MXPA99000339A - Hydroxyxide monoacilation procedure - Google Patents

Abstract

The present invention relates to: a method for the selective monoacylation of hydroxitaxane using a methylene salt imini

Description

PROCEDURE OF MONOACILACION OF HYDROXITAXANES The present invention relates to a process for the monoacylation of hydroxitaxanes. It relates more particularly to a process of selective monoacylation of desacetyl-10 baccatin III or its derivatives.

Deacetyl-10 baccatin III (10-DAB), represented by the general formula (I) in which Ri represents a hydrogen atom and baccatin III represented by the general formula (I) in which Ri represents an acetyl radical, can be extracted from yew leaves and are the interesting raw materials in the emission of paclitaxel (Taxol®), docetaxel (Taxotére®) and its derivatives.

REF .: 28994 However, 10-DAB is more easily accessible, and it is extracted from leaves in greater quantities than baccatin III.

It is known, after the works of F.

Guéritte-Voegelein et al., Tetrahedron, 42, 4451-4460 (1986), that the acetylation of 10-DAB with acetic anhydride is less selective. When the reaction takes place under the appropriate operating conditions (24 hours at 20 ° C), an equimolar mixture of the 7-monoacetyl and 7,10-diacetyl derivatives is formed. The most vigorous conditions (48 hours at 60 ° C) lead to the formation of 7,10 diacetyl and 7, 10, 13-triacetyl in equal amounts. At a higher temperature (24 hours at 80 ° C), the 7, 10, 13-triacetyl derivative is formed exclusively.

It is known again according to J-N. Denis et A.E. Greene, J. Am. Chem ,. Soc. 110, 5917-5919 (1988) that 10-DAB can be acetylated at the 10-position by acetyl chloride with the condition of protecting to selectively prevent hydroxyl at 7 with a triethylsilyl group.

In PCT International application O / 95/26961 the preparation of baccatin III from 10-DAB in three stages is described: protection of hydroxyl in 7 by the action of a trialkylsilyl halide, acetylation of hydroxide in 10 by the acetic anhydride and in short the deprotection of the trialkylsilyl group in 7 pyridium trifluoroacetic acid medium.

Taking these results into account, it is known that in the whole reaction the differentiation between free hydroxyl in positions 7 and 10 of 10-DAB or its derivatives remains, notably selective acylation is of great importance in the synthesis of taxoids.

The present invention describes, for the first time, a selective monoacylation reaction of the hydroxyl at the C-10 position of the < deacetyl-10 baccatin III or its derivatives in C / 2 and / or in C-4.

It is known after W. Kantlehner, Adv. Org.

Chem., Vol. 9, part 2, 65-141 and 181-277 (1976), that the halogenomethylene iminium can react with the alcohols to give the halides of the alkoxymethylene iminium intermediates, which then lead to hydrolysis with the corresponding esters with the elimination of an alkylamine.

It has now been found that deacetyl-10 baccatin III or its derivatives at C-2 and / or at C-4, can be selectively monoacylated at position 10 when a methylene iminium salt is used which corresponds to the general formula ( II): wherein R2 represents: - a hydrogen atom, - a linear or straight, branched or cyclic alkyl radical containing from 1 to 12 carbon atoms, - a linear or straight, branched or cyclic alkenyl radical containing from 2 to 12 carbon atoms, - a linear or straight or branched alkynyl radical containing from 3 to 12 carbon atoms, - an aryl radical, - an alkoxy, alkylamino, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl or alkylthiocarbonyl group in which the alkyl part contains 1 to 12 atoms carbon, or - a heterocyclic radical, saturated or unsaturated, containing 5 to 6 bonds and one or more heteroatoms selected from sulfur, oxygen or nitrogen. these radicals are optionally substituted by one or more substituents selected from: halogen atoms, alkyl radicals or haloalkyl radicals, the aryl radicals, - the alkylamino, piperidyl, piperazinyl, nitro or cyano groups, the alkoxy or alkoxycarbonyl groups, the alkyl parts of different radicals contain from 1 to 12 carbon atoms, and - the heterocyclic, saturated or unsaturated radicals contain from 5 to 9 bonds in one or more heteroatoms selected from sulfur, oxygen or nitrogen, or R2 and R3 or R2 and R4 can form, with the nitrogen atom and the methyl carbon, an indigo including from 4 to 7 bonds, such as 2-piperidone, 2-azetidinone, 2-pyrrolidinone, caprolactam.

R and R4 / identical or different, each represents: - a hydrogen atom, - a linear or straight, branched or cyclic alkyl radical containing from 1 to 12 carbon atoms, - a linear or straight, branched or cyclic alkenyl radical containing 2 to 12 carbon atoms, - a linear or straight or branched alkynyl radical containing 3 to 12 carbon atoms, or - an aryl radical, or R3 and R4 can form with the nitrogen atom a heterocycle containing 4 to 6 saturated or unsaturated bonds, optionally substituted.

