MXPA98002923A - Intermediary compounds for the detaxanism semisintesis and the preparation procedures of the mis - Google Patents

Abstract

The present invention relates to novel intermediates for the semisynthesis of taxanes and their methods of preparation. These are especially oxazolidine or oxazolidinone derivatives, as well as novel derivatives of baccatin III. The general procedure of synthesis of taxanes according to the invention, allows to obtain a product such as PACLITAXEL, in only five stages, from the products available in commerce, against the nine stages generally used by the procedures of the state of the technical

Description

INTERMEDIARY COMPOUNDS FOR THE TAXANE SEMISINTESIS AND THE PROCEDURES FOR PREPARING THEMSELVES The present invention relates to novel intermediates for the taxis seraisynthesis and its preparation methods. The taxanes, are natural substances in which the diterpene skeleton is generally esterified by a side chain of ß-amino acid, derived from N-alkyl- or N-aroyl-phenyl-isoserine, are known as anticancer agents. There are several dozen taxanes isolated from Taxaceos of the genus Taxus, such as, for example, PACLITAXEL (Rt = Ac, R = Ph, R3 = R4 = H), cephalomannine, its deacetylated derivatives at position 10, or baccatins (derivatives without side chain), represented by formulas 1 and 2 below.

REF: 27033 With the intention of not quickly exhausting their source of origin, Taxus brevi folia, the French researchers sought to isolate the PACLIT - AXEL from the renewable parts (the leaves), from T. bacca ta, the European yew. They also highlighted the probable biogenetic precursor of the taxanes, 10-desacetylbaccatine III, starting point of choice for semisynthesis, due to its relative abundance in the extracts of the leaves. The semisynthesis of taxanes, such as PACLITAXEL or DOCETAXEL (R = AC, R2 = t.butyloxy, R3 = R "= H), consists of esterifying the hydroxyl at 13 of a protected derivative of baccatine, or -desacetylbaccatin III, with a derivative of a β-amino acid. The different semi-synthesis procedures of PACLITAXEL or DOCETAXEL are described in the state of the (EP-0 253 738, EP-0 336 840, EP-0 336 841, EP-0 495 718, WO 92/09589, WO 94/07877, WO 94/07878, WO 94/07879, WO 94/10169 , WO 94/12482, EP-0 400 971, EP-0 428 376, WO 94/14787). Two recent works, [I. Georg. T.T. Chen, I Ojima, and D.M. Vyas, "Anticancer Agents of Taxano, Basic Science and Current Status", ACS Symposium Series 583, Washington (1995)], and above all [Matthew Suffnes, "TAXOL® Science and Applications" CRC press (1995) and 1500 cited references] , comprise the exhaustive compilations of the semisynthesis of the taxanes. The β-amino acid side chains derived from N-alkoyl- or N-aroylphenylisoserine from PACLITAXEL or from DOCETAXEL are of the (2R, 3S) configuration, and one of the main difficulties of the semisynthesis of the taxanes lies in obtaining of an enantiomerically pure product. The first problem is to obtain a pure enantiomer of the phenyl isoserine derivatives used in the semisynthesis of the taxanes. The second problem consists in preserving this enantiomeric purity during the course of the esterification of the baccatine derivative and the subsequent treatments of the products obtained (deprotection of the hydroxyls, etc.). Numerous asymmetric synthesis works bring into play the derivatives of ß-amino acids, they are focused in the chemistry of isoserin and its derivatives, ß-a inoacids in a cyclic, dehydrated form, and a β-lactam (EP-0 525 589). Most of the different syntheses of phenyl-isoserine derivatives, useful as precursors of the side chains of the taxanes, converge by a common intermediary, cis-β-phenyl-glycidic acid (2R, 3R), which becomes then in β-phenyl-isoserine, by reaction with ammonia (EP-0 495 718), or a nucleophile (Gou &Coll./ J. Org. Chem., 1983, 58, 1287-89). These different procedures require a number of important steps to obtain the ß-phenyl-isoserine configuration (2R, 3S), with necessarily a racemic splitting stage by the usual techniques of selective crystallization, or by β-phenyl-glycidic acid , either by β-phenyl-isoserine, or later, after transformation. Furthermore, in order to preserve the enantiomeric purity of the precursors of the side chains of the taxanes, during the course of the esterification of the baccatine derivative, different means have been proposed, in particular, using the cyclic intermediates of blocked configuration, which discard the Isomerization risks in esterification reactions under harsh reaction conditions. These are in particular ß-lactam derivatives (EP-0 400 971), of oxazolidines (WO) 92/09589, WO 94/07877, WO 94/07878, WO 94/07879, WO 94/10169, WO 94/12482), oxazinones (EP-0 428 376), or even oxazolines (WO 94/14787) . These cyclic precursors are prepared from a corresponding derivative of β-phenyl isoserine. As for the latter, the proposed procedures involve a large number of steps, and a necessary resolution of the racemate, to obtain the desired taxane side chain precursor. It is also important to point out a new path of improved synthesis of the precursor intermediates of the taxane side chain. in particular the enantiomers of cis-β-phenyl-glycidic acid, β-phenyl-isoserine and their cyclic derivatives. Finally, for the semisynthesis of the taxanes, and in particular of the PACLITAXEL, the only derivative of the appropriate baccatine, used up to the present, is that in which the 7-hydroxy radical is protected by a trialkylsilane (EP-0). 336 840, WO 94/14787), in which the deprotection is carried out exclusively in an acid medium. It is also equally important to use the novel protecting groups of the hydroxy function, which allow, in particular, the selective protection of the 7-hydroxy radical, which also allows a wider choice of operating conditions for the deprotection step.

The present invention relates in the first place to an improved process for the preparation of side chain precursors of taxanes. The process according to the invention consists of transforming a cis-β-aryl glycidate derivative of general formula I Ar-C * H - C'H-COOR \ / I 0 wherein Ar represents an aryl, in particular phenyl, and R represents a hydrocarbon radical, preferably a linear or branched alkyl, or a cycloalkyl optionally substituted by one or more alkyl groups, so as to specifically place it in a regional place. and stereo, the β-N-alkylamide and the α-hydrsyl, or their cyclic precursors in a single step, by a Ritter reaction. According to the reaction medium, two types of Ritter reaction are thus distinguished: one with the oxetane opening leading to a linear form of the direct chain and fully functionalized, the other leading to the direct formation of an oxazoline. The symbol "*" indicates the presence of an asymmetric carbon, of configuration R or S. In both In some cases, the Ritter reaction is stereospecific, with the retention of the configuration in C-2, and configuration inversion in C-3. Advantageously, the process according to the invention is carried out on one of the enantiomers of the cis-β-aryl glycidate derivative of general formula I, so that the corresponding enantiomer of the linear chain or oxazoline obtained is obtained, without needing a resolution of the racemate later. According to the mode of preparation of the cis-β-aryl glycidate derivative of general formula I, described later, R represents an optically pure enantiomer of a chiral hydrocarbon radical, with a strong steric hindrance, advantageously a cycloalkyl substituted by one or more alkyl groups, in particular a cyclohexyl, R will then preferably be one of the enantiomers of the menthyl radical, in particular (+) - menthyl. 1. Direct synthesis of the linear chain The direct synthesis of the linear chain by the Ritter reaction consists in reacting a cis-β-aryl glycidate derivative of the general formula I, defined hereinabove, with a nitrile of the formula R-CN wherein R 2 represents an aryl radical, preferably a phenyl, in the presence of a protonic acid such as sulfuric, perchloric, tetrafluoroboric, etc., and water acids.

A derivative of the β-aryl isoserine of the general formula lia is then obtained, R 7 -CONH I Ar-C'H-C'H-COOR iiü. I CH in which Ar, R and R2 are defined above. The reaction is carried out with an inversion of the C-3 configuration of the cis-β-phenyl glycidate derivative.

Thus, starting from a derivative of cis-β-phenyl-glycidate (2R, 3S), the corresponding derivative of the ß-aryl isoserine of configuration (2R, 3S) is obtained. The Ritter reaction is carried out in a suitable solvent, at a temperature between -75 and + 25 ° C. The appropriate solvent can be the nitrile itself, since it is liquid at the reaction temperature, either the acid itself, (sulfuric acid, perchloric or tetrafluoroboric acid), or a solvent, such as, for example, methylene chloride or ether ethyl. The protonic acids used so classic, can contain the water necessary for hydrolysis. When the benzonitrile (R2 = phenyl) is used, in the cis-β-aryl glycidate of general formula I, of configuration (2R, 3R), for which Ar represents a phenyl, the corresponding derivative of the β is obtained directly -aryl-isoserine, of general formula Ia, for which Ar and R2 represent a phenyl of configuration (2R, 3S), which is none other than the precursor of the side chain of PACLITAXEL. 2. Direct synthesis of the cyclic chain For this second eventuality, we also carry out a reaction of Ritter, with a nitrile of formula R'2-CN wherein R '2 represents R2 defined above, or a lower alkyl radical or a lower perhaloalkyl, such as trichloromethyl, in the presence of a Lewis acid, in particular the boron trifluoride-acetic acid complex, the trifluoride etherate boron, antimony pentachloride, tin tetrachloride, titanium tetrachloride, etc., or an acid proton such as, for example, tetrafluoroboric acid, the reaction is carried out in anhydrous medium. As for the synthesis of the linear chain, the solvent can be the nitrile itself, since it is a liquid at the reaction temperature, or else a suitable solvent, such as, for example, methylene chloride or ethyl ether. The reaction temperature is also between -75 and + 25 ° C. In the absence of water, an intramolecular Ritter reaction is performed, and the oxazoline of general formula 11b is obtained R ' N O ílb \ /? R-CJ ¡- CJ I-COOR in which, Ar, R and R '? are defined above. As in the Ritter reaction in the presence of water, the reaction is carried out with an inversion of the C-3 configuration of the cis-β-phenyl glycidate derivative. Thus, starting from a derivative of cis-β-phenyl-glycidate (2R, 3R), the corresponding oxazoline of configuration (2R, 3S) is obtained. For the two reactions of Ritter, in order to avoid the formation of a free carbocation, the cause of numerous potential secondary reactions, the addition of the reactants is preferably effected in the following order: i) first the complex is formed between the nitrile and the acid, then ii) the acid catalyst is added to the mixture formed of the oxirane and the nitrile . The products obtained by this first step, derivatives of the β-aryl isoserine of the general formula Ila, or the oxazoline of the general formula I Ib, can be transformed again into a second facultative step, described below, or converted into acid by . careful saponification, before coupling with a protected derivative of baccatine for the semisynthesis of the taxanes, in particular PACLITAXEL and its deacetylated derivatives in 10 or DOCETAXEL. In the case of derivatives of the β-aryl isoserine of the general formula Ia, the saponification of a conventional step of protection of the hydroxy by a suitable protecting group can be preceded. A derivative of the general formula Il'a is thus obtained R 7 -CO-NH I Ar-C * H-C * H-COOR-lyl-3. 1 OGP wherein Ar, R and R2 are defined above, and GP represents a protecting group of the hydroxy function, suitable for the synthesis of taxanes, in particular, chosen from the alkoxyether, aralkoxyether, aryloxyether or haloalkoxycarbonyl radicals, such as, for example, methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (ß-trimethylsilyl-ethoxy) -methyl groups, the tetrahydropyranyl, β-alkoxycarbonyl (TrOC) radicals, the β-halogenated ethers, alkylsilyl, or the alkoxyacetyl, aryloxyacetyl, haloacetyl or formyl radicals. 3. Eventual transformation of derivatives of formula lia or IIb The derivatives of general formula Ia or I Ib obtained above, can optionally be transformed into novel intermediates, precursors of the side chain in the semisynthesis of the taxanes. These transformations are made with the retention of the C-2 and C-3 configuration. The novel intermediates obtained will have the same stereochemistry as the derivatives of formula Ia or Ilb, from which they come. The products obtained in this second stage are then converted into acid by careful saponification, before effecting its coupling with a protected derivative of baccatine for the semisynthesis of the taxane, in particular of PACLITAXEL or DOCETAXEL. 3. 1 Cyclization of the derivatives of general formula The derivatives of general formula Ia can then be converted into oxazoline of formula 11b according to the usual methods of the state of the art (WO 94/14787). The β-aryl isoserine derivatives of the general formula Ia can also be converted into novel cyclic intermediates, the oxazolidinone of the general formula 111 'a OR II • C "V R" 7 -CO-N 'O Ill'a \ / Ar-C'H - C'H-COOR wherein Ar and R are defined above, and R "2 represents R 2 as defined above, an alkoxy radical, preferably t.butoxy, or a linear or branched alkyl radical, which comprising at least one unsaturation, for example, a 1-methyl-1-propylene radical, and the corresponding dialkylacetals. The oxazolidinones of the general formula III 'a are obtained by first reacting a derivative of the β-aryl isoserine of the general formula lía with a haloalkoxycarbonyl ester, in particular 2,2,2-trichloroethoxycarbonyl (TrOC), followed by cyclization in the presence of a strong organic base, such as diazabicyclo-undecene (DBU). An oxazolidinone derivative of general formula Illa is then obtained OR II -C HN O -] ^ \ I Ar-C'H - CJ f-COOR in which Ar and R are defined above. The derivatives of general formula Illa can also be obtained by direct synthesis, making reacting the ß-aryl glycidate derivatives of formula II 'a with urea. The acylated derivatives of general formula Ill'a are obtained by introducing the radical R "2-CO- according to the usual acylation techniques, in the presence of a suitable acylating agent, for example an acyl halide of formula R "2-CO-X, in which R" 2 is defined above, and X represents a halogen, or an anhydride of the corresponding acid. The dialkylacetals are obtained according to the usual techniques of acetal formation. 3. 2 Opening of oxazoline of general formula Ilb By the hydrolysis of the oxazoline of general formula Ilb, in an acid medium, the derivative of the β-aryl isoserine of general formula Illb is obtained, NH Ar-C * H - C * H-COOR pib I O - CO - IV 7 wherein Ar, R and R'2 are defined above. Advantageously, when R '2 represents a lower perhaloalkyl, such as trichloromethyl, the radical R'2-CO- constitutes a protective grouping of the hydroxy function. We can then transform this precursor of the side chain of taxanes into an amide of general formula IH'b R "2-CO-NH Ar-C" H • OH-COOR! | ['B i O - CO - R', wherein Ar, R, R '2 are defined above. We can thus indistinctly obtain the precursor of the side chain of PACLITAXEL (R "2 = phenyl) or DOCETAXEL (R" 2 = t.butoxy).

