CA2576943A1 - Intermediates for the hemisynthesis of taxanes and processes for their preparation - Google Patents

Abstract

The present invention relates to new intermediates for the hemisynthesis of taxanes and their preparation processes. It's about especially oxazolidine or oxazolidine derivatives, as well as new derivatives of the baccatin III. The general process for synthesizing taxanes according to the invention provides a product like PACLITAXELTM in just five steps from commercially available products, versus generally new steps for the prior art processes.

Description

!

INTERMEDIATES FOR HEMISYNTHESIS OF TAXANES AND THEIR
PREPARATION PROCESSES

This application is a division of the Canadian patent application no. 2,236,293 from international application no. PCT / FR96 / 01676 filed October 25, 1996.

The present invention relates to new intermediates for the hemisynthesis of tazanes and their preparation processes.
Taxaties, natural substances including the diterpene skeleton is generally esterified by an R-amino acid side chain derived N-alkyl or N-aroyl-phenyl-isoserine, are known as agents anticancer. There are several dozen taxanes isolated from Taxaceae of the genus Taxus, such as, for example, PACLITAXEL (R1 = Ac, R2 =
Ph, R3 = R4 = H), cephalomanin, their deacetylated derivatives in position 10, or the baccatines (derivatives without side chain) represented by the forniules l and 2 below.

R2CONH O ee O
to '12 11 \ 3, Z, 1,, Me 9 Me OR 16 20 O --- 13 15 19 3 pR4, a Me 77 17 Z 6 HO
BzO H
AcOO

the ORI
Me , e O
HO --- 13 - ~~ Me 9 Me OR3 14 ~ Me 8 7

2 3 HO
BzO H, --- H
Ac0 20 In order not to quickly exhaust its original source, Taxus brevifolia, French researchers sought to isolate the ACLI1'AXE.L
from renewable parts (the leaves) of T. baccaea, the European yew.
They have thus highlighted the likely biogenetic precursor of ta ~ donkeys, the 10-deacetylbaccatin III, springboard of choice for hemisynthesis, due its relative abundance in leaf extracts.
The hemisynthesis of taxanes, such as ACLITAXEL or DOCLTAXEL
(R1 = Ac, R2 = t.butylo ~ y, R3 = R4 = H), therefore consists in esterifying the hydroxy in 13 of a protected derivative of baccatin or 10-deacetylbaccatin III, with an acid derivative (i-amino.
Different hemisynthesis processes for PACLITAXEL or DOCETAXEL are described in the state of the art (EP-0 253 738, EP-0 336 840, EP-0 336 841, EP-0 495 718, WO 92/09589, WO 9-1 / 07877, WO 94/07878, WO
9-1 / 07879, WO 9-1 / 10169, WO 94/12482, EP-0 400 971, 13 -) - 0 428 376, WO
94/14787).
Two recent works [I. Georg, TT Chen, L Ojima, and DM Vyas, "Taxane Anticancer Agents, Basic Science and Current Status ", ACS Symposium Series 583, Washington (1995)] and above all [Matthew Suffness, "TAXOL Science and Applications "CRC press (1995) and 1500 references cited] include exhaustive compilations of taxane hemisyntheses.
The p-amino acid side chains derived from cic N-alkyl- or N-aroylphenylisoserine from PACLITAXEL or DOCETAXEL are configuration (2R, 3S), and one of the main difficulties in hemisynthesis taxanes resides in obtaining an enantiomerically pure product. The first problem is to obtain a pure enantiomer of the derivatives of the phenylisoserine used in the hemisynthesis of taxanes. The second problem is to maintain this enantiomeric purity during the esterification of the derivative of baccatiiie and subsequent treatments of products obtained (deprotection of hydroxyls, etc.).
Numerous asymmetrical synthesis works involving derived from P-amino acids focused on the chemistry of isoserine and his derivatives, p-amino acids of which a dehydrated cyclic form is a p-lactam (EP-0 525 589). Most of the different syntheses of phenyl-isoserine, useful as precursors of side chains of taNanes, converge through a common intermediate, cis-R-phenyl-glycidic acid (2R, 3R), which is then converted to (i-phenyl-isoserine by reaction with ammonia (EP-0 495 718) or a nucleophile (Gou & coll., J. Org. Chem., 1983, 58, 1287-89). These different processes require a number of steps !

3 important for obtaining p-phen ~ -l-isoserine configuration (21Z, 3S), with necessarily a step of duplication of racerique by techniques usual selective crystallization, either for the acid cis- (i-phen \ = l-gl \ = cidic, either for R-phen \ = 1-isoscrin, or later, after transformation.
By elsewhere, to preserve the enantiomeric purity of the precursors of side chains of taxanes during the esterification of the derivative of the baccatine, various movens have been proposed, in particular using cyclic intermediaries of blocked configuration, which discard the risks of isomerization during esterification reactions in conditions hard reaction. They are in particular derivatives of li-lactams (EP-0 400 971), o. \ Azolidines (WO 92/09589, WO 9-1 / 07 877, \ VO 9-1 / 07878, \ VO
94/07879, WO 94/10169, WO-94/12482), of oxazinones (EP-0 -128 376), or else o., ~ azolines (WO 9-4 / 1-1787). These c-cyclic precursors are prepared for from the corresponding derivative of li-phen \ 'l-isoserine. As for this last, the proposed methods involve a large number of steps, and a necessary racemic resolution to obtain the chain precursor lateral of taxanes sought. It was therefore important to develop a new and improved synthesis pathway for precursor intermediates side chain of taNanes, in particular enantiomers of cis-acid p-phen% -l-gl ~~ cidic, ~ -phenvl-isoserine and their cyclic derivatives.
Finally, for the hemisynthesis of taxanes, and in particular of PACLITA. ~ EL, the only derivative of suitable baccatin used to date is that for which the 7-hydroxy radical is protected by a triall: yl-silyl (EP-0 336 840, WO 94/14787), the deprotection of which is carried out exclusively in acidic environment. It was therefore also important to use new protective groups of the hydro ~ Y function, allowing in particular selective protection of the radical 7-h ~~ drox} -, authorizing ei1 in addition to a choice wider operating conditions for the deprotection step.
The present invention as claimed relates to a method improved preparation of taxane side chain precursors.
This process consists in transforming the cis-p-aryl-glycidate derivative of general formula I:

Ar-C * 1-1 - C * H-COOR
\ / _1

-4 in which Ar represents aryl, in particular phenyl and R represents a hydrocarbon radical, preferably a linear alkyl or branched or a cycloalkyl optionally substituted by one or more alkyl groups, so as to set up regio- and stereo-specific the (3-N-alcoyl-amide and α-hydroxyl or their cyclic precursors in a single step by a Ritter reaction. Depending on the reaction medium, a distinction is made between two types of Ritter reactions: one with oxetane opening leading to a linear form of the chain directly and completely 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 cases, Ritter's reaction is stereospecific, with configuration retention in C-2, and configuration inversion in C-3.
Advantageously, the method according to the invention is carried out on one enantiomers of the cis-R-aryl-gl} = cidate derivative of general formula l, so as to obtain the corresponding enantiomer of the linear chain or the oxazoline obtained, without subsequently requiring a resolution of racemic.
According to the method of preparation of the cis-p-aryl-glycidate derivative of formula general I, described later, R represents an optically enantiomer pure of a chiral hydrocarbon radical of large steric hindrance, advantageously a cycloalkyl substituted by one or more groups alkyl, in particular cyclohexyl. R will then preferably be one of enantiomers of the menthyl radical, in particular (+) - menihyl.
1. Direct synthesis of the linear chain Direct synthesis of the linear chain by the Ritter reaction, consists in reacting a cis- ~ -aryl-glycidate derivative of general formula 1 defined above, with a nitrile of formula R -) - CN
in which R2 represents an aryl radical, preferably a phenyl radical, in the presence of a protonic acid such as sulfuric, perchloric acids, tetrafluoroborics, etc. and water.
We then obtain a derivative of (3-aryl-isoserine of formula general IIa, R -) -CO-NH

Ar-C * H - C * H-COOI: II a CEi in which Ar, R and R2 are defined above.
The reaction is carried out with an inversion of the configuration of the

5 C-3 of the cis- ~ -phenY1-glycidate derivative. So, starting from a cis- derivative P-phenyl-glycidate (2R, 3R), the corresponding derivative of p-arvl- is obtained configuration isoserine (2R, 3S).
The Ritter reaction is carried out in an appropriate solvent at a temperature between - 75 and + 25'C.
The appropriate solvent may be the nitrile itself when it is liquid at reaction temperature, or the acid itself (ac.
sulfuric, perchloric or tetrafluoroboric), or a solvent such as example methylene chloride or ethyl ether. Acids conventionally used protonics can contain the water necessary to hydrolysis.
When using benzonitrile (R-) = phenyl) on the cis-P-aryl-glycidate of general formula 1 of configuration (2R, 3R) for which Ar represents a phenyl, the derivative is then obtained directly corresponding to g-aryl-isoserine of general formula Iia for which Ar and R2 represent a phenyl of configuration (2R, 3S), which is none other than the precursor of the PACLITAXEL side chain 2. Direct synthesis of the clinical chain For this second possibility, a reaction is also carried out from Ritter, with a nitrile of formula R'2-CN
in which R'2 represents RZ defined above, or a lower alkyl radical or lower perhaloalkyl, such as trichloromethyl, in the presence of a Lewis acid, in particular the trifluoride complex boron acetic acid, boron trifluoride etherate, pentachloride antimony, tin tetrachloride, titanium tetrachloride, etc., or of a protonic acid such as for example tetrafluoroboric acid, the reaction being carried out in an anhydrous medium.

G
As for the synthesis of the linear chain, the solvent can be the nitrile itself when it is liquid at the reaction temperature, or well an appropriate solvent such as for example methylene chloride or ethyl ether. The reaction temperature is also included between - 75 and + 25'C.
In the absence of water, an intra-Ritter reaction is carried out molecular, and we obtain the oxazoline of general formula IIb R'-) IIb NO

Ar-C * FI - C * H-COOR

in which Ar, R and R'2 are defined above.
As in the Ritter reaction in the presence of water, the reaction takes place with an inversion of the C-3 configuration of the cis- derivative (3-phenyl-glycidate. Thus, starting from a cis-13-phenyl-glycidate derivative (2R, 3R), we obtain the corresponding o ~ azoline of configuration (2R, 3S).
For both Ritter reactions, to avoid the formation of a free carbocation, cause of many potential side reactions, preferably add the reagents in the following order: i) first forms the complex between the nitrile and the acid, then ii) the catalyst acid is added to the mixture consisting of oxirane and nitrile.
The products obtained by this first step, derived from p-aryl-isoserine of general formula IIa or o. azoline of general formula IIb, can be further processed in an optional second step described below, or converted to acid by gentle saponification, before coupling to a protected derivative of baccatin for the hemisynthesis of taxanes, in particular PACLITAXEL and its derivatives deacetylated in 10 or DOCETAXEL. In the case of p-aryl derivatives isoserine of general formula Ila, one can precede the saponification of a usual step of protecting the hydroxy with an appropriate protective group.
We then obtain a derivative of general formula Il'a Ar-C * H - C * H-COOR II 'a OGP

in which Ar, R and R7 are defined above, and GP represents a hydroxy protecting group, suitable for the synthesis of taxanes, in particular chosen from radicals alhoxyether, aralkoxyether, aryloxyether or haloall: oxycarbonylc, such as for example the methoxymethyl, 1-etho groups: yethylc, benzyloxy-methyl, (P-trimethylsilyl-ethoxy) -methyl, tetrahydro radicals pyranyl, p-alko \ ycarbonyle (TrOC), p-halogenated, alkylsilyl ethers, or the alkoxyacetyl, aryloxyacetyl, haloacetyl or formyl radicals.
3. Possible transformation of derivatives of formula Ila or Ilb The derivatives of general formula Iia or fib obtained previously, can eventually be transformed into new intermediaries side chain precursors in the hemisynthesis of taxanes. These transformations are done with retention of the configuration of C-2 and C-3. The new intermediaries obtained will therefore have the same stereochemistry as the derivatives of formula Ila or Ilb from which they are derived. Products obtained in this second step are then converted to acid by saponification before coupling to a protected derivative of the baccatine for the hemisynthesis of taxane, in particular PACLI7'AXEL or DOC ETAXEL
3.1 Cyclization of derivatives of general formula Ita The derivatives of general formula Ila can then be transformed into oxazoline of formula Ilb, according to the usual methods of the state of the technique (WO 9-4 / 14757).
The 5-aryl-isoserine derivatives of general formula IIa can also be transformed into new cyclic intermediaries, oxazolidinone of general formula IIa O

R "~ -CO-N p I 11 'a Ar-C * H - C * H-COOR

in which Ar and R are defined previously, and R "Z represents R'2 defined previously, an allcoxy radical, preferably t.butoxy, or a radical linear or branched alkyl comprising at least one unsaturation, for example a 1-methyl-1-propylene radical, and dialkyl acetals correspondents.

