Process for the preparation of 3-amino-2-oxo-pyrrolidines, novel intermediates and their use

Abstract

The present invention relates to a process for the preparation of γ-lactams of the general formula I The invention relates also to novel advantageous intermediates of the general formulae V, IV and II and their salts and their use. The compounds of the general formula I are obtained by cyclising compounds of the general formula II which can be prepared from the intermediate compounds V.

What is claimed is:  
     
         1 . Process for the preparation of γ-lactams of the general formula I and their salts  
                 
 
       wherein 
 R 1  may represent H, (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 2 -C 8 )-alkoxyalkyl, (C 1 -C 8 )-acyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, (C 3 -C 7 )-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 1 -C 8 )-acyl, (C 1 -C 8 )-alkoxy, (C 2 -C 8 )-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, and/or may contain hetero atoms such as N, O, P, S in the ring, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, heteroaryl, such as furyl, pyrrolyl, pyridyl, heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 1 -C 8 )-acyl, (C 1 -C 8 )-alkoxy, (C 2 -C 8 )-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, N-bonded amino acid or peptide residue,  
 R 2  may represent H, (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 2 -C 8 )-alkoxyalkyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, (C 3 -C 7 )-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 1 -C 8 )-acyl, (C 1 -C 8 )-alkoxy, (C 2 -C 8 )-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, and/or may contain hetero atoms such as N, O, P, S in the ring, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, heteroaryl, such as furyl, pyrrolyl, pyridyl, heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, (C 1 -C 8 )-acyl, (C 1 -C 8 )-alkoxy, (C 2 -C 8 )-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms,  
 R 3  may represent H, ClCO, (C 1 -C 8 )-acyl, which may optionally be linear or branched, a C-bonded amino acid or a peptide residue or a conventional peptide-protecting group such as, for example, formyl, carbamoyl, benzyloxycarbonyl, tert.-butyloxycarbonyl, allyloxycarbonyl, trifluoroacetyl,  
 wherein derivatives of the general formula II  
                 
 
 wherein R 1 , R 2 , R 3  are as defined above and X represents an element from the group halogen, sulfonic acid ester, are cyclised to form compounds of the general formula I.  
 
     
     
         2 . Process according to    claim 1   , wherein the cyclisation is carried out under basic conditions.  
     
     
         3 . Process according to    claim 2   , wherein sodium hydroxide solution is used as a base.  
     
     
         4 . Process according to    claim 1   , wherein X is a sulfonic acid ester.  
     
     
         5 . Process according to    claim 4   , wherein X is a OSO 3 Me group.  
     
     
         6 . Process according to    claim 1   , wherein compound II a compound wherein R 1  is p-cyanophenyl or p-carbamoylphenyl, R 2  is H and R 3  is benzyloxycarbonyl.  
     
     
         7 . Process according to    claim 1   , wherein the cyclisation is carried out at temperatures of from −20 to 100° C.  
     
     
         8 . Process according to    claim 1   , wherein the compound of the general formula II is cyclised to form the compound of the general formula I without being isolated beforehand.  
     
     
         9 . Process according to    claim 1   , wherein compounds of the general formula II are prepared from derivatives of the general formula III  
                   
       wherein R 1 , R 2 , R 3  are as defined above.  
     
     
         10 . Process according to    claim 9   , wherein the compound of the general formula III is not isolated as an intermediate.  
     
     
         11 . Process according to    claim 9   , wherein the compound of the general formula III is prepared from derivatives of the general formula IV  
                   
       wherein R 1 , R 2 , R 3  are as defined above and R 4  represents (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 1 -C 8 )-alkoxy, (C 2 -C 8 )-alkenyloxy, which are optionally linear or branched and are optionally substituted by one or more halogen atoms, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, arylalkyloxy, such as benzyloxy.  
     
     
         12 . Process according to    claim 11   , wherein the compound of formula IV is converted into compounds of the general formula III by aminolysis.  
     
     
         13 . Process according to    claim 11   , wherein the compounds of the general formula IV are prepared from derivatives of the general formula V  
                   
       wherein R 2 , R 3 , R 4  are as defined above and R 5  represents H, or wherein R 3  and R 5  are bonded together via a C═O group to form a ring.  
     
     
         14 . Process according to    claim 13   , wherein compounds of the general formula V wherein R 5  represents H are activated by means of acid chlorides before being reacted to form compounds of the general formula IV.  
     