. Preparation of the sis-β-aryl-glycidic acid derivative of formula I The cis-β-aryl-glycidic acid derivative of Formula I can be prepared according to the usual procedures of the state of the art, or by simple esterification of cis-β-aryl glycidic acid with the corresponding R-OH alcohol. In order to improve the overall synthesis yield of the taxane chain precursors, a preparation is prepared with the process according to the invention. cis-ß-aryl glycidate derivative of general formula I Ar-H-C * H-COOR \ I 0 in which Ar is defined above and R represents an optically pure enantiomer of a chiral hydrocarbon radical of strong steric hindrance, by reacting the aldehyde of formula Ar-CHO with a haloacetate of formula X-CH2-COOR Ar, R are defined above and X represents a halogen, in particular a chlorine or bromine. Advantageously, the optically pure enantiomer of a chiral hydrocarbon radical of strong steric hindrance is a cycloalkyl substituted by one or more alkyl groups, in particular a cyclohexyl. It is a Darzens reaction, by which a mixture of two diastereoisomers, an ester of cis-β-aryl glycidic acids, (2R, 3R) and (2S, 3S), and an optically pure enantiomer is obtained of the chiral alcohol R-OH, since the Darzens reaction is carried out with a haloacetate strongly sterically hindered, essentially leads to the cis form of the β-aryl glycidate. In an advantageous way, the chiral hydrocarbon radical of strong steric hindrance will be chosen so as to allow the physical separation of the two diastereomers from the reaction medium, for example, by selective crystallization, if a stereospecific separation of the desired enantiomer is needed, at the end of the reaction, by the methods of crystallization or chromatography on a chiral column. Advantageously, R-OH represents menthol, one of the rare chiral alcohols of strong steric hindrance, economical and commercially available under their. two enantiomeric forms. In the synthesis process of a precursor of the side chain of the taxanes, it is sought to prepare a cis-β-phenyl-glycidate of configuration (2R, 3R). In this case, the chiral hydrocarbon radical of strong steric hindrance R will be selected, so that the diastereomer of the cis-β-phenyl glycidate of configuration (2R, 3R) first crystallizes from the reaction medium. When R-OH is menthol, (+) -mentol is advantageously employed. The asymmetric Darzens reaction is carried out in the presence of a base, particularly an alkali metal alcolate such as potassium tertiobutylate, or an amide, such as lithium bistrimethylsilamidide, in a suitable solvent, in particular an ether, such as ethyl ether, at a temperature between -78 ° C and 25 ° C. The reaction leads to a diastereomeric mixture composed almost exclusively of cis-glycidates, with a yield greater than 95%, almost 97%. The treatment of the isolated product in a suitable solvent, in particular a methanol-water mixture, allows the physical separation of the required diastereomers to be easily achieved. By fractional crystallization (2 steps), a rapid enrichment of the desired diastereomer is obtained, with a diastereomeric purity greater than 99%. This point is particularly important since it determines the isomeric purity of the final taxane, the undesired diastereoisomers, its own biological activity, different from that of the taxane sought. It is important to note that the selective use of the two enantiomers of the menthyl ester allows access, with the help of the same procedure, to the 2 diastereoisomers precursors of the two enantiomers of glycidic acid. In addition to a rather high yield in the isolated pure diastereomer (up to 45%), the diastereoisomeric purity of the main product of the reaction, the ease of carrying out the reaction, the simplicity and speed of the purification, the low cost of the reagents and catalysts, the industrial synthesis of this intermediate, key in the asymmetric synthesis of the ß-amino acids, becomes easy and economical access.

When the process according to the invention is used, a derivative of general formula I, obtained by an asymmetric reaction of Darzens, is thus obtained the derivatives of general formulas lia, II 'a, Illa, Illb and III 'b, defined above, for which R represents an optically pure enantiomer of a chiral hydrocarbon radical of strong steric hindrance, such as a cycloalkyl substituted with one or more alkyl groups, in particular a cyclohexyl, preferably menthyl , advantageously, the (+) -mentium. The present invention also relates to these derivatives, useful as intermediates in the synthesis of the taxane side chains. It is convenient to disclose that the present process constitutes a very rapid access to substituted chiral oxazolines already described in the literature (WO 94/14787), in 3 steps, instead of 6 to 8 from commercially available products.

. Careful saponification A careful saponification of the derivatives of general formulas lia, II 'a, Ilb, Illa, Illb and Ill'b, under mild conditions, so that the acid function is released, to preserve the structure of said derivatives, for example, in the presence of an alkali metal carbonate in a methanol / water mixture. After the careful saponification, the derivatives of general formulas Ia, II 'a, Ilb, Illa, Illb and Ill'b defined above are obtained, for which R represents a hydrogen atom, which can be used directly in the semisynthesis of taxanes by coupling with an appropriate derivative of baccatin III. 6. Semisynthesis of taxanes 6. 1 Esterifisation The present invention also relates to a semisynthesis process of taxanes of general formula IV, C-B IV in which C represents a side chain selected from the radicals of the following formulas: R 2 -CONH R 2 -CONH Ar-CJ H-C'H-COO Ar-CJi-CJ I-COO- I Ilia OH LLLa. 8p O NH R "-C N ^ ^ 0 'X ^ - Ar-C * H-C * H-COO \ I I? R-C * H -C * H-COO LL-Ü O - CO-R' 7 R "rCONH I Ar-C * HC * H-COO i LLLLÍL O - CO - R '2 in which Ar, R, R'2 / R"., R3 and GP are defined above, and B represents a radical derived of baccatine III of general formula V in which Ac represents the acetyl radical, Bz represents the benzoyl radical, Me represents the methyl radical, R4 represents an acetyl radical or a protective group of the hydroxy function GP1, and R5 represents a protective group of the hydroxy function GP2, by the esterification of a suitable derivative of baccatine III of general formula V, which has a hydroxy function at C13 , with one of the derivatives of general formulas Ia, Il'a, Ilb, Illa, Ill'a, 111b and Ill'b, defined above, for which R represents a hydrogen atom, under the usual conditions of preparation of the taxanes, such as those defined in the state of the art (especially: EP-0 253 738, EP-0 336 840, EP-0 336 841, EP-0 495 718, WO 92/09589, WO 94/07877, WO 94/07878, WO 94/07879, WO 94/10169, WO 94/12482 EP-0 400 971, EP-0 428 376, WO 94/14787). The protecting groups GP1 and GP2 are independently one of the others, the usual groups used in the semisynthesis of taxanes, such as trialkylsilyl (EP-0 336 840), or TrOC (EP-0 336 841). GP1 and GP2 also represent, independently of one another, haloalkoxycarbonyl radicals, linear or branched, comprising at least one halogen atom. Advantageously, these are radicals in which the alkyl portion comprises between 1 and 4 carbon atoms, and 3 or 4 halogen atoms, preferably chosen from 2, 2, 2-tribromoethoxycarbonyl, 2,2,2,1-tetrachloro-ethoxycarbonyl, 2,2,2-trichloro-t-butoxycarbonyl and trichloro-methoxycarbonyl radicals, all radicals hindered that the haloalkoxycarbonyl (TrOC) used hitherto to protect the taxanes in position 7. GP1 and GP2 also represent, independently of one another, acyl radicals in which the carbon in a of the carbonyl function has at least one oxygen atom. These acyl radicals are described in particular in the patent application EP-0 445 021. It is advantageously alkoxy or aryloxyacetyl radicals of the formula R6-0-CH2-CO wherein Re represents an esterically hindered alkyl radical, a cycloalkyl radical or a radical aryl, or the arylidenedioxyacetyl radicals of the formula O Ar "CH-CO N0 in which Ar" represents an arylidene radical. By "sterically hindered alkyl" is meant preferably a linear or branched C 1 -C 6 alkyl radical substituted by one or more bulky substituents, chosen from halogens, linear alkyl radicals or Branches of C? -C6, linear or branched alkoxy of C? -C6, or C3-C6 cycloalkyl or aryl. It will be, for example, a tert-butyl or trimethylphenyl radical. By cycloalkylPreferably, a C3-C6 cycloalkyl radical, optionally substituted by one or more bulky substituents selected from halogens, linear or branched alkyl radicals of C? -C6, linear or branched alkoxy of C? -C6, or aryl, is understood to be preferred. . Advantageously, it is a cyclohexyl radical, substituted by one or more linear or branched C 1 -C 6 alkyl radicals, such as, for example, methyl, its racemate, its enantiomers in all proportions. Aryl is preferably a phenyl, naphthyl, anthryl or phenanthryl radical, optionally substituted by one or more bulky substituents chosen from halogens, linear or branched alkyl radicals of Ci-Ce, linear or branched alkoxy of Ci-C6, or aryl, in particular phenyl. Preferentially, it is a phenyl radical, optionally substituted by one or two previous bulky substituents, ortho or ortho 'of the ether linkage. Finally, by arylidene, preference is given to a phenyl, naphthylene, antrylene or phenanthylene radical, optionally substituted by one or more bulky substituents chosen from halogens, linear or branched alkyl radicals of Cx-Cb, linear or branched alkoxy of O-C, -, or aryl, in particular phenyl. GP1 and GP2 also represent, independently of one another, a trialkylgermanyl radical or which together form a divalent radical of the formula -SiR7-0-SiRfl- in which R and R, j, independently of one another, represent an alkyl radical sterically hindered such as defined above, in particular R? and RI. each represents an isopropyl radical. 6. 2 Eventual opening When C represents a radical of formula Ilb or Illa, an opening of the oxazolinic cycle is carried out to obtain a derivative of taxanes of formula VI wherein Ac, Bz, Me, Ar, R2, R4 and R5 were defined above. The opening of the radicals Ilb, Illa, and III 'a is generally carried out by hydrolysis in acidic or basic medium. For the radical of formula Ilb, this opening can be carried out according to the methods described in the art (in particular WO 94/14787) by hydrolysis in an acid medium, followed by a treatment in basic medium to obtain the derivative of general formula VI. 6. 3 Deprotection Finally, the deprotection of the hydroxyls of the derivatives of general formula V or VI is carried out, replacing the protecting groups of the hydroxy GP function (when C represents the radical II 'a), GP1 (when R4 is different from an acetyl), and GP2 by a hydrogen atom according to the usual techniques. For derivatives of general formula V, for which C represents a radical of formula Ilb or Illa, and GP1 and / or GP2 are independent of one another, the usual groups used in the semisynthesis of taxanes, such as trialkylsilyl, Deprotection is carried out simultaneously to the opening described above.

