AU768838B2

AU768838B2 - Method for preparing an aza-macrolide with 4'' (R) NH2

Info

Publication number: AU768838B2
Application number: AU19870/00A
Authority: AU
Inventors: Laurent Garel; Ronan Guevel; Patrick Leon; Frederic Lhermitte; Gilles Oddon; Denis Pauze
Original assignee: Merial SAS
Current assignee: Boehringer Ingelheim Animal Health USA Inc
Priority date: 1999-01-18
Filing date: 2000-01-17
Publication date: 2004-01-08
Anticipated expiration: 2020-01-17
Also published as: NZ513025A; JP2003505340A; AU1987000A; DE60014849D1; FR2788524B1; EP1144428A1; CA2359967C; PT1144428E; BR0007593A; BR0007593B1; BRPI0007593B8; ZA200105825B; DK1144428T3; ATE279426T1; EP1144428B1; FR2788524A1; ES2232414T3; USRE40040E1; DE60014849T2; CA2359967A1

Abstract

The subject-matter of the invention is a process for the stereoselective preparation of a compound of general formula I by stereoselective displacement by a nitrogenous nucleophilic compound of the activated alcohol functional group present at this 4'' position in a corresponding derivative of formula II.

Description

WO 00/42056 PCT/FROO/00089 -1- 1 PROCESS FOR THE PREPARATION OF AN AZAMACROLIDE WITH 4"(R)-NH 2 A subject-matter of the present invention is a process of particular use in converting the 4"(S)-OH functional group of the cladinose unit of an azamacrolide to 4"(R)-NH 2 The present invention relates more particularly to the field of macrolide antibiotics of erythromycin type and more particularly their azamacrolide derivatives which form the subject-matter of Patent EP 508,699 and which correspond to the following general formula: NMe 2

QH

3

R..

2' CH N 8a CH CH3

OH

mCH3 CH OMe 3 1Me CH3 CH 3

'CH

3 0 4-

NH

2

CH

3 in which R is a hydrogen atom or a C 1 -Co 1 alkyl, C 2

-C

10 alkenyl or C 6

-C

12 arylsulphonyl group, which are, if appropriate, substituted.

These compounds are obtained from erythromycin and their synthesis involves two major stages: the creation of the 8a-azalide macrocycle starting from the oxime, which is subjected to a stereospecific Beckmann rearrangement, and the modification of the cladinose group at the 4" position, which consists of the conversion of 2 the 4"(S)-OH to 4"(R)-NH 2 that is to say with inversion of configuration, which can be illustrated as follows: RO M e RO OMe O H 2

'NH

2 In fact, the route currently used to provide for this conversion of the 4"(S)-OH to 4"(R)-NH 2 is not completely suitable for production on an industrial scale.

It involves, successively, an oxidation of the hydroxyl functional group at the 4" position to a ketone functional group and then the conversion of this ketone to an oxime, which, by reduction, results in an approximately 1 to 1 mixture of the expected amino derivative and of its 4" epimer.

This synthetic route consequently has the major disadvantage of requiring the formation of sp2 C-4" intermediates and- thus of losing the stereochemical information initially present at the sp3 C-4" of the cladinose unit. This result is all the more of a nuisance since the isomers, acquired on conclusion of 20 this synthetic route, are obtained with a low yield of about 20% and are in addition difficult to separate.

Thus, for a crude reaction yield of about 20%, only approximately 7% of the amino derivative with inversion of configuration is obtained.

Advantageously, at least one embodiment of the present invention may provide a new access route to these derivatives, aminated at the 4" position, which advantageously makes it possible to retain a significant stereoselectivity and provides a satisfactory yield.