The oxazolidinones of general formula III'a are obtained all first by reacting a 13-aryl-isoserine derivative of fornZule general IIa with a haloalkoxycarbonyl ester, in particular 2,2,2-trichloroethoxycarbonyl (TrOC), then by cyclization in the presence of a strong organic base, such as diazabicyclo-undecene (DBU). We obtain then an oxazolidinone derivative of general formula Illa II

HN p IIIa Ar-C * H - C * H-COOR

in which Ar and R are defined above.
The derivatives of general formula Illa can also be obtained by direct synthesis, by reacting the derivatives of R-aryl-glycidate of formula II'a with urea.
The acylated derivatives of general formula IIIa are obtained in introducing the radical R "-) - CO- according to the usual acylation techniques, in presence of a suitable acylating agent, for example an acyl halide of formula R "~ -CO-X, in which R", is defined above, and X represents a halogen, or a corresponding acid anhydride.
The dialkylacetals are obtained according to the usual techniques of formatiotl of acetals.
3.2 Opening of the oxaiolinc of general formula IIb By hydrolysis of oxazoline of general formula lIb in medium acid, the p-aryl-isoserine derivative of general formula Illb is obtained, NH?

Ar-C * H - C * H-COOR III b O- CO- R ', in which Ar, R and R'Z are defined above.

Advantageously, when R'2 represents a perhalogeno-75 lower alkyl, such as trichloromethyl, the radical R'2 - CO -constitutes a protective group for the hydroxy function.
We can then transform this side chain precursor of taxanes, as an amide of general formula III'b R '' ,, - CO-NH

Ar-C * H - C * H-COOR III 'b O - CO - R'- ~
in which Ar, R, R'z and R "2 are defined above.
We can therefore indiscriminately obtain the precursor of the chain lateral of PACLITAXEL (R "2 = phenvle) or DOCETAXEL (R" -) = t.butox ~ ').
4. Preparation of the cis- ~ -aryl-glycidic acid derivative formula I
The derivative of cis-g-aryl-gl, ~ = cidic acid of formula I can be prepared according to the usual processes of the state of the art, or by simple esterification of cis-5-ar \, l-glycidic acid with alcohol R-OH
corresponding. To improve the overall rendering synthesis of taxane chain precursors, the process is prepared according to the invention a cis-R-aryl-gl ~ -cidate derivative of general formula I

Ar-C * H - C * H-COOR
\ / I
O
in which Ar is defined above and R represents an optically pure enantiomer of a hydro- radical carbonic chiral with a large steric hindrance, by reacting the aldehyde of formula Ar-CHO
with the haloacetate of formula Ar, R being defined previously and X representing a halogen, in particular a chlorine oti ui1 bromine.
Advantageously, the optically pure enantiomer of a chiral hydrocarbon radical of large steric bulk, is a cycloalkyl substituted by one or more alkyl groups, in particular a cyclohexyl.
It is a Darzens reaction by which we obtain a mixture of the two diastereoisomers, ester of cis- (3-aryl-glycidic acids, (ZR, 3R) and (2S, 3S), and an optically pure enantiomer of chiral alcohol R-01-1, since the Darzens reaction carried out with a strongly haloacetate sterically hindered, essentially leads to the cis form of (i-aryl-gl} = cidate. Advantageously, the hydrocarbon radical will be chosen chiral of strong steric hindrance so that it allows the 5 physical separation of the two diastereoisomers from the reaction medium, by e ~ ample by selective crystallization, without requiring stereo- separation specific of the energy sought at the end of the reaction by the methods usual crystallization or chromatography on a chiral column.
Advantageously, R-OH represents menthol, one of the 10 rare chiral alcohols with a large steric, economic and commercially available in its two enantiomeric forms.
In the process for the synthesis of a side chain precursor of taxanes, we seek to prepare a cis-p-phenyl-glycidate of configuration (2R, 3R). In this case, we will select the hydro-chiral carbon with a large steric hindrance R, so that the diastereoisomer of the cis-p-phenyl-glycidate of configuration (2R, 3K) crystallizes first from the reaction medium. When R-OI-I is menthol, we advantageously uses (+) - menthol.
The asymmetric Darzens reaction is carried out in the presence of a base, particularly an alkaline alcoholate such as tertiary butylate potassium, or an amide, such as bis-trimethylsilylamide dc lithium 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 diastereoisomeric mixture made up almost exclusively of ? â cis-glycidates which can reach a yield greater than 95%, close to 97%. Treatment of the isolated product in an appropriate solvent, in particular a methanol-water mixture allows easy separation physics of the required diastereoisomers.
By fractional crystallization (2 stages), one obtains a rapid enrichment of the desired diastereoisomer with purity diastereoisomeric greater than 99%.
This last point is particularly important because it conditions the isomeric purity of the final taxane, the undesirable diastereoisoins presenting their own biological activity, different from that of taxane research.
It is remarkable to note that the selective use of the two enantiomers of the methyl ester provides access using the same :

process with the 2 precursor diastereoisomers of the two enantiomers of the acid glycidic.
In addition to a fairly high yield cn pure diastereoisomer isolated (up to 45%), the diastereoisomeric purity of the majority product of the reaction, the ease of carrying out the reaction, the simplicity and the rapid purification, low cost of reactants and catalysts, render of easy and economical access the industrial synthesis of this key intermediary in the asymmetric synthesis of p-amino acids.
When a derivative of general formula I obtained by an asymmetric Darzens reaction, we then obtains the derivatives of general formulas IIa, II'a, Ilb, IIIa, IIib and III'b defined above, for which R represents an optically enantiomer pure of a chiral hydrocarbon radical of large steric hindrance, such that a cycloalkyl substituted by one or more all: yl gi-oupes, in in particular a cyclohexyl, preferably menthyl, advantageously the (+) - menthyl.
The present invention also relates to these derivatives, which are useful as intermediates in the synthesis of side chains of taxanes.
It should be noted that the present process constitutes an access very fast to the substituted chiral oxazolines already described in the literature (WO 94/14787), in 3 steps from commercially available products instead of 6 to 8.
5. Sparse saponification We carry out a gentle saponification of the derivatives of formulas general conditions Ila, li'a, IIb, Illa, flIb and III'b under mild conditions, so as to release the acid function, while preserving the structure of said derivatives, for example in the presence of an alkali metal carbonate in a methanol / water mixture.
After gentle saponification, the derivatives of formulas are obtained general IIa, II'a, IIb, IIIa, IIIb and III'b defined previously, for which R represents a hydrogen atom, which can be used directly in the hemisynthesis of taxanes by coupling with an appropriate derivative of the baccatin III

6. Hemisynthesis of taxanes 6.1 Esterification The present invention therefore also relates to a method hemisynthesis of taxanes of general formula IV, CB IV
in which C represents a side chain chosen from the radicals of formulas following S

Ar-C * H - C * H-COO- Ar-C * H - C * H-COO-Iia CH IIa OGP
R'2 O
IIb C IIIa ii H ~
Ar-C * H - C * iI-C00- Ar-C * H - C! H-COO-O
11 NH ~

R "~ -CO-NC p III 'a Ar-C * H - C * H-COO-~ ~ IIIb Ar-C * H - C * H-COO- 0- CO - R '~
R '' - ~ -CO-NH
I
Ar-C * H - C * H-COO-III'b 1 O- CO- R ', in which Ar, R2, R'2, R "2, R3 and GP are defined above, and B represents a radical derived from baccatin III of general formula V
Me OR4 _ iZ 11 Me Me OR5 14 1 Me 8 7 IS

HO ~
BzO H, 4 5 --- H
AcO, 20 0 in which Ac represents the acetyl radical, Bz represents the benzoyl radical, hIe represents the methyl radical, R4 represents an acetyl radical or a group protecting the function hydroxy GP1, and R; represents a protecting group for the GP2 hydroxy function, by esterification of a suitable baccatin III derivative of formula general V, carrying a hydroxy function at C-13, with one of the derivatives of general formulas IIa, Il'a, Iib, Ifla, III'a, IIIb and III'b defined previously, for which R represents a hydrogen atom, in usual conditions for preparing taxanes such as detailed the state of the technique (in particular: EP-0 233 738, EP-0 336 840, EP-0 336 8-11, EP-0493 718, WO 92/09589, WO 9-4 / 07877, WO 94/07878, WO 9-4 / 0 7 8 7 9, WO
94/10169, WO 9-1 / 12482, EP-0 400 971, EP-0 428 376, WO 94/1478 7).
The protective groups GP1 and GP2 are independently one on the other, the usual groups used in the hemisynthesis of taxanes, such as trialkylsilyls (EP-0 336 840), or TrOC (EP-0 336 8-41).
GP1 and GP2 also represent, independently one of the other, hindered, linear or branched haloalkoxycarbonyl radicals comprising at least one halogen atom. Advantageously, it is radicals in which the alkyl residue contains between 1 and 4 carbon atoms, and 3 or -1 halogen atoms, preferably chosen from 2,2,2-tri- radicals bromoethoxycarbonyl, 2,2,2,1-tetrachloroétho ~ ycarbonyle, 2,2,2-trichloro-t-butoxvcarbonyle and trichlorométhoaycarbonyle, radicals all more cluttered than the haloalkozycarbonyl (TrOC) used so far for protect taxanes in position 7.
GP1 and GP2 also independently represent one of the other, acyl radicals whose carbon has carbonyl function carries at least one oxygen atom.
These acyl radicals are in particular described in the application for Patent EP-0 445 021. They are advantageously alkoxy- or aryloxyacetyl of formula R6-0-CH? -CO-3.5 in which R6 represents a sterically 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.
By sterically hindered alkyl is preferably meant a linear or branched C1-C6 alkyl radical substituted by one or more bulky substituents chosen from halogens, alkyl radicals linear or branched C1-C6, alkoxy linear or branched C1-C (6 or C3-C6 cycloalkyl or aryl. It will be for example a radical tertiobutyl or triphenylmethyl.
Cycloalkyl preferably means a cycloalkyl radical in C3-Cr6 optionally substituted by one or more bulky substituents chosen from halogens, linear or branched C 1-6 alkyl radicals C6, linear or branched C 1-C6 alkoxy or aryl. Advantageously, it is a cyclohexyl radical, substituted by one or more alkyl radicals linear or branched in C1-C6, such as menthyl, its racemic or its enantiomers and their mixtures in all proportions.
By aryl is preferably meant a phenyl, naphthyl radical, anthryl or phenanthryl, optionally substituted by 'one or more bulky substituents chosen from halogens, alkyl radicals linear or branched in CZ-Cr, alkoxy linear or branched in Ct-C (, or aryle, especially phenyl. Preferably, it is a radical phenyl, optionally substituted with one or two bulky substituents above, in ortho- and ortho'- of the ether bond.
Finally, by arylidene is preferably meant a radical phenylene, naphthylene, anthrylene or phenanthrylene, optionally substituted by one or more bulky substituents chosen from halogens, linear or branched C 1 -C 6 alkyl radicals, alkoNy linear or branched in C1-C6 or aryl, in particular phenyl.
GP1 and GP2 also independently represent one of the other, a trialkylgermanyl radical or together form a radical divalent formula -SiR7-0-SiR8-in which R7 and R8, independently of one another, represent an alkyl radical sterically hindered as defined above, in particular R7 and R8 each represents an isopropyl radical.
S 6.2 Possible opening When C represents a radical of formula Ilb or IIIa, an opening of the oxazolinic cycle to obtain a taxane derivative of formula VI
R 'CONH Me OR' 2 O 7th O
2 ",. T2" Me 0 - - - 13 15. ~ ", 6 9 Me ORS

OH 14 1 Me not z 3 6 HO

BzO H 4 5-= --- H
in which AcO20 O
Ac, Bz, Me, Ar, R2, R; 4 and R5 are defined above.

The radicals IIb, Illa and III'a are generally opened by hydrolysis in acidic or basic medium. For the radical of formula IIb, this opening can be carried out according to the methods described in the state of the technique (in particular WO 94/14787) by hydrolysis in an acid medium, followed a treatment in basic medium to obtain the derivative of general formula VI.
6.3 Deprotection Finally, deprotection of the hydroxyls of the derivatives of general formula V or VI, replacing the protecting groups of the hydroxy function GP (when C represents the radical II'a), GP1 (when R4 is different from acetyl), and GP2 by a hydrogen atom according to usual techniques.
For derivatives of general formula V for which C represents a radical of formula Ilb or IIIa, and GP1 and / or GP2 are independently one on the other, the usual groups used in the hemisynthesis of taxanes, such as trialkylsilyls, deprotection takes place simultaneously with the opening described above.