When GP1 and / or GP2 are haloalkoxycarbonyl radicals, bulky, the deprotection is carried out according to the usual techniques described for TrOC, by the action of zinc or zinc contaminated with heavy metals such as copper, in an organic solvent, in particular , in acetic acid, tetrahydrofuran or ethyl alcohol, with or without water. When GP1 and / or GP2 are acyl radicals where the carbon in a of the carbonyl function has at least one oxygen atom, the deprotection is carried out in basic medium, by saponification in methanol at low temperature, advantageously, with ammonia in methanol at a temperature below 10 ° C, preferably close to 0 ° C. For the case where C represents a radical of formula Ilb, the opening of the oxazoline is carried out simultaneously to the deprotection in basic medium to lead in one step to the corresponding taxane derivative, of general formula VI, for which R4 represents a radical acetyl or a hydrogen atom, and R5 represents a hydrogen atom, in a manner contrary to the opening in acid medium described in the state of the art, which needs a second step in basic medium. The known protecting groups are removed with the aid of known methods and the oxazoline chain, when present, shown by the hydrolysis, provides the taxanes identical in all to the reference taxanes. By way of example, to show the validity of the invention without limiting in any way the annotated, PACLITAXEL, 10-desacetyltaxol, can be obtained in the cephalomanin and DOCETAXEL from the corresponding protected derivatives. The deblocking of acyls in which the carbon in a of the carbonyl function has at least one oxygen atom, was first attempted under conditions conventionally considered to be the mildest, ie zinc acetate in methanolic medium. Reflux. In this case, the reaction was completed in a few hours (against a few days for the acetates), it was isolated constantly next to the desired product, its epimer in C-7, which results from the classic retroaldolization equilibrium. Assuming the same in neutral conditions, almost slightly acidic, the main responsible are methanol and above all the temperature, we return to the standard unblocking conditions of the acilos described by the first authors, for saponification in basic medium, in ethanol at low temperature. Under these conditions, no noticeable epimerization was found. By way of example, PACLITAXEL, 10-deacetyltaxol of cephalomannine and DOCETAXEL, in any identical point of the reference taxanes, were obtained from the corresponding alkoxy or aryloxyacetylated derivatives.

Finally, it should be noted that in all the methods described above, which aim to improve the overall yield of semisynthesis, consist of previously synthesizing the phenyl-isoserine chain, to transform it into one of the cyclic structures cited above (β-lactams, oxazolidines or oxazolines). Thus, paradoxically, the best apparent performances of the coupling of these cyclic structures only comate for the low overall performance caused by the addition of stages of cycle creation to the synthetic sequence of the linear chain (for a total of 9 stages). By the general procedure of synthesis of taxanes according to the invention, a product such as PACLITAXEL is obtained in only 5 steps: • (2R, 3R) -3-phenylglycidate of (SS, 2R, 5S) - (+) - Menthyl • (4S, 5R) -2,4-Diphenyl-4, 5-dihydroxazole-5-carboxylate of (1S, 2R, 5S) - (+) - mentyl • saponification • semi-synthesis (esterification) • ong and deprotection. The present invention relates to the synthesis intermediates of general formulas IV, V and VI described above, useful in the general synthesis of the taxanes object of the present invention.

In a general manner, by hydrocarbon radical, it is preferably understood, according to the invention, a saturated or unsaturated hydrocarbon radical, which may comprise one or more unsaturations, such as a linear or branched, optionally unsaturated alkyl, an optionally unsaturated cycloalkyl , an aralkyl or an aryl, each may optionally be substituted by one or more substituents, in particular alkyl. By linear or branched alkyl, it is preferably understood, according to the invention, a C?-Ce alkyl, in particular chosen from methyl, ethyl, propyl, isopropyl, butyl radicals and their various branched isomers, such as for example terbutyl , yl and hexyl, and their different branched isomers. This definition also applies to the alkyl radicals of the alkoxy or aralkoxy radicals. By cycloalkyl, it is preferably understood, according to the invention, a C3-C6 cycloalkyl, in particular, chosen from cyclopropyl, cyclobutyl, cycloyl or cyclohexyl radicals. By aryl, it is preferably understood, according to the invention, an aromatic or heteroaromatic radical, in particular chosen from the phenyl, naphthyl, anthryl, phenanthryl, pyridyl, pyrimidyl radicals, etc.

Finally, halogen is preferably chlorine, bromine or iodine. By haloalkoxycarbonyl radicals, it is preferably radicals in which the alkyl portion comprises between 1 and 4 carbon atoms, and 3 or 4 halogen atoms. The general procedure of synthesis of taxanes according to the invention is indicated in Scheme I below, wherein R represents (+) - mentyl, and R2 or R'2, represents phenyl. The last stage of the semisynthesis of the taxanes by the process according to the invention is summarized in schemes 2 and 3 below. Scheme 2 summarizes the synthesis of PACLITAXEL from derivatives of formula IV defined above, for which C represents a radical of formulas IIb or III 'a. Scheme 3 summarizes the synthesis of 10-desacetyltaxol from a derivative of formula IV, for which C represents a radical of formula Ilb. Of course, the same synthesis schemes can be retaken for the other definitions of the substituents.

SCHEME 1 SCHEME 2 20 SCHEME 3 -DEACETILTAXOL GP ,, GP¿ = TRIETILGERMA IO, 2, 2, 2-TRICL0R0-t-BUT0XICARB0NIL0 EXPERIMENTAL PART I. Precursors of the taxane side chain Example 1: (1S, 2R, 5S) - (+) -methyl Clorasetate A solution stirred at room temperature of 100 g (0.640 mol) of (IS, 2R, 5S) - (+) - mentol, in 1 L of dry dichloromethane, was added 57 mL (0.704 mol) of anhydrous pyridine. After a few minutes of agitation, then 56 mL (0.704 mol) of chloroacetyl chloride is added, and the reaction is allowed to continue for 30 minutes. After controlling for C.C.M., 50 g of crushed ice are added and the reaction medium is left for 1 h under strong agitation. After dilution with 100 mL of dichloromethane, the organic phase is washed several times with a saturated aqueous solution of sodium chloride (200 mL), dried over MgSO.i, and then concentrated under reduced pressure. After purification of the crude product thus obtained, by chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, /1), 146 g of (S, 2R, 5S) - (+) - methyl chloroacetate are obtained in the form of a syrup. The compound obtained has the following characteristics: '• H 400 MHz NMR (CDC13) (d ppm): 4.77 (1H, dt) / 4.06 and 4.02 (2H, 2d, J = 13.6 Hz ); 2.02 (1H, m, J = 11.8 Hz); 1.87 (1H, m, J = 7 and 2.6 Hz); 1.69 (2H, m); 1.50 (1H,); 1.43 (1H, m, J = 11.7 and 3 Hz); 1.07 (1H, m); 1.02 (1H, q, J = 11.8 Hz); 0.92 and 0.90 (6H, 2d, J = 6.4 Hz); 0.89 (1H, m); 0.77 (3H, d, J = 7 Hz).

Example 2: (2R, 3R) -3-Phenylglycidate of (1S, 2R, 5S) - (+) -mentyl To a stirred solution at room temperature of 152 g (0.653 mol) of (S, 2R, 5S) - (+) -methyl chloroacetate in 600 mL of anhydrous ethyl ether is added 69 mL (0.686 mol) of benzaldehyde. After several minutes of stirring, the solution is cooled to -78 ° C under an inert atmosphere, then a suspension of 85 g (0.718 mol) of potassium ter-butylate in 400 mL of ether is added in 2 hours. anhydrous ethyl, and allowed to stand in reaction medium at room temperature. After controlling with C.C.M., the organic part is diluted with 200 L of dichloromethane, washed several times with a saturated sodium chloride solution, dried over MgSO4 and concentrated under reduced pressure. 200 g of a crude product in the syrup state are thus obtained, which contains four diastereoisomers (of which two are cis and two are trans), and subjected to fractional crystallization. In a first time, the solution of the crude product with 2 L of methanol is brought to 60 ° C, to which 700 mL of water subjected to osmosis is progressively added, and left for 16 hours at room temperature and far from the vibrations A lower solid phase, yellow in color, rich in trans isomers is separated, and the white crystals of the upper phase, rich in cis isomers, are separated by filtration. The crystals thus obtained are put back into solution in 2 L of methanol and brought to 60 ° C, with the addition of 500 mL of water subjected to osmosis until obtaining a persistent turbidity, and left for 16 hours at room temperature. . Three additional crystallizations are carried out according to the same procedure, but with reduced volumes of methanol (1 L) and water (200 L), necessary to obtain 23 g of (2R, 3R) -3-phenylglycidate of (ÍS, 2R, 5S) - (+) -mentyl in crystalline state with a purity CLAP > 99% (Rdt = 12%). The compound obtained has the following characteristics: • F = 104 ° C • 400 MHz XH NMR (CDC13) (d ppm): 7.40 (2H, dd, J = 7.8 Hz and 1.7 Hz); 7.32 (3H, m); 4.58 (1H, dt, J = 10.9 Hz and 4.2 Hz); 4.26 (1H, d, J = 4.6 Hz); 3.83 (1H, d, J = 4.8 Hz); 1.6 to 0.85 (9H, m); 0.78 (3H, d, J = 7 Hz); 0.75 (3H, d, J = 6, 4 Hz); 0.62 (3H, d, J = 6.9 Hz).

X-ray diffraction of a (2R, 3R) -3-phenyl-glycidate (1S, 2R, 5S) - (+) -methyl monocrystal for the indirect determination of the absolute configuration: The monocrystal was obtained from a crystalline suspension resulting from the addition of heat from a non-solvent (water) to a semi-saturated solution of glycidate, in methanol. With slow re-cooling, the solution leaves fine needles of purity of 99.5% (CLAP) deposited, which are kept moist until the final selection. The selected sample (fine needle of dimensions 0.12 * 0.12 * 0.40 mm) is studied with an automatic diffractometer CAD4 ENRAF-NONIUS (molybdenum radiation with graphite) monochromatic), the parameters of the mesh were obtained by the tuning of a set of 25 reflections at a high theta angle, the data collection (2? max = 50 °, exporation? / 2? = 1 / traax = 60 s, HKL domain: H 0.6 K 0.14 L 0.28, controls intensity without significant deviation (0.1%), provided 1888 reflections with 1037 with I> 1.5s (I). C? 9H2503: Mr = 302.42, Orthorhombic, P2! 2? 2 ?, a = 5.709 (1 1), b = 12.908 (4), c = 24.433 (s) A, V = 1801 (5) A-3, Z = 4, Dx = 1. 116 Mg- "3,? (MoKa) = 0.70926 Á, μ = 0.69 cm" 1, F (000) = 656, T = 294 K, final R = 0.072 for 1037 observations. After the Lorenz corrections and the polarization corrections, the structure was solved with the help of Direct Methods that allow locating most of the non-hydrogenated atoms of the molecule, the remaining atoms are localized by Fourier differences and placed on scales successive After the isotropic refining (R = 0.125) after the anisotropic (R = 0.095), most of the hydrogen atoms are localized with the help of a Fourier difference (between 0.39 and 0.14 eÁ ~ 3), the others are localized by calculation, the complete structure is refined with a complete matrix (x, y, z, ßi3 for C and O, x, y, z for H; 200 variables and 1037 observations; w = 1 / s (F0) 2 = [s2 (I) + (0.04Fo2) 2] _12) lead to R = 0.080, Rw = 0.072 and Sw = 1.521 remainder? p < 0.21 el-3).

The diffusion factors are extracted from the International Tables of Crystallography [International Tables for Xray Cristallography (1974). Vol. IV. Birmingham: Kynoch Pres. (Current Distributor D. Reidel, Dordrecht)]. The calculations are made in a Hewlett Packard 9000-710 for the determination of the structure [SHELDRICK, G. M. (1985). Crystallographic Computing 3: Data Collection, Structure Determination, Proteins and Databases edited by GM Sheldrick, C. Krüger and R. Goddard Oxford: Clarendron Press] and in Digital Microphone VAX 3100 for the other calculations with the MOLEN program set [FAIR, CK (1990) . MOLEN. An Interactive Intelligent System for Crystal Structure Analysis, Enraf-Nonius, Delft, The Netherlands].

ORTEP DIAGRAM [JOHNSON, C. K. (1965). ORTEP. Report ORNL-3794. Oak Ridge National Laboratory Tennesse, E. U. A.] A sample of (2R, 3R) -3-phenyl-glycidate from (ÍS, 2R, 5S) - (+) -mentil, for the treatment with sodium methylate in methanol, allows to obtain the corresponding methyl phenylglycidate, in which the characteristics are the following: • [a] D? 8 = +12 (c = 1.15, chloroform) • NMR lK 400 MHz (CDC13) (d ppm): 7.40 (2H, d, J = 8 Hz); 7.32 (3H, m); 4.26 (1H, d, J = 4.6 Hz); 3.84 (1H, d, J = 4.46 Hz); 3.55 (3H, s).