X represents a halogen atom or a phosphinyloxy, phosphoranyloxy, halogenosulfinyloxy, halogenosulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkylaminosulfonyloxy, alkylcarbonyloxy, arylcarbonyloxy, halophofinyloxy, halophosphoranyloxy, haloalkylsulfonyloxy, haloalkyl carbonate, Y "represents an ion selected from halides, alkylsulfonates, arylsulfonates, alkylamine sulfonates, alkylcarboxylates, arylcarboxylates and phosphorodihalogenidates, or [M (Z) n]" in which 4 < n < 6, Z are a halogen atom and M is an element of the periodic table that can have an oxidation degree equal to or greater than 3 and preferably comprises between 3 to 5.

More particularly X represents: - a halogen atom such as a fluorine, chlorine, bromine or iodine atom, - a group (Hal) 4P-0-, (Hal) 2PO-0-, (Hal) SO-O-, (Hal) S02-0- RaS02-0- or RaC02 in which Ra represents a linear, branched or cyclic alkyl radical, a halogenoalkyl radical, an aryl radical * optionally substituted by a halogen atom or by an alkyl or nitro radical, and Hal represents a halogen atom selected from the fluorine, chlorine, bromine or iodine atoms.

Y "represents: a halide ion such as a fluoride, chloride, bromide or iodide ion, - an antagonist ion such as RaC02 ~, RaS03 ~ (Hal) 2P02 ~, in which Hal and Ra are defined as above, or - an entity as [M (Z) n] ~ in which 4 <n <6, Z are a halogen atom such as a fluorine or chlorine atom, and M is an element of the periodic table which may have a degree of oxidation equal to or greater than 3, selected from aluminum, boron, antimony, tin, titanium.

More particularly, in the general formula (II), R 2 represents a hydrogen atom or a methyl, ethyl radical or a phenyl radical.

By way of example, the following salts may be used: N, N-dimethyl trifluoromethanesulfonyloxy-1-methylidene-ammonium trifluoromethanesulfonate: (R2 = H, R3 = R4 = CH3, X = CF3S03, Y = CF3S03") N-methyl trifluoromethanesulfonyloxy-1-ethylidene-ammonium trifluoromethanesulfonate: (R2 = R3 = CH3 R4 = H, X = CF3, S03, Y "= CF3S03") N-methyl p-toluenesulfonyloxy-1-ethylidene-ammonium chloride: Y = C1") The N-methyl chloro-1-ethylidene-ammonium p-toluenesulfonate: (R2 = R3 = CH, R4 = H, X = C1, Y ~ = p-CH3-C6H4-S03 ~) N-methyl chloro-1-ethylidene-ammonium chloride: (R2 = R3 = CH3, R4 = H, X = C1, Y "= C1") The N-ethyl methanesulfonyloxy-1-ethylidene-ammonium chloride: (R2 = CH3, R3 = C2H5, R4 = H, X = CH3S03, Y "= C1") N-ethyl chloro-1-ethylidene-ammonium methanesulfonate: (R2 = CH3, R3 = C2H5, R4 = H, X = C1,? - = CH3S03") N-Ethyl dichlorophosphinnyloxy-1-ethylidene-ammonium chloride: (R2 = CH3, R3 = C2H5, R4 = H, X = 0-PO-Cl2, Y ~ = C1") or N-ethyl chloro-1 dichlorophosphonate. ethylidene-ammonium: (R2 = CH3, R3 = C2H5, R4 = H, X = C1, Y "= C12P02") The N, N-diethyl p-toluenesulfonyloxy-1-ethylidene-ammonium p-toluenesulfonate: (R2 = CH3, R3 = R4 = C2H5, X = p-CH3-C6H4-S03, Y "= p-CH3-C6H4-S03 ~) These salts can be prepared according to the methods described in the literature or inspired by them [see for example W. Kantlehner, Adv. Org. Chem., Vol. 9, part 2, 5-64 and 65-141 (1976), R.L. N. Harris, Synthesis, 841-842 (1980), H.S. Mosher et al., Synthetic Commun., 11, 733-736 (1981), A.G. Martinez et al., J. Chem. Soc, Chem. Commun., 1571-1572 (1990), H. Heaney et al., Tetrahedron, 49, 4015-4034 (1993), and P.L. Fuchs et al. J. Org. Chem., 59, 348-354 (1994)].

Methylene iminium (II) salts are prepared by the preparation in contact of an amide of formula with an electrophile reagent of formula XY. They can be isolated in "in situ" form. The amide can be used both as a reactant and as a solvent.

According to the invention, the methylene iminium salts can be reacted with the 10-DAB and / or its derivatives in C-2 and C4 of the general formula (III): wherein m can be equal to 0 or 1, R and R 5 identical or different represent: a linear or straight, branched or cyclic alkyl radical containing from 1 to 8 carbon atoms, a linear or straight, branched alkenyl radical or a clicyl containing from 2 to 8 carbon atoms, - a linear or straight, branched or cyclic alkynyl radical containing from 3 to 8 carbon atoms, - an aryl radical, and - a heterocyclic, saturated or unsaturated radical, containing from 4 to 6 bonds with one or more heteroatoms selected from the oxygen, nitrogen or sulfur atoms, the radicals are optionally substituted by one or more substituents chosen from: - halogen atoms such as fluorine, chlorine, bromine or iodine atoms, - alkyl, hydroxy, alkoxy, alkylthio, alkylamino, haloalkyl radicals, halogenoalkoxy, haloalkylthio in which the alkyl chain contains from 1 to 4 carbon atoms and heterocyclic radicals having from 4 to 6 bonds including one or more heteroatoms selected from the oxygen, nitrogen or sulfur atoms, optionally substituted, - the possibly substituted aryl radicals, the cyano, nitro or azido groups, or the carboxy or alkoxycarbonyl groups of which the alkyl part contains 1 to 4 carbon atoms, to provide a product of general formula (V): in which R, R2 and R5 are as previously defined, even passing intermediary by a product of the general formula (IV): (IV) wherein m, R, R2, R3, R, R5, X "and Y ~ are as previously defined hydrolysates in a product of the general formula (V).

