Process for phenylacetic acid derivatives

Abstract

A process for the production of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug ester thereof, comprising cleaving a lactam of formula II wherein the symbols are as defined, with a base; and precursors therefor and processes for the preparation of the precursors. The compounds of Formula I are pharmaceutically active compounds which are selective inhibitors of Cyclooxygenase II.

1 . process for the production of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug ester thereof, 
       
         
           
           
               
               
           
         
         wherein R is methyl or ethyl;
 R 1  is chloro or fluoro; 
 R 2  is hydrogen or fluoro; 
 R 3  is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; 
 R 4  is hydrogen or fluoro; and 
 R 5  is chloro, fluoro, trifluoromethyl or methyl, 
 
         provided that R 1 , R 2 , R 4  and R 5  are not all fluoro when R is ethyl and R 3  is H; comprising cleaving a lactam of formula II 
       
       
         
           
           
               
               
           
         
         wherein the symbols are as defiled above with a base; and in the above process, if desired, temporarily protecting any interfering reactive groups and then isolating the r in compound of the invent; and, if desired, converting the free carboxylic acid of the compound of formula I into a pharmaceutically acceptable ester derivative thereof; and/or if desired, converting the free acid of formula I into a salt or a resulting salt into the free acid or into another salt. 
       
     
     
         2 . A process selected from
 a) a process for the production of a lactam of formula II   
       
         
           
           
               
               
           
         
         which comprises oxidizing of a lactam of formula II 
       
       
         
           
           
               
               
           
         
         b) a process for the production of the lactam of formula II as defined in a) above, which comprises cyclisation of a compound of formula VII 
       
       
         
           
           
               
               
           
         
         c) a process for the preparation of a compound of formula III as defined above comprising coupling as aniline derivative of formula IV 
       
       
         
           
           
               
               
           
         
         
           with a cyclohexanone derivative of formula Va or an amino substituted cyclohexene derivative of formula Vb 
         
       
       
         
           
           
               
               
           
         
         
           wherein R is ethyl or methyl and R′ is lower alkyl or similar or NR′ 2  forms a ring as in piperidine or morpholine. 
         
         d) a process for the production of a compound of formula VII which comprises N-acylation of a diphenylamine of formula VIII 
       
       
         
           
           
               
               
           
         
         
           with a haloacetyl chloride 
         
         e) a process for the preparation of a compound of formula VIII which comprises rearrangement and hydrolysis of a compound of formula IX. 
       
       
         
           
           
               
               
           
         
         f) a process for the production of a compound of formula VIII which comprises coupling of a halobenzene derivative of formula XI with p-toluidine or 4-ethyl-aniline 
       
       
         
           
           
               
               
           
         
         
           where X is a halogen 
         
         g) a process for the production of a compound of formula VIII as defined in d) above which comprises coupling an aniline derivative of formula IV as defined in c) above with 4-bromotoluene or 1-ethyl-bromobenzene 
         h) a process for the production of a compound of formula VIII as defined in d) above which comprises cleavage of a compound of formula X 
       
       
         
           
           
               
               
           
         
         i) a process for the formation of a compound of formula X as defined in h) above which comprises rearrangement of a compound of formula IX as defined in e) above 
         j) a process for the product of a compound of formula IX as defined in e) above with comprises alkylation of a compound of formula XII 
       
       
         
           
           
               
               
           
         
         
           with 2-chloro-N-(4-methylphenyl)acetamide or 2 chloro-N-(4-ethylphenyl)acetamide 
         
         k) a process for the production of a compound of formula VIII as defined in d) above which comprises alkylation of a compound of formula XII as defined in j) above with 2-chloro-N-(4-methylphenyl)acetamide or 2 chloro-N-(4 ethylphenyl)acetamide followed by rearrangement and cleavage 
         l) a process for the production of a compound of formula VIII as defined in d) above comprising oxidation of the corresponding compound of formula XIII (or a tautomer thereof) 
       
       
         
           
           
               
               
           
         
       
       m) a process for the production of a compound of formula XIII as defined in l) above which comprises coupling 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexa-1,4-diene with an aniline derivative of formula IV as defined in c) above, and
 n) a process for the production of a compound of formula VIII as defined in d) above con-sing coupling 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexa-1,4-diene with an aniline derivative or formula IV as defined in c) above, followed by oxidation,
 wherein the symbols are as defined in  claim 1 . 
 
 
     
     
         3 . A process for the preparation of a compound of formula I as defined in  claim 1 . 
       
         
           
           
               
               
           
         
         which comprises one or more of processes a) to n) as defined in  claim 2  and optionally a process according to  claim 1 . 
       
