NZ513025A

NZ513025A - Process for the preparation of an azamacrolide with 4" (R) -NH2

Info

Publication number: NZ513025A
Application number: NZ513025A
Authority: NZ
Inventors: Denis Pauze; Laurent Garel; Gilles Oddon; Patrick Leon; Frederic Lhermitte; Ronan Guevel
Original assignee: Merial Sas
Priority date: 1999-01-18
Filing date: 2000-01-17
Publication date: 2003-11-28
Also published as: JP2003505340A; AU1987000A; DE60014849D1; FR2788524B1; EP1144428A1; CA2359967C; AU768838B2; PT1144428E; BR0007593A; BR0007593B1; BRPI0007593B8; ZA200105825B; DK1144428T3; ATE279426T1; EP1144428B1; FR2788524A1; ES2232414T3; USRE40040E1; DE60014849T2; CA2359967A1

Abstract

A process for azamacrolide compounds of formula (I), comprising: (a) activating the hydroxyl functional group at the 4" position in the compound of formula (II), in order to obtain a compound of formula (III), (b) the compound of formula (III) is brought into contact with a nitrogenous nucleophilic derivative to allow the stereoselective displacement of the hydroxyl functional group activated by the nucleophile, (c) deprotecting the hydroxyl functional group at the 2' position to produce a compound of formula (I).