When GP1 and / or GP2 are haloalkoxycarbonyl radicals congested, deprotection is carried out according to the usual techniques described for TrOC, by the action of zinc or zinc doped with heavy metals such that copper, in an organic solvent, in particular, in acid acetic acid, tetrahydrofuran or ethyl alcohol, with or without water.
When GP1 and / or GP2 are acyl radicals including carbon has a carbonyl function carries at least one oxygen atom, the deprotection takes place in a basic medium by saponification in the methanol at low temperature, advantageously with arnmoniaqûe in the methanol at a temperature below 10 C, preferably close to 0 C.
For the case where C represents a radical of formula lib, the opening of oxazoline takes place simultaneously with deprotectioii in basic niilieu to lead in one step to the corresponding taxane derivative of formula general VI, for which R.4 represents an acetyl radical or an atom of hydrogen, and R5 represents a hydrogen atom, unlike the opening in an acid medium described in the state of the art which requires a second step in basic environment.
The known protective groups are removed using known methods and the oxazolinic chain, quaiid it was present, deployed by hydrolysis, giving taxanes identical in every respect to reference taxanes. As an example, and to show the validity of the invention without however limiting its scope, one can obtain PACLITAXEL, 10-deacet \ -ltaxol, cephalomanin and DOCETAXEI. at from the corresponding protected derivatives.
Unblocking acyls whose function is carbon carbonyl carries at least one oxygen atom, was first attempted in conditions conventionally considered to be the mildest, that is to say zinc acetate in methanolic medium at reflux. In this case, the reaction being complete in a few hours (compared to a few days for acetates), we have constantly isolated next to the sought product, its epimer in C-7 resulting from the classic retroaldolization balance. Assuming that meme under neutral, even slightly acidic conditions, the main responsible were methanol and most importantly the temperature we are income under the standard conditions for unlocking acyls described by first authors, by saponification in basic medium in ethanol at low temperature. Under these conditions, no significant epimerization was noted. As an example, we obtained ACLITAXEL, 10-deacetyltaxol of cephalomanin and DOCGTA \ EIL cn any point identical to the reference taxanes, from alkoxy- or corresponding aryloxyacetylates.
Finally, it should be noted that all of the methods described previously, which however aim to improve the overall performance of hemisynthesis, consist in synthesizing beforehand the phenyl chain isoserine, in order to transform it into one of the cyclic structures mentioned above (p-lactams, oxazolidines or oxazolines). So, paradoxically, the better apparent performance of the coupling of these cyclic structures only compensate for the drop in overall yield caused by the addition of cycle creation steps to the synthetic sequence of the linear chain (a total of 9 steps). For the general process of synthesis of taxanes according to the invention, a product such as PACIITAXEL in just 5 steps:
= (2R, 3R) -3-phenylglycidate from (1S, 2R, 3S) - (+) - menthyl = (qS, 5R) -2,4-Diphenyl-4,5-dihydro. \ azole-5-carbox \ -late of (1 S, 2 I :, 5S
) - (+) -menthvle = saponification = hemisynthesis (esterification) = opening and deprotection.
The present invention finally relates to the intermediaries of synthesis of general formulas IV, V and VI described above, useful in the general synthesis of the taxanes which are the subject of the present invention.
In general, by hydroxycarbon radical is meant preferably according to the invention a saturated or unsaturated hydrocarbon radical, may include one or more unsaturations, such as alkyl linear or branched, optionally unsaturated, optionally a cycloalkyl iiisaturated, an aralkyl or an aryl, each possibly being substituted by one or more substituents, in particular alkyl.
By linear or branched alkyl is preferably understood according to the invention a C1-C6 alkyl, in particular chosen from radicals methyl, ethyl, propyl, isopropyl, butyl and its various isomers branched as for example terbutyl, pentyle and heayle and their different branched isomers. This definition also applies to remains alkyl of the alkoxy or aralkoxy radicals.

By cycloalkyl is preferably meant according to the invention a C3-C6 cycloalkyl, in particular chosen from cyclopropyl radicals, cyclobutyle, cyclopentyle ou cycloheNyle.
By aryl is preferably meant according to the invention a radical aromatic or heteroaromatic, in particular chosen from radicals phenyl, naphthyl, anthryl, phenanthryl, pyridyl, pyrimidylc, etc.
Finally, by halogen is preferably meant chlorine, bromine or iodine. For haloalkoxycarbonyl radicals, it is preferably radicals in which the alkyl residue contains between 1 and -4 carbon atoms, and 3 or 4 halogen atoms.
The geilateral process for synthesizing taxanes according to the invention is recalled in diagram 1 below, for R representing the (+) - menthvle, and l :?
or R ', representing phenyl.
The last step of hemisynthesis of taxanes by the process according to the invention is summarized in diagrams 2 and 3 below. Figure 2 summarizes a synthesis of PACLITAXEL from derivatives of formula IV defined more above, for which C represents a radical of formulas IIb or III'a. The diagram 3 summarizes the synthesis of 10-deacet ~ = ltaxol from a derivative of formula IV for which C rc represents a radical of formula lib.
Of course, the same synthetic diagrams can be used:
for other definitions of substituents.

DIAGRAM. 1 Me Me Me Me HOH
XCH2COO, .ArCHO O
Ar O
Even O
N ~ 0 Me Me BzNH O Me Me ~ Me Me Ar. HN O
-,, = HO =. ~ A r. ,, H 0 OH H
0 =
Me Me Me BzNH O ~
NO zR RN O
Ar, - H Ar 3 $ OH Ar.,. H
~: ~ 4S 5R ' II
L EXAMPLES OF RN 0 Ar = Phenyl AriH _ R = Benzoyl, Tigloyl, t-Butoxycarbonyl H C02- GP ,, GP2- Trialkylgermanyl, Haloalkoxycarbonyl, Alcoxyacetyl GP = Protective grouping BzNH
Ar ss zR CO2- OGPI
Me O

11 Me Me OGP2 /
~ Me \ HO, , - - H
Bz0 H.
N 0 Ac0 O
Ar., ~ H

'' Me OAc BzN OO
Ph me ~ Me OGPz O--H me O
HO ' Bz0 H. H
AcO 0 OAc BzNH O Me O
Me Me OAc Ph O-- Me OH
N ~ O 0 6H Me Ph H Me Me OGP2 '. ~ HO /.
O- - ' H 'Me BzO H --- H
AcO 0 HO
BzO, H
- H
PACLITAXEL
AcO 0 DIAGRAM. 3 ~

Me OGPI
N ~ 0 0 Ph O _ _ Me Me OGP2 H me HO ' Bz0 H - = H
AcO 0 OH
BzNH O Me ~ O
, ~ Me I Ph O - _ Me OH
1 b OH Me /
HO
BzO H --- H
AcO O

GPI, GP2 = TRIETHYLGERMANIUM, 2,2,2-TRICHLORO-t-BUTOXYCARBONYL

EXPERIMENTAL PART

1. Taxane side chain precursors Example 1:
(1S, 2R, 5S) - (+) - menthyl chloracetate Even CICHZCOO.
Me To a stirred solution at room temperature of 100 g (0.640 mol) of (1 S, 2R, 5S) - (+) - nienthol in 1 L of dichloromethane dry, 57 mL (0.704 nlol) of anhydrous pyridine are added. After some agitation times then 56 mI are added. (0.704 mol) of chloroacetyl chloride, and the reaction is allowed to continue for 30 niin. After checking by TLC, 50 g of ice are added crushed and the reaction medium is left for 1 hour with vigorous stirring.
After dilution with 100 μl of dichloromethane, the organic phase is washed several times with a saturated aqueous solution of chloride sodium (200 mL), dried over MgSO; then concentrated under pressure scaled down. After purification of the crude product thus obtained by chromatography on silica gel (15-40 m) (eluent: cyclohexane-ethyl acetate, 20/1) 146 g of chloroacetate are obtained.
(1 S, 2R, 5S) - (+) - menthyl in the form of a syrup.
The compound obtained has the following characteristics:
= 1 H NMR 400 MHz (CDCI3) (S ppm): 4.77 (1 H, dt); 4.06 and 4.02 (2H, 2d, J = 13.6 Hz); 2.02 (1H, ni, J = 11, S Hz); 1, S7 (IH, ni, J = 7 and 2.6 Hz); 1.69 (2H, m); 1.50 (1H, ni); 1.43 (1H, ni, J = 11.7 and 3 Hz); 1.07 (1H, m); 1.02 (1H, q, J = 1 1.8Hz); 0.92 and 0.90 (6H, 2d, J = 6.4 Hz); 0, S9 (1H, m); 0.77 (3H, d, J = 7 Hz).

Example 2:
(2R, 3R) -3-Phenylglycidate from (1 S, 2R, 5 S) - (+) - menthyl Even 3 ~ H 0 H
O.
3R 2R ' ~ O -Me T?

To a stirred solution at room temperature of 152 g (0.653 niol) of (1 S, 2R, 5S) - (+) - menthyl chloracetate in 600 niL of ether anhydrous ethvic, 69 mL (0.686 mole) of benzaldehyde is added.
After a few minutes of stirring, the solution is cooled to -78 C
under an inert atmosphere, a suspension of 85 is then added over 2 hours g (0.718 niol) of potassium tert-butoxide in 400 μl of ether anhydrous ethyl, and the reaction medium is allowed to return to ambient temperature. After control by CCM, the organic part is diluted with 200 mL of dichloromethane, washed several times with saturated sodium chloride solution, dried over MgSO.4 and concentrated under reduced pressure. 200 g of a product are thus obtained raw in syrup state, containing four diasterioisomers (two of which cis and two trRns), and that we see such that a crystallization fractional.
In a tenips container, the solution of the raw product in 2 L
methanol brought to 60 ° C, to which 700 are gradually added niL of osnlosed water, is left for 4 h at anti-asbestos temperature and at away from vibration. A lower solid phase of yellow color, rich in trailed isons, is discarded, and the white cristatixes of the phase stipérietire, rich in cis isomers, are separated by filtration. The crystals thus obtained are redissolved in 2 L of niethanol brought to 60 C, with the addition of 500 niL of osmosis water up to obtaining a persistent disorder, and abandoning 16 h at temperature anibiant. Three additional crystallizations performed according to the lead the process, but with reduced volumes of methanol (1 L) and water (200 mL), are necessary to obtain 23 g of (2R, 3R) -3-(1S, 2R, 5S) - (+) - menthyl phenylglucidate in the crystallized state with HPLC pttrety> 99% (Yield = 12%).
The compound obtained has the following characteristics:
= F = 104 C
= RMN'H 400 MHz (CDC13) (S ppm): 7.40 (2H, dd, J = 7.8 Hz and 1.7 Hz); 7.32 (3H, ni); 4.58 (1 H, dt, J = 1.09 Hz and 4.2 Hz); 4.26 (1 H, d, J = 4.6 Hz); 3.83 (1H, d, J = 4.8Hz); 1.6-0.85 (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 rnottocrystal of (2R, 3R) -3-phenyl-(1 S, 2R, SS) - (+) - inenthyle glycidate for determination indirect absolute configuration:

The monocrystal was obtained from a suspension crystalline resulting from the hot addition of the non-solvent (water) to a hemi-saturated solution of glycidate in niethanol. By slow cooling, the solution allowed to deposit fine needles purity 99.95% (HPLC), which were kept moist until Ia final selection.
The selected sample (fine needle of dimensions 0.12 * 0.12 * 0.40 mm) has been studied on an automatic diffractometer CAD4 ENRAF-NONIUS (radiation of niolybdenum with graphite monochromator). the parameters of the niaille were obtained by refining the sensitive end of 25 theta angle reflections Student. the data collection (20 ,,, ac = 50, w / 20 scan = I, = 60 s, HKL domain: H 0.6 K 0.14 L 0.28, iritensity controls without significant drift (0.1%)) provided 1838 reflections of which 1037 with I> 1.5cr (I).
Clql'I26O3: N1r = 302.42, orthorhombic, P2i2,2 ,, a = 5.709 (I1), b = 1 2. 9 0 8 (4), c = 24.433 (8) ~, V 1 8 0 1 (5) ~ '', Z = 4, DX = 1. 1 NIg.m'3, a. (: VloKa) = 0.70926 A, = 0.69 cm '', F (000) = 656, T = 294 K, final R = 0.072 for 1037 observations.
After Lorenz corrections and polarization corrections, the structure has been solved using Direct Methods which allow to locate the majority of non-hydrogen atonies of the nlolecule, the remaining atonies being located by Fourier differences and niises on successive scales. After isotropic refinement (R = 0.125) then anisotropic (R = 0.095), most of the hydrogen atoms are located using a Fourier difference (between 0.39 and 0.14 e ~ "'), the others being positioned by calculation. the complete structure was refined by whole matrix (x, y, z, [i; i for C and O, x, y, z for H; 200 variables and 1037 observations; , v = 1 / a (Fa) '- = [a' - (I) + (0.04FaZ) Z] '11Z) leading to R = 0.080, R. = 0.072 and S ,, = 1.52 1 (residue Ap s0.2 1 eA- ').
Diffusion factors are taken from Tables Internationales de crystallographie [International Tables for Xray Cristallography (1974). Vol. IV.Birminghani: Kynoch Press. (Present distributor D. Reidel, Dordrecht)]. The calculations were made on Hewlett Paclcard 9000-710 for structure determination [SHELDRICK, GM (1985). Crystallographic Computing 3: Data Collection, Structure Determination, Proteins and Databases, edited R

by GM Sheldrick, C. Kriiger and R. Goddard. Oxford: Clarendron Press] and on Digital MicroVAX 3100 for further calculations with the MOLEN program game [FAIR, CK (1990). MOLEN. Year Interactive Intelligent System for Crysta! Structure Analysis. Enraf-Nonius, Delft, The Netherlands].