     
     
         4 . A process according to  claim 3  for the preparation of a compound selected from: 
       5-methyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetic acid; 
       5-methyl-2-(2′, 3′, 5′,6′-tetrafluoroanilino)phenylacetic acid; 
       5-methyl-2-(2′, 3′, 4′,6′-tetrafluoroanilino)phenylacetic acid; 
       5-methyl-2-(2′,6′-dichloroanilino)phenylacetic acid; 
       5-methyl-2-(2′,6′-dichloroanilino)phenylacetic acid, potassium salt; 
       5-methyl-2-(2′,6′-dichloroanilino)phenylacetic acid, sodium salt; 
       5-methyl-2-(2′-chloro-6′fluoroanilino)phenylacetic acid; 
       5-methyl-2-(2′,6′-dichloro-4′-methylanilino)phenylacetic acid; 
       5-methyl-2-(2′-chloro-6′-methylanilino)phenylacetic acid; 
       5-methyl-2-(2′,4′-difluoro-6′-chloroanilino)phenylacetic acid; 
       5-methyl-2-(2′-fluoro-4′,6′-dichloroanilino)phenylacetic acid; 
       5-methyl-2-(2′-chloro-4′-fluoro-6′-methylanilino)phenylacetic acid; 
       5-methyl-2-(2′-fluoro-6′-chloroanilino)phenylacetic acid; 
       5-ethyl-2-(2′-chloro-6′-methylamino)phenylacetic acid; 
       5-ethyl-2-(2′,3′,6′-trifluroanilino)phenylacetic acid; 
       5-ethyl-2-(2′,3′,5′,6′-tetrafluoro-4′-ethoxyanilino)phenylacetic acid; 
       5-ethyl-2-(2′,3′,5′,6′-tetrafluoro-4′-ethoxyanilino)phenylacetic acid; 
       5-ethyl-2-(2′-chloro-4′,6-difluoroanilino)phenylacetic acid; 
       5-ethyl-2-(2′,4′-dichloro-6′-fluoroanilino)phenylacetic acid; 
       5-ethyl-2-(2′,4′-dichloro-6′-methylamino)phenylacetic acid; 
       5-ethyl-2-(2′-fluoro-4′-chloro-6′-methylanilino) phenylacetic acid; 
       5-ethyl-2-(2′,4′-difluoro-6′-methylanilino)phenylacetic acid 
       5-ethyl-2-(2′-chloro-4′-fluoro-6′-methylanilino)phenylacetic acid; 
       5-methyl-2-(2′-chloro-4′-hydroxy-6′-fluoroanilino)phenylacetic acid; 
       5-methyl-2-(2′-fluoro-6′-trifluoromethylanilino)phenylacetic acid, and 
       5-methyl-2-2′,4′-dichloro-6′-trifluoromethylanilino)phenylacetic acid, and pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof. 
     
     
         5 . A process according to  claim 3  for the preparation of a compound selected from: 
       5-methyl-2-(2′, 3′, 4′,6′-tetrafluoroanilino)phenylacetic acid; 
       5-methyl-2-(2′,6′-dichloroanilino)phenylacetic acid; 
       5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid; 
       5-methyl-2-(2′,6′-dichloro-4′-methylanilino)phenylacetic acid; 
       5-methyl-2-(2′-chloro-6′-methylanilino)phenylacetic acid; 
       5-methyl-2-(2′-chloro-4′-fluoro-6′-methylanilino)phenylacetic acid; 
       5-ethyl-2-(2′-fluoro-6′-chloroanilino)phenylacetic acid; 
       5-ethyl-2-(2′-chloro-6′-methylanilino)phenylacetic acid; 
       5-ethyl-2-(2′,3′,6′-trifluroanilino)phenylacetic acid, and 
       5-ethyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetic acid,
 and pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof. 
 
     
     
         6 . A compound of formula I, as defined in  claim 1   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug ester thereof, when prepared by a process as defined in  claim 3 . 
       
     
     
         7 . A compound selected from
 a) a compound of formula II   
       
         
           
           
               
               
           
         
         b) a compound of formula III 
       
       
         
           
           
               
               
           
         
         c) a compound of formula VII 
       
       
         
           
           
               
               
           
         
         d) a compound of formula VIII 
       
       
         
           
           
               
               
           
         
         e) a compound of formula IX 
       
       
         
           
           
               
               
           
         
         f) a compound of formula X 
       
       
         
           
           
               
               
           
         
         or 
         g) a compound of formula XIII 
       
       
         
           
           
               
               
           
         
         wherein the symbols are as defined in  claim 1 .