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 513025 5130 * « J wo 00/42056 pct/fr00/0q089 1 - PROCESS FOR THE PREPARATION OF AN AZAMACROLIDE WITH 4"(R)-NH: 10 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;;. 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: 15 in which R is a hydrogen atom or a Ci-Cio alkyl, C;-Ci0 alkenyl or C6-C12 arylsulphonyl group, which are optionally substituted. 20 These compounds are obtained from erythromycin and their synthesis involves two major stages: - the creation of the 8a-azalide macrocycle starting from the (Z) oxime, which is subjected to a stereospecific Beckmann rearrangement, and 25 - the modification of the cladinose group at the 4" position, which consists of the conversion of iPONZ ? 2 JUL am - 2 - the 4"(S)-0H to 4" (R)-NH2, that is to say with inversion of configuration, which can be illustrated as follows: "YYs- -V* CStxoh ► NH, In fact, the route currently used to provide 5 for this conversion of the 4"(S)-0H to 4"(R)-NH2 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 10 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 15 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. 25 The object of the present invention is to go some way towards providing 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 30 satisfactory yield, or at least provide the public with a useful choice. More specifically, a first subject-matter of the present invention is a process for the stereoselective preparation of a compound of general formula I 1PON2 2 2 JUL 2003 h3c. ,xch3 ch ch3 ch3 xCH3 (I) 3 na2 ch3 in which: - R is a hydrogen atom or a C1-C10 alkyl, C2-Cio alkenyl or Cg-Ci2 arylsulphonyl group, which are optionally substituted, and substituted by one or more aryl groups, which are themselves optionally substituted, hydrogen atom, an optionally substituted Ci-C8 alkyl group or an optionally substituted aryl group, 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 - A, which are identical or different, are • a hydrogen atom, • an optionally substituted nitrogen atom, • a C1-C4 alkyl group, which is optionally an R2CO or R2SO? group, with R2 being a h3cn ,ch3 n (") ch3 IP ONZ 22 JUL 2003 10 15 20 - 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 (iii) ch3 in which: - R and Pi 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, to produce a compound of general formula I. 25 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 IPONZ 2 2 JUL 2003 - 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. 5 Consequently, the claimed process proves to be particularly advantageous in preparing, especially with a very satisfactory yield, a 4"-(R)-NA2 derivative of general formula I' 10 with A and R as defined above, from a 4"(S)-OH azamacrolide derivative of general formula II' 15 CH3 in which R and PI are as defined above. As regards the leaving group represented by ORi 20 in general formula III, it is preferably selected from C1-C20 alkyl sulphonates, C5-Ce aryl or heteroaryl sulphonates or to C26 alkylaryl sulphonates, which are optionally substituted 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 BS02X or (BSO2) 2O IVA IVB with: - X being a halogen atom or a nitrogenous heterocycle, preferably an imidazole ring, and - B being a C1-C20 alkyl, C5-C6 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 SPONZ 27 JUL 2003 - 7 - organic organosoluble azide in order to result, by stereoselective nucleophilic displacement, in a compound of general formula V qh3 h3c /ch3 n ch3 0 ch3 (V) 5 in which R and Pi 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 10 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 15 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 20 those described by E.F.V. Scriven et al., Chem. Rev. (1988), J38, 297-368. A catalytic reduction with hydrogen or hydrazine in the presence of palladium-on-charcoal, for example, or of Raney nickel can in particular be carried out. 25 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? derivative is thus recovered with a satisfactory yield. Consequently, this alternative form of the claimed process is very particularly of use in the 5 preparation of the compounds of general formula I" H3C^ch3 in which: 10 - R is a hydrogen atom or a Ci-Cio alkyl, C2-C10 alkenyl or C6-Ci2 arylsulphonyl group, which are optionally substituted, from a compound of general formula II' as defined above. 15 Mention may very particularly be made, as illustration of the azides which are suitable for the present invention, of tetra(Ci to C-o alkyl)ammonium or -phosphonium azide, substituted or unsubstituted triarylsulphoniums and hexa (Ci to C20 alkyl)guani- 20 diniums. According to a preferred alternative form of the invention, it is a tetraalkylammonium azide and more particularly tetrabutyl- or tetraoctylammonium azide. 25 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 IPONZ 2 2 JUL 2003 - 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(Ci to C^o 5 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 10 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 15 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 20 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 25 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 30 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 35 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 -20 and 180°C. As a general rule, it is adjusted so as to 5 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 10 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 15 the invention, R is a methyl group in the general formulae I, I',II",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 HjCv ,CH3 N ch3 20 in which - P: is a hydrogen atom or a protective group, - R is a hydrogen atom or a Ci-Cio alkyl, C^-Cio alkenyl or Cr—Ci? arylsulphonyl group, which are 2 5 optionally substituted, and ORi is a leaving group. Also described are the compounds of general formula VI as intermediates in the preparation of a compound of general formula I. iPQNZ 22 JUL 2003 - 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 5 compounds of general formula VII H3C^ ,CH3 3 n ch3 in which - P; is a hydrogen atom or a protective group, R is a hydrogen atom or a Ci-Cio alkyl, C--C10 10 alkenyl or C6-Ci; arylsulphonyl group, which are optionally substituted, and - A, which are identical or different, are • an optionally substituted nitrogen atom, • a C1-C4 alkyl group, which is 15 substituted by one or more optionally substituted aryl groups. Also described are the compounds of general formula VII as intermediates in the preparation of a compound of general formula I. Preferably, R is a methyl group and NA2 an N3 20 group and more preferably the C-4" carbon has an R configuration. The examples which appear below are presented by way of illustration and without implied limitation of the present invention. IPONZ 2 2 JUl 2003 - 12 - example 1 Preparation of the compound 4"-dehydroxy-4"(R)-amino-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin hi. The synthetic scheme used is as follows: WO 00/42056 - 13 - PCT/FR00/00089 I 9 \ a P HO X MeN o- • ■■•Hll * o \ > o o- o \ P ) r— < o Y-Z A \ J W Z X ro i O S ►— J CD rc a x © WO 00/42056 PCT/FR00/00089 - 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: 5 Pyridine (39.5 mg, 0.51 mmol, 5 equiv.) is added to a solution of alcohol 2'-acetoxy-9-deoxo-8a-aza-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 10 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 (10 ml), the reaction mixture is cooled to 0°C and then 15 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 20 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-homo-erythromycin A are obtained with a purity greater of than or equal to 90%. The structure is confirmed by NMR 25 and MS analysis. 2)Formation of 4"-dehydroxy-4"(R)-azido-2'-acetoxy-9-deoxo-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 30 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 35 (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 5 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-homo-erythromycin A from the preceding stage (250.0 mg, 10 0.30 mmol, 1 equiv.). Hydrazine monohydrate (30 microlitres, 0.6 mmol, 2 equiv.) is added every 30 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 15 bicarbonate solution (10 ml) and then with water (10 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-8a-homoerythromycin A are obtained with a purity of 60%. 20 The structure is confirmed by NMR and MS analysis. EXAMPLE 2 Tetraoctylammonium azide (190.3 ml, 0.5 mmol, 5 equiv.) is added at room temperature to a solution of 4"(S)-trifluoromethanesulphonate-2'-acetoxy-9-deoxo-8a-25 aza-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 30 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, 1H NMR analysis shows the predominant presence of the compound 35 4"-dehydroxy-4"(R)-azido-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-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 5 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, NMR 10 analysis shows the predominant presence of the compound 4"-dehydroxy-4"(R)-azido-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A. EXAMPLE 4 Tetraoctylammonium methanesulphonate (217 mg, 15 0.38 mmol, 3.8 equiv.) and then tetrabutylammonium azide (158 mg, 2.5 mmol, 25 equiv.) are successively added to a solution of 4" (S) — trifluoromethanesulphonate-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A (92 mg, 0.1 mmol, 20 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 25 evaporating the solvents, 1H NMR analysis shows the predominant presence of the compound 4"-dehydroxy-4"(R)-azido-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A. EXAMPLE 5 30 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 35 mixture is subsequently diluted with ethyl acetate (10 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)- </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 17 - amino-2'-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homo-erythromycin A. wo 00/42056 pct/fr00/00089 - 18 -claims