The configuration of the compound according to the ORTEP diagram [JOHNSON, CK (1965). ORTEP. Report ORNL-3794. Oak Ridge National Laboratory Tennessee, USA.], Is illustrated on the attached drawing sheet.

A sample (2R, 3R) -3-phenyl-glvcidate from (1S, 2R, 5S) -(+) - menthyl, by treatment with sodium methylate in the methanol, made it possible to obtain methyl phenylglycidate correspondent whose characteristics are as follows:
= [a] D28 = + 12 (c = 1.15; chloroform) = NMR 'H 400 MHz (CDCI3) (5 ppm =): 7.40 (2H, -d;' J = 8 Hz); 7.32 (3H, m); 4.26 (1H, d, J = 4.6Hz); 3, S4 (1 H, d, J = 4.6 Hz); 3.53 (3H, s).

/

Example 3 (4S, 5R) -2,4-Diphenyl-4,5-dihydrooxazole-5-(1S, 2R, 5S) - (+) - methyl carboxylate Even NO
'O.

o Me To a solution stirred under an inert atmosphere at -65 ° C. of 30 g (0.0993 mol) of (2R, 3R) -3-phenylglycidate of (1S, 2R, 5S) - (+) -menthyl and 305 mL (2.98 nlol) of benzonitriledansl, 5 L of anhydrous dichloromethane, 15 ml (0.109 mol) of a solution are added at 54% tetrafluoroboric acid in ether in 10 min. We leave it there reaction continue at -65 C for 1 h and, after control by TLC, 300 ml of a saturated aqueous solution are added of sodiuni hydrogen carbonate and allowed to return to temperature ambient with agitation. After extraction of the aqueous phase with dichloromethane (2 x 200 mL), the combined organic phases are washed with saturated sodium chloride solution (200 mL), with water (50 mL) and dried over iti-1gSO.,. After concentration under reduced pressure and elimination of residual vacuum pushed to 50 ° C., the crude product obtained is purified by chromatography on silica gel (15-40 i.cni) (eluent: evclohexane-ethyl acetate, 20/1).
32 g of (4S, 5R) - ?, 4-diphenvl-4,5- are thus isolated.
(IS, 2R, 5R) - (+) - menthyl dihydrooxazole-5-carboxylate under the formulated with a colorless syrup (Yield = 80%) and which presents the following features:
= 1 H NMR 400 MHz (CDCl3) (S ppni): 8.10 (2H, d, J = 7.1 Hz); 7.54 (1 H, t, J = 7.4 Hz); 7.46 (2H, t, J = 7.4 Hz); 7.34 (5H, rn); 5.40 (1 H, d, J = 6.4 Hz); 4.88 (1H, d, J = 6.4Hz); 4.85 (1 H, dt, j = 10.9 and 4.4 Hz); 2.09 (1H, m); 1.84 (1H, m, J = 7 and 2.7Hz); 1.7 1 (1H, m); 1.69 (1 H, 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 4 (4S, 5R) -2,4-diphenyl-4,5-dihydrooxazole-5- acid carboxylic N / OH
'' 4S SR ' To a solution stirred at room temperature of 3.5 g (S, 64 rnniol) of (4S, 5R) -2,4-diphenyl-4,5-dihydrooxazole-5-carboxylate (IS, 2R, 5S) - (+) - menthyl in niethanol (70 niL), 25 mL are added of a solution of 6 S (43.2 mniol) of potassium carbonate in osmosis water, and the reaction is allowed to continue for 16 h at ambient temperature. After control by CCM, the environment reaction is concentrated under reduced pressure. The aqueous phase thus obtained is washed with dichloroniéttiane (3 x 100 mL), acidified to pH 2 by slow addition of 20 mL of an aqueous solution of 1M HCl, and extracted with ethyl acetate (: 3 x 100 mL). The the combined organic extraction phases are dried (MgSO;) and concentrated under reduced pressure.
2.26 g of acid (4S, 51t) -2.4-diphenyl-4.5- are thus obtained dihvdrooxazole-5-carboxylic resulting from a white powder (Yield = 98%) and which has the following characteristics:
= [a] p '-'- = + 27.7 (c = 0.99; CH, C12-MeOH, 1/1) = F = 201-202 C
= 1 H NMR 400 MHz (DMSO-d6) (â ppm): 7.99 (2H, d, J = 7.3 Hz);

7.64 (1H, t, J = 7.4Hz); 7.55 (2H, t, J = 7.7 Hz); 7.36 (5H, m); 5.40 (1 H, d, J = 6.3 Hz); 4.99 (1 H, d, d = 6.4 Hz).

i -Example 5 (2R, 3S) -N-Benzoyl-3-phenylisoserinate from (1S, 2R, 5S) -(+) - menthyl GHBZHHMMe e BzNH O Me Me Nz. ,, = ,, H OH
O
Even To a stirred solution at an anibiant temperature of 1 g (2.47 nimol) of (4S, 5R) -2,4-diphenN = I-4,5-dihydroo. \ azole-5-carboxvlate (1 S, 2R, 5S) - (+) - menthylin a mixture of methanol (15 mL) and tetrahydrofuran (15 mL), 15 mL of an aqueous solution is added of HCI 1NI. The reaction medium is brought to reflux for 1 hour, and after control by TLC and return to room temperature of a solution saturated aqueous sodium hydrogen carbonate (45 mL) is progressively added until a basic pH is obtained. After 48 h stirring at room temperature, the aqueous phase obtained after concentration under reduced pressure is extracted with dichloromethane (100 mL). The aqueous phase is washed with a saturated solution of sodium chloride (2 x 50 mL), dried over MgSO.4, concentrated under reduced pressure, and the residue obtained is chromatographed on dc gel silica (15-40 m) (eluent: dichloroniethanc-niethanol, 95/05).
We thus isolate 0, S35 g dc (2R, 3S) -N-Benzoyl-3-(1S, 2R, 5S) - (+) - nicnthylc phenoserisate in the form of a white solid (yield = 80%) and which has the characteristics following:
= 1 H NMR 400 ivHz (CDCl 3) (â ppm): 7.77 (2H, d, J = 7.2 Hz);
7.5 1 (1 H, t, J = 7.3 Hz); 7.45 (4H, ni); 7.36 (2H, t, J = 7.2 Hz); 7.29 (1 H, t, J = 7.2 Hz); 7.04 (1H, d, J = 9.2Hz); 5.78 (1 H, dd, J = 9.2 and 2.1 Hz); 4.79 (1 H, dt, J = 10.9 and 4.4 Hz); 4.63 (1H, br s); 3.35 (1 H, s larôe); 1.81 (2H, m); 1.67 (3H, ni); 1.5 to 1.30 (2H, m); 1.09 to 0.91 (2H, m); 0, S9 (3H, d, J = 6.9 Hz); 0.77 (3H, d, J = 6.5 1-k); 0.74 (3H, d, J = 6.9 Hz).

Example 6 (2R, 3S) -N-Benzoyl-O-triethylsilyl-3-phenylisoserinate of (I. S, 2R, 5S) - (+) - nienthyl BzNH O Me Me "
0.
OSiEtz Me To a solution of 0.8 g (1, S9 nimol) of (2R, 3S) -N-bcnzoyl-(1S, 2R, 5S) - (+) - menthvle 3-phenylisoserinate in 10 mL of 0.25 g (2.08 nimol) of 4- anhydrous dichloromethane dinlethylaminopyridine. After a few minutes of agitation at anibiant temperature, 477 L (2, S4 mniol) of chloride dc are added triethylsilyl in 5 niin. After 1 hour of agitation at anibiant temperature and control by TLC, the reaction medium is diluted with 100 ml of dichloroniethane. The organic phase is washed with a solution saturated aqueous sodium hydrogen carbonate (2 x 20 niL), with saturated sodiuni chloride solution (50 mL), dried stir iV1gSO, and concentrated under reduced pressure. After purification of the residue obtained by chroniatographic on silica gel (15-40 m) (eluent: cN = clohexane-ethyl acetate, 10/1), 0.74 g of (2 R, 3S) -N-bcnzovl-O-trieth \, Isilvl-3-phenylisoserine from (1S, 2R, 5S) - (+) - nienth \, Ic under the form of a colorless syrup (Itdt = 75 %).
The compound obtained has the following characteristics:
= 1 H NMR 400 MHz (CDCI3) (S ppni): 7.82 (2H, (1, 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 (1 H, dt, J = 11 and 4.3 Hz); 1.8 8 to 1.67 (m); 1.44 (2H, ni); 1.06-0.87 (m); 0.80 (or); 0.67 (3H, d, J = 7 Hz); 0.62 to 0.34 (m).

Example 7:
(2 R, 3 S) -N-Benzoyl-O-triethvlsilyl-3-phenylisoseria BzNH O

OH
OSiEt3 ~

To a solution stirred at room temperature of 0.5 g (0.931 mmol) of (2R, 3S) -N-benzoyl-O-triethvlsilyl-3-(1 S, 2R, 5S) - (+) methylphenylisoserinate in 15 mL of methanol, 0.64 g (4.655 nimol) dc is added to the solution sodiuni carbonate in 10 ml of osniosec water. After shaking 16 h at room temperature and control by TLC, the niilieu reaction is concentrated under reduced pressure, and the aqueous phase residual is washed with dichloromethane (3 x 50 mL) and then acidified to pH 2 by slow addition of a 1 M aqueous HCl solution (10 mL).
The aqueous phase is extracted with ethyl acetate (3 x 50 mL) and the combined organic phases are dried over itilgSOa and concentrated under reduced pressure.
0.320 g of (2R, 3S) -N-benzoyl-O-triethylsilyl-3- are obtained.
plienylisoserine in the form of a white powder (Yield = 90%) and which has the following characteristics:
= 1 H NMR 400 MHz (DMSO-db) (S ppni): 8.46 (1 H, d, J = 9.3 Hz);
7.82 (2H, d, J = 7.1 Hz); 7.54 (1H, t, J = 7.2Hz); 7.47 (4H, ni); 7.32 (2 H, t); 7.36 (1H, t); 5.44 (1 H, dd, J = 9.2 ct 5.5 Hz); 4.64 (1 H, d, J = 5.6 Hz); 0.77 (9H, m); 0.45 (6H, m).
Example 8 (2R, 3S) -N-Benzoyl-O- (2,2,2-trichloroethoxy) carbonvl-(1 S, 2R, 5S) - (+) - nlcnthylc 3-phenvlisoserinate BzNH O Me Me O.
I = =, OTroc Me To a solution stirred at room temperature under 1.38 g (3.3 mmol) inert atmosphere of (2R, 3S) -N-benzovl-3-(IS, 2R, 5S) - (+) - menthyl phenylisoserinate in 30 mL of anhydrous dichloromethane is added 480 mg (3.96 mmol) of 4-dimethylaminopyridine. After 10 min of stirring, 540 L are added (3.96 mmol) of 2,2,2-trichloroethoxycarbonyl chloride in 5 min.
After 2 h of stirring at room temperature and control by TLC, the organic phase is washed with a saturated solution sodium hydrogen carbonate (2 x 10 mL), with solution saturated with sodiuni chloride (10 mL), dried over MgSO. 4 and concentrated under reduced pressure. After purification of the residue obtained by chromatography on silica gel (15-40 m) (eluent:
cyclohexane-ethyl acetate 5/1) 1.60 g of (2R, 3S) -N- are obtained 5 benzoyl-O- (2,2,2-trichloroethoxy) carbonyl-3-phenylisoserine from (1 S, 2R, 5S) - (+) - menthyl in the form of a colorless syrup (Yield =
82%).
The compound obtained has the following characteristics:
= 1 H NMR 400 MHz (CDC13) (8 ppn,): 7.82 (2H, d, J = 7.4 Hz); 7.53 10 (1H, t, J = 7.4Hz); 7.44 (4H, m); 7.35 (2H, t, J = 7 Hz); 7.29 (1 H, t, J = 7 Hz); 7.09 (1H, d, J = 9.3Hz); 6.0 (1 H, dd, J 9.3 and 2.5 Hz);
5.45 (1H, d, J = 2.6Hz); 4.7 8 and 4.72 (2H, 2d, J = 1 1.9 Hz); 4.77 (1H, ni); 1.85 (1H, m) 1.79 (1H, m); 1.65 (2H, ni); 1.43 (1H, ni);
1.02 (1H, m); 0.96 (1H, m); 0.86 (1 H, ni); 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 (1 S, 2R, 5 S) - (+) - nlenthyle ~
HN ~ OH Me Me ~
O
= -.
HI

25 Me To a solution stirred under an inert atmosphere at temperature 3.96 g (6.62 mmol) ambient of (2R, 3S) -N-benzoyl-O- (2,2,2-(1 S, 2R, 5S) - (+) - trichloroetho: cy) -carbonyl-3-phenylisoserinate 30 menthyl in 30 μl of anhydrous dichloromethane, 1 ml is added (7.28 mmol) of 1,8-diazabicylo [5,4,0] undec-7-ene. After 30 min 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 by chromatography on silica gel (15-40 m) (eluent:
cyclohexane - ethyl acetate 7/3) 2.18 g of the above-mentioned compound are obtained in title in the form of a yellow syrup (Yield = 95%).
The compound obtained has the following characteristics:

= 1 NMR 400 MHz (CDCI,) (S ppni): 7.40 (5H, m); 6.09 (1H, s);
4.93 (1H, d, J = 5.3Hz); 4.8 6 (1 H, dt, J = 11 and 4.4 Hz); 4.73 (1 H, d, J = 5.4 Hz); 2.05 (1H, ni); 1, S 1 (1 H, ni); 1.7, 1 (2H, ni); 1.54 to 1.4 1 (3H, m); 1.07 (2H, ni); 0.94 (3H, d, J = 6.5 Hz); 0.8 8 (3H, d, J = 7 Hz); 0.77 (3H, d, J = 7 Hz).