The compounds of general formula (III) are defined according to the lines of PCT International Applications WO4 / 20484 and WO 95/33736.

According to a better suitable embodiment of the invention, an excess of the electrophilic reagent and / or the amide is used with respect to the substrate of the formula (III). According to a preferred mode, the excess of the electrophilic reagent is less than or equal to 10 equivalents and again more preferably about 5 equivalents with respect to a reagent of the general formula (III).

In general, the reaction is appropriate in an organic solvent, selected from the halogenated aliphatic hydrocarbons, preferably the chlorinated aliphatic hydrocarbons such as dichloromethane or dichloro-1,2-ethane, aromatic hydrocarbons such as benzene, toluene or xylene, aliphatic ethers such as ethyl ether or isopropyl ether, aliphatic nitriles such as acetonitrile or aliphatic amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-ethylacetamide and N, N-diethylacetamide. It is particularly advantageous to carry out the reaction in which the aliphatic amide is used for the preparation of methylene iminium (II) salts.

In general, the process according to the invention is suitable at a temperature which comprises between -78 ° C and the reflux temperature of the reaction mixture and preferably between -20 ° C and 25 ° C.

The process can be advantageous when exposed to a mineral or organic base selected from pyridine, trialkylamines, N-alkylmorpholines, carbonates or alkali metal hydrocarbonates.

The hydrolysis of the iminium salts of the general formula (IV) in a product of the general formula (V) can be carried out in water or in a medium of an aqueous solution of a mineral or organic base such as soda, pyridine, triethylamine, sodium acetate, sodium carbonate or sodium hydrogencarbonate.

The calculations of general formula (V) are particularly useful for the preparation of compounds of general formula (VI): wherein m, R, R2 and R5 are as defined above R6 represents a hydrogen atom, or forms a bond with R7 thus leading to a double bond between C6-and C-7.

R7 represents: - a hydrogen atom, - a halogen atom, or - a hydroxy group, 0RX, or 0-C0Rx, in which Rx represents a hydrogen atom or a linear or straight, branched or clicyl alkyl radical containing from 1 to 8 carbon atoms, a straight or branched alkenyl radical containing from 2 to 8 carbon atoms, a linear or straight or branched alkynyl radical containing from 3 to 8 carbon atoms, or an aryl radical, it being understood that these radicals can be optionally substituted, or - a group that increases the water solubility of the general formula -0-C0-A-C0Ry, wherein A is a radical alkenyl, cycloalkenyl or aryl containing at least one double bond, Ry represents: a hydroxyl group, an alkylamino, alkylaminoalkyloxy, alkylaminoaquityl, N, N-dialkylaminocarbonylalkoxy group containing from 1 to 4 carbon atoms optionally substituted, and R8 represents a methyl radical or forms a cyclopropyl Baccatin III of general formula (V) obtained according to the present invention is used, in particular for the preparation of products of general formula (VI) in which R 2 represents a methyl radical, Re represents a hydrogen atom, R 8 and R form a cyclopropyl, m is equal to 1, R represents a phenyl radical and R5 represents a methyl radical, either together by the action of trifluoromethanesulfonic anhydride, after an alkali metal halide (sodium chloride, sodium iodide, fluoride potassium), or with the alkali metal nitrogen (sodium sulfide), or with the quaternary ammonium salt or with an alkali metal phosphate, either by the action of DAST ("dimethylaminosulfur trifluoro").

Particularly advantageous is the use of baccatin III or its derivatives of the general formula (VI) obtained according to the process of the present invention, for the preparation of therapeutically active taxoids, in which the hydroxyl function in 7 is optionally modified, general formula (VII): wherein m is equal to 1, R represents a phenyl radical, R 2 represents R 1 a methyl radical, R 6 represents a hydrogen atom, R 7 represents two substituents as defined above, R 8 represents a methyl radical or forms with R 7 a cyclopropyl, and preferably Ar represents a phenyl radical and R9 represents a t-butoxy or phenyl radical.