Example 3: (4S, 5R) -2, -Diphenyl-, 5-dihydrooxazole-5-carboxylate of (1S, 2R, 5S) - (+) -mentyl 0 To a solution stirred under an inert atmosphere -65 ° C of 30 g (0.0993 mol) of (2R, 3R) -3-phenylglycidate of (1S 2R, 5S) - (+) - mentyl, and 305 mL (2.98 mol) of benzonitrile 1, 5 L of anhydrous dichloromethane, add 15 mL (0.109 mol) of a 54% solution of tetrafluoroboric acid in ether 5 for 10 minutes. The reaction is allowed to proceed at -65 ° C for 1 hour, and after control by C.C.F. - add 300 mL of a saturated aqueous sodium monoacid carbonate solution and allow it to react at room temperature with stirring. After extraction of the aqueous phase, with dichloromethane (2 x 200 mL), the combined organic phases are washed with a saturated solution of sodium chloride (200 mL), with water (50 mL) and dried over MgSO4. . After concentration under reduced pressure and removal of the residual benzonitrile under vacuum at 50 ° C, the crude product obtained is purified by gel chromatography. of silica (15-40 μm) (eluent: cyclohexane-ethyl acetate, 20/1). 32 g of (4S, 5R) -2, -diphenyl-4,5-dihydrooxazole-5-carboxylate of (SS, 2R, 5S) - (+) - mentyl, in the form of a colorless syrup (Rd. = 80%) and having the following characteristics: • 400 MHz H-NMR (CDC13) (d ppm): 8.10 (2H, d, J = 7.1 Hz); 7.54 (1H, t, J = 7.4 Hz); 7.46 (2H, t, J = 7.4 Hz); 7.34 (5H, m); 5.40 (1H, d, J = 6.4 Hz); 4.88 (1H, d, J = 6.4 Hz); 4.85 (1H, dt, J = 10.9 and 4.4 Hz); 2.09 (1H, m); 1.84 (1H, m, J- = 7 and 2.7 Hz); 1.71 (1H, m); 1.69 (1H, m); 0.94 (3H, d, J = 6.5 Hz); 0.9 (1H, m); 0.85 (3H, d, J = 7 Hz); 0.77 (3H, d, J = 7 Hz).

Example: Acid (4S, 5R) -2,4-difeni1-, 5-dihydrooxazole-5-carboxylic acid To a stirred solution at room temperature of 3.5 g (8.64 mmol) of (4S, 5R) -2, -d? Phenyl-4,5-dihydrooxazole-5- carboxylate of (SS, 2R, 5S) - (+) - mentyl in methanol (70 mL), add 25 mL of a solution of 6 g (43.2 mmol) of potassium carbonate in water subjected to osmosis, and let the reaction proceed for 16 hours at room temperature. After control by C.C.F., the reaction medium is controlled under reduced pressure. The aqueous phase thus obtained is washed with dichloromethane (3 x 100 mL), acidified to a pH of 2 by the slow addition of 20 mL of an aqueous solution of 1 M HCl, and extracted with ethyl acetate (3 x 100 L ). The combined organic phases are dried (MgSO) and concentrated under reduced pressure. 2.26 g of (4S, 5R) -2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid are also obtained in the form of a white powder (Rdt = 98%) and having the following characteristics: • [] D28 = + 27 (c = 0.99; CH2Cl2-MeOH, 1/1) • F = 201-200 ° C • 400 MHz XH NMR (DMS0-d6) (d ppm): 7.99 (2H , d, J = 7.3 Hz); 7.64 (1H, t, J = 7.4 Hz); 7.55 (2H, t, J = 7.7 Hz); 7.36 (5H, m); 5.40 (1H, d, J = 6, 3 Hz); 4.99 (1H, d, J = 6.4 Hz).

Example 5: (2R, 3S) -N-Benzoyl-3-f nylisoserine to (1S, 2R, 5S) (+) -mentyl To a stirred solution at room temperature of 1 g (2.47 mmol) of (4S, 5R) -2, -diphenyl-4,5-dihydrooxazole-5-carboxylate of (SS, 2R, 5S) - (+) - Menthyl, in a mixture of methanol (15 mL) and tetrahydrofuran (15 mL), 15 mL of an aqueous solution of 1 M HCl are added. The reaction medium is refluxed for 1 hour, and then monitored by TLC, and return to room temperature, a saturated aqueous sodium monoacid carbonate solution (45 mL) is added progressively until a basic pH is obtained.

After 48 hours of stirring at room temperature, the aqueous phase obtained after concentration under reduced pressure is extracted with dichloromethane (100 L). The aqueous phase is washed with a saturated solution of sodium chloride (2 x 50 mL), dried over MgSO,,, concentrated under reduced pressure, and the residue obtained is chromatographed on silica gel (15-40 μm) (eluent: dichloromethane-methanol, 95/05). 0.835 g of (2R, 3S) -N-Benzoyl-3-phenylisoserinate of (SS, 2R, 5S) - (+) - mentyl, in the form of a white solid (Rdt = 80 1) and having following characteristics: • 400 MHz H NMR (CDC13) (d ppm): 7.77 (2H, d, J = 7.2 Hz); 7.51 (1H, t, J = 7.3 Hz); 7.45 (4H, m); 7.36 (2H, t, J = 7.2 Hz); 7.29 (1H, t, J = 7.2 Hz); 7.04 (1H, d, J = 9.2 Hz); 5.78 (1H, dd, J = 9.2 and 2.1 Hz); 4.79 (1H, dt J = 10.9 and 4.4 Hz); 4.63 (1H, broad s); 3.35 (1H, broad s); 1.81 (2H, m); 1.67 (3H,); 1.5 to 1.36 (2H, m); 1.09 to 0.91 (2H, m); 0.89"(3H, d, J = 6.9 Hz), 0.77 (3H, d, J = 6.5 Hz), 0.74 (3H, d, J = 6.9 Hz).

Example 6: < 2R, 3S) -N-Benzoyl-O-triethylsilyl-3-phenylisoserinate (lS, 2R, 5S) - (+) -methyl Me To a solution of 0.8 g (1.89 mmol) of (2S, 3S) -N-benzoyl-3-phenylisoserinate of (SS, 2R, 5S) - (+) - methyl in 10 mL of anhydrous dichloromethane, 0.255 g (2.08 mmol) of 4-dimethylaminopyridine are added. After several minutes of stirring at room temperature, 477 μL (2.84 mmol) of triethylsilyl chloride are added over 5 minutes. After 1 h of stirring at room temperature and control by C.C.F., the reaction medium is diluted with 100 mL of dichloromethane. The organic phase is washed with a saturated aqueous sodium monoacid carbonate solution (2 x 20 mL), and with a saturated solution of sodium chloride (50 mL), dried over MgSO and concentrated under reduced pressure. After purification of the residue obtained by chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 10/1), 0.74 g of (2R, 3S) -N-Benzoyl-O are obtained -triethylsilyl-3-phenylisissinate from (SS, 2R, 5S) - (+) - methyl in the form of a colorless syrup (Rdt = 75%). The compound obtained has the following characteristics: • RM? XH 400 MHz (CDC13) (d ppm): 7.82 (2H,, J = 7 Hz); 7.52 (1H, t, J = 7.4 Hz); 7.45 (2H, t, J = 7 Hz); 7.37 (2H, d, J = 7.2 Hz); 7.32 (2H, t, J = 7.2 Hz); 7.26 (2H, m); 5.60 (1H, dd); 4.73 (1H, dt, J = 11 and 4.3 Hz); 1.88 to 1.67 (m); 1.44 (2H, m); 1.06 to 0.87 (m); 0.80 (m); 0.67 (3H, d, J = 7 Hz); 0.62 to 0.34 ().

Example 7: (2R, 3S) -N-Benzoyl-O-triethylsilyl-3-phenylisoserine To a solution at room temperature of 0.5 g (0.931 mmol) of (2R, 3S) -N-benzoyl-O-triethylsilyl-3-phenylisoserinate of (IR, 2R, 5S) - (+) - methyl in 15 mL of methanol, a solution of 0.644 g (4.655 mmol) of sodium carbonate in 10 L of water subjected to osmosis is added. After stirring for 16 h at room temperature, and control by CC'F., The reaction medium is concentrated under reduced pressure, the residual aqueous phase is washed with dichloromethane (3 x 50 mL), then acidified to a pH of 2 by the slow addition of an aqueous solution of HCl IM (10 mL). The aqueous phase is extracted with ethyl acetate (3 x 50 mL) and the combined organic phases are dried over MgSO 4 and concentrated under reduced pressure. 0.320 g of (2R, 3S) -N-Benzoyl-O-triethylsilyl-3-phenylisoserine are obtained in the form of a white powder (Rdt = 90%) and having the following characteristics: • 400 MHz LH NMR (DMSO-d6) (d ppm); 8.46 (1H, d, J = 9, 3 Hz); 7.82 (2H, d, J = 7.1 Hz); 7.54 (1H, t, J = 7.2 Hz); 7.47 (4H, m); 7.32 (2H, t); 7.36 (1H, t); 5.44 (1H, dd, J = 9.2 and 5.5 Hz); 4.64 (1H, d, J = 5, 6 Hz); 0.77 (9H, m); 0.45 (6H, m).

Example 8: (2R, 3S) -N-Benzoyl-O- (2,2,2-trichloroethoxy) carbonyl-3-phenylisoserinate (1S, 2R, 5S) - (+) -methyl Me To a stirred solution at room temperature under an inert atmosphere of 1.38 g (3.3 mmol) of (2R, 3S) -N-benzoyl-3-phenylisoserinate of (SS, 2R, 5S) - (+) - methyl in 30 mL of anhydrous dichloromethane, 480 mg (3.96 mmol) of 4-dimethylaminopyridine are added. After 10 minutes of stirring, 540 μL (3.96 mmol) of 2,2,2-trichloroethoxycarbonyl chloride is added 5 minutes. After 2 h of stirring at room temperature, by control by C.C.F., the organic phase is washed with a saturated carbonate solution sodium monoacid (2 x 10 mL), with saturated sodium chloride solution (10 mL), dried over MgSO4 and concentrated under reduced pressure. After purification of the residue obtained by chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 5/1) 1.6 g of (2R, 3S) -N-Benzoyl-O are obtained ((1S, 2R, 5S) - (+) - methyl (2,2, 2-trichloroethoxy) carbonyl-3-phenylisoserinate in the form of a colorless syrup (Rdt = 82%). The compound obtained has the following characteristics: • RM? X H 400 MHz (CDC13) (d ppm): 7.82 (2H, d, J = 7.4 Hz); 7.53 (1H, t, J = 7.4 Hz); 7.44 (4H, m); 7.35 (2H, t, J = 7 Hz); 7.29 (1H, t, J = 7 Hz); 7.09 (1 H, d, J = 9.3 Hz); 6.0 (1H, dd, J = 9.3 and 2.5 Hz); 5.45 (1H, d, J = 2.6 Hz); 4.78 and 4.72 (2H, 2d, J = 11.9 Hz); 4.77 (1H,); 1.85 (1H, m) 1.79 (1H, m) 1.65 (2H,); 1.43 (1H, m); 1.02 (1H;); 0.96 (1H,); 0.86 (1H, m); 0.83 (3H, d, J = 7 Hz); 0.78 (3H, d, J = 6.5 Hz); 0.68 (3H, d, J = 6.9 Hz).

Example 9: (4S, 5R) -4-Phenyloxazolidin-2-one-5-carboxylate of (1S, 2R, 5S) - (+) - methyl A solution stirred at room temperature under an inert atmosphere of 3.96 g (6.62 mmol) of (2R, 3S) -N-benzoyl-10- (2,2,2-trichloroethoxy) carbonyl-3-phenylisoserinate from (SS, 2R, 5S) - (+) - methyl in 30 mL of anhydrous dichloromethane, add 1 L (7.28 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene. After 30 minutes of stirring at room temperature, the organic phase is washed with 10 mL of a saturated solution of sodium chloride, dried over MgSO4 and concentrated under reduced pressure. After purification of the residue obtained by chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 7/3) 2.18 g of the title compound are obtained in the form of a yellow syrup (Rdt = 95%). The compound obtained has the following characteristics: • RM? 400 MHz (CDCl J (d ppm): 7.40 (5H, m), 6.09 (LH, 3), 4.93 (1H, d, J = 5.3 Hz), 4.86 (1H ) dt, J = 11 and 4.4 Hz); 4.73 (1H, d, J = 5.4 Hz); 2.05 (1 H,); 1.81 (1H, m); 1.71 (2H, m); 1.54 to 1.41 (3H, m); 1.07 (2H,); 0.94 (3H, d, J6 ^ 5 Hz); 0.88 (3H, d, J = 7 Hz); 0.77 (3H, d, J = 7 Hz).

