Process for the manufacture of fused piperazin-2-one derivatives

Abstract

Disclosed are processes for the preparation of fused piperazin-2-one derivatives of general formula (I) wherein the groups R 1 to R 5 , A 1 and A 2 have the meanings given in the claims and in the description, particularly the preparation of 7,8-dihydro-5H-pteridin-6-one derivatives and intermediates thereof.

1. A Process for preparing compounds of the formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  denotes a group selected from the group consisting of chlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl, trifluoromethanesulphonyl, para-toluenesulphonyl, CH 3 S(═O)— and phenylS(═O)—, 
 R 2  denotes hydrogen or C 1 -C 3 -alkyl, 
 R 3  denotes hydrogen or a group selected from the group consisting of optionally substituted C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl and C 6 -C 14 -aryl, or
 a group selected from the group consisting of optionally substituted and/or bridged C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 7 -C 12 -polycycloalkyl, C 7 -C 12 -polycycloalkenyl, C 5 -C 12 -spirocycloalkyl and saturated or unsaturated C 3 -C 12 -heterocycloalkyl, which contains 1 to 2 heteroatoms, 
 
 R 4 , R 5  which may be identical or different denote hydrogen or optionally substituted C 1 -C 6 -alkyl, or 
 
       R 4  and R 5  together denote a 2- to 5-membered alkyl bridge, which may contain 1 to 2 heteroatoms, or
 R 4  and R 3  or R 5  and R 3  together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge, which may optionally contain 1 heteroatom, and 
 
       “A1 and A2 denote —N═”, comprising 
       a) hydrogenating with hydrogen in the presence of a hydrogenation catalyst and a compound of formula II 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  to R 5 , A 1  and A 2  have the meanings given above and 
 R 6  denotes C 1 -C 4 -alkyl, and 
 
       b) adding a copper, iron or vanadium compound,
 wherein in which steps a) and b) may take place simultaneously or successively wherein step b) followed by follows step a). 
 
     
     
       2. The Process according to  claim 1 , wherein in step b) a copper compound is added. 
     
     
       3. The Process according to  claim 1 , wherein in step b) an iron compound is added. 
     
     
       4. The Process according to  claim 1 , wherein in step b) a vanadium compound is added. 
     
     
       5. The Process according to  claim 1  wherein steps a) and b) are carried out successively wherein step b) follows step a). 
     
     
       6. The Process according to  claim 5 , wherein that after the first step a) the intermediate product of formula III is first obtained, which may optionally be isolated, 
       
         
           
           
               
               
           
         
       
       and after the subsequent step b) a compound of formula I is obtained. 
     
     
       7. The Process according to  claim 1 , wherein steps a) and b) are carried out simultaneously. 
     
     
       8. The Process according to  claim 1 , wherein the hydrogenation catalyst is selected from the group consisting of rhodium, ruthenium, iridium, platinum, palladium and nickel. 
     
     
       9. The Process according to  claim 1 , wherein the amount of hydrogenation catalyst added is between 0.1 and 10 wt.-%, based on the compound of formula (II) used. 
     
     
       10. The Process according to  claim 1 , wherein the amount of copper, iron or vanadium compound added is between 0.01 and 10 wt-%, based on the compound of formula (II) used. 
     
     
       11. The Process according to  claim 1 , wherein the reaction is carried out in a solvent or mixture of solvents selected from the group consisting of dipolar, aprotic solvents, alcohols, ethers, esters, carboxylic acids, apolar solvents, acetonitrile, methylene chloride and water. 
     
     
       12. The Process according to  claim 1 , wherein the reaction temperature is between 0° C. and 150° C. 
     
     
       13. The Process according to  claim 1 , wherein the hydrogen pressure is from 1 bar to 100 bar. 
     
     
       14. A Process for preparing compounds of the formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  denotes a group selected from the group consisting of chlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl, trifluoromethanesulphonyl, para-toluenesulphonyl, CH 3 S(═O)— and phenylS(═O)—, 
 R 2  denotes hydrogen or C 1 -C 3 -alkyl, 
 R 3  denotes hydrogen or a group selected from the group consisting of optionally substituted C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl and C 6 -C 14 -aryl, or
 a group selected from the group consisting of optionally substituted and/or bridged C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 7 -C 12 -polycycloalkyl, C 7 -C 12 -polycycloalkenyl, C 5 -C 12 -spirocycloalkyl and saturated or unsaturated C 3 -C 12 -heterocycloalkyl, which contains 1 to 2 heteroatoms, 
 
 R 4 , R 5  which may be identical or different denote hydrogen or optionally substituted C 1 -C 6 -alkyl, or 
 R 4 , R 5  together denote a 2- to 5-membered alkyl bridge, which may contain 1 to 2 heteroatoms, or 
 R 4  and R 3  or R 5  and R 3  together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge, which may optionally contain 1 heteroatom, and 
 A 1  and A 2  denote —N═, comprising 
 
       hydrogenating a compound of formula III with hydrogen in the presence of a hydrogenation catalyst and a copper, iron or vanadium compound 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  to R 5  and A 1 , A 2  have the meanings given above in this claim. 
 
     
     
       15. The Process according to claim 11, wherein the solvent or mixture of solvents is:
 alcohols selected from ethanol, 1-propanol and 2-propanol,   ethers selected from diethyl ether, methyl-tert.-butylether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and dimethoxyethane,   esters selected from ethyl acetate, 2-propylacetate or 1-butylacetate,   acetic acid, acetonitrile, methylene chloride or water.   
     
     
       16. The Process according to claim 15, wherein the solvent is 2-propanol or tetrahydrofuran or mixtures thereof.