More particularly, baccatin III or its derivatives in C-7, prepared according to the process of the present invention, can be used for the synthesis of paclitaxel (Taxol®) or its derivatives of general formula (VII) in which m is equal to, R represents a phenyl radical, R 2 and R 5 each represent a methyl radical, Re represents a hydrogen atom, R 8 and R 7 form a cyclopropyl, Ar represents a phenyl radical and R 9 represents a t-butoxy radical as described according to International Application WO 94/13654. The following examples illustrate the present invention. EXAMPLE 1 Preparation of 4-acetoxy-2a-benzoyloxy-5β, 20-epoxy-10β-formyloxy-1,7β, 13a-trihydroxy-9-oxo-tax-ll-ene In a 50 ml monocol, fitted with a thermometer and a magnetic stirrer, 12 ml of N, N-dimethylformamide were charged under a nitrogen atmosphere. (155 mmol), 0.495 ml of pyridine (6.1 mmol) and 3 g of 4-acetoxy-2a-benzoyloxy-5β, 20-epoxy-1, 7β, 10β, 13α-tetrahydroxy-9-oxo-tax-11-ene (10-DAB) at 97.7% (5.4 mmol). After cooling to -20 ° C, the intermediate was added in 10 minutes with a syringe of 1.08 ml of anhydride triflicle (6.4 mmol). The reaction mixture is kept for 10 minutes at -20 ° C, then hydrolyzed with 60 ml of water. After 3 hours at 0 ° C, the suspension is filtered and the product obtained is dried under reduced pressure at room temperature overnight. This yields, with a yield of approximately 90%, 2.87 g (4.9 mmol) of 4-acetoxy-2a-benzoyloxy-5β, 20-epoxy-10β-formyloxy-1, 7β, 13α-trihydroxy-9- oxo-tax-ll-ene where the purity determined by CLHP is 97% and where the characteristics are the following: - 1 H NMR spectrum (400 MHz, CDC13, d in ppm): 1,11 (s, 3 H, CH 3 ); 1.13 (s, 3H, CH 3); 1.69 (s, lH, OH-1); 1.71 (s, 3R, CH3): 1.87 and 2.58 (2m, IH each, CH2-6); 2.08 (s, 3H, CH3); 2.18 (d, J = 5.0 Hz, IH, OH-13); 2.25 (d, J = 5.0 Hz, 1H, OH-7); 2.29 (s, 3R, COOCH3); 2.32 (d, J = 9.0 Hz, 2H, CH2-14); 3.91 (d, J = 7.0 Hz, IH, H-3); 4.16 and 4.33 (2d, J = 8.5 Hz, IH each, CH2-20); 4.47 (m, IH, H-7); 4.91 (m, 1H, H-13); 5.00 (d long, J = 10.0 Hz, IH, H-5); 5.64 (d, J = 7.0w Hz, 1H, H-2); 6.46 (s, 1H, H-10); 7.50 (t, J = 7.5 Hz, 2H, H-metha in C6H5COO); 7.64 (t, J = 7.5 Hz, IR, H-para in C6H5C0); 8.13 (d, 1 = 7.5 Hz, 2H, H-ortho in C6H5CO); 8; 23 (s, 1H, RCO). IR spectrum (KBr, v in cm "1): 3622 and 3517 (OH of H20) 3400 (OH alcohols + H20), 3061 and 3019 (aromatic CH), 2990 to 2850 (CH2, CH3), 1739 (C = 0 acetate); 1715 (C = 0 format + acetone); 1704 (C = 0 benzoate); 1271 (0-C = 0 benzoate); 1250 (0-C = 0 acetate): 1156 (OC = 0 format); 1100 to 1000 (C-0 alcohols); 977 (C-0 oxétane); 719 (aromatic CH). mass spectrum (NH3) M / Z: 590 (M + NH4 +); 573 (M + H +); 544 (M-CHO + NH 4 +); 527 (544-OH).

EXAMPLE 2 Pration of 4, 10β-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-1, 7β, 13a-trihydroxy-9-oxo-tax-ll-ene (baccatin III) In a 250 ml double jacket reactor, fitted with a thermometer and a magnetic stirrer, 60 ml of N-ethylacetamide (627 mmol) were charged under nitrogen. After cooling to -20 ° C, the intermediate was added in 15 minutes with a syringe 7.2 ml of mesyl chloride (92 mmol). The solution is maintained for 30 minutes at -20 ° C more, for about 17 hours at 0 ° C. 10 g (10.7 mmol) of 4-acetoxy-2a-benzoyloxy-5β, 20-epoxy-1, 7β, 10β, 13α-tetrahydroxy-9-oxo-tax-ll are added to the solution at 0 ° C. -eno (10-DAB) to 97.5%, then the suspension is maintained under stirring for 30 hours at 0 ° C. After transferring it to a one liter reactor, a solution of 15 g of sodium acetate in 300 ml of water is added to the reaction mixture, then the obtained suspension is maintained for 25 hours at room temperature. The analyzer for CLHP of an aliquot of the reaction mixture allows to detect less than 1% of the monoacetyl derivatives in 7 and diacetyl in 7.10. After filtration, the product is successively washed three times with 50 ml of water and dried overnight at 50 ° C under reduced pressure. This yields, with a yield of 79%, 9 g (14.1 mmol) of 4,10β-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β, 13a-trihydroxy-9-oxo-tax- ll-ene, where the purity is 92%, and "where the characteristics are the following: -XH NMR spectrum (400 MHz, CDC13, d in ppm): 1.12 (s, 6H, CH3); 1.68 (s, 4H, CH3 and OH-1); 1.88 and 2.58 (2m, 1H each, CH2-6); 2.08 (s, 3H, CH3); 2.27 and 2.31 (2s, 3H each, CH3CO and CH3COO); 2.32 (d, J = 9.0 Hz, 2H, CH2-14); 3.90 (d, J = 7.0 Hz, 1H, H-3); 4.17 and 4.33 (2d, J = 8.5 Hz, 1H each, CH2-20); 4.48 (dd J = 11.0 Hz and 7.0 Hz, 1H, H-7); 4.91 (long t, J = 9.0 Hz, 1H, H-13); 5.00 (long d, J = 10.00 Hz, 1H, H-5); 5.64 (d, J = 7.0 Hz, 1H, H-2); 6.34 (s, 1H, H-10); 7.50 (t, J = 7.5 Hz, 2H, H-meta in C6H5COO); 7.64 (t, J = 7.5 Hz, 1H, H-para in C6H5COO); 8.13 (d, J = 7.5 Hz, 2H, H-ortho in C6H5COO).

