g are added to a solution of 1.03 g of the compound obtained in Example 4 in 50 ml of methanol
Li2C03 and 50 ml of water. 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 of a sodium dihydrogen phosphate buffer at pH 2.1, (adjusted with phosphoric acid) containing 1 mM of dodecylsulphate as a counterion. 0.49 g of 6ssDglucuronide of morphine is obtained, i.e. a 71% yield.

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

EXAMPLE 7
Preparation of morphine 6pDglucuronide.

To a solution of 3.44 g of the compound obtained in Example 4 in 100 ml of methanol, 3.69 g of
Li2CO3 and 100 ml of water. 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 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 6ssDglucuronide 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 6ssDglucuronide.

To a solution of 1.0 g of the compound obtained in Example 4 in 50 ml of methanol, 0.46 g of
LiOH, H2O. The reaction mixture is stirred for 2 hours at room temperature and then the methanol is evaporated. The residue is dissolved in 50 ml of water and 0.55 g of LiOH, H2O 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 6ssD-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 is added,
H2O and 16.65 g of bromo-deoxy-1 tri-O-acetyl methylglucopyranuronate. 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 ssD glucopyranoside) are obtained - 3 yl-3 morphine) methyl uronate.

To a solution of 3.0 g of (2,3,4-triacetyl-2,3,4 ssglucopyranoside) -3 yl-3 morphine] methyl uronate in 100 ml of benzene redistilled over sodium, is added to a 2-liter three-necked flask 3.18 g of carbonate of silver then 6.42 g of bromo-la-deoxy-1 triacetyl-2,3,4
Methyl dglucopyranuronate in 150 ml of redistilled benzene on 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 CH2Cl2. The organic phases are combined, washed with 300 ml of distilled water, dried over anhydrous Na2SO4, 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 70 ° C. for 1 night. Yield: 3.0 g.

 To a solution of 2.5 g of the above derivative in 50 ml of methanol, 1.70 g of Li2CO3 and 50 ml of water are added. 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 pD glucuronide of morphine is obtained, ie a yield during the hydrolysis step of 35%.

Elementary analysis for: C29H35N015
Theory (%): C = 54.63; H = 5.53; 0 = 37.64;
N = 2.20.

Found (%): C = 54.60; H = 5.62; 0 = 37.59
N = 2.19.

EXAMPLE 10
Preparation of morphine 3ssDglucuronide.

 To a solution of 3.0 g of morphine base in 50 ml of methanol, 1.1 g of LiOH, H2O and 14.62 g of bromo-deoxy-1 tri-O-acetyl-2,3,4 are added. Methyl dglucopyranuronate. After stirring for 5 hours at room temperature, 3.11 g of Li2CO3 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 3PDglucuronide of morphine are obtained, ie a yield during the hydrolysis step of 45 *.

The analytical data are as follows: P.F. = 243248 C (decomposition); aD (c = 2, H2O) = -132; NMR (D20, 200 MHz): 6.56 (d, 1H, H2, J1-2 = 8.0 Hz); 6.42 (d, 1H, H1); 5.83 (d, 1H, H7, J7-8 10.0 Hz); 5.47 (d, 1H, H8); 5.25 (d, 1H, H5, J5-6 = 6.0 Hz); 2.66 (s, 3H, N-CH 3).

Elementary analysis for: C23H27NOg.

Theory (9): C = 59.86; H = 5.90; N = 3.04.

Found (*): C = 59.93; H = 5.86; N = 3.02.

Claims (8)

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

 in which  R1 represents a hydrogen atom, a hydroxyl radical, a lower alkoxy radical, an acyloxy radical or an oxy-ss-D-glucopyranosyl radical,  - R2 and R3 together represent the non-OR group  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-B-D-glucopyranosyl radical, it being understood that the vertices 7 and 8 can be joined by a single or a double bond,  - R4 represents a hydrogen atom or a hydroxyl radical,  R5 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 pharmaceutically acceptable addition salts, anhydrous, solvated, hydrated, polymorphic forms and optical antipodes of the compounds of formula I, 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 R1, R2 and R3 cannot represent the oxy-ss-D-glucopyranosyl radical, with a derivative of formula II

 in which  - X represents a halogen atom, preferably  this 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 converting acetyl radicals into hydroxyl radicals, and which 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 used in metallic form or in the form of at least one salt.  2. Method according to claim 1, characterized in that the lithium salt used in the hydrolysis step consists of lithium methylate, lithium hydroxide or lithium carbonate or their mixtures, and preferably with lithium carbonate.  3. Method according to claims 1 and 2, characterized in that when the alkali metal consists of sodium and / or potassium, the salt used in the hydrolysis step consists of hydroxide, carbonate or bicarbonate or their mixtures, and preferably carbonate.  4. Method according to claims 1 to 3, characterized in that the compound resulting from the reaction of a compound of formula I 'with a derivative of formula II is used, in the hydrolysis step, in the form of 'a salt.  5. Method according to claim 4, characterized in that the salt used in the hydrolysis step is a hydrochloride.  6. Method according to claims 1 to 5, characterized in that the acetylation, if necessary, of the compound I 'is carried out in a carbonate buffer.  7. Method according to claim 6, characterized in that the carbonate buffer is the buffer KHC03 + K2CO3.  8. Method according to claims 1 to 7, characterized in that the derivative of formula II is prepared in crystallized form, by crystallization in strict absence of alcohol.