Substituted quinolinylcyclohexylpropanamide compounds and improved methods for their preparation

Abstract

The disclosure is directed to improved methods for preparing substituted quinolinylcyclohexylpropanamide compounds.

1 . A method of making a compound of formula I, or a stereoisomer thereof: 
       
         
           
           
               
               
           
         
         comprising 
         contacting a compound of formula II, or a stereoisomer thereof: 
       
       
         
           
           
               
               
           
         
         wherein R 1  is C 1-6 alkyl, aryl, or C 1-6 haloalkyl; 
         with a mixture of a C 1-6 alkoxide salt and a di-C 1-6 alkyl-malonate, in a suitable organic solvent; 
         for a time and at a temperature sufficient to displace the sulfonate moiety and to produce a compound of formula III, or a stereoisomer thereof: 
       
       
         
           
           
               
               
           
         
         and 
         contacting the compound of formula III, or a stereoisomer thereof, with a suitable organic acid, in a suitable aqueous organic solvent, for a time and at a temperature sufficient for hydrolysis and decarboxylation and to produce the compound of formula I, or a stereoisomer thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the C 1-6 alkoxide salt is sodium t-amylate and the di-C 1-6 alkyl-malonate is di-tert-butyl malonate. 
     
     
         3 . The method of  claim 1 , wherein the organic acid is methanesulfonic acid. 
     
     
         4 . The method of  claim 1 , wherein R 1  is methyl. 
     
     
         5 . The method of  claim 1 , wherein the compound of formula II, or a stereoisomer thereof, is prepared by
 contacting a compound of formula IV:   
       
         
           
           
               
               
           
         
         with a Lewis acid and a hydride source, in a suitable alcoholic organic solvent, for a time and at a temperature sufficient to produce reduce the carbonyl and to produce a compound of formula V, or a stereoisomer thereof: 
       
       
         
           
           
               
               
           
         
         and 
         contacting the compound of formula V, or a stereoisomer thereof, with X—SO 2 —R 1 , wherein X is halo, or with R 1 —SO 2 —O—SO 2 —R 1  in the presence of an alkyl-amine base, in a suitable anhydrous organic solvent, for a time and at a temperature sufficient for X displacement to produce the compound of formula II, or a stereoisomer thereof. 
       
     
     
         6 . The method of  claim 5 , wherein the cerium halide is CeCl 3 , or a hydrate thereof, and the hydride source is NaBH 4 . 
     
     
         7 . The method of  claim 5 , wherein X is Cl and R 1  is methyl. 
     
     
         8 . The method of  claim 5 , wherein the alkyl-amine base is Et 3 N. 
     
     
         9 . The method of  claim 5 , wherein the compound of formula IV is prepared by contacting a compound of formula VI-A or VI-B: 
       
         
           
           
               
               
           
         
         wherein n is 1 or 2; 
         with a compound of formula VII 
       
       
         
           
           
               
               
           
         
         wherein Y is halo; 
         in the presence of a suitable C 1-6 alkylsilylamine base, in a suitable organic solvent, for a time and at a temperature sufficient for Y displacement to produce a compound of formula VIII-A or formula VIII-B; 
       
       
         
           
           
               
               
           
         
         and 
         contacting the compound of formula VIII-A or formula VIII-B with a suitable hydroxide base, in a suitable aqueous solvent, for a time and at a temperature sufficient for hydrolysis to produce a compound of formula IX-A or formula IX-B; 
       
       
         
           
           
               
               
           
         
         and 
         contacting the compound of formula IX-A or formula IX-B, with a suitable mineral acid, in a suitable aqueous solvent, for a time and at a temperature sufficient for hydrolysis and decarboxylation to produce the compound of formula IV. 
       
     
     
         10 . The method of  claim 9 , wherein n is 1. 
     
     
         11 . The method of  claim 9 , wherein Y is Cl. 
     
     
         12 . The method of  claim 9 , wherein the C 1-6 alkylsilylamine is NaHMDS. 
     
     
         13 . The method of  claim 9 , wherein the hydroxide base is KOH or NaOH. 
     
     
         14 . The method of  claim 9 , wherein the mineral acid is HCl. 
     
     
         15 . The method of  claim 1 , wherein the compound of formula I is: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 1 , wherein the compound of formula II is: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A method for preparing Compound 1, or a stereoisomer thereof, 
       
         
           
           
               
               
           
         
         comprising: 
         converting a compound of formula I, or a stereoisomer thereof, prepared according to any one of the preceding claims, to a Compound 2, or a stereoisomer thereof: 
       
       
         
           
           
               
               
           
         
         wherein R is phenyl or benzyl; and 
         converting the Compound 2, or a stereoisomer thereof, to a Compound 3, or a stereoisomer thereof 
       
       
         
           
           
               
               
           
         
         and 
         converting the Compound 3, or a stereoisomer thereof, to a Compound 4, or a stereoisomer thereof. 
       
       
         
           
           
               
               
           
         
         and converting the Compound 4, or a stereoisomer thereof, to the Compound 1, or a stereoisomer thereof, and 
         optionally preparing a pharmaceutically acceptable salt or co-crystal, for example, a methanesulfonic acid salt, of the Compound 1. 
       
     
     
         18 . The method of  claim 17 , wherein the Compound 1 is 
       
         
           
           
               
               
           
         
       
     
     
         19 . Compound 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for example, methanesulfonic acid salt, or a co-crystal thereof, prepared according to  claim 17 . 
     
     
         20 . A compound that is 
       
         
           
           
               
               
           
         
         methanesulfonic acid. 
       
     
     
         21 . A compound that is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or a co-crystal thereof. 
       
     
     
         22 . A compound that is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.