IR spectrum (KBr, v in cm "1): 3400 (OH alcohols + H20); 3071 (aromatic CH); 2990 to 2850 (CH2 and CH3); 1730 (C = 0 acetate); 1712 (C = 0 format + acetone + benzoate); 1271 (0-C = 0 benzoate); 1243 (0-C = 0 acetate); 1100 to 1000 (C-0 alcohols); 982 (C-0 oxetane); 710 (aromatic CH). mass spectrum (NH3) M / Z: 604 (M + NH4 +); 587 (M + H +); 544 (M-CH 3 COOH + NH 4 +); 527 (M + CH 3 COOH + H +); 509 (M-CH3COOH-H20 + H +).

EXAMPLE 3 Into a 25 ml Erlenmeyer flask, fitted with a magnetic stirrer, 3.9 g of N-methylacetamide (53 mmol) and 5 ml of 1,2-dichloroethane were charged under nitrogen. After cooling to -10 ° C, 0.42 ml of triflic anhydride (2.5 mmol) was added, then the solution was maintained for 30 minutes at -10 ° C, and for 1 hour at 0 ° C. 0.5 g (approximately 0.9 mmol) of 4-acetoxy-2a-benzoyloxy-5β, 20-epoxy-1, 7β, 10β, 13α-tetrahydroxy-9-oxo is added to the solution at 0 ° C. -tax-ll-ene, (10-DAB). The resulting reaction mixture is kept under stirring overnight at 0 ° C. 15 ml of a 5% aqueous solution of sodium acetate are then added and then kept overnight at room temperature. The reaction mixture is diluted by the addition of 1,2-dichloroethane until complete dissolution. The organic phase is sated by decantation, then the solvent is evaporated under reduced pressure. The obtained extract is measured by CLHP approximately 3 mg of 4,10β-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β, 13a-trihydroxy-9-oxo-tax-11-ene (baccatin III). The yield is close to 6%.

* • EXAMPLE 4 Into a 25 ml Erlenmeyer flask, fitted with a magnetic stirrer, are charged to room temperature nitrogen, 5 ml of acetonitrile, 3.9 g of N-methylacetamide (53 mmol), and, 9 g of tosyl chloride (4.7 mmol) then the solution is maintained for 20 minutes at room temperature. 0.5 g (approximately 0.9 mmmol) of 4-acetoxy-2a-benzoyloxy-5β, 20-epoxy-1, 7β, 10β, 13α-tetrahydroxy-9-oxo-tax-11- are added to the obtained solution. ene (10-DAB), then the reaction mixture is kept under stirring for about 17 hours at room temperature. 15 ml of an aqueous 5% sodium acetate solution are then added and then kept under stirring overnight at room temperature. The analysis of CLHP of an aliquot does not allow the detection of monoacetyl derivatives in 7 or diacetyl in 7.10. The reaction mixture is extracted with 1,2-dichloroethane, the organic phase is separated after decantation and the solvent is evaporated under reduced pressure. In the botenido extract, measured by CLHP approximately 86 mg of 4, 10β-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β, 13a-trihydroxy-9-oxo-tax-ll-ene has a yield of approximately 16% ** EXAMPLE 5 In a 25 ml Erlenmeyer flask, fitted with a magnetic stirrer, 5 ml of 1,2-dichloroethane, 3.9 g of N-methylacetamide (53 mmol) are charged to nitrogen at room temperature. After cooling to 0 ° C, 0.4 ml of oxalyl chloride (4.6 mmol) flows, then the solution is maintained for 25 minutes at 0 ° C (gas formation). 0.5 g (approximately 0.9 mmol) of 4-acetoxy-2a-benzoyloxy-5β, 20-epoxy-1, 7β1β, 13α-terahydroxy-9-oxo-tax-11-ene are added to the obtained solution. 10-DAB), then the reaction mixture is kept under stirring for about 19 hours at 0 ° C. 15 ml of an aqueous 5% sodium acetate solution are then added and kept overnight at room temperature. The reaction mixture is extracted with 1,2-dichloroethane. The organic phase is separated by decantation and the solvent is evaporated under reduced pressure. In the obtained extraction, approximately 212 mg of 4,10ß-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β, 13a-trihydroxy-9-oxo-tax-ll-ene (baccatin III) are measured by CLHP. , with a yield of approximately 40%. 1.2% of the monoacetyl derivative is detected in 7. The diacetyl derivative is not in 7.10.