1. A process for the stereoselective preparation of a compound of general formula I in which: - R is a hydrogen atom or a Ci-Cio alkyl, C2-Cio alkenyl or C^-Ci- arylsulphonyl group, which are, 10 optionally substituted, and 15 substituted by one or more aryl groups, which are, themselves optionally substituted, • an R2CO or R2SO; group, with R- being a hydrogen atom, an optionally substituted Ci-C? alkyl group or an optionally substituted aryl group, 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 (I) £h3 5 - A, which are identical or different, are • a hydrogen atom, • an optionally substituted nitrogen atom, • a C1-C4 alkyl group, which is optionally SPONZ 2 2 JUL 2003 - 19 - h3cv ,ch3 9Ha p,csA chAa (II) 10 - 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 H3C^ch3 (ill) ch, in which: 15 - 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 5 displacement of the hydroxyl functional group activated by the said nitrogenous nucleophile, and deprotecting the hydroxyl functional group at the 2' position, to produce a compound of general formula I. 10

2. a process according to claim 1, characterized in that a 4"-(R)-NA2 derivative of general formula I' HaC^CHa ch3 15 with A and R being as defined in claim 1 is prepared from a 4"(S)-OH azamacrolide derivative of general (10 iPONZ 12 JUL 2003 formula II' h3c ,ch3 n 20 ch3 10 - 21 - (followed by page - 21a -) in which R and PI are as defined in claim 1.

3. A process according to claim 1 or 2, characterized in that the leaving group represented by ORi in general formula III is selected from Ci-C2o alkyl sulphonates, C5-C6 aryl or heteroaryl sulphonates or C6-C26 alkylaryl sulphonates, which are optionally substituted by one or more halogen atoms and/or a nitro, cyano or trifluoromethyl group.

4. A process according to claim 3, wherein the leaving group represented by ORi in general formula III is selected from C1-C20 alkyl sulphonates, C5-C6 aryl or heteroryl sulphonates or C5-C26 alkylaryl sulphonates which are optionally substituted by one or more fluorine atoms. ^

5. A process according to any one of claims 1 to 4, characterized in that the leaving group represented by ORi in general formula III is a triflate group.

6. A process according to any one of claims 1 to 5, characterized in that the leaving group derives from 20 the activation of the hydroxyl functional group at the 4" position in the general formula II by a compound of formula IVA or IVB BS02X or (BS02)20 IVA IVB 25 with: X being a halogen atom or a nitrogenous heterocycle, and - B being a C1-C20 alkyl, C5-C6 aryl or heteroaryl 30 or C6-C26 alkylaryl sulphonate group, which are optionally substituted by one or more halogen atoms, and/or a nitro, cyano or trifluoromethyl group. 35 IPQNZ 2 2 JUL 2003 - 21a -(followed by page - 22 -)

7. A process according to claim 6 wherein X is an imidazole ring.

8. A process according to either claim 6 or 7 wherein B is a Ci-C2o alkyl, C5-C6 aryl or heteroaryl or C6-C26 alkylaryl sulphonate group substituted by one or more fluorine atoms.

