Processes for Preparing Quinoline Derivatives

Abstract

A process for preparing a compound of Formula I is disclosed, comprising the steps: wherein: R 1 is halo; R 2 is halo; R 3 is (C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl optionally substituted with heterocycloalkyl; R 4 is (C 1 -C 6 )alkyl; and Q is CH or N; comprising: (a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar aprotic solvent; (b) adding and a tertiary amine base to the mixture of step (a) to form a compound of Formula A; and (c) coupling a compound of Formula A with an amine of Formula B to form a compound of Formula I.

What is claimed is: 
     
         1 . A processes for preparing a compound of Formula A: 
       
         
           
           
               
               
           
         
         wherein R 2  is H, F, Cl, or Br; 
       
       comprising
 (a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar aprotic solvent; and 
 (b) adding 
 
       
         
           
           
               
               
           
         
       
       and a tertiary amine base to mixture of step (a). 
     
     
         2 . The process for  claim 1 , wherein the polar aprotic solvent is selected form the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, dimethylformamide, acetonitrile, and dimethylsulfoxide, or combinations thereof. 
     
     
         3 . The process for  claim 1 , wherein the polar aprotic solvent is isopropyl acetate. 
     
     
         4 . The process for  claim 1 , wherein approximately 5 to 10 volumes of polar aprotic acid are used relative to volume of 1,1-cyclopropanedicarboxylic acid that is used. 
     
     
         5 . The process for  claim 1 , wherein approximately 8 volumes of polar aprotic acid are used relative to volume of 1,1-cyclopropanedicarboxylic acid that is used. 
     
     
         6 . The process for  claim 1 , wherein approximately 1.01 to 1.2 molar equivalents of thionyl chloride are used. 
     
     
         7 . The process for  claim 1 , wherein approximately 1.05 molar equivalents of thionyl chloride are used. 
     
     
         8 . The process for  claim 1 , wherein the mixture of step (a) is stirred at ambient temperature for 2 to 24 hours. 
     
     
         9 . The process for  claim 1 , wherein the mixture of step (a) is stirred at approximately 24-26° C. for 6 to 16 hours. 
     
     
         10 . The process for  claim 1 , wherein the optionally substituted aniline and the tertiary amine base is added as a mixture in a polar aprotic solvent to the step (a) mixture. 
     
     
         11 . The process for  claim 10 , wherein the aniline is 4-fluoroaniline and the tertiary amine base is triethyl amine. 
     
     
         12 . The process for  claim 10 , wherein approximately 1.01 to 1.5 molar equivalents of aniline are used relative to the number of moles of 1,1-cyclopropanedicarbopxylic acid that are used and approximately 1.01 to 1.5 molar equivalents of tertiary amine base are used relative to the number of moles of 1,1-cyclopropanedicarbopxylic acid that are used. 
     
     
         13 . The process for  claim 10 , wherein the polar aprotic solvent in step (b) is selected form the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, dimethylformamide, acetonitrile, and dimethylsulfoxide, or combinations thereof. 
     
     
         14 . The process for  claim 10 , wherein the polar aprotic solvent in step (b) is isopropyl acetate. 
     
     
         15 . The process for  claim 14 , wherein approximately 2 volumes of isopropyl acetate are used. 
     
     
         16 . The process for  claim 1 , wherein the mixture resulting mixture of step (b) is allowed to stir for approximately 0.75 to 4 hours at ambient temperature. 
     
     
         17 . The process for  claim 1 , further comprising quenching the mixture of step (b) with a concentrated aqueous base. 
     
     
         18 . The process for  claim 17 , wherein the aqueous base is selected from the group consisting of NaOH, KOH, or K 3 PO 4 . 
     
     
         19 . A process for preparing a compound of Formula A 
       
         
           
           
               
               
           
         
         wherein R 2  is H, F, Cl, or Br; 
       
       comprising
 (a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature; 
 (b) adding 
 
       
         
           
           
               
               
           
         
       
       triethyl amine to the mixture of step (a);
 (c) quenching the mixture with concentrated aqueous sodium hydroxide; 
 (d) extracting compound A into dilute aqueous base; 
 (e) acidifying the mixture with HCl; and 
 (f) isolating Compound A by filtration. 
 
     
     
         20 . A process for preparing a compound of Formula A-1: 
       
         
           
           
               
               
           
         
       
       comprising
 (a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature; and 
 (b) adding a mixture comprising 4-fluoroaniline and a triethyl amine in isopropyl acetate to the mixture of step (a). 
 
     
     
         21 . A process for preparing a compound of Formula A-1: 
       
         
           
           
               
               
           
         
       
       comprising
 (a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature; a 
 (b) adding a mixture comprising 4-fluoroaniline and a triethyl amine in isopropyl acetate to the mixture of step (a); 
 (c) quenching the mixture of step (b) with concentrated aqueous sodium hydroxide; 
 (d) extracting compound A-1 into dilute aqueous base; 
 (e) acidifying the mixture of step (d) with HCl; and 
 (f) isolating Compound A by filtration. 
 
     
     
         22 . The process for  claims 1 - 21  wherein the product Compound A or A-1 is contaminated with approximately 5 percent or less of the bisamide. 
       
         
           
           
               
               
           
         
       
     
     
         23 . A process for preparing a compound of Formula I as defined above, comprising the steps: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is halo; 
         R 2  is halo; 
         R 3  is (C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl optionally substituted with heterocycloalkyl; 
         R 4  is (C 1 -C 6 )alkyl; and 
         Q is CH or N; 
       
       comprising:
 (a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar aprotic solvent; 
 (b) adding 
 
       
         
           
           
               
               
           
         
       
       and a tertiary amine base to the mixture of step (a) to form a compound of Formula A; 
       
         
           
           
               
               
           
         
         (c) coupling a compound of Formula A with an amine of Formula B to form a compound of Formula I. 
       
       
         
           
           
               
               
           
         
       
     
     
         24 . The process of  claim 23 , wherein the compound of Formula I is compound 1. 
       
         
           
           
               
               
           
         
       
     
     
         25 . The process of  claim 23 , wherein the compound of Formula I is compound 2. 
       
         
           
           
               
               
           
         
       
     
     
         26 . A process for mono-amidating a dicarboxylic acid, comprising
 (a) contacting a dicarboxylic acid with thionyl chloride in a polar aprotic solvent; and   (b) adding a primary amine and a tertiary amine base to the mixture of step (a).