Thienopyridine derivatives, their intermediates and production thereof

Abstract

The present invention provides an intermediate for producing a thienopyridine derivative useful as a GnRH antagonist as well as an efficient and safe method for producing the same in an industrial scale at a high yield.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 11a  represents hydrogen or halogen, and R 41a  represents C 16  alkyl, C 16  alkoxy or C 6-10  aryl, with proviso that R 41a  is not ethoxy when R 11a  is hydrogen, or a salt thereof.  
     
     
         2 . A compound of  claim 1  or a salt thereof, wherein R 11a  is hydrogen or bromo.  
     
     
         3 . A compound of  claim 1  or a salt thereof, which is 7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-oxo-2-phenylthieno[2,3-b]pyridine.  
     
     
         4 . A compound of  claim 1  or a salt thereof, which is 3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxo-2-phenylthieno[2,3-b]pyridine.  
     
     
         5 . A compound of  claim 1  or a salt thereof, which is 3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-4-oxo-2-phenylthieno[2,3-b]pyridine-5-carboxylic acid ethyl ester.  
     
     
         6 . A process for producing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X represents halogen, R 12a  represents a divalent hydrocarbon group which may be substituted, R 3a  represents a hydrocarbon group which may be substituted, R 4a  represents a hydrocarbon group or a hydrocarbon-oxy group, and R 22a  represents a hydrocarbon group substituted by nitro, or a salt thereof, which comprises subjecting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 21a  represents a hydrocarbon group and other symbols are as defined above, or a salt thereof to nitration.  
     
     
         7 . A process of  claim 6 , wherein R 12a  is methylene, R 21a  is phenyl, R 22a  is nitrophenyl, R 3a  is difluorophenyl-methyl, and R 4a  is isopropyl or ethoxy.  
     
     
         8 . A process for producing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X represents halogen, R 12a  represents a divalent hydrocarbon group, and R 4a  represents a hydrocarbon group or a hydrocarbon-oxy group, or a salt thereof, which comprises subjecting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1a  represents a hydrocarbon group which may be substituted and the other symbol is as defined above, or a salt thereof to halogenation.  
     
     
         9 . A process of  claim 8 , wherein the halogenation is carried out in the presence of methyl acetate.  
     
     
         10 . A process of  claim 8 , wherein X is bromo, R 1a  is methyl, R 12a  is methylene, and R 4a  is isopropyl or ethoxy.  
     
     
         11 . A process for producing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X represents halogen, R 12a  represents a divalent hydrocarbon group which may be substituted, R 3a  represents a hydrocarbon group which may be substituted, R 4a  represents a hydrocarbon group or a hydrocarbon-oxy group, and R 22a  represents a hydrocarbon group substituted by nitro, or a salt thereof, which comprises subjecting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1a  and R 2a  each represents a hydrocarbon group which may be substituted and other symbols are as defined above, or a salt thereof to halogenation to obtain a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein each symbol is as defined above, or a salt thereof, and then subjecting the resultant compound to nitration.  
     
     
         12 . A process of  claim 11 , wherein R 1a  is methyl, R 12a  is methylene, R 2a  is phenyl, R 22a  is nitrophenyl, R 3a  is difluorophenyl-methyl, and R 4a  is isopropyl or ethoxy.  
     
     
         13 . A process for producing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1a , R 2a  and R 3a  each represents a hydrocarbon group which may be substituted, and R 5a  and R 6a  each represents a hydrocarbon group, or a salt thereof, which comprises reacting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein each symbol is as defined above, or a salt thereof with a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein each symbol is as defined above, or a salt thereof.  
     
     
         14 . A process of  claim 13 , wherein R 1a  is methyl which may be substituted by N-benzyl-N-methylamino, R 2a  is phenyl which may be substituted by isobutyrylamino, R 3a  is difluorophenyl-methyl, and R 5a  and R 6a  are methyl.  
     
     
         15 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 11  represents C 1-6  alkyl, R 21  represents phenyl which may be substituted, or R 11  and R 21  form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, R 3  represents a hydrocarbon group which may be substituted, and R 5  represents hydrogen or a hydrocarbon group, or a salt thereof.  
     
     
         16 . A compound of  claim 15  or a salt thereof, wherein the substituent of the phenyl which may be substituted for R 21  is isobutyrylamino or methoxy.  
     
     
         17 . A compound of  claim 15  or a salt thereof, which is 4-hydroxy-5-isobutyryl-3-methyl-2-phenylthieno[2,3-b]pyridine.  
     