Example 10 (4S, 5R) -N-tButoxycarbonyl-4-phenyloxazolidin-2-one-5-carboxylic acid (1S, 2R, 5S) - (+) -methyl ester Me A to a stirred solution at -40 ° C under an inert atmosphere of 1.91 g (5.52 mmol) of (4S, 5R) -4-phenyloxazolidin-3-na-5-carboxylate of (1S, 2R, 5S) - (+) -methyl in 20 mL of anhydrous tetrahydrofuran, add 3.8 mL (6.07 mmol) of a 1.6 M solution of -n-butyllithium in hexane. After 10 min of stirring at -40 ° C, a solution of 1.81 g is added. (8.28 mmol) of butocarbonic anhydride in solution in 5 mL of tetrahydrofuran, and the reaction medium is allowed to concentrate at room temperature for 15 min. After dilution with 50 L of dichloromethane and washing with an aqueous solution of 2% HCl, until obtaining a pH = 5, the organic phase is dried (MgSO-J, and concentrated under reduced pressure. the purification of the product Crude chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 5/1) gave 2.12 g of the title compound in the form of a colorless syrup (Rdt = 86%). The obtained compound has the following characteristics: • 400 MHz NMR (CDC13) (d ppm): 7.45 to 7.26 (5H, m); 5,19 (1H, d, J = 3.7 Hz); 4.86 (1H, dt, J = 10.9 and 4.5 Hz); 4.66 (1H, d, J = 3.7 Hz); 2.05 (1H, na); 1.79 (1H, m); 1.73 (2H) m); 1.62 to 1.24 (3H, m); 1.33 (9H, 5); 1.11 (2H, m); 0.94 (3H, d, J = 6.5 Hz) and (1H, m); 0.89 (3 H, d, J = 7 Hz); 0.77 (3H, d, J = 7 Hz). Example 11 (4S, 5R) -3-N-Benzoyl-4-phenyloxazolidin-3-one-5-carboxylate (1S, 2R, 5S) - (+) - methyl Me To a stirred solution at room temperature under inert atmosphere, of 500 g (1.45 mmol) of (4S, 5R) -3-phenyloxazolidin-3-one-5-carboxylate of (SS, 2R, 5S) - (+ ) -methyl and 176 mg (1.16 mmol) of 4-pyrrolidinopyridine in 7 mL of anhydrous dichloromethane, 0.25 L (2.17 mmol) of benzoyl chloride are added. After 3 h of stirring at 50 ° C, the reaction medium is brought back to room temperature and diluted with 20 mL of dichloromethane. The organic phase is washed with 10 mL of a saturated solution of sodium chloride, dried over MgSO4 and concentrated under reduced pressure. After purification of the crude product by chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 5/1), 300 mg of the title compound are obtained in the form of a colorless syrup (Rdt = 46%). The compound obtained has the following characteristics: • 400 MHz XH NMR (CDC13) (d ppm): 8.16 (2H, d, J = 7.1 Hz); 7.68 (1H, t); 7.53 (4H,); 7.43 (3H, m); 5.57 (1H, d, J = 4.4 Hz); 4.90 (1H, dt, J = 10.9 and 4.4 Hz); 4.85 (1H) d, J = 4.3 Hz); 2.07 (1H, m); 1.80 (1H, m); 1.72 (2H,); 1.47 (3H, m); 1.09 (2H, m); 0.95 (3H, d, J = 6.5 Hz); 0.88 (3H, d, J = 7 Hz); 0.78 (3H, d, J = 7 Hz).

Example 12 Asido (4S, 5R) -3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylic acid To a stirred mixture at room temperature of 120 mg (0.266-mmol) of (4S, 5R) -3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylate of (SS, 2R, 5S) - (+ ) -methyl in 2 mL of methanol, add a solution of 75 mg (0.543 mmol) of potassium carbonate in 1 mL of water. After 30 min of stirring, the reaction medium is diluted with 100 mL of water and the aqueous phase is washed with 5 L of dichloromethane. After acidification at pH = 4 by means of HCM, the residual aqueous phase is extracted with ethyl acetate (3 x 10 mL). The combined organic phases are washed with 5 mL of a saturated sodium chloride solution, dried over MgSO4 and concentrated under reduced pressure. 40 mg of (4S, 5R) -3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylic acid are obtained in the form of a white powder (Rdt = 52%), and having the following characteristics: • NMR: H 400 MHz (DMS0-d, J (d ppm): 12.98 (1H, long 5), 7.95 (2H, d, J = 7.1 Hz), 7.63 (1H, t , J = 7.4 Hz), 7.50 (2H, t, j = 7.5 Hz), 7.42 (2H, m), 7.37 (3H, m), 4.90 (1H, d) , J = 5 Hz), 4.77 (1H, d, J = 5 Hz).

Example 13 (4S, 5R) -4-Phenyloxazolidin-3-one-5-carboxylic acid To a stirred solution at 0 ° C under an inert atmosphere of 300 mg (0.867 mmol) of (4S, 5R) -4-phenyloxazolidin-2-one-5-carboxylate of (SS, 2R, 5S) - (+) -methyl 3 mL of methanol, then 0.5 mL of water in 6.5 mL of pyridine, 10 L of a homogeneous solution of 360 mg (8.67 mmol) of NaOH, 3 mL of methanol and 0.5 mL are quickly added. mL of water in pyridine. After 20 min of stirring at 0 ° C, the reaction medium is diluted with water (30 mL) and washed with dichloromethane (30 mL). After acidification at pH = 1, the residual aqueous phase is extracted with ethyl acetate (3 x L), and the combined organic phases are dried (MgSO 4), and concentrated under reduced pressure.

This gives 86 mg of (4S, 5R) -4-phenyloxazolidin-3-one-5-carboxylic acid in the form of a yellow syrup (Rdt = 53%), and has the following characteristics: • NMR lE 400 MHz (DMS0-d) (d ppm): 13.33 (1H, long 5); 8.46 (1H, 5); 7.38 (5H, m); 4.89 (1H, d, J = 5 Hz); 4.75 (1 H, d, J = 5 Hz).

II. Derivatives of baccatin III Example 4 7-O-Triethylsilyl-10-desacetylbacsatin III To a solution stirred at room temperature under an inert atmosphere of 10 g (18.3 mmol) of 10-deacetylbaccatin III and 8.17 g (54.9 mmol) of 4-pyrrolidinopyridine in 500 mL of anhydrous dichloromethane are added 6 g. , 2 mL (36.6 mmol) of triethylsilyl chloride for 10 min. After 3 h of reaction at room temperature, 10 g of ice are added chopped and the mixture is left 10 min with strong agitation. The residual organic phase is washed with water (200 L), dried over MgSO 4 and concentrated under reduced pressure. After treatment of the crude product obtained with the minimum of ethyl acetate, 11.2 g of 7-0-triethylsilyl-10-deacetylbaccatin III are obtained in crystalline state (Rdt = 92.3%). The product thus obtained has the following characteristics: • 400 MHz XH NMR (CDC13) (d ppm): 8.10 (2H, d, J = 7.4 Hz); 7.60 (1H, t, J = 7.5 Hz); 7.47 (2H, t, J = 7.6 Hz); 5.60 (1H, d, J = 7 Hz); 5.17 (1H, d, J = 1.9 Hz); 4.96 (1H, d, J = 8 Hz); 4.86 (1H,); 4.41 (1H, dd, J = 10.6 and 6.6 Hz); 4.31 and 4.16 (2H, 2d, J = 8.4 Hz); 4.26 (1H, d, J = 1.9 Hz); 3.95 (1H, d, J = 6.9 Hz); 2.48 (1H, ddd, J = 14.5, 9.7 and 6.7 Hz); 2.29 (3H, s); 2.27 (2H, m); 2.08 (3H, s), 1.90 (1H,); 1.73 (3H, s); 1.62 (1H, s); 1.08 (6H, s); 0.94 (9H, t, J = 8 Hz); 0.56 (6H,).

Example 15: 7-O-Triethylgermanil-10-desacetylbaccatine III To a stirred solution at room temperature and under inert atmosphere of 100 mg (0.183 mmol) of 10-deacetylbaccatin III and 41 mg (0.275 mmol) of 4-pyrrolidinopyridine in 4 L of anhydrous dichloromethane, 80 μL (0.476 mmol) of triethylgermanyl chloride for 10 minutes, and the mixture is stirred at 50 ° C for 13 hours. After cooling of the reaction medium, and dilution with 15 mL of dichloromethane, 1 g of crushed ice is added and the mixture is left under vigorous stirring for 10 minutes. The residual organic phase is washed with a saturated sodium monoacid carbonate solution (5 L), a saturated solution of sodium chloride (5 mL), dried over MgSO4 and concentrated under reduced pressure. After crude chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 25/75), 67 mg of 7-0-triethylgermanyl-10-deacetylbaccatin III are obtained in the form of a syrup. colorless.

The product thus obtained has the following characteristics: • -RMN H 400 MHz (CDC13) (d ppm): 8.09 (2H, d, J = 7.1 Hz); 7.60 (1H, t, J = 7.4 Hz); 7.48 (2H, t, J = 7.6 Hz); 5.63 (1 H, d, J = 7.1 Hz); 5.24 (1H, s); 4.99 (1H, d, J = 8 Hz); 4.78 (1H, t); 4.32 (1H, d, J = 8.3); 4.28 (1H,); 4.17 (2H, m); 3.97 (1H, d, J = 7 Hz); 2.59 (1H, m); 2.30 (3H, s); 2.24 (1H, m); 2.10 (1H, m); 2.03 (3H, s); 1.82 (1H, m); 1.73 (3H, s); 1.11 (9H, m); 1.0 (6H, t, J = 7.7 Hz).

Example 16: 7-0- (2,2,2-Trichloro-t-butoxycarbonyl) -10-desacetyl-baccatine III To a solution stirred at 40 ° C under an inert atmosphere of 5 g (9.19 mmol) of 10-deacetylbaccatin III and 1.1 mL of anhydrous pyridine in 250 L of dry dichloromethane were added. 3.3 g (13.8 mmol) of 2,2,2-trichloro-t-butoxycarbonyl chloride are added over 2 hours. After an additional 30 minutes of reaction, and return to room temperature, the organic solution is washed with an aqueous solution of 2% HCl (30 L), washed with water subjected to osmosis (2 x 100 mL), Dry over MgSO4 and concentrate under reduced pressure (Rdt = 55%). After chromatography of the crude product on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 60/40), 7-0- (2, 2, 2-trichloro-t-butoxycarbonyl) is obtained. -10-desacetylbaccatine "III" in the form of a white powder The product obtained has the following characteristics: • XH 400 MHz NMR (CDC13) (d ppm): 8.10 (2H, d, J = 7 Hz); , 62 (1H, t, J = 7.4 Hz), 7.49 (2H, t, J = 7.6 Hz), 5.65 (1H, d, J = 6.9 Hz), 5.44 (1H, dd, J = 10.8 and 7.3 Hz), 5.39 (1H, d), 4.98 (1H, d, J = 7.5 Hz), 4.39 H, m); 35 and 4.20 (2H, 2d, J = 8.4 Hz), 4.10 (1H, d, J = 7 Hz), 4.01 (1H, d, J = 1.8 Hz), 2, 64 (1H, m), 2.31 (3H, s), 2.29 (1H, m), 2.11 (3H, d), 2.05 (2H,), 1.89 (3H, s) 1.09 (3H, s); 1.07 (3H, s).

Example 17: a) 7-O-Triethylsilylbaccatine III To a solution stirred at room temperature under an inert atmosphere of 1 g (1.5 mmol) of 7-tritylsilyl-10-deacetylbaccatin III and 1.25 mL (15 mmol) of pyridine in 15 mL of dry dichloromethane., 0.54 mL (7.5 mmol) of acetyl chloride is added over 10 minutes. After 2 hours of reaction at room temperature and controlled by C.C.F., 1 g of crushed ice is added and the mixture is left under vigorous stirring for 10 minutes. The residual organic phase is washed with water (2 x 10 mL), dried over MgSO4 and concentrated under reduced pressure. After chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 60/40), 0.756 g of 7-O-triethylsilylbaccatin III is obtained in the form of a white powder (RdL = 70%). The compound obtained has the following characteristics: • 400 MHz aH NMR (CDC13) (d ppm): 8.11 (2H, d, J = 7.1 Hz); 7.6 (1H, t, J = 7.4 Hz) / 7.48 (2H, t, J = 7.7 Hz); 6.46 (1H, s); 5.63 (1H, d, J = 7 Hz) / 4.96 (1H, d, J = 8.1 Hz); 4.83 (1H, m); 4.49 (1H, dd, J = 10.4 and 6.7 Hz); 4.31 and 4.15 (2H, 2d, J = 8.3 Hz); 3.88 (1H, d, J = 7 Hz); 2.53 (1H, m); 2.29 (3H, s); 2.27 (2H,); 2.19 (3H, d, J = 0.8 Hz); 2.18 (3H, s); 2.12 (1 H, d); 1.88 (1H, m); 1.68 (3H, s); 1.65 (1H, s); 1.2 (3H, s); 1.04 (3H, s); 0.92 (9H, t); 0.59 (6H,).

Example 18: 7 -. 7 -O- (2,2, 2-Trichloro-t-butoxycarbonyl) baccatine III To a solution stirred at room temperature under an inert atmosphere of 260 mg of 7 -O- (2,2,2-trichloro-t-butoxycarbonyl-10-deacetylbaccatin III and 127.5 mg (1.04 mmol) of 4-dimethylaminopyridine. In 2.5 mL of dry dichloromethane, add 50 μL (0.695 mmol) of acetyl chloride.After 1 hour of reaction at room temperature, the organic phase is washed with an aqueous solution of 2% HCl until obtained pH = 6, dried over MgSO4 and concentrated under reduced pressure. residue on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 6/4), 0.23 g of 7-0- (2, 2, 2-trichloro-t-butoxycarbonyl) - is obtained. Baccatin III in solid state (Rdt = 83%). The compound obtained has the following characteristics: • 400 MHz XH NMR (CDC13) (d ppm): 8.11 (2H, d, J = 7, 1 Hz); 7.62 (1H, t, J = 7.4 Hz); 7.49 (2H, t, J = 7.6 Hz); 6.39 (1H, s); 5.64 (1 H, d, J = 6.9 Hz); 5.61 (1H, dd, J = 10.7 and 7.2 Hz); 4.99 (1H, d, J = 8.2 Hz); 4.87 (1H, m); 4.33 and 4.16 - (2H, 2d, J = 8.4 Hz); 4.02 (1H, d, J = 6, 9 Hz); 2.64 (1H, ddd, J = 14.4, 9.5 and 7.2 Hz); 2.30 (3H, s) and (2H, ra); 2.17 (3H, s); 2.13 (3H, d, J = 0.8 Hz); 2.04 (1H, m); 1.83 (3H, s); 1.63 (1H, s); 1.14 (3H, s); 1.09 (3H, s).

