Methods and compounds useful in the synthesis of orexin-2 receptor antagonists

Abstract

The present disclosure provides compounds and methods that are useful for the preparation of compounds useful as orexin-2 receptor antagonists.

1 .- 139 . (canceled) 
     
     
         140 . A process for making a compound of Formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein Ar is aryl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, and haloC 1-6 alkyl; and 
 
         R 1  is a sulfonate ester leaving group, 
         comprising reacting a compound of Formula III: 
       
       
         
           
           
               
               
           
         
         wherein Ar is as given above, 
         with a compound selected from the group consisting of: tosyl chloride, mesyl chloride, nosyl chloride, toluenesulfonyl chloride, toluenesulfonic anhydride and methanesulfonic anhydride, wherein said reacting is carried out in an organic solvent in the presence of a base, to thereby make said compound of Formula IV. 
       
     
     
         141 . The process of  claim 140 , wherein Ar is phenyl. 
     
     
         142 . The process of  claim 140 , wherein Ar is optionally substituted 1-3 times with a halo independently selected from the group consisting of chloro, fluoro, bromo, and iodo. 
     
     
         143 . The process of  claim 140 , where said reacting is carried out for a time of from 10 minutes to 2 hours. 
     
     
         144 . The process of  claim 140 , wherein the base is potassium carbonate or an organic amine. 
     
     
         145 . The process of  claim 144 , wherein the organic amine is selected from the group consisting of triethylamine, diisopropylethylamine, and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). 
     
     
         146 . The process of  claim 140 , wherein the base is pyridine. 
     
     
         147 . The process of  claim 140 , wherein the organic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, and ethyl acetate. 
     
     
         148 . The process of  claim 140 , wherein the organic solvent is dichloromethane. 
     
     
         149 . The process of  claim 140 , wherein the organic solvent is 2-methyltetrahydrofuran. 
     
     
         150 . The process of  claim 140 , wherein Ar is phenyl optionally substituted 1-3 times with substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, and halo C 1-6 alkyl,
 and wherein said compound of Formula III is produced by a process comprising reacting a mixture of:
 i) a compound of Formula Ia: 
   
       
         
           
           
               
               
           
         
         wherein Ar is as given above;
 ii) vinyl acetate; 
 iii) a lipase; and 
 iv) an organic solvent, 
 
         for a time of from 5 to 36 hours, 
         to thereby make the compound of Formula III. 
       
     
     
         151 . The process of  claim 150 , wherein said lipase is a  Candida Antarctica  lipase. 
     
     
         152 . The process of  claim 150 , wherein said lipase is a  Candida Antarctica  B lipase coupled to an acrylic resin. 
     
     
         153 . The process of  claim 150 , wherein Ar is optionally substituted 1-3 times with a halo independently selected from the group consisting of chloro, fluoro, bromo, and iodo. 
     
     
         154 . The process of  claim 150 , wherein the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, an ether solvent, acetone, or acetonitrile. 
     
     
         155 . The process of  claim 150 , wherein the reacting step is carried out for a time of from 7 to 18 hours. 
     
     
         156 . The process of  claim 150 , further comprising steps of filtering the mixture after said reacting to produce a filtrate, and concentrating the filtrate to produce a concentrated filtrate. 
     
     
         157 . The process of  claim 156 , further comprising the step of washing the concentrated filtrate with water or water comprising a salt. 
     
     
         158 . The process of  claim 156 , further comprising the step of washing the concentrated filtrate with a solution of 15-20% NaCl in water. 
     
     
         159 . The process of  claim 150 , wherein said compound of Formula III is: 
       
         
           
           
               
               
           
         
       
     
     
         160 . The process of  claim 150 , wherein the compound of Formula IV is a compound of Formula IVa: 
       
         
           
           
               
               
           
         
       
     
     
         161 . The process of  claim 160 , wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 80%. 
     
     
         162 . The process of  claim 160 , wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 85%. 
     
     
         163 . The process of  claim 160 , wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 90%. 
     
     
         164 . The process of  claim 160 , wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 95%. 
     
     
         165 . The process of  claim 160 , wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 98%.