     
         18 . A compound of  claim 15  or a salt thereof, which is 4-hydroxy-5-isobutyryl-2-(4-isobutyrylaminophenyl)-3-methylthieno[2,3-b]pyridine.  
     
     
         19 . A process for producing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  each represents a hydrocarbon group which may be substituted, or R 1  and R 2  form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, R 3  represents a hydrocarbon group which may be substituted, and R 5  represents hydrogen or a hydrocarbon group, or a salt thereof, which comprises subjecting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 4  represents a hydrocarbon group and other symbols are as defined above, or a salt thereof to cyclization.  
     
     
         20 . A process of  claim 19 , wherein R 1  is methyl, R 2  is phenyl which may be substituted by isobutyrylamino or methoxy, or R 1  and R 2  form, taken together with adjacent two carbon atoms, tetrahydrobenzene ring, R 3  is methyl, isopropyl or phenyl, R 4  is ethyl, and R 5  is hydrogen.  
     
     
         21 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  each represents a hydrocarbon group which may be substituted, or R 1  and R 2  form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, R 3  represents a hydrocarbon group which may be substituted, R 4  represents a hydrocarbon group, and R 5  represents hydrogen or a hydrocarbon group, or a salt thereof.  
     
     
         22 . A compound of  claim 21  or a salt thereof, wherein R 1  is methyl, R 2  is phenyl which may be substituted by isobutyrylamino, methoxy or nitro, or R 1  and R 2  form, taken together with adjacent two carbon atoms, tetrahydrobenzene ring, R 3  is methyl, isopropyl or phenyl, R 4  is ethyl, and R 5  is hydrogen.  
     
     
         23 . A compound of  claim 21  or a salt thereof, which is 4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)amino]-5-phenylthiophene-3-carboxylic acid ethyl ester.  
     
     
         24 . A compound of  claim 21  or a salt thereof, which is 5-(4-isobutyrylaminophenyl)-4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)amino]thiophene-3-carboxylic acid ethyl ester.  
     
     
         25 . A process for producing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  each represents a hydrocarbon group which may be substituted, or R 1  and R 2  form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, R 3  represents a hydrocarbon group which may be substituted, R 4  represents a hydrocarbon group, and R 5  represents hydrogen or a hydrocarbon group, or a salt thereof, which comprises reacting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein each symbol is as defined above, or a salt thereof, with a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 6  represents hydrogen, sodium, potassium or a hydrocarbon group and other symbols are as defined above, or a salt thereof.  
     
     
         26 . A process of  claim 25 , wherein R 1  is methyl, R 2  is phenyl which may be substituted by isobutyrylamino, methoxy or nitro, or R 1  and R 2  form, taken together with adjacent two carbon atoms, tetrahydrobenzene ring, R 3  is methyl, isopropyl or phenyl, R 4  is ethyl, and R 5  is hydrogen.  
     
     
         27 . A process for producing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  each represents a hydrocarbon group which may be substituted, or R 1  and R 2  form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, R 3  represents a hydrocarbon group which may be substituted, and R 5  represents hydrogen or a hydrocarbon group, or a salt thereof, which comprises reacting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 4  is a hydrocarbon group and other symbols are as defined above, or a salt thereof with a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 6  represents hydrogen, sodium, potassium or a hydrocarbon group, and other symbols are as defined above, or a salt thereof, to obtain a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein each symbol is as defined above, or a salt thereof, and then subjecting the resultant compound to cyclization.  
     
     
         28 . A process of  claim 27 , wherein R 1  is methyl, R 2  is phenyl which may be substituted by isobutyrylamino or methoxy, or R 1  and R 2  form, taken together with adjacent two carbon atoms, tetrahydrobenzene ring, R 3  is methyl, isopropyl or phenyl, R 4  is ethyl, and R 5  is hydrogen.  
     
     
         29 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 22  represents isobutyrylamino or methoxy, or a salt thereof.  
     
     
         30 . A compound of  claim 29  or a salt thereof, which is 7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4-isobutyrylaminophenyl)-3-methyl-4-oxothieno[2,3-b]pyridine.  
     
     
         31 . A process for producing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 23  represents phenyl which may be substituted by isobutyrylamino or methoxy, and R 3  represents a hydrocarbon group which may be substituted, or a salt thereof, which comprises reacting a compound of the formula;  
       
         
           
           
               
               
           
         
       
       wherein each symbol is as defined above, or a salt thereof, with a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X represents halogen, or a salt thereof.  
     
     
         32 . A dibasic acid salt of 7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-4-oxothieno[2,3-b]pyridine.