Process for preparing benzoxaboroles

Abstract

The present invention is a process comprising contacting a compound of formula 6: or a pharmaceutically acceptable salt thereof; with a deprotecting reagent to form a compound of formula A: or a pharmaceutically acceptable salt thereof; where R is H or OR 1 ; R 1 and each R 1′ are protecting groups; R 1″ is H or OH, and n is 0, 1, 2, 3, 4, or 5.

1 . A process comprising contacting a compound of formula 6: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         with a deprotecting reagent to form a compound of formula A: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         where R is H or OR 1 ; R 1  and each R 1′  are each independently protecting groups; R 1″  is H or OH; and n is 0, 1, 2, 3, 4 or 5. 
       
     
     
         2 . The process of  claim 1  wherein
 R is OR 1 ; 
 R 1  is —CH(R a )-phenyl-(R b ) x , trialkylsilyl, tetrahydropyranyl, —CH 2 OCH 3 , or —CH 2 OCH 2 CH 2 OCH 3  groups, where R a  is H or methyl; R b  is methoxy or C 1 -alkyl, C 2 -alkyl, or C 3 -alkyl; and x is 0, 1 or 2; and 
 each R 1′  is independently —CH(R c )-phenyl-(R d ) y , where R c  is H or methyl, each R d  is independently methoxy or C 1 -alkyl, C 2 -alkyl, or C 3 -alkyl; n is 0, 1, 2 or 3, and y is 0, 1 or 2. 
 
     
     
         3 . The process of  claim 1  wherein R is OR 1 ; R 1  and each R 1′  are benzyl groups; the deprotecting reagent is a reducing reagent; n is 1; and the compound of formula 6 is reduced in the presence of HCl to form the hydrochloride salt of the compound of formula A. 
     
     
         4 . The process of  claim 3  wherein the deprotecting reagent is Pd/C or Pt/C in the presence of H 2  or a mixture thereof, H 2  over palladium hydroxide, or catalytic transfer hydrogenating reagent conditions. 
     
     
         5 . The process of any of  claims 1  to  4  wherein the compound of formula 6 is prepared by contacting a compound of formula 5: 
       
         
           
           
               
               
           
         
         or a salt thereof with a borylating reagent characterized by the following formula: 
       
       
         
           
           
               
               
           
         
         in the presence of an alkylithium reagent, where each R 2  is independently C 1 -C 6 -alkyl, or together with the oxygen atoms to which they are attached form a 5- or 6-membered ring; and 
         R 3  is C 1 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, C 6 -alkyl. 
       
     
     
         6 . The process of  claim 5  wherein the borylating reagent is isopropylpinacolborate, or a tri-C 1 -borate, tri-C 2 -borate or tri-C 3 -borate; n is 0 to 3; and the alkyl lithium reagent is n-BuLi, n-hexyllithium, or sec-BuLi. 
     
     
         7 . The process of either  claim 5  or  6  wherein the borylating reagent is isopropylpinacolborate or trimethyl borate; n is 2 and the alkyl lithium reagent is n-BuLi. 
     
     
         8 . The process of  claim 5  wherein the compound of formula 5 or a salt thereof is prepared either by enantioselective reduction of a compound of formula 10 
       
         
           
           
               
               
           
         
         or a salt thereof; 
         or by contacting under basic conditions R 1′ X with a compound of formula 4: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         where X is a leaving group. 
       
     
     
         9 . The process of  claim 8  wherein the compound of formula 5 or a salt thereof is prepared using H 2  and Naud catalyst or H 2  and Noyori catalyst; and n is 2. 
     
     
         10 . The process of  claim 8  wherein the compound of formula 5 or a salt thereof is prepared by contacting the compound of formula 4 or a salt thereof with benzyl bromide in the presence of a carbonate or a hydroxide. 
     
     
         11 . The process of  claim 10  wherein the compound of formula 4 or a salt thereof is prepared by contacting formula 2: 
       
         
           
           
               
               
           
         
         with nitromethane in the presence of a chiral reagent, to form a compound of formula 3: 
       
       
         
           
           
               
               
           
         
         then reducing the nitro group to an amine group. 
       
     
     
         12 . The process of  claim 11  wherein the chiral reagent is
 1,7,7-trimethyl-N-(pyridin-2-ylmethyl)bicyclo[2.2.1]heptan-2-amine di-hydrochloride; (4S)-4-ethyl-2-{1-ethyl-1-[(4 S)-4-(1-methylethyl)-4,5-dihydro-1,3-oxazol-2-yl]propyl}-4,5-dihydro-1,3-oxazole; (S)-4-(tert-butyl)-2-(2-((S)-4-methyl-4,5-dihydrooxazol-2-yl)propan-2-yl)-4,5-dihydrooxazole; or N1,N2-bis[(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1,2-ethanediamine and Cu(OAc) 2 ; and n is 2. 
 