EXAMPLE 6 In a 50 ml Erlen eyer flask equipped with a mechanical stirrer, 5 ml of 1,2-dichloroethane and 1.5 g of p-toluenesulfonic anhydride (4.5 mmol) are charged to nitrogen at room temperature. After cooling to 0 ° C, 4 ml of N, N-diacetylamide (32 mmol) are added, then the solution is maintained for 35 minutes at 0 ° C. 0.5 g is added to the suspension obtained (approximately 0.9 mmol) of 4-acetoxy-2a-benzoyloxy-5β, 20-epoxy-1, 7β, 10β, 13α-tetrahydroxy-9-oxo-tax-11-ene (10-DAB). The reaction mixture is kept under stirring for about 1 hour to 30 minutes at 0 ° C then, 4 hours and 30 minutes at room temperature.

An aliquot of the solution is suitable and hydrolyzed in a mixture of acetonitrile / water (diluent CLHP). The measurement is per CLHP, in the totality of the solution, in approximately 347 mg of 4,10ß-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β, 13a-trihydroxy-9-oxo-tax- ll-ene (baccatin III), there is a yield of approximately 66%. None of the monoacetyl and diacetyl derivatives are detected in 7,10.

^ EXAMPLE 7 Into a 25 ml Erlen eyer flask, fitted with a mechanical stirrer, 4 ml of N-ethylacetamide (42 mmol) and 5 ml of 1,2-dichloroethane are charged under nitrogen at room temperature. 0.42 ml of phosphorus oxychloride (4.6 mmol) are added. The solution is maintained for 15 minutes at room temperature. 0.5 g (approximately 0.9 mmol) of 4-acetoxy-2a-benzoyloxy-5β, 20-epoxy-1, 7β, 10β, 13α-tetrahydroxy-9-oxo-tax-11-ene are added to the solution. (19-DAB). The resulting reaction mixture is maintained under stirring for about 3 hours. An aliquot of the solution is prewashed and hydrolyzed in a mixture of acetonitrile / water (diluent CLHP). In the total solution, measured by CLHP, approximately 116 mg of 4,10ß-diacetoxy-2a-benzoyloxy-5β, 20-epoxy-l, 7β, 13a-trihydroxy-9-oxo-tax-ll-ene (baccatin) III) have a yield of approximately 22%. The monoacetyl derivatives in 7 and diacetyl in 7.10 are not detected.

It is noted that, in relation to this date, the best method known by the Applicant to carry out the aforementioned invention, is that which is clear from the manufacture of the objects to which it refers. Having described the invention as above, the content of the following is claimed as property.

Claims (23)

1. Selective monoacylactic process of the desacetyl-10 baccatin III or its derivatives in C-2 and C-4, which have two free hydroxyl groups in positions C-7 and C-10, characterized in that the acylation is carried out. -deacetylbaccatin II or its derivatives in C-2 and C-4 to provide a methylene iminium salt.

2. Process according to claim 1, characterized in that the methylene iminium salt corresponds to the general formula (II): wherein R2 represents: - a hydrogen atom, - a linear or straight, branched or cyclic alkyl radical containing from 1 to 12 carbon atoms, - a linear or straight, branched or cyclic alkenyl radical containing from 2 to 12 carbon atoms, - a linear or straight or branched alkynyl radical containing from 3 to 12 carbon atoms, - an aryl radical, - an alkoxy group, alkylamino, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl or alkylthiocarbonyl in which the alkyl part contains 1 to 12 carbon atoms, or - a heterocyclic, saturated or unsaturated radical, containing 5 to 6 bonds and one or more heteroatoms selected from sulfur, oxygen or nitrogen. these radicals are optionally substituted by one or more substituents selected from: - halogen atoms, alkyl or haloalkyl radicals, - aryl radicals, alkylamino, piperidyl, piperazinyl, nitro or cyano groups, - alkoxy or alkoxycarbonyl groups, alkyl portions of different radicals contain from 1 to 12 carbon atoms, and heterocyclic radicals, saturated or unsaturated, contain from 5 to 9 bonds in one or more heteroatoms selected from sulfur, oxygen or nitrogen, or R2 and R3 or R and R4 can form, with the nitrogen atom and the methyl carbon, an indigo including 4 to 7 bonds, such as 2-piperidone, 2-azetidinone, 2-pyrrolidinone, caprolactam. R3 and R4, identical or different, each represent: a hydrogen atom, a linear or straight, branched or cyclic alkyl radical containing from 1 to 12 carbon atoms, - a linear or straight, branched or cyclic alkenyl radical containing 2 to 12 carbon atoms, - a linear or straight or branched alkynyl radical containing 3 to 12 carbon atoms, or - an aryl radical, or R3 and R4 can form with the nitrogen atom a heterocycle containing 4 to 6 saturated or unsaturated bonds, optionally substituted. X represents a halogen atom or a phosphinoyloxy, phosphoranyloxy, halogenosulfinyloxy, halogenosulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkylaminosulfonyloxy, alkylcarbonyloxy, arylcarbonyloxy, halophofinyloxy, halophosphoranyloxy, haloalkylsulfonyloxy, haloalkyl carbonate, Y "represents an ion selected from the halides, the alkylsulfonates, the arylsulfonates, the alkylaminosulfonates, the alkylcarboxylates, the arylcarboxylates and the phosphorodihalogenidates, or [M (Z) n] 'in which 4 < n < 6, Z are a halogen atom and M is an element of the periodic table which may have an oxidation degree equal to or greater than 3 and preferably comprises between 3 to 5.