More specifically, a first subject-matter of the present invention is a process for the stereoselective preparation of a compound of general formula I 3 CH3 CHr 3 'F I /fln3 1 0 NA 2 CH3 in which: R is a hydrogen atom or a Ci-Cio alkyl, C2-C 1 0 alkenyl or C 6

-C

12 arylsulphonyl group, which are, if appropriate, substituted, and A, which are identical or different, are a hydrogen atom, a nitrogen atom, if appropriate substituted, a Ci-C4 alkyl group, which is optionally substituted by one or more aryl groups, which are, if appropriate, substituted, an R 2 CO or R 2 S0 2 group, with R 2 being a hydrogen atom, a Ci-C 8 alkyl group or an aryl group, which are, if appropriate, substituted, and the symbol V indicates that there has been inversion of configuration at the C-4" carbon with respect to the compound of general formula II, from a compound of general formula II

H

3 C N,CH 3

N

CH

3

H

H I HBa HO"' 0 O CH 4 with: R as defined in general formula I and Pi being a protective group for the hydroxyl functional group at the 2' position, characterized in that it comprises at least the stages consisting in: activating the hydroxyl functional group at the 4" position in the compound of general formula II, in order to obtain a compound of general formula III

H

3 C ,.CH3

QH

3 CHH3 3 CH 8a

CH

3 z 0 C ot'CH3

HOOR,

CH

3 in which: R and P 1 are as defined in general formulae I and II and ORI is a leaving group, in bringing the said compound of general formula III thus obtained into contact with a nitrogenous nucleophilic derivative under conditions which are sufficient to allow the stereoselective displacement of the hydroxyl functional group activated by the said nitrogenous nucleophile, and deprotecting the hydroxyl functional group at the 2' position, in order to result in the expected compound of general formula I.

The claimed process thus has the significant advantage of not requiring the formation of the sp2 C-4" intermediate necessarily generated in the conventional synthetic route discussed above. It involves only an 5 inversion of configuration at the 4" position and this inversion is obtained efficiently by displacement by a nitrogenous nucleophile of the activated alcohol functional group present at this 4" position.

Consequently, the claimed process proves to be particularly advantageous in preparing, especially with a very satisfactory yield, a 4"-(R)-NA 2 derivative of general formula I'

H

3

%C.CH

3 CH N 8 a CH HO"* 0

CH

3 HO""

OH

CH' C H3 oCHC3 H) S

NA

2 with A and R as defined above, from a 4"(S)-OH azamacrolide derivative of general formula II' formula III in which R and P1 are as defined above.

As regards the leaving group represented by ORI in general formula III, it is preferably selected from C1-C20 alkyl sulphonates, C5-C6 aryl or heteroaryl 6 sulphonates or CE to C26 alkylaryl sulphonates, which are substituted, if appropriate, by one or more halogen atoms, preferably fluorine, and/or a nitro, cyano or trifluoromethyl group.

The leaving group represented by ORi in general formula III is preferably a group selected from mesylate, triflate and tosylate and is more preferably a triflate group.

Use may in particular be made according to the invention, as nitrogenous nucleophilic compound, of compounds of the following types: ammonia, amines which may or may not be substituted by deprotectable groups, such as, for example, a benzyl group or one of its derivatives, amides, imides, sulphonamides, sulphonimides, hydrazines or azides.

According to a preferred alternative form of the claimed process, it is more preferably an organic organosoluble azide which can be generated in situ.

The leaving groups deriving from the activation of the hydroxyl functional group at the 4" position in the general formula II by a compound of general formula IVA or IVB

BSO

2 X or (BSO 2 2 0 IVA IVB with: X being a halogen atom or a nitrogenous heterocycle, preferably an imidazole ring, and B being a Ci-C20 alkyl, C 5

-C

6 aryl or heteroaryl or C6-C26 alkylaryl sulphonate group, which are or are not substituted by one or more halogen atoms, preferably fluorine, and/or a nitro, cyano or trifluoromethyl group, are very particularly suitable for the invention.

According to a preferred alternative form of the invention, the compound of general formula III obtained by activation with a compound of general formula IVA or IVB is brought into contact with an 7 organic organosoluble azide in order to result, by stereoselective nucleophilic displacement, in a compound of general formula V

H

3 C\ NCH 3

H

3 H O D O H0 CH CH 3

OCH

3

V

CHI O CH>''IH CS< 0 0 0

N

3 CH3 in which R and P 1 are as defined in general formula II and the symbol V indicates that there has been inversion of configuration at the C-4" carbon with respect to the compound of general formula II, Preferably, the C-4" carbon of the compound of general formula II has an S configuration and that of the compound of general formula V an R configuration.