     
     
         13 . The process of  claim 8  wherein the compound of formula 10 or a salt thereof is prepared by contacting HN(R 1′ ) 2  with a base and a compound of formula 9: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The process of  claim 13  wherein the compound of formula 9 is prepared by bromination of a compound of formula 8: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A process comprising the steps of:
 a) contacting a compound of formula 2:   
       
         
           
           
               
               
           
         
         with nitromethane in the presence of a chiral reagent to make a compound of formula 3: 
       
       
         
           
           
               
               
           
         
         where R is H or OR 1 ; R 1  is a protecting group; and n is 0, 1, 2, 3, 4 or 5; 
         b) reducing the compound of formula 3 to form a compound of formula 4: 
       
       
         
           
           
               
               
           
         
         or a salt thereof; 
         c) contacting the compound of formula 4 or a salt thereof with R 1′ X with a base to form a compound of formula 5: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein R 1′  is a protecting group and X is a leaving group; 
         d) contacting the compound of formula 5 or a salt thereof with a borylating reagent characterized by the following formula: 
       
       
         
           
           
               
               
           
         
         in the presence of n-BuLi to form a compound of formula 6: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         where each R 2  is independently C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, C 6 -alkyl, or together with the oxygen atoms to which they are attached form a 5- or 6-membered ring; and R 3  is C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, C 6 -alkyl; and 
         e) contacting the compound of formula 6 or a pharmaceutically acceptable salt thereof with a deprotecting reagent to form a compound of formula A or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         where R 1″  is H or OH. 
       
     
     
         16 . The process of  claim 15  wherein:
 R 1  and each R 1′  are benzyl groups; 
 n is 2; 
 the chiral reagent is Cu(OAc) 2  and 1,7,7-trimethyl-N-(pyridin-2-ylmethyl)bicyclo[2.2.1]heptan-2-amine di-hydrochloride; (4S)-4-ethyl-2-{1-ethyl-1-[(4S)-4-(1-methylethyl)-4,5-dihydro-1,3-oxazol-2-yl]propyl}-4,5-dihydro-1,3-oxazole; (S)-4-(tert-butyl)-2-(2-((S)-4-methyl-4,5-dihydrooxazol-2-yl)propan-2-yl)-4,5-dihydrooxazole; or N1,N2-bis[(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1,2-ethanediamine; 
 X is a leaving group selected from Br, Cl, I, tosyl or triflyl; 
 the borylating reagent is isopropylpinacolborate or trimethylborate; and 
 the deprotecting agent is hydrogenation in the presence of a Pd/C catalyst, Pt/C catalyst or a mixture of Pd/C+Pt/C catalysts. 
 
     
     
         17 . A process comprising the steps of:
 a) brominating a compound of formula 8:   
       
         
           
           
               
               
           
         
         to form a compound of formula 9: 
       
       
         
           
           
               
               
           
         
         where R is H or OR 1 ; R 1  is a protecting group; and n is 0, 1, 2, 3, 4 or 5; 
         b) contacting the compound of formula 9 with HN(R 1′ ) 2  to form a compound of formula 10: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         where each R 1′  is a protecting group; 
         c) enantioselectively reducing the compound of formula 10 or a salt thereof to form a compound of formula 5: 
       
       
         
           
           
               
               
           
         
         or a salt thereof; 
         d) contacting the compound of formula 5 or a salt thereof with a borylating reagent characterized by the following formula: 
       
       
         
           
           
               
               
           
         
         in the presence of n-BuLi, to form a compound of formula 6: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         where each R 2  is independently C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, C 6 -alkyl, or together with the oxygen atoms to which they are attached form a 5- or 6-membered ring; and R 3  is C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, C 6 -alkyl; and 
         e) contacting the compound of formula 6 or a pharmaceutically acceptable salt thereof with a deprotecting reagent to form a compound of formula A or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         where R 1″  is H or OH. 
       
     
     
         18 . A compound of formula 6a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, where R 1″  is H or OH; and R 1′  is a protecting group. 
       
     
     
         19 . The compound of  claim 18  wherein R 1′  is benzyl, 1-phenylethyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, or diphenylmethyl; R 1″  is OH; and n is 0, 1, 2 or 3. 
     
     
         20 . The compound of either  claim 18  or  19  wherein R 1′  is benzyl and n is 2.