Method for producing 2-(2-aminopyrimidin-4-yl)-1h-indole-5-carboxylic acid derivatives

Abstract

This disclosure relates to a novel process for obtaining a compound of formula I: wherein the values of R1, R2, and R3 and P are as described in the specification, and intermediates thereof.

What is claimed is: 
     
         1 . A compound of formula II 
       
         
           
           
               
               
           
         
         or a physiologically compatible salt of the compound of the formula II, where 
         R1 is
 a hydrogen atom, 
 —(C 1 -C 12 )-alkyl, 
 —(C 6 -C 14 )-aryl, 
 —(C 3 -C 8 )-cycloalkyl or 
 a 4- to 15-membered Het ring, 
 
         with the proviso that R1 is not a hydrogen atom when P is a hydrogen atom and D is —N(R2)-R3 in which R2 is a hydrogen atom and R3 is —(C 1 -C 4 )-alkyl; 
         P is
 a hydrogen atom; 
 —C(O)—O—R6 in which R6 is:
 a hydrogen atom, 
 —(C 1 -C 12 )-alkyl, 
 —(C 6-14 )-aryl where aryl is unsubstituted or mono-, di- or tri-substituted by —(C 1 -C 6 )-alkyl, 
 —(C 3 -C 8 )-cycloalkyl, or 
 a 4- to 15-membered Het ring; 
 
 —SO 3 —R6; 
 —O—SO 2 —R6; 
 —Si—R6; or 
 benzyl; and 
 
         D is
 —N(R2)-R3, 
 halogen 
 —O—SO 2 —R2 or 
 —O—C(O)—R2, 
 
         in which R2 and R3 are the same or different and are each independently
 a hydrogen atom, 
 —(C 1 -C 12 )-alkyl, 
 —(C 6-14 )-aryl where aryl is unsubstituted or mono-, di- or trisubstituted by —(C 1 -C 6 )-alkyl, 
 —(C 3 -C 6 )-cycloalkyl or 
 a 4- to 15-membered Het ring. 
 
       
     
     
         2 . The compound of formula II as claimed in  claim 1 , in which
 R1 is
 a hydrogen atom, 
 —(C 1 -C 6 )-alkyl, 
 phenyl or 
 —(C 3 -C 6 )-cycloalkyl; 
   D is chlorine, bromine, iodine, fluorine or —N(R2)-R3 where
 R2 and R3 are the same or different and are each independently a hydrogen atom or —(C 1 -C 4 )-alkyl; and 
   P is
 a hydrogen atom; 
 —C(O)—O—R6 in which 
 R6 is 
 a hydrogen atom, 
 —(C 1 -C 6 )-alkyl, 
 —(C 6 -C 14 )-aryl where aryl is selected from the group of phenyl, naphthyl, anthryl and fluorenyl, and in which aryl is unsubstituted or mono-, di- or trisubstituted by —C 1 -C 6 )-alkyl, 
 —(C 3 -C 6 )-cycloalkyl or 
 a radical from the group of acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl; 
 —SO 3 —R6; 
 —O—SO 2 —R6; 
 —Si—R6; or 
 benzyl. 
   
     
     
         3 . The compound of formula II as claimed in  claim 1 , in which
 R1 is a hydrogen atom or ethyl;   D is chlorine or —N(R2)-R3 where R2 and R3 are the same or different and are each independently a hydrogen atom or —(C 1 -C 4 )-alkyl; and   P is a hydrogen atom, —O-tosylate or benzyl.   
     
     
         4 . The compound as claimed in  claim 1 , which is ethyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate. 
     
     
         5 . The compound as claimed in  claim 1 , which is 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid sodium salt. 
     