According to this alternative form of the claimed process, a reduction of the said compound of formula V can additionally be carried out, prior or otherwise to the deprotection of the hydroxyl functional group at the 2' position, so as to obtain a compound of general formula I in which A is a hydrogen atom. This reduction of the azide functional group can be carried out by any conventional method, such as those described by E.F.V. Scriven et al., Chem. Rev.

(1988), 88, 297-368. A catalytic reduction with hydrogen or hydrazine in the presence of palladium-oncharcoal, for example, or of Raney nickel can in particular be carried out.

On conclusion of this reduction, the expected amino derivative, that is to say with inversion of configuration the 4" position, and preferably the 8 4"(R)-NH 2 derivative is thus recovered with a satisfactory yield.

Consequently, this alternative form of the claimed process is very particularly of use in the preparation of the compounds of general formula I"

H

3 C NCH 3

CH

3 SHO' H

OH

CH O CH ,CH 3

CH

3 O CH3

CH

3 0

NH

2 CH3 in which: R is a hydrogen atom or a C1-Cio alkyl, C2-C10 alkenyl or C6-C12 arylsulphonyl group, which are, if appropriate, substituted, from a compound of general formula II' as defined above.

Mention may very particularly be made, as illustration of the azides which are suitable for the present invention, of tetra(Cl to C20 alkyl)ammonium or -phosphonium azide, substituted or unsubstituted triarylsulphoniums and hexa(C1 to C20 alkyl)guanidiniums.

According to a preferred alternative form of the invention, it is a tetraalkylammonium azide and more particularly tetrabutyl- or tetraoctylammonium azide.

In a specific embodiment of the invention, the azide derivative is formed in a two-phase medium and more specifically in solid/liquid phase transfer. In this case, the organosoluble azide is generated in situ 9 from an inorganic azide, such as sodium azide, and from a phase transfer agent in the presence of the compound of general formula III in an organic solvent. The phase transfer agent is preferably a tetra(C 1 to C 20 alkyl)ammonium or -phosphonium methanesulphonate.

As regards the compound of general formula II, it is generally obtained beforehand by protection of the hydroxyl functional group at the 2' position in the corresponding derivative. Of course, this protection is carried out conventionally using a conventional protective group for the hydroxyl functional group, such as those which appear in "Protective Groups in Organic Synthesis", Second Edition, Theodora W. Greene and P. G. Wuts, Wiley Intersciences, p. 10-142. The procedures for carrying out the protecting and deprotecting operations are also described in the work referred to above.

Following this protection of the hydroxyl functional group at the 2' position, the hydroxyl functional group at the 4" position is activated. This activation of the compound of general formula II is also carried out under conventional operating conditions, such as those described in "Protective Groups in Organic Synthesis", Second Edition, Theodora W. Greene and P. G. M. Wuts, Wiley Intersciences, p.

117-118. The examples submitted below describe a detailed procedure for the activation of the 4" hydroxyl functional group with triflic anhydride.

As regards the nucleophilic displacement of the leaving group at the 4" position, it is carried out in an organic solvent, preferably an anhydrous organic solvent. In the preferred alternative form of the invention employing an organosoluble azide, aromatic solvents, such as benzene and toluene, or ethers, such as THF or methyl tert-butyl ether, are suitable in particular as solvents.

The nitrogenous nucleophilic compound, preferably the azide, is used in a proportion of approximately 1 to 30 equivalents with respect to the 10 compound of formula III and preferably in a proportion of approximately 1 to 5 equivalents.

The temperature is conventionally between and 180°C. As a general rule, it is adjusted so as to favour the kinetics of the reaction without harming the stability of the compounds.

According to a preferred alternative form of the invention, in the first stage, the hydroxyl functional group at the 4" position is activated by a trifluoromethanesulphonate group and the nucleophilic substitution is carried out with inversion of configuration with tetrabutyl- or tetraoctylammonium azide in toluene at room temperature.