     
         15 . Process according to    claim 13   , wherein an acid addition salt of the compound of the general formula VI  
                   
       wherein R 2 , R 4  are as defined above and Y ⊖  is the corresponding base of an inorganic acid, is reacted with an acylating reagent derived from R 3  to form the compound of the general formula V.  
     
     
         16 . Process according to    claim 15   , wherein phosgene is used as the acylating reagent.  
     
     
         17 . Process according to    claim 15   , wherein an acylating reagent from the group of the organic anhydrides, activated esters, halocarbonic esters is used.  
     
     
         18 . Process according to    claim 17   , wherein the acylation is carried out in aqueous solution at a pH of from 4 to 9.  
     
     
         19 . Process according to    claim 17   , wherein the acylation is carried out in an organic solvent in the presence of a tertiary base.  
     
     
         20 . Process according to    claim 15   , wherein the acid addition salt of the general formula VI is prepared by reaction of compounds of the general formula VII  
                   
       wherein R 2  is as defined above, in a mixture of R 4 COOH and R 4 COCl or R 4 COBr, wherein R 4  is as defined above.  
     
     
         21 . Process according to    claim 20   , wherein first the carboxylic acid and the carboxylic acid halide are mixed and then the compound of the general formula VII is added to that mixture.  
     
     
         22 . Process according to    claim 20   , wherein the reaction is carried out at a temperature of from −20° C. to 50° C.  
     
     
         23 . Process according to    claim 13   , wherein a compound of the general formula VIII  
                   
       wherein the radicals R 2 , R 3  are as defined above and R 5  represents H, is reacted with the reagent R 4 COZ, wherein R 4  is as defined above and Z represents an activating radical, to form the compound of the general formula V.  
     
     
         24 . Process according to    claim 23   , wherein when Z=Cl or Br, the corresponding carboxylic acid is used as solvent.  
     
     
         25 . Process according to    claim 24   , wherein the sodium salt of the corresponding carboxylic acid used as solvent is added to the reaction mixture as base.  
     
     
         26 . Compounds of the general formula V and their salts  
                   
       wherein R 2 , R 3  are as defined in    claim 1    and R 4  is as defined in    claim 11    and R 5  is as defined in    claim 13   , wherein, when R 2 is H, R 3  may not be H.  
     
     
         27 . Compounds of the general formula V wherein R 2  is H, R 3  is benzyloxycarbonyl or tert.-butyloxycarbonyl or trifluoroacetyl, R 4  is methyl and R 5  is H.  
     
     
         28 . Compounds of the general formula V wherein R 2  is H, R 4  is methyl and wherein R 3  and R 5  are bonded together via a C═O group to form a ring.  
     
     
         29 . Compounds of the general formula IV and their salts  
                   
       wherein R 1 , R 2 , R 3  are as defined in    claim 1    and R 4  is as defined in    claim 11   .  
     
     
         30 . Compounds of the general formula IV wherein R 2  is H, R 3  is benzyloxycarbonyl or tert.-butyloxycarbonyl or trifluoroacetyl, and R 4  is methyl.  
     
     
         31 . Compounds of the general formula IV wherein R 2  is H, R 3  is benzyloxycarbonyl, R 4  is methyl and R 1  is p-cyanophenyl or p-carbamoylphenyl.  
     
     
         32 . Compounds of the general formula II and their salts  
                   
       wherein R 1 , R 2 , R 3  are as defined in    claim 1    and X represents an element from the group halogen, sulfonic acid ester.  
     
     
         33 . Compounds of the general formula II wherein R 2  is H, R 3  is benzyloxycarbonyl or tert.-butyloxycarbonyl or trifluoroacetyl, and X is a sulfonic acid ester.  
     
     
         34 . Compounds of the general formula II wherein R 2  is H, R 3  is benzyloxycarbonyl, X is the OSO 3 Me group, and R 1  is p-cyanophenyl or p-carbamoylphenyl.  
     
     
         35 . Use of the compound according to    claim 26    for the preparation of intermediates for biologically active substances.  
     
     
         36 . Use of the compound according to    claim 29    for the preparation of intermediates for biologically active substances.  
     
     
         37 . Use of the compound according to    claim 32    for the preparation of intermediates for biologically active substances.