     
         6 . A compound of formula IV 
       
         
           
           
               
               
           
         
       
       where
 R1 is
 a hydrogen atom, 
 —(C 1 -C 12 )-alkyl, 
 —(C 6 -C 14 )-aryl, 
 —(C 3 -C 6 )-cycloalkyl or 
 a 4- to 15-membered Het ring; 
 
 R4 and R5 are the same or different and are each independently
 —OH, 
 —O—(C 1 -C 12 )-alkyl, 
 —O—(C 6 -C 14 )-aryl, 
 —O—(C 3-8 )-cycloalkyl, 
 —(C 1 -C 12 )-alkyl or 
 —O-Het, where Het is a 4- to 15-membered Het ring; 
 
 or 
 R4 and R5, together with the boron atom to which they are bonded, form a ring having 4, 5, 6 or 7 carbon atoms in the ring and the ring may, instead of the particular carbon atoms, contain two oxygen atoms or two oxygen atoms and one nitrogen atom; 
 P is a hydrogen atom;
 —C(O)—O—R6, where R6 is:
 a hydrogen atom, 
 —(C 1 -C 12 )-alkyl, 
 (C 6 -C 14 )-aryl where aryl is unsubstituted or mono-, di- or trisubstituted by —(C 1-6 )-alkyl, —(C 3 -C 8 )-cycloalkyl, or 
 a 4- to 15-membered Het ring; 
 
 —SO 3 —R6; 
 —O—SO 2 —R6; 
 —Si—R6; or 
 benzyl; 
 
 with the proviso that R4 and R5 are not —OH or —O—(C 1 -C 12 )-alkyl when P is —C(O)—O—(C 1 -C 12 )-alkyl. 
 
     
     
         7 . The compound of formula IV as claimed in  claim 6  where
 R1 is
 a hydrogen atom; 
 —(C 1 -C- 8 )-alkyl; 
 —(C 6 -C 14 )-aryl where aryl is selected from the group of phenyl, naphthyl, anthryl and fluorenyl; 
 —(C 3 -C 6 )-cycloalkyl; or 
 a 4- to 15-membered Het ring, in which Het is a radical selected from the group consisting of acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, benzoimidazolyl, isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl; 
 
 R4 and R5 are the same or different and are each independently
 —OH, 
 —O—(C 1 -C 12 )-alkyl, 
 —O—(C 6 -C 14 )-aryl, where aryl is as defined above, 
 —O—(C 3 -C 6 )-cycloalkyl, 
 —(C 1-6 )-alkyl or 
 —O-Het, where Het is a 4- to 15-membered Het ring and is as defined above; or 
 
 R4 and R5, together with the boron atom to which they are bonded, form a ring selected from the group consisting of borolane, borinane, borepane, borocane, [1,3,2]dioxaborolane, [1,3,2]dioxaborinane, [1,3,2]dioxaborepane, [1,3,2]dioxaborocane and [1,3,6,2]dioxazaborocane; and 
 
       P is a hydrogen atom. 
     
     
         8 . A process for preparing the compound of the formula IV as claimed in  claim 6 , said process comprising reacting a compound of the formula XI 
       
         
           
           
               
               
           
         
       
       in which R1 and P are each as defined in  claim 7  for the compound of the formula IV, with one or more bases and then with the boric ester B(R4)-R5 in which R4 and R5 are each as defined in  claim 7  for the compound of the formula IV, to give a compound of the formula IV; 
       and detaching any nitrogen protecting group present. 
     
     
         9 . A compound of the formula X 
       
         
           
           
               
               
           
         
       
       where
 R1 is
 a hydrogen atom, 
 —(C 1 -C 12 )-alkyl, 
 —(C 6 -C 14 )-aryl, 
 —(C 3 -C 8 )-cycloalkyl or 
 a 4- to 15-membered Het ring; 
 
 R2 and R3 are the same or different and are each independently
 a hydrogen atom, 
 (C 1 -C 12 )-alkyl, 
 —(C 6 -C 14 )-aryl where aryl is unsubstituted or mono-, di- or trisubstituted by —(C 1-6 )-alkyl, 
 —(C 3 -C 8 )-cycloalkyl or 
 a 4- to 15-membered Het ring. 
 
 
     
     
         10 . A compound of formula XVI 
       
         
           
           
               
               
           
         
       
       where
 R1 is
 a hydrogen atom, 
 —(C 1 -C 12 )-alkyl, 
 —(C 6 -C 14 )-aryl, 
 —(C 3 -C 8 )-cycloalkyl or 
 a 4- to 15-membered Het ring.