According to a preferred alternative form of the invention, R is a methyl group in the general formulae I, II, II', III and V and A a hydrogen atom in the general formula I and I' Another subject-matter of the present invention is the compounds of general formula VI

H

3 C CH 3 ooo eeoo *eoo* .ae *e o.

ft in which

P

2 is a hydrogen atom or a protective group, R is a hydrogen atom or a C 1 -Cio alkyl, C2-C1o alkenyl or C6-C12 arylsulphonyl group, which are, if appropriate, substituted, and ORI is a leaving group, as intermediate in the preparation of a compound of general formula I.

11 Preferably, R is a methyl group, ORI is a triflate group and more preferably the C-4" carbon has an S configuration.

The present invention also relates to the compounds of general formula VII

H

3 C'N CH 3

CH

3 P20FN2' CH 83

CH

3 HOe' 0 0

CH

3

OH

CHI" 0 CH 3

CH

3

(VII)

in which

P

2 is a hydrogen atom or a protective group, R is a hydrogen atom or a Ci-Clo alkyl, C2-C10 alkenyl or C6-C12 arylsulphonyl group, which are, if appropriate, substituted, and A, which are identical or different, are a nitrogen atom, if appropriate substituted, a CI-C4 alkyl group, which is optionally substituted by one or more aryl groups, which are, if appropriate, substituted, as intermediate in the preparation of a compound of general formula I.

Preferably, R is a methyl group and NA 2 an N 3 20 group and more preferably the C-4" carbon has an R configuration.

P:'OPERKbm\2438164 206 do.-2507/03 -12- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this.

specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

The examples which appear below are presented by way of illustration and without implied limitation of the present invention.

EXAMPLE 1 Preparation of the compound 4"-dehydroxy-4" (R)-amino- 2'acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin 20 A: The synthetic scheme used is as follows: 0 0 0 0 0

C~I

e) 0 01 0 NMe 2 WO 00/42056 PCT/FROO/00089 14 All the tests are carried out under an inert atmosphere.

1) Formation of 4"(S)-trifluoromethanesulphonate-2'acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A: Pyridine (39.5 mg, 0.51 mmol, 5 equiv.) is added to a solution of alcohol 2'-acetoxy-9-deoxo-8aaza-8a-methyl-8a-homoerythromycin A (0.1 g, 0.12 mmol, 1 equiv.) in anhydrous dichloromethane (0.4 ml). The solution is cooled to 0°C and then a solution of triflic anhydride (42.3 mg, 0.15 mmol, 1.2 equiv.) is added dropwise. The solution is stirred for 1 h at 0°C and then 30 min at room temperature. After diluting the reaction mixture with anhydrous dichloromethane ml), the reaction mixture is cooled to 0°C and then hydrolysed by addition of a saturated aqueous- sodium bicarbonate solution (10 ml). The organic phase is separated and then washed with distilled water (10 ml), dried over magnesium sulphate and evaporated. The crude product is taken up in heptane (10 ml) in order to remove any trace of residual pyridine by azeotropic distillation. 110.4 mg of 4"(S)-trifluoromethanesulphonate-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A are obtained with a purity greater of than or equal to 90%. The structure is confirmed by NMR and MS analysis.

2)Formation of 4"-dehydroxy-4"(R)-azido-2'-acetoxy-9deoxo-8a-aza-8a-methyl-8a-homoerythromycin A: A 0.58M solution of tetrabutylammonium azide in toluene (4.5 ml; app. 1.3 equiv.) is added to unpurified 4"(S)-trifluoromethanesulphonate-2'-acetoxy- 9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A from the preceding stage (1.84 g, 2.0 mmol, 1 equiv.) at room temperature. The reaction mixture is stirred for 3 days at room temperature and then diluted with toluene (25 ml). This solution is washed three times with distilled water (3 x 10 ml), then dried over magnesium sulphate and evaporated. 1.63 g of 4"-dehydroxy-4"(R)azido-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homo- 15 erythromycin A are obtained with a purity of 70%. The structure is confirmed by NMR and MS analysis.