Example 19: 7-O-Phenoxyaceti1-10-desacetylbacsatin III To a stirred solution at room temperature and under an inert atmosphere of 1.03 g (1.88 mmol) of 10-deacetylbaccatin III and 0.06 mL (7.5 mmol) of anhydrous pyridine in 100 mL of dry dichloromethane are added. 1.05 μL (7.5 mmol) of phenoxyacetyl chloride for 10 minutes. After 30 minutes of reaction at room temperature, and controlled by TLC, the organic solution is washed with an aqueous solution of HCl 2%, until obtaining a pH = 2, washed with water subjected to osmosis (2 x 50 L), dried over MgSO4 and concentrated under reduced pressure (Rdt = 70.5%). After chromatography of the crude product on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 60/40), 7-O-phenoxyacetyl-10-deacetylbaccatin III is obtained in the form of a powder White. The product obtained has the following characteristics: • MN XH 400 MHz (CDC13) (d ppm): 8.09 (2H, d, J = 7.3 Hz); 7.61 (1H, t, J = 7.4 Hz); 7.48 (2H, t, J = 7.6 Hz); 7.31 (2H, t, J = 7.7 Hz); 6.99 (3H, m); 6.42 (1H, s), 5.61 (1H, d, J = 7 Hz); 4.97 (1H, d, J = 7, 8 Hz); 4.86 (3H, m), 4.44 (1H, dd, J = 10.6 and 6.8 Hz); 4.30 and 4.15 (2H, 2d, J = 8.4 Hz); 3.86 (1H, d, J = 7 Hz); 2.56 (1H, m); 2.27 (3H, s); 2.27 (2H,); 2.05 ((3H, s); 1.86 (1H, m); 1.68 (3H, s); 1.01 (3H, s); 0.98 (3H, s).

Example 20: 7-10-O-Di- (phenoxyacetyl) -10-desacetylbascatine III To a stirred solution at room temperature and under an inert atmosphere of 500 mg (0.92 mmol) of 10-deacetylbaccatin III and 0.06 mL (7.36 mmol) of anhydrous pyridine in 50 mL of dry dichloromethane, add 0, 5 mL (3.68 mmol) of phenoxyacetyl chloride for 10 minutes. After 6 hours of reaction at room temperature, and controlled by C.C.F. , the solution is washed with an aqueous solution of 2% HCl, until obtaining a pH = 2, washed with water subjected to osmosis (2 x 20 mL), dried over MgSO4 and concentrated under reduced pressure. After chromatography of the crude product on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 6/4), 0.55 g of 7, 10-O-bis- (phenoxyacetyl) - are obtained. 10- desacetylbaccatine in the form of a white powder (Rdt = 74%). The product obtained has the following characteristics: • 400 MHz XH NMR (CDC13) (d ppm): 8.09 (2H, d, J = 7, 1 Hz); 7.61 (1H, t, J = 7.4 Hz); 7.48 (2H, t, J = 7.6 Hz); 7.29 (2H, t, J = 6.8 Hz); 7.22 (2H, t, J = 7.5 Hz); 6.96 (4H, m); 6.84 (2H, d, J = 7.9 Hz); 6.42 (1H, s); 5.69 (1H, dd, J = 10.5 and 7.1 Hz); 5.60 (1H, d, J = 6, 9 Hz); 4.96 (1H, d, J = 8.2 Hz); 4.84 (1H, t, J = 7.4 Hz); 4.8 (2H, s); 4.65 and 4.41 (2H, 2d, J = 15.8 Hz); 4.32 and 4.14 (2H, 2d, J = 8.4 Hz); 3.98 (1 H, d, J = 6.8 'Hz); 2.65 (1H, m) / 2.28 (3H, s); 2.26 (2H, m); 2.09 (3H, s); 1.80 (3H, s); and (1H, m); 0.98 (6H, s).

Example 21: 7- -Foxoxiacetylbacsatin III To a stirred solution at room temperature and under an inert atmosphere of 1.11 g (1.64 mmol) of 7-0-phenoxyacetyl-10-deacetylbaccatin III in 40 mL of anhydrous pyridine are added 0.233 mL (3.27 mmol). of acetyl chloride for 10 minutes. After 16 hours of reaction at room temperature, and controlled by C.C.F., the reaction medium is diluted with 50 mL of water subjected to osmosis, and the aqueous phase is extracted with ethyl acetate (3 x 30 mL). The combined aqueous phases are washed with water (2 x 20 mL), dried over MgSO 4, and concentrated under reduced pressure (Hdt: 84.5%). After chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 60/40), 7-phenoxyacetylbaccatin III is obtained in the crystallized state. The product obtained has the following characteristics: • 400 MHz NMR (CDC13) (d ppm): 8.10 (2H, d, J = 7.1 Hz); 7.61 (1H, t, J = 7.4 Hz); 7.48 (2H, t, J = 7.7 Hz); 7.27 (2H, t, J = 8 Hz); 6.95 (3H,); 6.26 (1H, s); 5.71 (1H, dd, J = 10.4 and 7.2 Hz); 5.62 (1H, d, J = 6, 9 Hz); 4.96 (1H, d, J = 8.3 Hz); 4.80 (1H, m); 4.81 and 4.53 (2H, 2d, J = 16 Hz); 4.32 and 4.14 (2H, 2d, J = 8.5 Hz); 4.0 (1H, d, J = 6, 9 Hz); 2.64 (1H, m); 2.29 (2H, m); 2.28 (3H, s); 2.24 (1H, d, J = 5 Hz); 2.16 (3H, s); 2.09 (3H, d, J = 0.7 Hz); 1.81 (1H, m); 1.78 (3H, s); 1.13 (3H, s); 1.08 (3H, s).

Example 22: 7-10-O- (1, 1,3, 3-Tetraisopropyl-l, 3-disiloxandylyl) 10-desacetyl bacsatin III To a stirred solution at -40 ° C and under an inert atmosphere of 500 mg (0.93 mmol) of 10-deacetylbaccatin III in 20 mL of anhydrous tetrahydrofuran, 1.28 mL (2.05 mmol) of n-butyl are added. lithium in 1.6 M solution in hexane for 10 minutes. "After 5 minutes of stirring, 350 μL are added (1.12 mmol) of 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane and allow the reaction medium to concentrate at room temperature for 10 minutes. After 1 hour of stirring at room temperature, 225 mg (2.05 mmol) of 4-dimethylaminopyridine are added and the reaction medium is left for an additional 1 hour under stirring. After the addition of 20 mL of a saturated aqueous solution of sodium chloride, the medium it is extracted with dichloromethane (3 x 30 mL). The combined organic phases are washed with a saturated aqueous solution of sodium chloride (20 mL), dried over MgSO 4, and concentrated under reduced pressure. After purification by chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 60/40), 480 mg of 7, 10-O- (l, 1, 3, 3) are obtained tetraisopropyl-l, 3-disiloxandyl) -10-deacetylbaccatin III in amorphous state (Rdt = 65%). The product obtained has the following characteristics: • 400 MHz XH NMR (CDC13) (d ppm): 8.10 (2H, d, J = 7.2 Hz); 7.60 (1H, t, J = 7.4 Hz); 7.47 (2H, t, J = 7.6 Hz); 5.60 (1H, t, s); 5.59 (1H, d); 4.97 (1H, d, J = 7.9 Hz); 4.87 (1H,); 4.68 (1H, dd, J = 10.4 and 6.9 Hz); 4.30 and 4.17 (2H, 2d, J = 8.5 Hz); 3.92 (lh, d, J = 7.1 Hz); 2.49 (1H, m); 2.28 (3H, s); 2.27 (1H, m); 2.04 (1H, m); 1.91 (1H, m); 1.67 (3H, s); 1.55 (1H, s); 1.32 to 0.85 (34 H, m).

Example 23: 13-0- [[(4S, 5R) -2, 4-Dif nyl-4, 5-dihydroxazol-5-yl] -sarboni1] -7-O-triethylsilyl-baccatine III To a stirred solution at room temperature and under an inert atmosphere of 2.67 g (10 mmol) of (4S, 5R) -2,4-diphenyl-4,5-dihydroxazole-5-carboxylic acid in 55 mL of anhydrous toluene, 2.06 g (10 mmol) of dicyclohexylcarbodiimide are added. After stirring for 5 minutes, 3.5 g (5 mmol) of 7-O-triethylsilylbaccatine III and 0.61 g (5 mmol) of 4-dimethylamino-pyridine are added and the reaction mixture is brought to 70 ° C. for 1 hour. After returning to room temperature and eliminating insolubles by filtration, the organic phase is concentrated under reduced pressure. After purification of the crude product by chromatography on silica gel (15-25 μm) (eluent: cyclohexane-ethyl acetate, 90/10). 4.62 g of 13-0- [[(4S, 5R) -2,4-diphenyl-4,5-dihydroxazol-5-yl] -carbonyl-7-O-triethylsilylbaccatin III is obtained in crystallized state (Rdt = 97). The compound thus obtained has the following characteristics: • 400 MHz XH NMR (CDC13) (d ppm): 8.23 (2H, d, J = 7.2 Hz); 8.07 (2H, d, J = 7.3 Hz); 7.63 (1H, t, J = 7.4 Hz); 7.58 (1H, t, J = 7.4 Hz); 7.49 (4H, m); 7.38 (5H, m); 6.42 ((1H, s); 6.18 (1H, t, J = 8.2 Hz); 5.68 (1H, d, J = 7.1 Hz); 5.60 (1H, d, J = 6.5 Hz), 4.95 (2H, d), 4.50 (1H, dd, J = 10.5 and 6.7 Hz), 4.29 (1H, d, J = 8.4) Hz), 4.14 (1H, d, J = 8.4 Hz), 3.83 (1 H, d, J = 7.1 Hz); 2.55 (1H, m); 2.37 (1H, dd, J = 15.3 and 9.3 Hz); 2.26 (1H, dd, J = 15.3 and 8.6 Hz); 2.16 (3H, s); 2.07 (3H, s); 1.99 (3H, s); 1.89 (1H, m); 1.72 (1H, s); 1.69 (3H, s); 1.23 (3H, s); 1.19 (3H, s); 0.92 (9H, t, J = 8 Hz); .0.57 (6H, m).

Example 24: 13-0- [[4S, 5R] -2,4-Diphenyl-4,5-dihydrooxazol-5-yl] carbonyl] -7-O-phenoxyacetylbaccatin III To a stirred solution at room temperature and under an inert atmosphere of 490 mg (1.83 mmol) of (4S, 5R) -2,4-diphenyl-4,5-dihydrooxazole-5-carbonyl acid in 10 -mL of anhydrous toluene , 380 mg (1.84 mmol) of dicyclohexylcarbodii ida are added. After 5 minutes of stirring, 660 mg (0.92 mmol) of 7-O-phenoxyacetylbaccatin III and 112 mg (0.92 mmol) of 4-dimethylaminopyridine are added, and the reaction mixture is brought to 70 ° C for 2 hours. hours. After returning to room temperature and eliminating the insolubles by filtration, the organic phase is concentrated under reduced pressure. After purification of the crude product by chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 99/1), 800 mg of 13-0- [[4S, 5R] -2 are obtained , 4-diphenyl-4,5-dihydrooxazol-5-yl] -carbonyl-7--phenoxyacetylbaccatin III in crystalline state (Rdt = 90%). The compound thus obtained has the following characteristics: • MN XH 400 MHz (CDCl 3) (d ppm): 8.18 (2H, d, J = 7 Hz); 8.07 (2H, d, J = 7.3 Hz); 7.63 (1H, t, J = 7.4 Hz); 7.59-7.32 (10H, m); 7.28 (2H, t, J = 7.5 Hz); 6.94 (3H, m); 6.23 (1H, s) and (1H, m); 5.70 (1H, dd, J = 10.4 and 7.1 Hz); 5.67 (1H, d, J = 7.3 Hz); 5.58 (1H, d, J = 7 Hz); 4.93 (2H, d); 4.79 and 4.53 (2H, 2d, J = 15.9 Hz); 4.30 and 4.13 (2H, 2d, J = 8.5 Hz); 3.97 (1H, d, J = 6.9 Hz); 6.97 (1H, m); 2.38 (1H, dd, J - .2 and 9.3 Hz); 2.26 (1H, dd, J = 15.2 and 8.4 Hz); 2.15 (3H, s); 2.02 (3H, s); 1.95 (3H, s) and (1H, m); 1.80 (3H, s); 1.74 (1H, s); 1.25 (3H, s); 1.17 (3H, s).

