Quinoline Intermediates of Receptor Tyrosine Kinase Inhibitors and the Synthesis Thereof

Abstract

This invention is directed to methods of preparing 4-substituted quinoline compounds as intermediates in the manufacture of receptor tyrosine kinase inhibitors and intermediate compounds used in the methods thereof, wherein the 4-substituted quinoline compound has the following general formula (I): wherein substitutions at LG″, PG, A, G, R 1 and R 4 are set forth in the specification.

1 . A method of preparing a 4-substituted quinoline compound comprising the step of reacting a compound of the following formula (II): 
     
       
         
         
             
             
         
       
       with a reagent of formula POLG′ 3 , wherein LG′ is halo, to provide a compound of the following formula (I): 
     
     
       
         
         
             
             
         
       
     
     wherein;
 LG is a leaving group selected from the group consisting of morpholino, o-mesyl, o-tosyl, trifilate; 
 LG″ is a leaving group selected from the group consisting of morpholino, o-mesyl, o-tosyl, trifilate and halogen; 
 PG is a protecting group selected from the group consisting of acyl, CH 3 OC(O)—, EtOC(O)—, Fmoc, trifluoroacetamide, Troc, Phenoc, benzamide, Teoc, pthalimide, maleimide and 2,5-dimethylpyrrole; 
 A is O, NR, or S; 
 R is H, alkyl, alkenyl, or alkynyl; and 
 G, R 1  and R 4  are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phthalimide, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, 
 
     
       
         
         
             
             
         
       
       R 7 —(C(R 6 ) 2 ) g —Y—, R 7 —(C(R 6 ) 2 ) p -M-(C(R 6 ) 2 ) k —Y—, or Het-(C(R 6 ) 2 ) q W—(C(R 6 ) 2 —Y—; 
       or R 1  and R 4  are as defined above and G is R 2 —NH—; 
       or if any of the substituents R 1 , R 4  or G are located on contiguous carbon atoms then they may be taken together as the divalent radical —O—C(R 6 ) 2 —O; 
       Y is a divalent radical selected from the group consisting of 
       —(CH 2 ) a —, —O—, and 
     
     
       
         
         
             
             
         
       
       R 7  is —NR6R6, —OR6, -J, —N(R6)3+, or —NR6(OR6); 
       M is >NR6, —O—, >N—(C(R6)2)pNR6R6, or >N—(C(R6)2)p—OR 6 ; 
       W is >NR6, —O— or is a bond; 
       Het is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and 
     
     
       
         
         
             
             
         
       
     
     wherein Het is optionally mono- or di-substituted on carbon or nitrogen with R 6 , optionally mono- or di-substituted on carbon with hydroxy, —N(R 6 ) 2 , or —OR 6 , optionally mono or di-substituted on carbon with the mono-valent radicals —(C(R 6 ) 2 ) s OR 6  or —(C(R 6 ) 2 ) s N(R 6 ) 2 , and optionally mono or di-substituted on a saturated carbon with divalent radicals —O— or —O(C(R 6 ) 2 ) s O—;
 R 6  is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms; with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom; 
 R 2 , is selected from the group consisting of 
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       R 3  is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, 
     
     
       
         
         
             
             
         
       
       R 7 —(C(R 6 ) 2 ) s —, 
       R 7 —(C(R 6 ) 2 ) p -M-(C(R 6 ) 2 ) r —, R 8 R 9 —CH— 
       M-(C(R 6 ) 2 ) r —, or 
       Het-(C(R 6 ) 2 ) q —W—(C(R 6 ) 2 ) r —; 
       R 5  is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl carboalkyl of 2-7 carbon atoms, 
     
     
       
         
         
             
             
         
       