3) Formation of the compound 4"-dehydroxy-4"(R)-amino- 2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin

A:

Raney nickel (200 mg) is added to a solution in isopropanol (5 ml) of unpurified 4"-dehydroxy-4"(R)azido-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A from the preceding stage (250.0 mg, 0.30 mmol, 1 equiv.). Hydrazine monohydrate microlitres, 0.6 mmol, 2 equiv.) is added every minutes. The reaction time is 2 h. The reaction mixture is diluted with ethyl acetate (10 ml) and filtered. The filtrate is washed with a saturated aqueous sodium bicarbonate solution (10 ml) and then with water ml). After drying over magnesium sulphate, the filtrate is evaporated. 230 mg of 4"-dehydroxy-4"(R)amino-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8ahomoerythromycin A are obtained with a purity of The structure is confirmed by NMR and MS analysis.

EXAMPLE 2 Tetraoctylammonium azide (190.3 ml, 0.5 mmol, equiv.) is added at room temperature to a solution of 4"(S)-trifluoromethanesulphonate-2'-acetoxy-9-deoxo-8aaza-8a-methyl-8a-homoerythromycin A (92.3 mg, 0.1 mmol, 1 equiv.) in toluene (0.2 ml) After stirring for two days at room temperature, tetraoctylammonium azide (58 mg, 0.15 mmol, 1.5 equiv.) is again added. After stirring for an additional two days at room temperature, the reaction mixture is diluted with toluene (10 ml) and washed with water (10 ml). The organic phase is separated and dried over sodium sulphate. After evaporating the solvents, 'H NMR analysis shows the predominant presence of the compound 4"-dehydroxy-4"(R)-azido-2'-acetoxy-9-deoxo-8a-aza-8amethyl-8a-homoerythromycin A.

EXAMPLE 3 Tetrabutylphosphonium methanesulphonate (355 mg, 1 mmol, 5 equiv.) and then sodium azide 16 (325 mg, 5 mmol, 25 equiv.) are successively added to a solution of 4"(S)-trifluoromethanesulphonate-2'acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A (185 mg, 0.2 mmol, 1 equiv.) in toluene (0.4 ml) at room temperature. After stirring for three days at room temperature, the reaction mixture is diluted with toluene (10 ml) and washed with water (10 ml). The organic phase is separated and dried over sodium sulphate. After evaporating the solvents, 1 H NMR analysis shows the predominant presence of the compound 4"-dehydroxy-4"(R)-azido-2'-acetoxy-9-deoxo-8a-aza-8amethyl-8a-homoerythromycin A.

EXAMPLE 4 Tetraoctylammonium methanesulphonate (217 mg, 0.38 mmol, 3.8 equiv.) and then tetrabutylammonium azide (158 mg, 2.5 mmol, 25 equiv.) are successively added to a solution of trifluoromethanesulphonate-2'-acetoxy-9-deoxo-8a-aza- 8a-methyl-8a-homoerythromycin A (92 mg, 0.1 mmol, 1 equiv.) in toluene (0.25 ml) at room temperature.

After reacting for 4 days at room temperature, the reaction mixture is diluted with toluene (10 ml) and washed with water (10 ml). The organic phase is separated and dried over sodium sulphate. After evaporating the solvents, H NMR analysis shows the predominant presence of the compound 4"-dehydroxy- 4"(R)-azido-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8ahomoerythromycin A.

EXAMPLE A solution of 4"(S)-trifluoromethanesulphonate- 2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A (21.4 mg, 0.023 mmol) in N-methylpyrrolidinone is saturated with gaseous ammonia. This solution is stirred for 48 h at room temperature. The reaction mixture is subsequently diluted with ethyl acetate ml) and washed with water (15 ml). The organic phase is separated, dried over sodium sulphate and evaporated. LC/MS analysis shows the formation of 22%, by internal standardization, of 4"-dehydroxy-4"(R)- 17 amino-2' -acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A.

