Process for the preparation of alpha-acyloxy beta-formamido amides

Abstract

The present invention relates to a process for the preparation of a compound of the general Formula (I), comprising: a) reacting a compound of the general Formula (II) with a compound of the Formula III R 2 COOH and a compound of the general Formula IV R 3 NC under such conditions that compound I is formed, wherein R 1 represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R 2 represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R 3 represents a substituted or unsubstituted alkyl, alkenyl, or alkynyl structure. In further aspect the subject invention relates to the use of the the obtained products as intermediates for various peptidomimetics, and preferably as a building block in a convergent synthesis of prolyl dipeptide structures.

1 - 23 . (canceled) 
     
     
         24 . A compound of formula VI: 
       
         
           
           
               
               
           
         
         wherein R 1  represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tri-cyclic, or heterocyclic group, 
         R 2  represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tri-cyclic, or heterocyclic group, and 
         R 3  represents a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or a reversibly attached protective group. 
       
     
     
         25 . The compound according to  claim 24  having a structure of formula VII: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound according to  claim 24  having a structure of formula VIII: 
       
         
           
           
               
               
           
         
         wherein R 1  represents a lower carboxylic acid group, and 
         R 2  represents a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or a protective group that can be reversibly removed. 
       
     
     
         27 . A process for preparing a compound of formula VI of  claim 24 , comprising:
 a) reacting a compound of formula II:   
       
         
           
           
               
               
           
         
         with a compound of formula III:
   R 2 —COON   (III),
 
 
         and a compound of formula IV:
   R 3 —NC   (IV)
 
 
         under such conditions that a compound of formula I is formed, 
       
       
         
           
           
               
               
           
         
         b) isolating the compound of formula I from the reaction mixture, and 
         c) subjecting the compound of formula I obtained in b) to dehydrating conditions to obtain a compound of formula VI. 
       
     
     
         28 . The process according to  claim 27 , wherein c) is performed by treatment of the formamido compound (I) with phosgene, diphosgene (trichloromethyl chloroformate), triphosgene [bis(trichloromethyl)carbonate], and/or POCl 3 . 
     
     
         29 . The process according to  claim 28 , wherein c) is performed in the presence of a base, preferably a tertiary amine base such as triethylamine or N-methylmorpholine. 
     
     
         30 . The process according to  claim 27 , wherein R 1  is an alkyl group, such as n-propyl, or an alkylcycloalkyl group, preferably —CH 2 -cyclopropyl or —CH 2 -cyclobutyl. 
     
     
         31 . The process according to  claim 27 , wherein R 2  represents hydrogen, a straight chain alkyl, a branched chain alkyl, a cycloalkyl, an alkylene-cycloalkyl, an aryl or alkylene aryl. 
     
     
         32 . The process according to  claim 27 , wherein, R 3  is a cycloalkyl or hydrogen, or a protective group as usually employed to reversably protect primary amines. 
     
     
         33 . The process according to  claim 27 , wherein, R 1 , R 2  and R 3  are chosen such that the compound of formula VI has a structure according to formula VII: 
       
         
           
           
               
               
           
         
       
     
     
         34 . The process according to  claim 27 , wherein R 1 , R 2  and R 3  are chosen such that the compound of formula VI has a structure according to formula VIII: 
       
         
           
           
               
               
           
         
         wherein R 1  represents a lower carboxylic acid group, preferably acetate, and 
         R 2  represents reversibly attached protective group. 
       
     
     
         35 . The process according to  claim 27 , comprising reacting the compound of formula VI with a compound of formula IX: 
       
         
           
           
               
               
           
         
         or the respective diastereomers, and a compound of formula X:
   R 7 —COON   (X),
 
 
         under conditions that a compound of formula XI is formed, to obtain a compound of formula XI or its respective diastereomers: 
       
       
         
           
           
               
               
           
         
         wherein R 4  represents each independently, or jointly a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and 
         R 5  represents each independently a hydrogen atom, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tri-cyclic, or heterocyclic structure, 
         R 6  represents a structure derived from a compound of formula I, and 
         R 7  represents a substituted or unsubstituted alkyl, alkenyl, or alkynyl, or an aromatic or non-aromatic aromatic or non-aromatic, mono-, di- or tri-cyclic, or heterocyclic structure. 
       
     
     
         36 . The process according to  claim 35 , wherein in the case of R 5  being different from hydrogen, the diastereomers of formula IX include compounds of formulae IXa and IXb, respectively: 
       
         
           
           
               
               
           
         
         resulting predominantly in the compounds of formulae XIa and XIb, respectively: 
       
       
         
           
           
               
               
           
         
       
     
     
         37 . The process according to  claim 36 , wherein both substituents R 5  represent hydrogen, and both substituents R 4  jointly form a substituted or unsubstituted 3-, 4-, 5- , 6-, 7- or 8-membered ring structure. 
     
     
         38 . The process according to  claim 37 , wherein R 4  is chosen such that the compound of formula I has the structure according to formula XII: 
       
         
           
           
               
               
           
         
         according to formula XIII: 
       
       
         
           
           
               
               
           
         
         or according to formula XIV: 
       
       
         
           
           
               
               
           
         
       
     
     
         39 . The process according to  claim 35 , wherein R 7  represents a structure according to formula XV: 
       
         
           
           
               
               
           
         
         wherein R a  and R b  each independently represents a hydrogen atom, a halogen atom, a lower alkyl group comprising from 1 to 4 carbon atoms, a lower alkyl group substituted by halogen, a cycloalkyl group, an aryl group, a lower alkoxy group, a lower thioalkyl group, a cycloalkyloxy group, an aralkyloxy group or an alkanoyl group; a hydroxyl group, a nitro group, a formyl group, an amino group which may be protected or substituted, a cycloalkyloxy, aralkyloxy, alkanoyl, ureido or mono-, di- or tricyclic heterocyclic group, all of which groups may optionally be substituted. 
       
     
     
         40 . The process according to  claim 39 , wherein a compound of formula XII 
       
         
           
           
               
               
           
         
         is reacted with a compound of formula XVI: 
       
       
         
           
           
               
               
           
         
         and a compound of formula VII to obtain a compound of formula XVII: 
       
       
         
           
           
               
               
           
         
       
     
     
         41 . The process according to  claim 40 , further comprising isolating a compound of formula XVII from the reaction mixture. 
     
     
         42 . The process according to  claim 40 , further comprising subjecting the compound of formula XVII to a saponification reaction to remove the acetate from the secondary alcohol at the α-hydroxy-β-amino acid structure. 
     
     
         43 . The process according to  claim 42 , wherein the saponification is carried out by contacting the compound of formula XVII with an alkaline metal carbonate, preferably K 2 CO 3  in a suitable solvent, to obtain a saponified secondary alcohol product. 
     
     
         44 . The process according to  claim 42 , subjecting the compound of formula XVIIa comprising the secondary alcohol to a selective oxidation to a ketone to form a compound of formula XVIII. 
       
         
           
           
               
               
           
         
       
     
     
         45 . The compound of formula XVII or XXI: 
       
         
           
           
               
               
           
         
         wherein R 1  is acetate, and R 2  is a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, or a protective group that can be reversibly removed.