Example 10:
(4S, 5R) -N-'Butoxycarbonyl-4-phenyloxazolidin-2-one-(1S, 2R, 5S) - (+) - menthyl 5-carboxylate Even BocN OH
\ / == õ ~~ O.
= -, HI

Me To a solution stirred at -40 ° C. under an inert atmosphere of 1.91 g (5.52 mmol) of (4S, 5R) -4-phenyloxazolidin-3-one-5-carboxvlate (1 S, 2R, 5S) - (+) - nienthyl in 20 niL of tetrahydrofuran anh ~, dre, 3.8 mL (6.07 mmol) of a 1.6 M solution of -i-butvl are added lithium in the hexanc. After 10 minutes of stirring at -40 ° C., one adds a solution of 1.81 g (S, 2S nimol) of butoxcarbonic anhydride in solution in 5 μl of tetrahydrofuran, and the medium is left reaction return to room temperature in 15 min / after dilution with 50 μl of dichloroniethane and washing with an aqueous solution 2% of HCl until a pH = 5 is obtained, the organic phase is dried (MgSOi) and concentrated under reduced pressure. After purification of the crude product by deep silica chromatography (15-40 m) (eluent: cyclohexane-ethyl acetate, 5/1) 2.12 g are obtained of the title compound in the form of a colorless syrup (Yield = 86 %).
The compound thus obtained has the characteristics following:
1 H NMR 400 MHz (CDCl3) (ppm ppm): 7.45 to 7.26 (5H, m); 5.19 (1H, d, J = 3.7 Hz); 4.86 (1 H, dt, J = 10.9 and 4.5 Hz); 4.66 (1 H, d, J = 3.7 Hz); 2.05 (1H, m); 1.79 (1H, m); 1.73 (2H, m); 1.62-1.24 (3H, m);
1.33 (9H, s); 1.11 (2H, m); 0.94 (3H, d, J = 6.5 Hz) and (1H, m); 0.89 - ~

(3H, d, J = 7Hz); 0.77 (3H, d, J = 7 Hz).
Example 11:
(4S, 5R) -3-N-Benzoyl-4-plienyloxazolidin-3-onc-5-(1 S, 2R, 5 S) - (+) - menthyl carboxylate CBZNO H Me Me O
==, HI

Me To a solution stirred under an inert atmosphere at temperature 500 mg (1.45 nimol) ambient (4S, 5R) -4-phenyloxazolidin-3-one-5-carboxvlate of (1 S, 2 R, 5 S) - (+) -menthvle and 176 mg (1.16 mmol) of 4-pyrrolidinopvridine in 7 µl of dichloromethane anhydrous, 0.25 mL (2.17 niniol) of benzoyl cliloride is added.
After 3 h of stirring at 50 ° C., the reaction medium is brought to anibiant temperature and diluted with 20 μl of dichloromethane. The organic phase is washed with 10 μl of a saturated solution of sodium chloride, dried over MgSO4 and concentrated under pressure scaled down. After purification of the crude product by chromatography on silica gel (15-40 m) (eluent: cvclolicxane - ethyl acetate 5/1) on obtains 300 nig of the title compound in the form of a syrup colorless (yield = 46%).
The coniposive thus obtained has the characteristics following:
= 1 H NMR 400 MHz (CDCI,) (S ppni): 8.16 (2H, d, J = 7.1 Hz); 7.68 (1H, t); 7.53 (4H, m); 7.43 (3H, ni); 5.57 (1H, d, J = 4.4Hz); 4.90 (1 H, dt, J = 10.9 and 4.4 Hz); 4.85 (1H, d, J = 4.3Hz); 2.07 (1H, m);
1, SO (1H, m); 1.72 (2H, m); 1.47 (3H, ni); 1.09 (2H, m); 0.95 (3H, d, J = 6.5 Ii z); 0.88 (3H, d, J = 7 Hz); 0.78 (3H, d, J = 7 Hz).

Y

-, -, Exentple 12 Acid (4S, 5 R) -3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylic O
BzN OH

' OH
H

To a stirred mixture at room temperature of 120 nig (0.266 mmol) of (4S, 5R) -3-N-benzoti, l-4-plienyloxazolidin-3-one-5-(1S, 2R, 5S) - (+) - menthvie carboxvlate in 2 niL of methanol, we add a solution of 75 nig (0.543 mniol) of potassium carbonate in 1 mL of water. After 30 min of stirring, the reaction medium is diluted with 10 mL of water and the aqueous phase is washed with 5 mL of dichloroniethane. After acidification at pH = 4 using HCl 1iVt, the residual aqueous fold 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 nig of acid (4S, 5R) -3-N-13cnzoyl-4- are obtained.
phenyloxazolidin-3-one-5-carboxyl in the form of a powder white (Yield = 52%), and which has the following characteristics:
= RivtN'H 400 MHz (DMSO - dj (â ppm): 12.98 (1H, broad s); 7.95 (2H, d, J = 7.1 Hz); 7.63 (1H, t, J = 7.4Hz); 7.50 (2H, t, J = 7.5 Hz);
7.42 (2H, ni); 7.3 7 (3H, m); 4.90 (1 H, d, J = 5 Hz); 4.77 (1 H, d, J =
5 Hz).

Example 13 Acid (4S, 5R) -4-PhenyloYazolidin-3-one-5-carboxylic O
~
HN OH
OH
HI

~ 4 To a solution stirred at 0 C under an inert atmosphere dc 300 nig (0.867 mniol) of (4S, 51:) - 4-phenylozazolidin-2-one-5-carboxylate of (1 S, 2R, 5S) - (+) - menthvle, 3 niL of methanol, then 0.5 mL of water in 6.5 mL of pyridine, 10 mL of a 360 mg (8.67 mmol) honiogenic solution of NaOH, 3 mL dc methanol and 0.5 mL of water in pyridine. After 20 niin of agitation at 0 ° C., the reaction milieti is diluted with water (30 ml) and washed with dichoroniethane (30 mL). After acidification to pH = 1, the phase residual aqueous is extracted with ethyl acetate (3 x 20 mL), and the the combined organic phases are dried (iigSO,), and concentrated under reduced pressure.
86 mg of (4S, 5R) -4-phenyloxazolidin- acid are thus obtained.
3-one-5-carboxylic in the form of a yellow syrup (Yield = 53%), and which has the following characteristics:

- NMR 'H 400MHz (DMSO-db) (ô ppni): 13.33 (1 H, broad s); 8.46 (1 H, s); 7.38 (5H, m); 4.89 (1H, d, J = 5 Hz); 4.75 (1 H, d, J =
5 Hz).
II.Baccatin III derivatives Example 14:
7-O-TriethylsiIyI- I 0-deacetylbaccatin 111 Me OH
O
HO - Me Me OSiEt3 Me HO BzO H, - - H
AcOO
To a solution stirred at room temperature and under 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, 6.2 mL (36.6 mmol) of chloride are added of triethylsilyl in 10 min. After 3 h of reaction at temperature anibiant, 10 g of crushed ice are added and the mixture is left for 10 min under strong agitation. The residual organic phase is washed with water (200 mL), dried over MgSO.4 and concentrated under reduced pressure.

;

After treating the raw product obtained with niininlum ethyl acetate, I obtain I 1.2 g of 7-0-triethylsilyl- 10-deacetylbaccatin III in the crystallized state (yield = 92.3%).
The product thus obtained has the characteristics following:
= 1 H NMR 400 MHz (CDCI 3) (S ppni): S, 10 (2 H, d, J = 7.4 Hz); 7.60 (1 H, 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 = 1.9Hz); 4.96 (1H, d, J = S Hz); 4.86 (1H, ni); 4.41 (1 H, dd, J = 1 0, 6 and 6.6 Hz); 4.3 1 and 4, 1 6 (2H, 2d, J = 8.4 Hz); 4.26 (1 H, d, J = 1.9 Hz); 3.95 (1 H, d, J = 6.9 Hz); 2.48 (1 H, ddd, J =
14.5, 9.7 and 6.7 Hz); 2.29 (3H, s); 2.27 (2H, ni); 2.08 (3H, s); 1.90 (1H, m); 1.73 (3H, s); 1.62 (1H, s); 1.08 (6H, s); 0.94 (9H, t, J = 8 hz); 0.56 (6H, m).

Example 15 7-O-Triethylgermanyl- 1 0-deacetylbaccatin III
OH
Me O
HO--: eMe0: eE3 HO

Bz0 H, - - H
Ac0 0 To a solution stirred at room temperature and under inert atmosphere of 100 mg (0.183 mniol) of 10-deacetylbaccatin III and 41 nig (0.275 niniol) of 4-pyrrolidinopyridine in 4 mL of anhydrous dichloromethane, add 80 L (0.476 nimol) of chloride of triethylgernianyl in 10 min, and the mixture is stirred at 50 ° C.
for 1 p.m. 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 for 10 min with vigorous stirring. The organic phase residual is washed with saturated hydrogen carbonate solution sodium (5 mL), saturated sodium chloride solution (5 mL), dried on iY1gSO., and concentrated under reduced pressure. After chromatography of the crude product on silica gel (15-40 m) (eluent:
cyclohexane-ethyl acetate, 25/75) 67 mg of 7-0- are obtained triethylgermanyl-10-deacetylbaccatin III in the form of a syrup colorless.

The product thus obtained has the characteristics following:
= 1 H NMR 400 MHz (CDCI 3) (S ppni): 8.09 (2H, d, J = 7.1 Hz); 7.60 (1 H, t, J = 7.4 Hz); 7.48 (2H, t, J = 7.6 Hz); 5.63 (1H, d, J = 7.1Hz);
5.24 (1H, s); 4.99 (1 H, d, J = 8 Hz); 4.78 (1H, t); 4.32 (1 H, d, J =
S, 3); 4.28 (1H, m); 4.1 7 (2H, ni); 3.97 (1H, d, J 7Hz); 2.59 (1 H, m); 2.30 (3H, s); 2.24 (1H, m); 2.10 (1H, ni); 2.03 (3H, s); 1.82 (1H, rn); 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) - 1 0-deacetyl-baccatin III

Me OH
O
) j HO_- Me Me OCOOC (CH3) 2CCI, Me HO
Bz0 H. H
AcO0 To a solution stirred at 40 ° C. under an inert atmosphere of 5 g (9.19 mniol) of 10-deacetvlbaccatin III and 1.1 mL of anhydrous pyridine in 250 niL of dichloronia: dry thane, add 3.3 g (13.8 mmol) of 2,2,2-trichloro-t-butoxycarbonyl chlortire in 2 h. After 30 additional reaction niins, and return to temperature anibiant, the organic solution is washed with an aqueous solution 2% HCl (30mL), washed with RO water (2 x 100 mL), dried on MgSO4, and concentrated under reduced pressure (Yield = 55%). After chromatography of the crude product on silica gel (15-40 ni) (eluent : cyclohexane-ethyl acetate, 60/40) we obtain the 7-0- (2,2,2-trichloro-t-butoxycarbonyl) -10-deacetylbaccatin III in the form of a white powder.
The product obtained has the following characteristics:
- 1 H NMR 400 MHz (CDCI 3) (S ppm): 8.10 (2H, d, J = 7 Hz); 7.62 (1H, t, J = 7.4 Hz); 7.49 (2H, t, J = 7.6 Hz); 5.65 (1H, d, J = 6.9 Hz);
5.44 (1 H, dd, J = 10.8 and 7.3 Hz); 5.39 (1H, d); 4.98 (1 H, d, J = 7.5 Hz); 4.89 (1H, m); 4.35 and 4.20 (2H, 2d, J = 8.4 Hz); 4.10 (1 H, d, J
= 7Hz); 4.01 (1H, d, J = 1.8 Hz); 2.64 (1H, m); 2.31 (3H, s); 2.29 T

.37 (1H, m); 2.11 (3H, d); 2.05 (2H, ni); 1.89 (3H, s); 1.09 (3H, s); 1.07 (3H, s).