Claims

1. Process for the stereoselective preparation of a compound of general formula I H3CN CH3 H 3 2N CH Na CH 3 a HU. i ar.0 0 C H3 HO"*9 OH CH" CH 3 ,*CH 3 (I) CH 3 CH 'CH 3 0 0 r NA 2 8H 3 in which: R is a hydrogen atom- or a C 1 -Cio alkyl, C 2 -C 10 alkenyl or C 6 -C 1 2 arylsulphonyl group, which are, if 10 appropriate, substituted, and A, which are identical or different, are a hydrogen atom, a nitrogen atom, if appropriate substituted, a C 1 -C 4 alkyl group, which is optionally substituted by one or more aryl groups, which are, if appropriate, substituted, an R 2 CO or R 2 SO2 group, with R 2 being a hydrogen atom, a Ci-C 8 alkyl group or an aryl group, which are, if appropriate, substituted,.and 20 the symbol V indicates that there has been inversion of configuration at the C-4" carbon with respect to the compound of general formula II, from a compound of general formula II 19 CH 3 (II) with R as defined in general formula I and P 1 being a protective group for the hydroxyl functional group at the 2' position, said process comprising at least the stages consisting- in: activating the hydroxyl functional group at the 4" position in the compound of general formula II, in order to obtain a compound of general formula III r r HOllI... r r r r (III) in which: R and Pi are as defined in general formulae I and II and ORI is a leaving group, 20 in bringing the said compound of general formula III thus obtained into contact with a nitrogenous nucleophilic derivative under conditions which are sufficient to allow the stereoselective displacement of the hydroxyl functional group activated by the said nitrogenous nucleophile, and deprotecting the hydroxyl functional group at the 2' position, in order to result in the expected compound of general formula I.

2. Process according to claim 1, wherein a 4"-(R)-NA 2 derivative of general formula I' H 3 CN.CH 3 2 CH 3 CH Na H HO" to. CH 3 HO J" OH C H O CH'3 CH 3) H C CHOH 15 cH H3 C CH 3 i N A 2 HC3 with A and R being as defined in claim 1 is prepared from a 4"(S)-OH azamacrolide derivative of general formula II' H 3 C CH 3 N H 3 P CH J C CH 3 H. s CH 3 I, CH 3 CH 3 (Ir 21 in which R and P1 are as defined in claim 1.

3. Process according to claim 1 or 2, wherein the leaving group represented by ORi in general formula III is selected from C 1 -C 20 alkyl sulphonates, Cs-C 6 aryl or heteroaryl sulphonates or C6-C26 alkylaryl sulphonates, which are substituted, if appropriate, by one or more halogen atoms, preferably fluorine, and/or a nitro, cyano or trifluoromethyl group.

4. Process according to any one of claims 1 to 3, wherein the leaving group represented by ORi in general formula III is a triflate group. Process according to any one of claims 1 to 4, wherein the leaving group derives from the activation of the hydroxyl functional group at the 4" position in the general formulaII by a compound of formula IVA or IVB BSO 2 X or (BSO 2 2 0 IVA IVB with: -X being a halogen atom or a nitrogenous heterocycle, preferably an imidazole ring, and B being a C 1 -C 20 alkyl, C

5 -C 6 aryl or heteroaryl 25 or C 6 -C 26 alkylaryl sulphonate group, which are substituted, if appropriate, by one or more halogen atoms, preferably fluorine, and/or a nitro, cyano or trifluoromethyl group.

6. Process according to any one of claims 1 to wherein the nitrogenous nucleophilic compound is o selected from ammonia, amines which may or may not be substituted by deprotectable groups, amides, imides, 35 sulphonamides, sulphonimides, hydrazines or azides.

7. Process according to any one of the preceding claims, wherein the nitrogenous nucleophilic compound is used in a proportion of 22 approximately 1 to 30 equivalents with respect to the compound of general formula III.

8. Process according to any one of claims 1 to 7, wherein the nitrogenous nucleophilic compound is an organic organosoluble azide, generated, if appropriate, in situ.

9. Process according to claim 8, wherein the compound of general formula II is activated with a compound of general formula IVA or IVB as defined in claim the compound of general formula III thus obtained is subsequently brought into contact with an organic organosoluble azide in order to result, by stereoselective nucleophilic displacement, in a compound of general formula V H 3 C N,CH 3 N r o.. 20 in which R and P, are as defined in general formula II and the symbol V indicates that there has been inversion of configuration at the C-4" carbon with respect to the compound of general formula II.