Example 25: 13-0- [[4S, 5R) -2, -Dif-enyl-4,5-dihydrooxazol-5-yl] -carbonyl] -7-O- (2, 2, 2-trichloro-t-butoxycarbonyl) baccatine III To a stirred solution at room temperature and under an inert atmosphere of 35 mg of (4S, 5R) -2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid in 3 mL of anhydrous toluene, 27 mg (0.degree. , 13 mmol) of dicyclohexylcarbodiimide. After 5 minutes of stirring, 51 mg (0.065 mmol) of 7 -O- (2,2,2-trichloro-t-butoxycarbonyl) baccatine III and 8 mg (0.065 mmol) of 4-dimethylaminopyridine are added, and the mixture it is brought to 70 ° C for 1 hour. After the return to room temperature and the elimination of insolubles by filtration, the organic phase is concentrated under reduced pressure, and the residue obtained is purified by chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 9/1). 0.99 g of the compound mentioned in the title are thus obtained in the form of a white solid (Rdt = 67%) and having the following characteristics: • -RMN XH 400 MHz (CDC1) (d ppm): 8.18 (2H, d, J = 7.2 Hz); 8.07 (2H, d, J = 7.3 Hz); 7.65 (1H, t, J = 7.4 Hz); 7.59 (1H, t, J = 7.3 Hz); 7.52 (4H, m); 7.39 (5H, m); 6.35 (1H, 's); 6.24 (1H, t, J = 8.4 Hz); 5.68 (1H, d, J = 7.1 Hz); 5.59 (1H, d, J = 7 HZ) and (1H, dd), 4.95 (1H, d), 4.94 (1H, d, J = 7 Hz); 4.31 and 4.15 (2H, 2d, J = 8.4 Hz); 3.97 (1H, d, J = 6, 9 Hz); 2.64 (1H, m); 2.37 (1H, dd, J = 15, 1 and 6 Hz); 2.27 (1H, dd, J = 15.2 and 8.5 Hz); 2.16 (3H, s); 2.01 (3H, s); 1.98 (3H, s); 1.83 (3H, s); 1.72 (1H, s); 1.25 (3H, s); 1.18 (3H, s).

Example 26: 13-0- [[4S, 5R) -2,4-Diphenyl-4,5-dihydrooxazol-5-yl] -carbonyl] -7, 10-O- (1, 1,3, 3-tetraisopropyl-1, 3- disiloxandil) -10-desacetylbaccatin III To a stirred solution at room temperature, and under an inert atmosphere of 4 mg (0.015 mmol) of (4S, 5R) ~ 3,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid in 0.5 mL of anhydrous toluene , 7 mg (0.06 mmol) of dicyclohexylcarbodiimide are added. After 5 minutes of stirring, a solution of 5 mg (0.0065 mmol) of 7,10-0- (1,1,3, 3-tetraisopropyl-1,3-disiloxandyl) -10-desacetyl-baccatine is added. III and 1 mg (0.0078 mmol) of 4-dimethylaminopyridine in 1 mL of anhydrous toluene. After 20 minutes of stirring at room temperature, the mixture is brought to 50 ° C for an additional 20 minutes. After returning to room temperature, the organic phase is diluted with 5 mL of dichloromethane, washed with 2 mL of a saturated aqueous solution of sodium chloride, dried over MgSO4 and dried under reduced pressure. After purification of the crude product by chromatography on silica gel (15-25 μm) (eluent: cyclohexane-ethyl acetate, 7/3) 6 mg of the title derivative (Rdt = 90%) are obtained in amorphous state. The compound obtained has the following characteristics: • 400 MHz XH NMR (CDC13) (d ppm): 8.21 (2H, d, J = 7.2 Hz); 8.07 (2H, d, J = 7.6 Hz); 7.63 (1H, t, J = 7.5 Hz); 7.59 (1H, t, J = 7.4 Hz); 7.50 (2H, t, J = 7.4 Hz); 7.39 (5H, m); 6.26 (1H, t); 5.64 (1H, d, J = 7 Hz); 5.59 (1H, d, J = 6.9 Hz); 5.54 (1H, s); 4.93 (1H, d, J = 6, 8 Hz); and (1H, m); 4.68 (1H, dd); 4.28 and 4.16 (2H, 2d, J = 8 Hz); 3.84 (1H, d, J = 7.3 Hz); 2.48 (1H, m); 2.35 and 2.25 (2H, 2dd); 2.02 (3H, s); 1.88 (3H, s) and (1H, m); 1.67 (3H, s); 1.63 (1H, s); 1.30 to 0.90 (34H, m).

Example 27 13-0- [[(4S, 5R) -3-N-Benzoyl-4-phenyloxazolidin-3-on-5-yl] -carbonyl] -7-O-triethylsilylbaccatin III To a stirred solution under inert atmosphere at room temperature, of 40 mg (0.137 mmol) of (4S, 5R) -3-N-Benzoyl-4-phenyloxazolidin-3-on-5-carboxylic acid in 2 mL of anhydrous toluene, 28 mg (0.136 mmol) of dicyclohexylcarbodiimide are added. After 5 minutes of stirring, 30 mg (0.043 mmol) of 7-O-triethylsilylbaccatin III and 8 mg (0.066 mmol) of 4-dimethylaminopyridine are added, and the reaction mixture is brought to 60 ° C for 13 hours. After returning to room temperature, the reaction medium is diluted with 10 mL of dichloromethane, and the organic phase is washed with 5 mL of a saturated sodium chloride solution, dried over MgSO4 and concentrated under reduced pressure. After purification by chromatography on silica gel (15-14 μm) (eluent: cyclohexane-ethyl acetate 2/1) 13 mg of the title derivative is obtained in the amorphous state (Rdt = 31%). The compound obtained has the following characteristics: • 400 MHz XH NMR (CDC13) (d ppm): 8.06 (2H, d, J = 7.3 Hz); 7.72 (2H, d, J = 7 Hz); 7.63 (1H, t, J = 7.4 Hz); 7.58 (1H, t, J = 7.4 Hz); 7.54 to 7.44 (8H, m); 7.40 (1H, t); 6.44 (1H, s); 6.33 (1H, t); 5.73 (1H, d, J = 5.7 Hz); 5.67 (1H, d, J = 5.7 Hz); 4.96 (1H, d, J = 5, 8 Hz); 4.88 (1H, d, J = 8.3 Hz); 4.45 (1H, dd, J = 10.4 and 6, 6 Hz); 4.27 and 4.12 (2H, 2d, J = 8.3 Hz); 3.80 (1H, d, J = 7 Hz); 2.50 (1H, m); 2.26 (2H,); 2.19 (3H, s); 2.07 (3H, s); 1.98 (3H, s); 1.85 (1H, m); 1.76 (1H, s); 1.67 (3H, s); 1.24 (3H, s); 1.23 (3H, s); 0.91 (9H, t, J = 7.9 Hz); 0.56 (6H, m).

Example 28 13-0- [[(4S, 5R) -4-phenyloxazolidin-3-on-5-yl] -carbonyl] -7, 10-O-di- (phenoxyacetyl) -10-deacetylbaccatin III To a stirred solution at room temperature and under an inert atmosphere of 78 mg (0.293 mmol) of (4S, 5R) -2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid in 3 mL of anhydrous toluene, add 65 mg (0.315 mmol) of dicyclohexylcarbodiimide. After 5 minutes of stirring, a solution of 237 mg (0.293 mmol) of 7,10-O-bis- (phenoxyacetyl) -10-deacetylbaccatin III and 36 mg (0.295 mmol) of 4-dimethylaminopyridine in 3 mL of toluene, and the mixture The reaction is carried at 60 ° C for 1 hour. After returning to room temperature and eliminating the insolubles by filtration, the organic phase is concentrated under reduced pressure, and the pure product obtained is purified by chromatography on silica gel (15-14 μm) (eluent: cyclohexane-acetate). ethyl 1/1). This gives 280 mg of the title compound in the amorphous state (Rdt = 90%), and has the following characteristics: • 400 MHz t NMR (CDC13) (d ppm): 8.18 (2H, d, J = 7 Hz); 8.06 (2H, d, J = 7.1 Hz); 7.64 (1H, t, J = 7.4 Hz); 7.58 (1H, t, J = 7.3 Hz); 7.51 (4H, m); 7.39 (5H,); 7.25 (4H,); 6.96 (4H, m); 6.85 (2H, d, J = 8 Hz); 6.33 (1H, s); 6.19 (1H, t, J = 9 Hz); 6.68 (1H, dd, J = 10.5 and 7.1 Hz); 6.65 (1H, d, J = 6.96 Hz); 5.59 (1H, d, J = 7 Hz); 4.93 (2H, d, J = 7.1 Hz); 4.79 (2H, s); 4.63 and 4.40 (2H, 2d, J = 15.9 Hz); 4.30 and 4.13 (2H, 2d, J = 8.4 Hz); 3.94 (1H, d, J = 6, 9 Hz); 2, 68 (1H, m); 2.37 (1H, dd, J = 15.3 and 9.3 Hz); 2.24 (1H, dd, J = 15.3 and 8.7 Hz); 2.02 (3H, s); 1.95 (3H, s); 1.80 (3H, s) and (1H, m); 1.69 (1H, s), 1.12 (3H, ~ s); 1.01 (3H, s).

III. Semisynthesis Example 29: Preparation of paclitaxel a) From 13-0-1 [(4S, 5R) -2,4-diphenyl-4,5-dihydrooxazol-5-yl] -carbonyl] -7-0-triethylsilylbacsa ina III To a stirred solution at room temperature and under an inert atmosphere of 90 g (0.095 mol) of 13-0 - [[(4S, 5R) -2,4-diphenyl-4,5-dihydrooxazol-5-yl] -carbonyl] -7-0-triethyl-silylbaccatine III in a mixture of tetrahydrofuran (1.2 L) and methanol (1.2 L), 0.6 L (0.6 mol) of an aqueous solution of 1 M HCl are added. , and the reaction mixture is stirred at room temperature for 4 hours 30 minutes. After the addition of 3.5 L of a saturated aqueous sodium monoacid carbonate solution, the solution is kept homogeneous by the addition of 6 L of tetrahydrofuran and 6 L of water, and the reaction medium is stirred 1 hour 30 minutes supplementary After the addition of 15 L of ethyl acetate and 15 L of water subjected to osmosis, the residual aqueous phase is extracted with ethyl acetate (15 L). The organic phase is dried over MgSO4, concentrated under reduced pressure, and the crude product thus obtained is purified by chromatography on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 1.1). Thus 75 g of taxol are isolated in crystallized state (Rdt = 95%) in which the characteristics are at all points according to the data of the literature. b) From 13-0- [[(4S, 5R) -2,4-dipheni1-4,5-dihydrooxazol-5-yl] -carbonyl] -7-O- (2, 2, 2-trichloro) -t-butoxycarbonyl) -bascatine III To a stirred solution at room temperature and under an inert atmosphere of 15 mg (0.0148 mmol) of 13-0 - [[(4S, 5R) -2,4-diphenyl-4,5-dihydrooxazol-5-yl] - carbonyl] -7-O- (2, 2, 2-trichloro-t-butoxycarbonyl) baccatine III in a mixture of tetrahydrofuran (0.18 mL) and methanol (0.18 mL), 90 μL (0.09 mmol) are added ) of an aqueous solution of 1 M HCl, and the reaction mixture is stirred at room temperature for 8 hours. After the addition of 0.6 mL of a saturated aqueous sodium monoacid carbonate solution, the solution is kept homogeneous by the addition of 1 mL of tetrahydrofuran and 1 mL of water, and the reaction medium is stirred for 1 hour 30 minutes supplementary After the addition of 2.5 mL of ethyl acetate and 2.5 mL of water subjected to osmosis, the residual aqueous phase is extracted with ethyl acetate (2.5 mL). The combined organic phases are dried over MgSO4, and concentrated under reduced pressure. Thus, 14 mg of 7-0- (2, 2, 2, -trichloro-t-butoxycarbonyl) -taxol in crude state (Rdt = 93%) are obtained, which are used without any further purification in the next step. To a stirred solution at room temperature of 13 mg (0.0128 mmol) of 1 -0- (2, 2, 2-trichloro-t-butoxycarbonyl) -taxol in 2 mL of ethyl acetate, 30 μL (0.525) are added. mmol) of acetic acid and 22.5 mg (0.344 mmol) of zinc powder. After 2 hours 30 minutes of stirring at room temperature and controlled by C.C.F., and after dilution of the reaction medium with 3 mL of ethyl acetate, the organic phase is washed with water subjected to osmosis (1 mL), with a saturated aqueous sodium monoacid carbonate solution (1 mL), again with water, dried over MgSO4 and concentrated under reduced pressure. After chromatography of the crude product on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 6/4), 9.5 mg of taxol are thus isolated in the crystallized state (Rdt = 89%).It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as background, property is claimed as contained in the following:

Claims (26)

1. A process for the preparation of precursors of the side chain of the taxanes, characterized in that a derivative of the β-aryl glycidate of general formula I is transformed Ar-C * H - C * H-COOR \ / I 0 wherein Ar represents an aryl radical, and R represents a hydrocarbon radical, preferably a linear or branched alkyl, or a cycloalkyl optionally substituted with one or more alkyl groups, so that the β- and stereospecifically Nalcoylamine and the α-hydroxyl, or their cyclic precursors in a single step, by means of a Ritter reaction, consisting of: a in the direct synthesis of a linear chain, reacting a derivative of cis-β-aryl-glycidate of general formula I defined above, with a nitrile of formula R - - CN wherein R2 represents an aryl radical, in the presence of a protonic acid and water, to obtain a derivative of the β-aryl isoserine of general formula Ia, R? -CO-NH I Ar-C-H-OH-COOR LU. I OH in which, Ar, R and R2 were previously defined, b in the direct synthesis of a cyclic chain, reacting a cis-β-aryl glycidate derivative of the general formula I, defined above, with a nitrile of the formula R'2-CN in which R '2 represents R 2 defined above, or a lower alkyl radical or lower perhalogenoalkyl, such as trichloromethyl, in the presence of a Lewis acid or a protonic acid, in anhydrous medium, to obtain an oxazoline of the general formula I lb R, 7 N O U / Ar-CJ I - CJ I-COOR in which Ar, R and R'2 were previously defined.