Example 17 a) 7-O-Triethylsilylbaccatin III
Me OAc O
BO- _ = Me Me OSiEta Me HO
Bz0 H - - H
AcO0 To a solution stirred at room temperature under inert atmosphere of 1 g (1.5 niniol) of 7-O-trieth, ylsilyl- 10-deacetylbaccatin III and 1.25 mL (15 mmol) of pyridine in 15 mL of dry dichloromethane, 0.54 niL (7.5 mmol) of chloride is added acetyl in 10 min. After 2 hours of reaction at room temperature and control by TLC, 1 g of crushed ice is added and the mixture is left under vigorous stirring for 10 min. The organic phase residual is washed with water (2 x 10 mL), dried over MgSO. 4 and concentrated with reduced pressure. After dc gel chromatography silica (15-40 ni) (eluent: c), clohexane-ethyl acetate, 60/40) on obtains 0.756 g of 7-O-triethylsilvlbaccatine III in the form of tine white powder (Yield = 70%).
The compound obtained has the following characteristics:
= 1 H NMR 400 MHz (CDCI 3) (S ppni): 8.11 (2H, d J = 7.1 Hz); 7.6 (1 H, t, J = 7.4 Hz); 7.48 (2H, t, J = 7.7 Hz); 6.46 (1H, s); 5.63 (1 H, d, J = 7 Hz); 4.96 (1H, d, J = 8.1Hz); 4.83 (1H, m); 4.49 (1 H, dd, J
= 10.4 and 6.7 Hz); 4.3 1 and 4.15 (2H, 2d, J = 8.3 Hz); 3.88 (1 H, d, J
= 7 Hz); 2.53 (1H, m); 2.29 (3H, s); 2.27 (2H, m); 2.19 (3H, d, J =
0.8 Hz); 2.18 (3H, s); 2.12 (1H, 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, m).

Y

~ O
Example 18 7-0- (2,2,2-Trichloro-t-butoxycarbonyl) baccatin III
Me OAc O
j - Me Me OCOOC (CH3) zCCI3 HO
Me HO
Bz0 H '- - H
AcO0 A solution stirred at room temperature under inert atmosphere of 260 mg 7-0- (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 L (0.695 mmol) of acetyl chloride. After 1 h dc reaction at room temperature, the organic phase is washed with a 2% aqueous solution of HCl until a pH = 6, dried on Mg SOi and concentrated under reduced pressure. After chroniatography of the residue obtained on silica gel (15-40 μm) (eluent: cyclohexane-ethyl acetate, 6/4) 0.23 g of 7-0- is obtained (2,2,2-Trichloro-t-btrtoxycarbonvl) -baccatine III in solid state (Yield = 83%).
The compound obtained has the following characteristics:
- 1 H NMR 400 MHz (CDCI3) (S ppni): 8.11 (2H, d, J = 7.1 Hz); 7.62 (1 H, t, J = 7.4 Hz); 7.49 (2H, t, J = 7.6Hz); 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 H z); 4, S 7 (1H, m); 4.33 and 4.16 (2H, 2d, J = 8.4 Hz); 4.02 (1 H, d, J
= 6.9 Hz); 2.64 (1 H, ddd, J = 14.4, 9.5 and 7.2 Hz); 2.30 (3H, s) and (2H, m); 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).

Y

Example 19 7-O-Phenoxyacetyl-10-deacetylbaccatin IlI
Me OH
O
J HO - 'Me Me OCOCH2OPh Me HO
Bz0 H 'H
AcOO
To a solution stirred at room temperature and under 1.03 g (1.88 mniol) inert atnosphere of 10-deacetylbaccatin III
and 0.6 niL (7.5 mmol) of anhydrous pyridine in 100 niL of dry dichloromethane, 1.05 niL (7.5 niniol) of chloride is added 10 niin phenoxyacetyl. After 30 min of reaction at temperature ambient and control by TLC, the organic solution is washed with a 2% aqueous HCl solution until a pH = 2, washed with osniosée water (2 x 50 mL), dried over MgSOa and concentrated under reduced pressure (Yield = 70.5%). After chroniatography of crude product on silica gel (15-40 gm) (eluent: cyclohexane-acetate ethyl, 60/40) 7-O-phenoxyacetvl-10- is obtained deacetvlbaccatin III in the form of a white powder.
The product obtained has the following characteristics:
= 1 H NMR 400 MHz (CDCl 3) (S ppni): 8.09 (2H, d, J = 7.3 Hz); 7.61 (1 H, t, J = 7.4 Hz); 7.48 (2H, t, J = 7.6 Hz); 7.3 1 (2H, t, J = 7.7 Hz);
6, 9 9 (3 H, ni); 6.42 (1H, s); 5.6 1 (1 H, d, J = 7 Hz); 4.97 ( 1 H, d, J =
7.8 Hz); 4, S6 (3H, ni); 4.44 (1H, dd, J = 10.6 and 6.8Hz); 4.30 and 4.15 (2H, 2d, J = 8.4 Hz); 3.8 6 (1 H, d, J = 7 Hz); 2.56 (1H, m); 2.27 (3H, s); 2.27 (2H, m); 2.05 ((3H, s); 1, S6 (1H, m); 1.68 (3H, s); 1.01 (3H, s); 0.98 (3H, s).

Exeniple 20 7, 1 0-O-Di- (phenoxyacetyl) - 1 0-deacetyibibatin III
Me OCOCH2OPh 5 HO-- Me Me OCOCHZOPh Me HO
BzO H '- H
10 AcO O

To a solution stirred at room temperature and under 500 mg (0.92 niniol) inert atniosphere of 10-deacetylbaccatin III and 0.6 niL (7.36 mmol) of anhydrous pyridine in 50 mL of 15 dry dichloroniethane, 0.5 niL (3.6S mmol) of chlortire phenoxyacetyl in 10 min. After 6 h of reaction at temperature anibiant and control by TLC, the solution is washed with a 2% aqueous HCl solution until pH = 2, washed with reverse osmosis water (2 x 20 mL), dried over Mg SO.4 and concentrated 20 under reduced pressure. After chroniatography of the raw product on gel silica (15-40 m) (eluent: cyclohexane-ethyl acetate, 6/4) obtains 0.55 g of 7,10-O-bis- (phenoxyacetyl) - 1 0-deacetylbaccatin III under the form of a white powder (Yield = 74 The product obtained has the following characteristics:
25 'H NMR 400 MHz (CDCl3) (S ppm): 8.09 (21-1, 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 (1 H, s); 5.69 (1 H, dd, J = 10.5 and 7.1 Hz); 5.60 (1 H, d, J = 6.9 Hz);
4.96 (1H, d, J- 8.2Hz); 4.84 (1H, t, J = 7.4Hz); 4.8 (2H, s); 4.65 30 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-O-Phenoxyacetylbaccatin III
Me OAc O
HO- - .Me Me 2 OCOCHOPh Me HO = ' 8z0 H, - - H
AcO 0 To a solution stirred at room temperature and under 1.11 g (1.64 nimol) inert atmosphere of 7-O-phenoxyacetyl-10-deacetylbaccatin III in 40 mL of anhydrous pyridine, add 0.233 niL (3.27 mmol) of acetyl chloride in 10 niin. After 4 p.m.
reaction at room temperature and control by TLC, the niilieu reaction is diluted with 50 mL of RO water, and the aqueous phase is extracted with ethyl acetate (3 x 30 mL). The aqueous phases combined are washed with water (2 x 20 mL), dried over MgSOi and concentrated under reduced pressure (Yield: 84.5%). After chronology on silica gel (15-40 m) (eluent: cyclohexane-ethyl acetate, 60/40) 7-O-phenoxyacetylbaccatin III is obtained in the crystallized state.
The product obtained has the following characteristics:
= 1 H NMR 400 MHz (CDCl3) (S 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 = S Hz);
6.95 (3H, m); 6.26 (1H, s); 5.71 (1 H, dd, J = 10.4 and 7.2 Hz); 5.62 (1 H, d, J = 6.9 Hz); 4.96 (1H, d, J = 8.3Hz); 4.50 (1 H, ni); 4, S 1 and 4.5 3 (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 (1 H, d, j = 5 H z); 2.16 (3H, s); 2.09 (3H, d, J = 0.7 Hz); 1.8 1 (1H, m);
1.75 (3H, s); 1.13 (3H, s); 1.05 (3H, s).

t Example 22 7, 10-0- (1, 1,3,3 - Tetraisopropyl-1,3-disiloxanediyl) -10-deacetvl baccatin III

~ M
Me e / If - O Me Me O \ _ O i ~ Me HO- - Me Me O
Me HO
, ' Bz0 H, - - H
AcO0 A solution stirred at -40 ° C. and under an inert atmosphere 500 nig (0.93 nimol) of 10-deacety Ibaccatin 111 in 20 niL of anhydrous tetrahydrofuran, 1.28 nil (2.05 mmol) of n-butyl is added lithium in 1.6 M solution in hexane in 10 min. After 5 min stirring, 350 L (1, 1 2 mnzol) of 1, 3-dichloro- 1, 1,3,3- are added tetraisopropyldisyloxane and the reaction medium is allowed to return to anibiant temperature in 20 min. After 1 hour of stirring at temperature ambient, 225 mg (2.05 mmol) dc 4-dimethylaminopyridinc and the reaction medium is left for 1 hour stipplémentaire under agitation. After adding 20 mL of a saturated aqueous solution of sodiuni chloride, niilieu is extracted with dichloromethane (3x 30 mL). The combined organic phases are washed with a saturated aqueous solution of sodium chloride (20 ml), dried over MgSO4 and concentrated under reduced pressure. After purification by chromatography on silica gel (15-40 m) (eluent:
cyclohexane-ethyl acetate, 60/40) 480 mg of 7.10-0-0 is obtained (1,1,3,3-tetraisopropyl-1,3-disyloxanediyl) - 1 0-deacetylbaccatinI II
in an amorphous state (Yield = 65%).
The product obtained has the following characteristics:
1 H NMR 400 Mhz (CDCI 3) (S ppm): 8.10 (2H, d, J = 7.2 Hz); 7.60 (1 H, t, J = 7.4 Hz); 7.47 (2H, t, J = 7.6Hz); 5.60 (1H, s); 5.59 (1 H, d); 4.97 (1H, d, J = 7.9Hz) 4.87 (1H, m); 4.68 (1 H, dd, J = 10.4 and 6.9 Hz); 4.30 and 4.17 (2H, 2d, JS, 5 Hz); 3.92 (1H, d, J = 7.1Hz);
2.49 (1H, m); 2.23 (3H, s); 2.27 (1H, m); 2.04 (1H, m); 1.91 (1H, m);

rt 1.67 (3H, s); 1.55 (1H, s); 1.32 to 0.85 (34 H, ni).
Example 23 13-0 - [[(4S, 5 R) -2,4-Diphenyl-4,5-dih ,, Fdroxazol-5-yl] -carbonyl] -7-O-triethylsilyl-baccatin III

NO Me OAc Ar O
Me Me OSiEt Me O
HO
Bz0 H ~ - - H
Ac p To a solution stirred at room temperature and under 2.67 g (10 nimol) inert atniosphere (4S, SR) -2,4-diphenyl- acid 4,5-dihydroxazol-5-carboxylic acid in 55 n1L of anhydrous toluene, add 2.06 g (10 mmol) of dicyclohexylcarbodiirnide. After 5 niin stirring, 3.5 g (5 niniol) of 7-O-trieth, ylsilylbaccatine III are added and 0.61 g (5 mnlol) of 4-dimethylaniino-pyridine, and the mixture the reaction is brought to 70 ° C. for 1 h. Return to temperature anlbiant and elimination of insolubles by filtration, the phase organic is concentrated under reduced pressure. After purification of the crude product by chroniatography on silica gel (15-25 ni) (eluent:
cyclohexane-ethyl acetate, 90/10).
4.62 g of 13-0 - [[(4S, 5R) -2,4-diphenyl-4,5- are obtained.
dihydroxazol-5-yi] -carbonyl-7-O-triethylsilylbaccatine III in the state crystallized (Yield = 97%).
The compound thus obtained has the characteristics following:
= 1 H NMR 400 MHz (CDCl3) (S 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 (1 H, t, J = 7.4 Hz); 7.49 (4H, m); 7.38 (5H, m); 6.42 ((1 H, s); 6.18 (1 H, t, J = 8.2 Hz); 5.68 (1H, d, J = 7.1Hz); 5.60 (1H, d, J = 6.5Hz); 4.95 (2H, d);
4.50 (1 H, dd, J = 10.5 and 6.7 Hz); 4.29 (1H, d, J = 8.4Hz); 4.14 (1 H, d, J = 8.4 Hz); 3.83 (1H, d, J = 7.1Hz); 2.55 (1H, m); 2.37 (1 H, dd, J = 15.3 and 9.3 Hz); 2.26 (1 H, dd, J = 15.3 and 8.6 Hz); 2.16 (3H, s);

2.07 (3H, s); 1.99 (3H, s); 1.39 (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, ni).
Example 24 13-0 - [[4S, 5R) -2,4-Diphenyl-4,5-dihydrooxazol-5-yl] -carbonyl] -7-O-phenoxyacetylbaccatin III

