Process of use in converting the 4″(S)-OH functional group of the cladinose unit of an azamacrolide to 4″(R)-NH2

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.

1. A process for the stereoselective preparation of a compound of formula I 
                 
  wherein:  
 R is a hydrogen atom or a C 1 -C 10  alkyl, C 2 -C 10  alkenyl or C 6 -C 12  arylsulphonyl group, optionally substituted;  
 A, each of which is identical or different, is 
 a hydrogen atom,  
 a nitrogen atom, optionally substituted,  
 a C 1 -C 4  alkyl group, which is optionally substituted by one or more aryl groups, which are, in turn, optionally substituted,  
 an R 2 CO or R 2 SO 2  group, with R 2  being a hydrogen atom, a C 1 -C 8  alkyl group or an aryl group, which are, optionally substituted; and  
 
 ∇ indicates that the C in the 4″ position has undergone an inversion of configuration  
 with respect to the formula II, from a compound of formula II: 
                 
 
  wherein:  
 R as defined in formula I and  
 P 1  is a protective group for the hydroxyl functional group at the 2′ position, comprising the steps of: 
 (i) activating the hydroxyl functional group at the 4″ position in the compound of formula II, in order to obtain a compound of formula III: 
                 
 
  wherein: 
 R and P 1  are as defined in formulae I and II and  
 OR 1  is a leaving group;  
 
 (ii) contacting the compound of formula III 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  
 (iii) deprotecting the hydroxyl functional group at the 2′ position.  
 
 
     
     
       2. The process according to  claim 1 , wherein a 4″-(R)—NA 2  of formula I′: 
                 
 
       wherein A and R are as defined in  claim 1 , is prepared from a 4″-(S)—OH derivative of formula II′: 
                 
 
       wherein R and P 1  are as defined in  claim 1 . 
     
     
       3. The process according to  claim 1 , wherein the leaving group represented by OR 1  in formula III is selected from the group consisting of C 1 -C 20  alkyl sulphonates, C 5 -C 6  aryl sulphonates, C 5 -C 6  heteroaryl sulphonates and C 6 -C 26  alkylaryl sulphonates, which are optionally substituted by one or more halogen atoms and/or a nitro, cyano or trifluoromethyl group. 
     
     
       4. The process according to  claim 1 , wherein the leaving group represented by OR 1  in formula III is a triflate group. 
     
     
       5. The process according to  claim 1 , wherein the leaving group derives from the activation of the hydroxyl functional group at the 4″ position in the formula II by a compound of formula IVA or IVB:
   BSO 2 X or (BSO 2 ) 2 O  IVA or IVB  
 
       wherein:
 X is a halogen atom or a nitrogenous heterocycle; and  
 B is a C 1 -C 20  alkyl, C 5 -C 6  aryl or heteroaryl, or C 6 -C 26  alkylaryl group, which is optionally substituted by one or more halogen atoms and/or a nitro, cyano or trifluoromethyl group.  
 
     
     
       6. The process according to  claim 1 , wherein the nitrogenous nucleophilic compound is selected from the group consisting of ammonia and amines, optionally substituted by deprotectable groups, amides, imides, sulphonamides, sulphonimides, hydrazines or azides. 
     
     
       7. The process according to  claim 1 , wherein the nitrogenous nucleophilic compound is used in a proportion of approximately 1 to 30 equivalents with respect to the compound of formula III. 
     
     
       8. The process to  claim 1 , wherein the nitrogenous nucleophilic compound is an organic organosoluble azide, optionally generated in situ. 
     
     
       9. The process according to  claim 1 , further comprising:
 activating the compound of formula II with a compound of formula IVA or IVB 
   BSO 2 X or   IVA  
   (BSO 2 ) 2 O   IVB  
 
  wherein: 
 X is a halogen atom or a nitrogenous heterocycle; and  
 B is a C 1 -C 20  alkyl, C 5 -C 6  aryl or heteroaryl or C 6 -C 26  alkylaryl group, which are optionally substituted by one or more halogen atoms and/or a nitro, cyano or trifluoromethyl group; and  
 
 contacting the compound of formula III with an organic organosoluble azide in order to result, by stereoselective nucleophilic displacement, in a compound of formula V 
                 
 
 
       wherein R and P 1  are as defined in formula I and ∇ indicates that the C in the 4″ position has undergone an inversion of configuration with respect to the formula II. 
     
     
       10. The process according to  claim 1 , further comprising:
 activating the compound of formula II with a compound of formula IVA or IVB 
   BSO 2 X or   IVA  
   (BSO 2 ) 2 O   IVB  
 
  wherein: 
 X is a halogen atom or a nitrogenous heterocycle, and  
 B is a C 1 -C 20  alkyl, C 5 -C 6  aryl or heteroaryl or C 6 -C 26  alkylaryl group, optionally substituted by one or more halogen atoms and/or a nitro, cyano or trifluoromethyl group;  
 
 contacting the compound of formula III with an organic organosoluble azide resulting, by stereoselective nucleophilic displacement, in a compound of formula V: 
                 
 
  wherein: 
 R and P 1  are as defined in formula I and ∇ means that the C in the 4″ position has undergone an inversion of configuration with respect to the formula II; and  
 
 reducing the compound of formula V, so as to obtain a compound of formula I in which A is a hydrogen atom.  
 