10. Process according to claim 9, wherein a reduction of the said compound of formula V is additionally carried out, so as to obtain a compound of general formula I in which A is a hydrogen atom. P:'OPER\Kbln2438164 206 doc-280 7 /03 -23-

11. Process according to claim 9 or 10, wherein the C- 4" carbon of the compound of general formula II has an S configuration and that of the compound of general formula V an R configuration.

12. Process according to claim 11 wherein a reduction of the said compound of formula V is additionally carried out, so as to obtain a compound of general formula I": H 3 C N CH 3 CH3 N HOlllno. OH CH CH Nia O H C Z O C O CH3/ 00 /C 3H 3 CH3 HCH3 0 4 S 10 CH3 NH 2

13. Process according to any one of claims 8 to 12, wherein the organic organosoluble azide is selected from tetra(Cl to C 20 alkyl)ammonium or -phosphonium 15 azide, substituted or unsubstituted triarylsulphoniums S* and hexa(CI to C 20 alkyl)-guanidiniums.

14. Process according to any one of claims 8 to 13, wherein the azide is tetrabutylammonium azide or tetraoctylammonium azide.

P:\OPER\Kbm\2438164 206,doc.28/07/03 -24- Process according to any one of claims 8 to 14, wherein the nucleophilic displacement of the leaving group at the 4" position by an organic organosoluble azide is carried out in a solvent selected from aromatic solvents, such as benzene and toluene, and ethers, such as methyl tert-butyl ether and THF.

16. Process according to any one of the preceding claims, wherein in the first stage, the hydroxyl functional group at the 4" position is activated by a trifluoromethanesulphonate group and the nucleophilic substitution is carried out with inversion of configuration with tetrabutyl- or tetraoctylammonium azide in toluene at room temperature.

17. Process according to any one of the preceding claims, wherein R is a methyl group in the general formulae I, II, II', III and V and A a hydrogen atom in the general formulae I and I'.

18. Compound of general formula VI P* w w CH C' H 3 H3 (VI) **CH3 ,41CH 0V OR, n P:\OPER\Kbn\2438164 206 doc-28,'07/03 in which P 2 is a hydrogen atom or a protective group, R is a hydrogen atom or a C-Clo alkyl, C 2 -C 10 alkenyl or C6-C12 arylsulphonyl group, which are, if appropriate, substituted, and ORI is a leaving group, as intermediate in the preparation of a compound of general formula I.

19. Compound of general formula VI according to claim 18, wherein R is a methyl group and OR 1 a triflate group.

Compound of general formula VI according to claim 18 or 19, wherein the C-4" carbon has an S configuration.

21. Compound of general formula VII *H 3 C CH 3 H P 2 H a CH HUC' '00 b 0 CH3 OH CH CH ,CH 3 C CHH 4 C H 3 *NA 2 8H 3 in which P 2 is a hydrogen atom or a protective group, R is a hydrogen atom or a Ci-Co 1 alkyl, C 2 -C 1 0 alkenyl or C 6 -C 12 arylsulphonyl group, which are, if appropriate, substituted, and P: OPERKbnm2438164 206.doc-28107/03 -26- A, which are identical or different, are a nitrogen atom, if appropriate substituted, a Ci-C 4 alkyl group, which is substituted by one or more aryl groups, which are, if appropriate, substituted, as intermediate in the preparation of a compound of general formula I.

22. Compound of general formula VII according to claim 21, wherein R is a methyl group and NA 2 an N 3 group.

23. Compound of general formula VII according to claim 21 or 22, wherein the C-4" carbon has an R configuration.

24. A process for the stereoselective preparation of a compound of general formula according to claim 1, substantially as hereinbefore described with reference to the Examples.

25. A compound of formula prepared by the process of any one of claims 1 to 17.

26. A compound of general formula VI according to 20 claim 18, substantially as hereinbefore described with reference to the Examples.

27. A compound of general formula VII according to claim 21, substantially as hereinbefore described with reference to the Examples. *.Oo DATED this 2 8 th day of July, 2003 Merial By DAVIES COLLISON CAVE Patent Attorneys for the Applicants