NO Me OAc Ar, O
Me Me OCOCHZOPh H
Me O
HO
Bz0 H. - - H
AcO0 To a solution stirred at room temperature and under inert atnosphere of 490 mg (1.83 nimol) of acid (4S, 5R) -2.4-diphenyl-4,5-dihydrooYazol-5-carboxylic acid in 10 niL of toluene anhydrous, 380 mg (1.84 niniol) of dicyclohcxvlcarbodiimide are added.
After 5 min of stirring, 660 mg (0.92 mmol) of 7-0- is added.
phenoxyacetylbaccatin III and 112 mg (0.92 mmol) of 4-dimethylaminopyridine, and the reaction mixture is brought to 70 ° C.
for 2 h.
After returning to ambient temperature and elimination of the insolubles by filtration, the organic phase is concentrated under reduced pressure.
After purification of the crude product by chromatography on gel of silica (15-40 m) (eluent: cyclohexane-ethyl acetate, 99/1), we obtains 800 mg of 13-0 - [[4S, 5R) -2,4-diphenyl-4,5-dihydrooxazol-5-, yl] -carbonyl-7-O-phenoxyacetylbaccatin III in the crystallized state (Yield = 90%).
The compound thus obtained has the characteristics following:
= 1 H NMR 400 MHz (CDCl 3) (S ppm): 5.13 (2H, d, J = 7 Hz); 8.07 (2H, d, J = 7.3 Hz); 7.63 (1H, t, J = 7.4Hz); 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 (1 H, dd, J = 10.4 and 7.1 Hz); 5.67 (1H, d, J = 7.3Hz); 5.58 (1 H, d, J = 7 Hz); 4.93 (2H, d); 4.79 and 4.53 (2H, 2d, J = 15.9 Hz); 4.30 and ti 4.13 (2H, 2d, J = 8.5 Hz); 3.97 (1H, d, J = 6.9Hz); 2.67 (1H, ni);
2.3S (1 H, dd, J = 15.2 and 9.3 Hz); 2.26 (1 H, dd, J = 15.2 and 8.4 Hz);
2.15 (3H, s); 2.02 (3H, s); 1.95 (3H, s) ct (1H, m); 1, SO (3H, s); 1.74 (1H, s); 1.25 (3H, s); 1.17 (3H, s).

Example 25 1 3-0 - [[(4S, 5 R) -2,4-Diphenyl-4,5-dihydrooxazol-5-yl] -carbonyl] -7-0- (2,2,2-trichloro-t-butoxycarbonyl) baccatin III
i OAc NO Me O
Ar. H - Me O-- Me OCOOC (CHl) 2CCI1 HI Me O
HO
Bz0 H '- H
AcOO
To a solution stirred at room temperature and under 35 mg inert atniosphere of acid (4S, 5R) -2,4-diphenyl-4,5-dihydro-27 mg of oxazol-5-carboxylic acid in 3 μL of toluene antydra (0.13 mmol) of dicyclohexylcarbodiimide. After 5 minutes of agitation, we ajotite 51 ni g (0.065 ni mol) of 7-0- (2,2,2-trichloro-t-butoxycarbon ~ II) baccatin III and S nig (0.065 mmol) of 4-dimethylaminopyridine, and the mixture is brought to 70 ° C. for 1 hour.
After returning to anibiant temperature and eliminating the insoluble matter by filtration, the organic phase is concentrated under reduced pressure, and the residue obtained is purified by chromatography on silica gel (15-40 m) (eluent: cyclohexane-ethyl acetate, 9/1).
0.99 g of the title compound under form of a white solid (Yield = 67%), and which presents the following features:
- RNM 'H 400 MHz (CDCI3) (S ppm): S, 18 (2H, d, J = 7.2 Hz); 8.07 (2H, d, J = 7.3 Hz); 7.65 (1H, t, J = 7.4Hz); 7.59 (1H, t, J = 7.3Hz);
7.52 (4H, m); 7.39 (5H, m); 6.35 (1H, s); 6.24 (1 I-1, t, J = 8.4 Hz);
5.68 (1H, d, J = 7.1Hz); 5.59 (1 H, d, J = 7 Hz) and (1 H, dd); 4.95 (1 H, d); 4.94 (1H, d, J = 7Hz); 4.3 1 and 4.15 (2H, 2d, J = 8.4 Hz);

ti 3.9 7 (1 H, d, J = 6.9 Hz); 2.64 (1H, m); 2.3 7 (1 H, dd, J = 15.1 and 6 Hz); 2.27 (1H, dd, J = 15.2 and 3.5 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] -7.10-0- (1,1,3,3-tetraisopropyl-1,3-disiloxanediyl) -10-deacetylbaccatin III

Me Me Si'O Me O \
N ~ O Me O If __ ~
Ar H Me . Me Me O
HI Me HO
Bz0 H,, - - H
AcOO
To a solution stirred at room temperature, and under inert atmosphere of 4 mg (0.015 niniol) of acid (4S, 5R) -2,4-diphenyl-4,5-dihydrooxazol-5-carboxylic in 0.5 niL of toluene anhydrous, 7 mg (0.06 mmol) of dicyclohexvlcarbodiiniide are added.
After 5 min of stirring, a 5 mg solution (0.0065) is added.
mmol) of 7.10-0- (1.1, 3.3-tetraisopropyl-1, 3-disiloxanedi), l) -10-deacetylbaccatin III and 1 nig (0.0078 mmol) of 4-dimethylamino-pyridine in 1 mL of anhydrous toluene. After 20 min of agitation at room temperature, the mixture is brought to 50 C for 20 min additional. After returning to anibiant temperature, the phase organic is diluted with 5 mL of dichloromethane, washed with 2 mL
of a saturated saturated solution of sodium chlortire, dried on MgSO4, and concentrated under reduced pressure. After purification of the crude product by chromatography stir gel of ilice (1 5-25 m) (eluent:
cyclohexane-ethyl acetate, 7/3) 6 mg of the derivative mentioned in title (yield = 90%) in an amorphous state.
The compound obtained has the following characteristics:
= RMN'H 400 MHz (CDC13) (S ppm): 8.21 (2H, d, J = 7.2 Hz); 8.07 (2H, d, J = 7.6 Hz); 7.63 (1 H, t, 1 = 7.5 Hz); 7.59 (1 H, t, J = 7.4 Hz); 7.50 (2H, t, J = 7.4 Hz); 7.39 (5H, ni); 6.26 (1H, t); 5.64 (1 H, d, J = 7 Hz); 5.59 (1 H, d, J = 6.9 Hz); 5.54 (1H, s); 4.93 (1 H, d, J = 6.8 Hz) and (1 H, ni); 4.68 (1H, dd); 4, 2 8 and 4, 1 6 (2H, 2d, J = S
Hz); 3.84 (1H, d, J = 7.3Hz); 2.48 (1H, ni); 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 at 0.90 (34H, m).

Example 27 13-0 - [[(4S, 5R) -3-N-Benzoyl-4-plienyloxazolidin-3-one-5-yl] -carbonyl] -7-O-triethylsilylbaccatin III
O
BzN O Me OAc O
Ph.
O__ Me Me OSiEts Me HO
Bz0 HH
AcO0 To a solution stirred under an inert atmosphere at temperature 40 nig (0.137 mmol) ambient (4S, 5R) -3-N-Benzoyl-4-phenyloxazolidin-3-one-5-carboxyliquc in 2 niL dc toluene anhvdre, 28 mg (0.136 mmol) of dicyclohexvlcarbodiimide are added.
After 5 niin of agitation, 30 nig (0.043 niniol) of 7-0- are added.
triethyisilvibaccatin 111 and S mg (0.066 mmol) of 4-diniethylaminopyridine, and the reaction mixture is brought to 60 C
for 1 p.m. After returning to room temperature, the medium reaction is diluted with 10 mL of dichloromethane, and the phase organic is washed with 5 μl of saturated chloride solution sodium, dried over MgSO4 and concentrated under reduced pressure. After purification by chromatography on silica gel (15-14 days) (eluent:
cyclohexane-ethyl acetate 2/1) 13 mg of the derivative mentioned in title in the amorphous state (Yield = 31%).
The compound obtained has the following characteristics:
= 1 H NMR 400 MHz (CDCI3) (5 ppm): 8.06 (2H, d, J = 7.3 Hz); 7.72 (2H, d, J = 7 Hz); 7.63 (1H, t, J = 7.4Hz); 7.58 (1H, t, J = 7.4Hz);
7.54 to 7.44 (8H, m); 7.40 (1H, t); 6.44 (1H, s); 6.33 (1H, t); 5.73 (1 H, d, J = 5.7 Hz); 5.67 (1H, d, J = 5.7Hz); 4.96 (1 H, d, J = 5.8 Hz); 4.88 (1H, d, J = 8.3Hz); 4.45 (1 H, dd, J = 10.4 and 6.6 Hz); 4.27 and 4.12 (2H, 2d, J = 8.3 Hz); 3.80 (1H, d, J = 7Hz); 2.50 (1 H, ni);
2.26 (2H, m); 2.19 (3H, s); 2.07 (3H, s); 1.98 (3K 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 1 3-0 - [[(4S, 5 R) -4-phenyloxazolidin-3-one-5-yl] -carbonyl] -7, 1 0-O-di- (phenoxyacetyl) - 1 0-deacetylbaccatinIlI

N 0 Me OCOCH2OPh Ph .., H _ 0 I 5 O__ Me Me OCOC1A 20Ph H
Me O
HO =, ' Bz0 H - - H
AcOO
To a solution stirred at room temperature and under inert atniosphere of 78 nig (0.293 mnlOl) of acid (4S, 5R) -2.4-4,5-diphenyl-dihti, drooxazol-5-carboxylic in 3 mL of toluene anhvdre, 65 mg (0.3 nimol) of dicyclohexylcarbodiimide are added.
After 5 minutes of stirring, a solution of 237 mg (0.293 is added) mmol) of 7,10-O-bis- (phenoxyacetyl) -10-deacetylbaccatin IIlet 36 mg (0.295 niniol) of 4-diniethvlaminopyridine in 3niL of toluene, and the reaction mixture is brought to 60 ° C. for 1 h. After return at room temperature and elimination of the insolubles by filtration, the organic phase is concentrated under reduced pressure, and the product crude product obtained is purified by chromatography on silica gel (15-40 m) (eluent: cyclohexane-ethyl acetate, 1/1).
280 mg of the title compound are thus obtained in the form amorphous (Yield = 90%), and which has the following characteristics:
- NMR 'H 400MHz (CDCI3) (S ppm): 8.18 (2H, d, J = 7 Hz); 8.06 (2H, d, J = 7.1 Hz); 7.64. (1 H, t, J = 7.4 Hz); 7.58 (1H, t, J = 7.3 Hz);
7.51 (4H, m); 7.39 (5H, m); 7.25 (4H, m); 6.96 (4H, m); 6.85 (2H, d, J = 8 Hz); 6.33 (1H, s); 6.19 (1H, t, J = 9Hz); 5.68 (1 H, dd, J =
10.5 and 7.1 Hz); 5.65 (1 H, d, J = 6.9 Hz); 5.59 (1H, d, J = 7Hz); 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 = 6.9Hz); 2.65 (1 H, or); 2.37 (1 H, dd, J = 15.3 and 9.3 Hz); 2.24 (1 H, dd, J = 15.3 ct 8.7 Hz); 2.02 (3H, s); 1.95 (3H, s); 1, S0 (3H, s) and (1H, ni); 1.69 (1H, s);
1, 1 2 (3H, s); 1.01 (3H, s).