       R 7 —(C(R 6 ) 2 ) s —, 
       R 7 —(C(R 6 ) 2 ) p -M-(C(R 6 ) 2 ) r , R 8 R 9 —CH— 
       M-(C(R 6 ) 2 ) r —, or 
       Het-(C(R 6 ) 2 ) q —W—(C(R 6 ) 2 ) r —; 
       R 8 , and R 9  are each independently —(C(R 6 ) 2 ) r NR 6 R 6 , or —(C(R 6 ) 2 ) r OR 6 ; 
       J is independently hydrogen, chlorine, fluorine, or bromine; 
       Q is an alkyl of 1-6 carbon atoms or hydrogen; 
       a=0 or 1; 
       g=1-6; 
       k=0-4; 
       n is 0-1; 
       m is 0-3; 
       p=2-4; 
       q=0-4; 
       s=1-6; 
       u=0-4 and v=0-4, wherein the sum of u+v is 2-4; 
       x=0-3; 
       y—0-1; 
       z=0-3; 
       or a salt thereof. 
     
   
   
       2 . The method of  claim 1 , wherein LG′ is chloro. 
   
   
       3 . The method of  claim 1 , further comprising the step of substituting the LG″ group on a compound of formula (I) with a nucleophile. 
   
   
       4 . The method of  claim 1 , further comprising the step of forming the compound of formula (II) by condensing an active methylene compound of formula (IV): 
     
       
         
         
             
             
         
       
     
     with an arylformimidate compound of formula (III): 
     
       
         
         
             
             
         
       
     
     wherein LG, PG, A and G are as previously defined. 
   
   
       5 . The method of  claim 4 , wherein LG is morpholino, PG is acyl, A is amino and G is ethoxy. 
   
   
       6 . The method of  claim 4 , further comprising the step of forming the arylformimidate by reacting an arylamine of formula (V): 
     
       
         
         
             
             
         
       
     
     with orthoformate, wherein PG, A and G are as previously defined. 
   
   
       7 . The method of  claim 6 , wherein the arylamine compound is N-(4-amino-2-ethoxyphenyl)acetamide. 
   
   
       8 . The method of  claim 6 , wherein the orthoformate is triethyl orthoformate. 
   
   
       9 . The method of  claim 1 , further comprising the step of forming the compound of formula (II) by reacting an alkoxymethylene compound of formula (VI): 
     
       
         
         
             
             
         
       
     
     with an arylamine of formula (V): 
     
       
         
         
             
             
         
       
     
     wherein LG, PG, A and G are as previously defined. 
   
   
       10 . The method of  claim 9 , wherein LG is morpholino, PG is acyl, A is amino and G is ethoxy. 
   
   
       11 . The method of  claim 9 , further comprising the step of forming the alkoxymethylene compound by condensating an active methylene compound of formula (IV): 
     
       
         
         
             
             
         
       
     
     with orthoformate, wherein LG is as previously defined. 
   
   
       12 . The method of  claim 11 , wherein the active methylene compound is morpholinocyanoacetate. 
   
   
       13 . The method of  claim 11 , wherein the orthoformate is triethyl orthoformate. 
   
   
       14 . The method of  claim 1 , wherein the treatment of the compound of formula (II) with phosphoryl chloride occurs at a temperature in the range of 60 to 100° C. 
   
   
       15 . The method of  claim 1 , wherein a compound of the following formula (VII): 
     
       
         
         
             
             
         
       
     
     is an intermediate formed after the reaction of a compound of formula (II) with POLG′ 3 , but before the formation of a compound of formula (I), wherein LG, LG′, PG, A, G, R 1  and R 4  are as previously defined. 
   
   
       16 . The method of  claim 15 , wherein LG is morpholino. 
   
   
       17 . The method of  claim 16 , wherein the compound of formula (VII) is N-[3-cyano-7-ethoxy-4-(4-moropholinyl)-6-quinolinyl]acetamide. 
   
   
       18 . The method of  claim 1 , wherein the compound of formula (I) is N-[4-chloro-3-cyano-7-hydroxy-6-quinolinyl]acetamide. 
   
   
       19 . The method of  claim 1 , wherein the compound of formula (II) is morpholinocyanoenamine. 
   
   
       20 .- 25 . (canceled)