     
     
       11. The process according to  claim 1 , further comprising:
 activating the compound of formula II with the C-4″ carbon having S configuration with a compound of formula IVA or IVB 
   BSO 2 X or   IVA  
   (BSO 2 ) 2 O   IVB  
 
  wherein: 
 X is a halogen atom or a nitrogenous heterocycle, and  
 B is a C 1 -C 20  alkyl, C 5 -C 6  aryl or heteroaryl or C 6 -C 26  alkylaryl group, optionally substituted by one or more halogen atoms and/or a nitro, cyano or trifluoromethyl group;  
 
 contacting the compound of formula III with an organic organosoluble azide in order to result, by stereoselective nucleophilic displacement, in a compound of formula V 
                 
 
 
       wherein R and P 1  are as defined in formula I, the C-4″ carbon has a R configuration and ∇ indicates that the C in the 4″ position has undergone an inversion of configuration with respect to the formula II. 
     
     
       12. The process according to  claim 1 , wherein the nitrogenous nucleophilic compound is an organic organosoluble azide selected from the group consisting of tetra-(C 1  to C 20  alkyl) ammonium azide, tetra-(C 1  to C 20  alkyl) phosphonium azide, substituted or unsubstituted triarylsulphoniums and hexa (C 1  to C 20  alkyl)-guanidiniums. 
     
     
       13. The process according to  claim 1 , wherein the nitrogenous nucleophilic compound is a tetrabutylammonium azide or tetraoctylammonium azide. 
     
     
       14. The process according to  claim 1 , wherein the nitrogenous nucleophilic compound is an organic organosoluble azide and the nucleophilic displacement of the leaving group at the 4″ position by the organic organosoluble azide is carried out in a solvent selected from the group consisting of aromatic solvents and ethers. 
     
     
       15. The process according to  claim 1 , 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-ortetraoctylammonium azide in toluene at room temperature. 
     
     
       16. The process according to  claim 1 , wherein R is a methyl group in the formula I, I′, II, II′, III and V and A a hydrogen atom in the formula I and I′. 
     
     
       17. A compound of formula VI 
                 
 
       wherein:
 P 2  is a hydrogen atom or a protective group;  
 R is a hydrogen atom or a C 1 -C 10  alkyl, C 2 -C 10  alkenyl or C 6 -C 12  arylsulphonyl group, optionally substituted; and 
 OR 1  is a leaving group.  
 
 
     
     
       18. The compound of formula VI according to  claim 17 , wherein R is a methyl group and OR 1  is a triflate group. 
     
     
       19. The compound of formula VI according to  claim 18 , wherein the C-4″ carbon has a S configuration. 
     
     
       20. A compound of formula VII 
                 
 
       wherein:
 P 2  is a hydrogen atom or a protective group;  
 R is a hydrogen atom or a C 1 -C 10  alkyl, C 2 -C 10  alkenyl or C 6 -C 12  arylsulphonyl group, optionally substituted; and  
 A, each of which is identical or different, is 
 a nitrogen atom, optionally substituted, or  
 a C 1 -C 4  alkyl group, which is optionally substituted by one or more aryl groups, which are, in turn, optionally substituted, wherein A is not a hydrogen atom or a R 2 CO or R 2 SO 2  group, with R 2  being a hydrogen atom, a C 1 -C 8  alkyl group or an aryl group, which are, optionally substituted.  
 
 
     
     
       21. The compound of formula VII according to  claim 20 , wherein R is a methyl group and N(A) 2  is a N 3  group. 
     
     
       22. The compound of formula VI according to  claim 20 , wherein the C-4″ carbon has a R configuration. 
     
     
       23. The process according to  claim 3 , wherein the halogen atom is fluorine. 
     
     
       24. The process according to  claim 5 , wherein the nitrogenous heterocycle is an imidazole ring. 
     
     
       25. The process according to  claim 5 , wherein the halogen atom is fluorine. 
     
     
       26. The process according to  claim 9 , wherein the nitrogenous heterocycle is an imidazole. 
     
     
       27. The process according to  claim 10 , wherein the nitrogenous heterocycle is an imidazole. 
     
     
       28. The process according to  claim 10 , wherein the halogen atom is fluorine. 
     
     
       29. The process according to  claim 11 , wherein the nitrogenous heterocycle is an imidazole. 
     
     
       30. The process according to  claim 11 , wherein the halogen atom is fluorine. 
     
     
       31. The process according to  claim 14 , wherein the ether is selected from the group consisting of methyl tert-butyl ether and THF. 
     
     
       32. The process according to  claim 14 , wherein the solvent is selected from the group consisting of benzene and toluene.