III. Hemisynthesis Example 29 Paclitaxel preparation a) From 13-0 - [[(4S, 5R) -2,4-diphenyl-4,5-di-hydrooxazol-5-yl] -carbonyl] -7-O-triethylsilylbaccatin III
To a solution stirred at room temperature and under 90 g (0.095 niol) inert atniosphere of 13-0 - [[((4S, 5R) -2,4-diphenyl-4,5-dihydrooxazol-5-yl] -carbonyl] -7-0-triethylsilylbaccatin III in a mixture of tetrahydro-furan (1,2 L) and methanol (1.2 L), 0.6 L (0.6 mol) of a 1 M aqueous HCl solution, and the reaction mixture is stirred at room temperature for 4 h 30. After adding 3.5 L of a saturated aqueous solution of hydrogen carbonate sodium, the solution is kept honiogenic by adding 6 L of tetrahydrofuran and 6 L of water, and the reaction medium is stirred an additional 1 hour 30 minutes.
After adding 15 L of ethyl acetate and 15 L of osniosated water, the residual aqueous phase is extracted with ethyl acetate (15 L). The organic phase is dried over MgSOa, concentrated under pressure reduced, and the crude product thus obtained is purified by chromatography on silica gel (15-40 m) (eluent: cyclohexane-ethyl acetate, 1/1).
75 g of Taxol * are thus isolated in the crystallized state (yield = 95%) whose characteristics are fully consistent with the data of Literature.

b) From 13-0 - [[(4S, 5R) -2,4-diphenyl-4,5-dihydrooxazol-5-yl] -carbonyl] -7-0- (2, 2, 2-trichloro-t -butoxycarbonyl) -baccatin III
To a solution stirred at room temperature and under 15 mg inert atnosphere (0.0148 mmol) 13-0 - [[((4S, 5R) -2.4-diphenyl-4,5-dihydrooxazol-5-yl] -carbonyl] -7-0- (2,2,2-trichloro-t-~ (trademark) *

butoxvcarbonvl) baccatine III in a mixture of tetrahvdrofuran (0.18 mL) and methanol (0.18 mL), add 90} tL (0.09 niniol) of a 1Nt aqueous HCl solution, and the reaction mixture is stirred at room temperature for 5 h. After addition of 0.6 tnL
5 of an aqueous solution drawn from soditini hydrogen carbonate, solution is maintained honiogenic by addition of 1 niL of tetrahvdroftirane and 1 µL of water, and the reaction mixture is stirred for 1 h 30 additional. After addition of 2.5 mL of ethyl acetate and 2.5 niL of osmosis water, the residual aqueous phase is extracted with acetate 10 ethyl (2.5 mL). The combined organic phases are dried over Mg SO ;, and concentrated with reduced pressure.
This gives 14 mg dc 7-0- (2,2,2-trichloro-t-butoxvcarbonyl) -taxol in the brtit state (Yield = 93%) which is used without further purification in the next step.
15 To a stirred solution at room temperature of 13 mg (0.0128 mmol) of 7-0- (2,2,2-trichloro-t-butoxvcarbonyl) -taxol in 2 mL of ethyl acetate, 30 L (0.525 mmol) of acid are added acetic acid and 22.5 nig (0.344 nimol) of zinc powder. After 2:30 a.m.
stirring at room temperature and control by TLC, and after 20 dilution of the reaction medium with 3 μl of ethyl acetate, the phase organic is washed with osniated water (1 mL), with a solution saturated aqueous hydrogen carbonate from sodiuni (1 mL), again with water, dried over Mg SO4 and concentrated under reduced pressure.
After chromatography of the crude product on silica gel (1-5 25 ni) (eluent: cyclohexane-ethyl acetate, 6/4) 9.5 are thus isolated nig of 7hxol in the crystallized state (Yield = 89%).

* (trademark)

Claims (35)

1. Process for the preparation of a side chain precursor of taxanes of formula Ila or Ilb as defined below, in which transforms a cis-.beta.-aryl-glycidate derivative of general formula I

in which Ar represents an aryl radical, and R represents a hydrocarbon radical, so as to set up regio- and stereo-specifically the .beta.-Nalcoylamide and I'.alpha.-hydroxyle or their cyclic precursors in a single step per a Ritter reaction, which consists either:
a) in the direct synthesis of a linear chain by reacting a cis-p-aryl-glycidate derivative of general formula I defined above, with a nitrile of formula in which R2 represents an aryl radical, in the presence of a protonic acid and water, to obtain the derivative of the .beta.-aryl-isoserine of general formula Ila, in which Ar, R and R2 are defined above; is b) in the direct synthesis of a cyclic chain by reacting a cis-.beta.-aryl-glycidate derivative of general formula I defined above, with a nitrile of formula R'2-CN

in which R'2 represents R2 defined above, or a lower alkyl radical or lower perhaloalkyl, in the presence of a Lewis acid or a protonic acid, in an anhydrous medium, to obtain the oxazoline of general formula IIb in which Ar, R and R'2 are defined above. 2. Method according to claim 1, characterized in that R
represents a linear or branched alkyl or a cycloalkyl optionally substituted by one or more alkyl groups. 3. Method according to claim 1, characterized in that R
represents an optically pure enantiomer of a chiral hydrocarbon radical of strong steric hindrance. 4. Method according to claim 3, characterized in that R
represents a cycloalkyl substituted by one or more alkyl groups. 5. Method according to claim 4, characterized in that R
represents a cyclohexyl. 6. Method according to claim 3, characterized in that R is a enantiomer of the menthyl radical. 7. Method according to claim 6, characterized in that R is the (+) - menthyl. 8. Method according to any one of claims 1 to 7, characterized in that R'2 represents trichloromethyl. 9. Method according to any one of claims 1 to 8, characterized in that the cis-.beta.-phenyl-glycidate derivative of formula general I is configuration (2R, 3R) and derivatives of general formulas IIa and IIb obtained are of configuration (2R, 3S). 10. Method according to any one of claims 1 to 9, characterized in that Ar and R2 represent phenyl. 11. Method according to any one of claims 1 to 10, characterized in that the protonic acid in step a) is chosen from acid sulfuric, perchloric acid and tetrafluoroboric acid, Lewis in step b) is chosen from the acid boron trifluoride complex acetic, boron trifluoride etherate, antimony pentachloride, tetrachloride tin and titanium tetrachloride, and protonic acid in step b) East tetrafluoroboric acid. 12. Method according to claim 1, characterized in that the derivative .beta.-aryl-isoserine of general formula IIa is transformed by protection of hydroxy by a protective group (GP) to obtain a derivative of formula general II'a in which Ar, R and R2 are defined as in claim 1 and GP represents a group protector of the hydroxy function, suitable for the synthesis of taxanes. 13. Method according to claim 12, characterized in that the group GP protector is chosen from alkoxyether, aralkoxyether, aryloxyether and haloalkoxycarbonyl, tetrahydro-pyranyl radicals and .beta.-alkoxycarbonyl, .beta.-halogenated and alkylsilylated ethers, and radicals alkoxyacetyl, aryloxyacetyl, haloacetyl and formyl. 14. Method according to claim 13, characterized in that the group GP protector is chosen from methoxymethyl, 1-ethoxyethyl groups, benzyloxy-methyl and (.beta.-trimethylsilyl-ethoxy) -methyl. 15. Method according to claim 1, characterized in that the derivative .beta.-aryl-isoserine of general formula IIa is transformed into new cyclic intermediates, oxazolidinone of general formula IIIa in which:
Ar and R are defined as in claim 1 by reacting a derivative of the .beta.-aryl-isoserine of general formula IIa with an ester haloalkoxycarbonyl, then by cyclization in the presence of a strong organic base, possibly then transformed into the corresponding amide of general formula III'a in which Ar and R are defined as in claim 1, and R "2 represented R'2 as defined in claim 1, an alkoxy radical, or a radical alkyl, linear or branched comprising at least one unsaturation, in the presence of a acylating agent of formula:

R "2-CO-X
in which:
R "2 is defined as above and X represents a halogen, or a corresponding acid anhydride. 16. Method according to claim 15, characterized in that the ester haloalkoxycarbonyle is 2,2,2-trichloroethoxycarbonyl (TrOC) and the base strong organic is diazabicyclo-undecene (DBU). 17. Method according to claim 1, characterized in that one hydrolyzes the oxazoline of general formula IIb in an acid medium, to obtain the derivative of .beta.-aryl-isoserine of general formula IIIb, in which Ar, R and R'2 are defined as in claim 1, optionally then transformed into the corresponding amide of formula general III'b in which Ar, R and R'2 are defined as in claim 1 and R "2 is defined as in claim 15. 18. Method according to any one of claims 1 to 17, characterized in that, by gentle saponification, the derivatives of formulas IIa, II'a, IIb, IIIa, III'a, IIIb and III'b defined as in claims 1, 12, 15 and 17, but in which R represents a hydrogen atom. 19. Compound precursor of side chains of taxanes, characterized in that it is selected from the derivatives of general formulas IIa, IIb, He, IIIb and III'b below:

in which Ar, R2, and R'2 are defined as in claim 1;
GP is defined as in claim 12;
R "2 is defined as in claim 15; and R represents an optically pure enantiomer of a hydro-carbon radical chiral of strong steric hindrance. 20. Compound according to claim 19, characterized in that R is a enantiomer of the menthyl radical. 21. Compound according to claim 20, characterized in that R is the (+) - menthyl. 22. Compound according to any one of claims 19 to 21, characterized in that the derivatives of general formulas IIa, IIb, IIIb, and III'b are configuration (2R, 3S). 23. Compound precursor of side chains of taxanes, characterized in that it is selected from the derivatives of general formulas Illa and III'a following:

in which:
Ar and R are defined as in claim 1 or R represents a hydrogen atom, and R "2 is defined as in claim 15. 24. Compounds according to claim 23, characterized in that it is configuration (2R, 3S). 25. Process for the preparation of a taxane of general formula IV, CB IV
in which:

B represents a radical 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 group protecting the function hydroxy GP1, and R5 represents a protecting group for the hydroxy function GP2, and C represents a side chain chosen from the radicals of formulas Ila, II'a, llb, Illa, III'a, Illb and III'b:

in which Ar, R2 and R'2 are defined as in claim 1, GP
is defined as in claim 12 and R "2 is defined as in claim 15, by esterification of a suitable derivative of baccatin III
of general formula V, carrying a hydroxy function at C-13, with one of the derivatives of formulas IIa, II'a, IIb, IIIa, III'a, IIIb and III'b, for which R represents a hydrogen atom, as obtained by the process according to claim 20. 26. The method of claim 25, characterized in that the protective groups GP1 and GP2 are independently of each other usual groups used in the hemisynthesis of taxanes, or GP1 and GP2 together form a divalent radical of formula -SiR7-O-SiR8-in which R7 and R8, independently of one another, represent a radical sterically hindered alkyl. 27. The method of claim 26, characterized in that the protective groups GP1 and GP2 are independently chosen from among trialkylsilyles, 2,2,2-trichloroethoxycarbonyl, haloalkoxy-hindered, linear or branched carbonyl comprising at least one atom halogen, acyl radicals whose carbon has carbonyl function carries at least one oxygen atom, and the trialkylgermanyl radical. 28. The method of claim 27, characterized in that the acyl radicals including carbon in .alpha. of the carbonyl function leads to minus one oxygen atom are chosen from - the alkoxy- or aryloxyacetyl radicals of formula in which R6 represents a sterically hindered alkyl radical, a radical cycloalkyl or an aryl radical, and - the arylidenedioxyacetyl radicals of formula in which Ar "represents an arylidene radical. 29. Method according to claim 28, characterized in that:
the sterically hindered alkyl radical is a linear alkyl radical or branched in C1-C6 substituted by one or more bulky substituents chosen among halogens, C1-C6 or branched alkyl linear radicals, alkoxy linear or branched in C1-C6 or cycloalkyl in C3-C6 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 C1-C6 alkyl radicals, alkoxy linear or branched C1-C6 or aryl, substituted by one or more alkyl radicals linear or branched in C1-C6, the aryl radical is a phenyl, naphthyl, anthryl or phenanthry radical, optionally substituted by one or more bulky substituents chosen among the halogens, the linear or branched C1-C6 alkyl radicals, alkoxy linear or branched C1-C6 or aryl, optionally substituted by one or two bulky substituents above, in ortho- and ortho '- of the bond ether, and the arylidene radical is a phenylene, naphthylene, anthrylene radical or phenanthrylene, optionally substituted with one or more substituents bulky chosen from halogens, linear alkyl radicals or branched in C1-C6, linear alkoxy or branched in C1-C6 or aryl. 30. Method according to claim 29, characterized in that:
the cycloalkyl radical is menthyl, its racemic, one of its enantiomers or their mixtures, and the aryl radical is a phenyl. 31. Method according to any one of claims 25 to 27, characterized in that R4 represents an acetyl radical, and GP2 represents a trialkylsilyl radical, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxy-carbonyl, 2,2,2,1-tetrachloroethoxy-carbonyl, 2,2,2-trichloro-t-butoxy-carbonyl, trichloromethoxycarbonyl, phenoxy-acetyl or trialkyl-germanyl. 32. Method according to any one of claims 25 to 27, characterized in that R4 represents a group GP1, and GP1 and GP2 represent a 2,2,2-trichloroethoxycarbonyl or phenoxyacetyl radical, or together form a divalent radical of formula -SiR7-O-SiR8-in which R7 and R8 each represent an isopropyl radical. 33. Method according to any one of claims 25 to 31, characterized in that C represents a radical of formula IIa, in which Ar and R2 represents phenyl, and R4 represents an acetyl radical. 34. Method according to any one of claims 25 to 33, characterized in that the deprotection of the hydroxy of the derivatives of general formula IV, and where appropriate, simultaneously or separately, the opening of the oxazolinic cycle of the radicals of formula IIb, for obtain a taxane derivative of general formula VI:

in which Ac, Bz and Me are defined as in claim 25, R'2 defined as in claim 1;

R4 represents a hydrogen atom or an acetyl radical, and R5 represents a hydrogen atom. 35. A taxane derivative of general formula IV
CB IV
wherein C is defined as in any one of claims 25 to 33 and B is defined as in claim 25, with the exception of derivatives for which C represents a radical of formula IIa, II'a, IIb, IIIb or III'b, and GP1 and / or GP2 are independently of each other of the usual groupings employed in the hemisynthesis of taxanes.