9. A process according to any one of claims 1 to 8, characterized in that the nitrogenous nucleophilic compound is selected from ammonia, amines which may or may not be substituted by deprotectable groups, amides, imides, sulphonamides, sulphonimides, hydrazines or azides.

10. A process according to any one of the preceding claims, characterized in that the nitrogenous nucleophilic compound is used in a proportion of iPONZ 2 2 JUL 2003 10 15 - 22 - approximately 1 to 30 equivalents with respect to the compound of general formula III.

11. A process according to any one of claims 1 to 10, characterized in that the nitrogenous nucleophilic compound is an organic organosoluble azide.

12. A process according to claim 11 wherein the organosoluble azide is generated in situ.

13. A process according to claim 11 or claim 12 . characterized in that - the compound of general formula II is activated with a compound of general formula IVA or IVB as defined in claim 6, - 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 20 25 h3cn ,ch3 n <r - M '•••ch3 Nc ch3 in which R and Pi 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.

14. A process according to claim 13, that 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. 1PONZ 2 2 JUL 2003 - 23 -

15. A process according to claim 13 or 14, characterized in that 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 5 configuration.

16. A process according to any one of claims 11 to 15, characterized in that the organic organosoluble azide is selected from tetra (Ci to C2o alkyl) ammonium or -phosphonium azide, substituted or unsubstituted 10 triarylsulphoniums and hexa(Ci to C:o alkyl)-guanidiniums.

17. A process according to any one of claims 11 to 16, characterized in that the azide is tetrabutylammonium azide or tetraoctylammonium azide. 15

18. A process according to any one of claims 11 to 17, characterized in that 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 and ethers. 20

19. A process according to claim 18 wherein the aromatic solvent is benzene or toluene.

20. A process according to claim 18 wherein the ether solvent is methyl tert-butyl ether or THF.

21. A process according to any one of the preceding claims, characterized in that the hydroxyl functional group at the 4" position is activated by a trifluoromethanesulphonate group and the nucleophilic substitution is carried out, with inversion 30 of configuration, with tetrabutyl- or tetraoctylammonium azide in toluene at room temperature.

22. A process according to any one of the preceding claims, characterized in that R is a methyl group in the general formulae I, I', I", II, II', III and V and A a hydrogen atom in the general formulae I and I'.

23. A compound of general formula VI !PONZ i 2 JUL 2003 - 24 -n (VI) in which - P2 is a hydrogen atom or a protective group, - R is a hvdrogen atom or a CT-Cin alkvl, C?-Cm alkenyl or C^-Ci? arylsulphonyl group, which are optionally substituted, and - ORi is a leaving group. 10 15

24. A compound of general formula VI according to claim 23, characterized in that R is a methyl group and ORi a triflate group.

25. A compound of general formula VI according to claim 23 or 24, characterized in that the C-4" carbon has an S configuration.

26. A compound of general formula VII H3C^ ,CH3 3 n CH f (VII) IPONZ 22 JUL 2003 - 25 - in which - P; is a hydrogen atom or a protective group, P. is a hydrogen atom or a C1-C10 alkyl, C^-Ciq alkenyl or C^-Ci? arylsulphonyl group, which are 5 optionally substituted, and - A, which are identical or different, are • an optionally substituted nitrogen atom, • a C1-C4 alkyl group, which is a C1-C4 alkyl group, which is substituted by one or more 10 optionally substituted aryl groups.

27. A compound of general formula VII according to claim 26, characterized in that R is a methyl group and 15 NA2 an N3 group.

28. A compound of general formula VII according to claim 26 or 27, characterized in that the c-4" carbon has an R configuration.

29. A process as defined in claim 1, substantially as herein described with reference to any example thereof.

30. A compound of general formula VI as defined in claim 23, substantially as herein described with reference to any example thereof.

31. A compound of general formula VII as defined in claim 26, substantially as herein described with reference to any example thereof. SPONZ 22 JUL 2003 </div>