3. Process according to claim 2, characterized in that in the general formula (II), X represents: - a halogen atom - a group (Hal) 4P-0-, (Hal) 2P0-0-, (Hal) SO-O-, (Hal) S02-0- RaS02-0- or RaC? 2 in which Ra represents an alkyl radical, linear, branched or cyclic, a halogenoalkyl radical, an aryl radical optionally substituted by a halogen atom or by an alkyl or nitro radical, and Hal represents a halogen atom selected from fluorine atoms , chlorine, bromine or iodine. Y "represents: - a halide ion, - an antagonist ion such as RaC02", RaS03"(Hal) 2P02 ~, in which Hal and Ra are defined as above, or - an entity such as [M (Z) n] ~ wherein 4 <n <6, Z are a> halogen atom such as a fluorine or chlorine atom, and M is an element of the periodic table which may have an oxidation degree equal to or greater than 3, selected from aluminum, boron, antimony, tin, titanium. R2 represents hydrogen, a methyl, ethyl radical or a phenyl radical.

4. Process according to claims 1 to 3 in which the iminium salts used are N, N-dimethyl trifluoromethanesulfonyloxy-1-methylidene-ammonium trifluoromethanesulfonate: (R2 = H, R3 = R4 = CH3, X = CF3S03, Y = CF3S03"), N trifluoromethanesulfonate -methyl trifluoromethanesulfonyloxy-1-ethylidene-ammonium: (R2 = R3 = CH3, R4 = H, X = CF3, S03, Y "= CF3S03"), the N-methyl chloride p-toluenesulfonyloxy-1-ethylidene-ammonium: (R2 = R3 = CH3, Y = C1"), and the N-methyl chloro-1-ethylidene-ammonium p-toluenesulfonate: (R2 = R3 = CH, R4 = H, X = C1, Y" = p-CH3-C6H4 -S03"), N-methyl chloro-1-ethylidene-ammonium chloride: (R2 = R3 = CH3, R = H, X = C1, Y" = C1"), N-ethyl methanesulfonyloxy-1-ethylidene chloride ammonium: (R2 = CH3, R3 = C2H5, R4 = H, X = CH3S03, Y "= C1") and N-ethyl chloro-1-ethylidene-ammonium methanesulfonate: (R2 = CH3, R3 = C2H5, R4 = H, X = C1, Y ~ = CH3S03 ~), the N-ethyl dichlorophosphinnyloxy-1-ethylidene-ammonium chloride: (R2 = CH3 / R3 = C2H5, R4 = H, X = 0-P0-C12, Y " = C1"), or N-ethyl chloro-1-ethylidene-ammonium dichlorophosphonate: (R2 = CH3, R3 = C2H5, R = H, X = C1, Y" = C12P02"), the p N, N-diethyl p-toluenesulfonyloxy-1-ethylidene-ammonium toluene sulphonate: (R2 = CH3, R3 = R4 = C2H5, X = p-CH3-C6H4-S03, Y "= p-CH3-C6H4-S03") .

5. Process according to claim 1, characterized in that the desacetyl-baccatin III and / or its derivatives in C-2 and C-4 correspond to the general formula (III): wherein m can be equal to O or 1, R and R5 identical or different represent: a linear or straight, branched or cyclic alkyl radical containing from 1 to 8 carbon atoms, a linear or straight, branched alkenyl radical or a clicyl containing from 2 to 8 carbon atoms, - a linear or straight, branched or cyclic alkynyl radical containing from 3 to 8 carbon atoms, - an aryl radical, and - a heterocyclic, saturated or unsaturated radical, containing from 4 to 6 bonds with one or more heteroatoms selected from the oxygen, nitrogen or sulfur atoms, the radicals are optionally substituted by one or more substituents selected from: halogen atoms, alkyl, hydroxy, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, haloalkylthio in which the alkyl chain contains from 1 to 4 carbon atoms heterocyclic radicals having from 4 to 6 bonds including one or more heteroatoms s selected from among the oxygen, nitrogen or sulfur atoms, optionally substituted, the aryl radicals optionally substituted, the cyano, nitro or azido groups, or the carboxy or alkoxycarbonyl groups of which the alkyl part contains 1 to 4 carbon atoms,

6. Process according to claim 5, characterized in that, in the general formula (III), m is equal to l, R represents a phenyl radical and R 5 represents a methyl radical.

7. Process according to claim 1, characterized in that a methylene iminium salt, as defined in one of claims 2 to 5, is reacted in a derivative of 10-DAB as defined in one of claims 6 and 7 for obtain a product of the general formula (IV): (IV) wherein R2, R3, R4, X and Y are as defined in one of claims 2 to 5 and wherein m, R, are as defined in one of claims 6 or 7, which are hydrolyzed in a product of the general formula (V): wherein R2 is as defined in one of claims 2 to 4, and m, R and R5 are as defined in one of claims 5 and 6.