2. The process according to claim 1, characterized in that R represents an optically pure enantiomer, of a chiral hydrocarbon radical, of strong steric hindrance, advantageously, a cycloalkyl substituted by one or more alkyl groups, in particular a cyclohexyl.

3. The process according to claim 2, characterized in that R is one of the enantiomers of the menthyl radical, in particular (+) - menthyl.

4. The process according to one of claims 1 to 3, characterized in that the cis-β-phenyl glycidate derivative of the general formula I, having the configuration (2R, 3S), and the derivatives of the general formulas lia and Ilb obtained , they have the configuration (2R, 3S).

5. The process according to one of claims 1 to 4, characterized in that Ar and R2 represent phenyl.

6. The process according to one of claims 1 to 5, characterized in that the protonic acid in step a is chosen from sulfuric acid, perchloric acid or tetrafluoroboric acid, the Lewis acid in step b is chosen from the boron trifluoride complex acetic acid, boron trifluoride etherate, antimony pentachloride, tin tetrachloride or titanium tetrachloride, and the protonic acid of stage b is tetrafluoroboric acid.

7. The method according to one of claims 1 to 6, characterized in that the derivative of the ß-aryl isoserine, of general formula I, is transformed by a protection of the hydroxy by a suitable protecting group (GP), to obtain a derivative of general formula II 'a R i -CO-N'H I Ar-CH - C'H-COOR I ['a OGP wherein Ar, R and R2 are defined according to claim 1, and GP represents a protective group of the hydroxy function, suitable for the synthesis of the taxanes, in particular it is chosen from the radicals alkoxyether, aralkoxyether, aryloxyether or haloalkoxycarbonyl, such as, for example, methoxymethyl, 1-ethoxyethyl, benzyloxy-methyl, (ß-trimethylsilyl-ethoxy) -methyl groups, tetrahydropyranyl, β-alkoxycarbonyl radicals, ß-halogenated ethers, alkylsilyl, or radicals alkoxyacetyl, aryloxyacetyl, haloacetyl or formyl.

8. The process according to one of claims 1 to 6, characterized in that the β-aryl isoserine derivative of the general formula Ila is converted into the novel cyclic intermediates, the oxazolidinone of the general formula Illa Or II HN 0 l ?. \ I Ar-C * H - C * H-C00R wherein Ar and R were identified according to claim 1 by reacting a derivative of the β-aryl isoserine of general formula Ia, according to one of claims 1 to 5, with a haloalkoxycarbonyl ester, in particular , 2, 2-trichloroethoxycarbonyl (TrOC), then, by cyclization in the presence of a strong organic base, such as diazabicyclo-undecene (DBU), optionally subsequently transformed into the corresponding amide of general formula III 'a 0 II R "9 -CO-N 0 LL1 ^ - \ I Ar-C * H - C'H-COOR wherein Ar and R de define according to claim 1, and R "2 represents R ', as defined according to claim 1, an alkoxy radical, or an alkyl radical, linear or branched, which comprises at least one unsaturation.

9. The process according to one of claims 1 to 6, characterized in that the oxazoline of general formula Ilb is hydrolyzed in an acid medium, to obtain the derivative of the β-aryl isoserine of general formula Illb, NH Ar-C * H - C'H-COOR í b O • CO-R '7 wherein Ar, R and R'2 are defined in accordance with claim 1, possibly subsequently transformed into the corresponding amide of general formula Ill'b R'yCO-NH I Ar-C * H - C * H-COOR m'b i O - CO - R "7 in which Ar, R, R '2 and R "2 are defined in accordance with claim 1.

10. The process according to one of claims 1 to 9, characterized in that the β-aryl glycidate derivative of general formula I Ar-C * H - C * H-COOR \ / O wherein Ar is defined according to claim 1, and R represents an optically pure enantiomer of a chiral hydrocarbon radical, of strong steric hindrance, is prepared by reacting the aldehyde of formula Ar-CHO with a haloacetate of formula X-CH2-COOR Ar, R are defined according to claim 1, and - X represents a halogen, in particular chlorine or bromine.

11. The process according to one of claims 1 to 10, characterized in that, by careful saponification, the derivatives of the formulas lia, Il'a, Ilb, Illa, Ill'a, Illb and Ill'b are obtained, defined in accordance with claims 1,7,8 and 9, for which R represents a hydrogen atom.

12. The precursors of the side chains of the taxanes, characterized in that they are selected from among the derivatives of the following general formulas I, Ha, Hb, H'a, IHb and IH'b: Ar-C * H - C * H-COOR 9-CO-NH a la / I O I Ar-C * H-C * ll-COOR I a-i Ilb R7-CO-NII ll'a N O I / Ar-C * H - C * H-COOR Ar-C * H - C'H-COOR I OGP NH Illb R "7-CO-NH Hl'b I Ar-C'H - C'H-COOR Ar-C * H-C * H-COOR I I O - CO - R '9 O - CO - R * 7 wherein Ar, R2, R'2, R "2 and GP are defined according to one of claims 1 to 3 and 5, and R represents an optically pure enantiomer of a chiral hydrocarbon radical of strong steric hindrance.

13. The compounds according to claim 12, characterized in that R is one of the enantiomers of the menthyl radical, in particular the. (+) -mentyl.

14. The compounds according to claim 12 or 13, characterized in that the cis-β-phenyl glycidate derivative of the general formula I has the configuration (2R, 3S), and the derivatives of the general formulas Ha, IIb, IHb, and IH'b have the configuration (2R, 3S).

15. The precursors of the side chains of taxanes, characterized in that they are selected from among the derivatives of general formulas Illa and III 'a below: Illa IH'a wherein Ar, R and R "2 are defined in accordance with claims 1 and 8, or R represents a hydrogen atom.

16. The compounds according to claim 15, characterized in that they have the (2R, 3S) configuration.

17. A process for the preparation of taxanes, of general formula IV, C-B IV in which B represents a radical of general formula V Ac represents the acetyl radical, Bz represents the benzyl radical, Me represents the methyl radical, R4 represents an acetyl radical or a protective group of the hydroxy function GP1, and R5 represents a protective group of the hydroxy function GP2, and C represents a chain selected from the radicals of the following formulas Ha, H'a, Hb, Illa, III 'a, IHb and IH'b: R, -CO-NH R, -CO- \ H Ar-C * H-C * H-COOR Ar-C * H-C * H-COOR l The OGP RVCO-NH.? X-C * H-C * H-COOR 11 V b O - CO - R ", wherein Ar, R2, R'2, R "'2 and GP are defined in accordance with claims 1, 7 and 8, by the esterification of a suitable derivative of baccatine III of general formula V, which has a function hydroxy at C-13, with one of the derivatives of the formulas Ha, II 'a, Hb, Illa, III' a, IHb and IH'b, for which R represents a hydrogen atom, obtained by the process in accordance with claim 11.

18. The process according to claim 17, characterized in that the protecting groups GP1 and GP2 are independently of one another, the usual groups used in the semisynthesis of the taxanes, such as the trialkylsilyls or the TROC, or the bulky haloalkoxycarbonyl radicals, linear or branched, comprising at least one halogen atom, the acyl radicals in which the carbon in a of the carbonyl function has at least one oxygen atom, a trialkylgermanyl radical or, GP1 and GP2 form together, a divalent radical of formula -SiR7-0-SiR8-in which R7 and Rßr independently of each other, represent an esterically hindered alkyl radical.

19. The process according to one of claims 17 or 18, characterized in that the acyl radicals, wherein the carbon in a of the carbonyl function has at least one oxygen atom, are selected from the group consisting of alkoxy- or aryloxyactyl radicals of the formula R6-0-CH2-CO- in which R6 represents an esterically hindered alkyl radical, a cycloalkyl radical or an aryl radical, - or the arylidenedioxyacetyl radicals of formula O Ar "CH-CO-? ' in which Ar "represents an arylidene radical.

20. The method according to claim 19, characterized in that; the sterically hindered alkyl radical is a linear or branched alkyl radical of C6-C6, substituted with one or more bulky substituents, chosen from halogens, linear or branched alkyl radicals of Ci-Cß, linear or branched C-alkoxy radicals ? -C6 or C3-C6 cycloalkyl or aryl, the cycloalkyl radical is a C3-C6 cycloalkyl radical optionally substituted by one or more bulky substituents, chosen from halogens, linear or branched C 1 -C 6 alkyl radicals, linear or branched C 1 -C 5 alkoxy or aryl alkoxy, preferably a cycloalkyl radical, substituted by one or more linear or branched C 1 alkyl radicals; -C6, for example menthyl, its racemate or its enantiomers and their mixtures in all proportions, the aryl radical, is a phenyl, naphthyl, anthryl or phenanthryl radical, optionally substituted with one or several bulky substituents, chosen from halogens , straight or branched alkyl radicals of C? -C6, linear or branched alkoxy of Ci-Cß or aryl, in particular phenyl, preferably a phenyl radical, optionally substituted with one or two bulky substituents above, in ortho- and ortho ' - of the ether bond, and the arylidene radical, is a phenylene, naphthylene, antrylene or phenanthrylene radical, optionally substituted with one or more bulky substituents, selected from the halogen radicals Examples are linear or branched alkyl radicals of G, -C6, linear or branched alkoxy of C, -C6 or aryl, in particular phenyl.

21. The process according to one of claims 17 or 18, characterized in that Rj represents an acetyl radical, and GP2 represents a trialkylsilyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl radical, 2,2, 2,1-tetrachloroethoxy-carbonyl, 2, 2, 2-trichloro-t-butoxy-carbonyl, trichloromethoxycarbonyl, phenoxy-acetyl? or trialkyl-germanyl.

22. The process according to one of claims 17 or 18, characterized in that R4 represents a group GP1, and GP1 and GP2 represent a 2,2,2-trichloroethoxycarbonyl or phenoxyacetyl radical, or together they form a divalent radical of the formula -SiR7-0 -SiR8-in which R7 and Rs each represent an isopropyl radical.

23. The process according to one of claims 17 to 21, characterized in that C represents a radical of formula Ha, with Ar and R 2 representing a phenyl, and R 4 represents an acetyl radical.

24. The process according to one of claims 17 to 23, characterized in that, in addition, the deprotection of the hydroxy derivatives of the general formula IV is carried out, and if necessary, simultaneously or separately, the opening of the oxazole radical cycle of the formula Hb or Illa, to obtain a taxane derivative of general formula VI wherein Ac, Bz, Me and R '2 are defined according to one of the preceding claims, R4 represents a hydrogen atom or an acetyl radical, and R5 represents a hydrogen atom.

25. Taxane derivatives of general formula IV CB IV in which C and B are defined according to one of claims 17 to 23, with the exception of derivatives in which C represents a radical of formula Ha, II 'a, Hb , IHb or III 'b, and GP1 and / or GP2 are independently of one another, the usual groups used in the semisynthesis of taxanes, such as trialkylsilyls or TrOC.

26. The baccatine III derivatives, useful for the semisynthesis of taxanes, characterized in that they are chosen from the derivatives of general formula V, HO wherein Ac represents the acetyl radical, Bz represents the benzoyl radical, Me represents the methyl radical, R4 represents an acetyl radical or a protective group of the hydroxy function GP1, R5 represents a protective group of the hydroxy function GP2, and GP1 and GP2 are independently of each other, the bulky haloalkoxycarbonyl radicals, with the exception of TrOC, the acetyl radicals in which the carbon in a of the carbonyl function has at least one oxygen atom, the tria quilgermanyl or GP1 and GP2 radicals together they form a divalent radical of formula -SiR7-0-SiR8- in which R7 and R8 independently of one another represent an alkyl radical hinically or sterically.