8. Process according to claims 1 to 7, characterized in that it is operated in an organic solvent.

9. Process according to claim 8, characterized in that the organic solvent is selected from organic halogen solvents, aromatic hydrocarbons, aliphatic ethers, aliphatic nitriles or aliphatic amides.

10. Process according to claim 8, characterized in that the organic halogen solvents are selected from the chlorinated aliphatic hydrocarbons such as dichloromethane or dichloro-1,2-ethane, the aromatic hydrocarbons are selected from benzene, toluene or xylene, the aliphatic ethers are selected from ethyl ether or isopropyl ether, aliphatic nitriles such as acetonitrile, or aliphatic amides are selected from N, N-dimethylformamide, N, N-dimethylacetamide, N-ethylacetamide and N, N-diethylacetamide .

11. Process according to any one of the preceding claims, characterized in that the methylene iminium salt of formula (II) is prepared by the condensation of the amide of formula O with an electrophilic reagent of formula XY

12. Process according to any one of claims 1 to 10, characterized in that the methylene iminium salt is prepared in situ or is previously isolated.

13. A process according to claims 1 to 12, characterized in that it is operated in the presence of an excess of electrophilic reagent less than or equal to 10 equivalents, with respect to the substrate of the general formula (III).

14. Process according to claim 13, characterized in that the electrophilic reagent is close to 5 equivalents with respect to a substrate of the general formula (III).

15. Process according to claim 1, characterized in that the reaction of the methylene iminium salt of the general formula (II) with the substrates of the general formula (II) is prepared at a temperature comprised between -78 ° C and the reflux temperature of the reaction mixture.

16. Process according to claim 15, characterized in that the temperature is between -20 ° C and 25 ° C.

17. Process according to claim 7, characterized in that the hydrolysis of the iminium salt of the general formula (IV) is carried out in water or in a medium of an aqueous solution containing an inorganic or organic base.

18. Process according to claim 17, characterized in that the base is selected from soda, pyridine, triethylamine, sodium acetate, sodium carbonate and sodium hydrogencarbonate

19. Novel derivatives of baccatin III of general formula (IV): wherein R2, R3, R4 X ~ and Y "are defined according to claims 2 to 5, and m, R and R5 are as defined in one of claims 6 or 7.

20. Use of the products obtained according to any one of the two preceding claims for the preparation of the baccatin III analogs of the general formula (VI): wherein, R2 is as defined in one of claims 2 to 4 m, R, and Rs are as defined in one of claims 5 or 6 R5 represents a hydrogen atom, or forms a bond with R7 leading thus to a double bond between C6-and C-7. R7 represents: a hydrogen atom, - a halogen atom, or - a hydroxy group, 0RX, or 0-CORx, in which Rx represents a hydrogen atom or a linear or straight, branched or clicyl alkyl radical containing 1 to 8 carbon atoms, a linear or straight, branched alkenyl radical containing from 2 to 8 carbon atoms, a linear or straight or branched alkynyl radical containing from 3 to 8 carbon atoms, or an aryl radical, it being understood that these radicals can be optionally substituted, or - a group that increases the water solubility of the general formula -0-CO-A-CORy, in which A is an alkenyl, cycloalkenyl or aryl radical containing at least one double bond, Ry represents: a hydroxyl group, an alkylamino, alkylaminoalkyloxy, alkylaminoaquityl, N, N-dialkylaminocarbonylalkoxy group containing from 1 to 4 carbon atoms optionally substituted, and RB represents a methyl radical or forms a cyclopropyl with R7.

21. Use of the derivatives obtained according to the process of one of the preceding claims, characterized in that for the preparation of the derivative of the formula (VI) in which R2 represents a methyl radical, Re represents a hydrogen atom, R8 and R7 form a cyclopropyl , m is equal to 1, R represents a phenyl radical and R 5 represents a radical methy, or the baccatin III is reacted with trifluoromethanesulfonic anhydride, then with an alkali metal halide or with an alkali metal sulphide or with a salt of quaternary ammonium or an alkali metal phosphate or baccatin III is reacted with DAST (diethylaminosulfur trifluoride).

22. Use of the derivatives of general formula (VI) obtained according to one of claims 20 to 21 for the preparation of therapeutically active taxoids of the general formula (VII): wherein m is equal to 1, R represents a phenyl radical, R 2 represents a methyl radical, R 6 represents a hydrogen atom, R represents two substituents as defined above, R 8 represents a methyl radical or forms with R 7 a cyclopropyl, Ar represents a phenyl radical R9 represents a t-butoxy or phenyl radical.

23. Use of the derivatives of general formula (VI) obtained in one of claims 20 or 21 for the preparation of taxoids as defined in claim 22 in which m is equal to 1, R represents a phenyl radical, R2 and R5 each represents a methyl radical, Rβ represents a hydrogen atom, R7 represents a hydroxy radical, Ar represents a phenyl radical and R9 represents a benzoyl radical or m is equal to 1, R represents a phenyl radical, R2 and R5 represent each one a methyl radical, R6 represents a hydrogen atom, Rs and R form a cyclopropyl, Ar represents a phenyl radical and R9 represents a t-butoxy radical.