Preparation of 4-amino-1-naphthol ethers

Abstract

The present invention describes a process for preparing 4-amino-1-naphthol ethers which is characterized in that naphthol ethers are first prepared from 1-naphthols, the former are then converted to the corresponding 4-acetamino-1-naphthol ethers and then the acyl group is cleaved off, and further describes 4-acetamino-1-naphthol ethers obtained thereby.

1 . Process for preparing 4-amino-1-naphthol ethers, comprising reacting: 
 a) substituted or unsubstituted 1-naphthols with reactive alkyl compounds to give 1-naphthol ethers,    b) converting the 1-naphthol ethers to the corresponding 4-acylamino-1-naphthol ethers using hydroxylammonium salts and carboxylic acids and    c) converting the 4-acylamino-1-naphthol ethers to the free 4-amino-1-naphthol ethers or analogous ammonium salts by acidic or basic acyl group cleavage.    
   
   
       2 . Process according to  claim 1 , wherein the substituted or unsubstituted 1-naphthols have the general formula (I)  
     
       
         
         
             
             
         
       
     
     where 
 R 2  is hydrogen, halogen or C 1 -C 4 -alkyl and  
 R 3  is hydrogen, halogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy and  
 n is zero, one, two, three or four and  
 R 4  are each independently halogen, nitro, cyano, protected formyl, C 1 -C 8 -alkyl, C 7 -C 10 -arylalkyl, C 1 -C 8 -hydroxyalkyl, C 1 -C 8 -haloalkyl or C 6 -C 10 -aryl or substituents of the general formula (II),  
   D-E-F  (II)  
 where, independently,  
 D is absent or is a C 1 -C 8 -alkylene radical and  
 E is a carbonyl group or sulphonyl group and  
 F is R 6 , OR 6 , NH 2 , SR 6 , NHR 6  or NR 6 R 7 ,  
 and where  
 R 6  and R 7  are each independently substituted or unsubstituted C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 7 -C 12 -arylalkyl or C 6 -C 10 -aryl or  
 NR 6 R 7  together is a 5- to 8-membered heterocycle.  
 
   
   
       3 . Process according to  claim 1  wherein the substituted or unsubstituted 1-naphthols have the general formula (I)  
     where 
 R 2  is hydrogen and  
 R 3  is hydrogen and  
 n is zero, one or two and  
 R 4  are each independently halogen, nitro, cyano, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl or substituents of the general formula (II),  
 where, independently,  
 D is absent and  
 E is a carbonyl group or sulphonyl group and  
 F is R 6 , OR 6 , NH 2 , NHR 6  or NR 6 R 7  and where  
 R 6  and R 7  are each independently substituted or unsubstituted C 1 -C 4 -alkyl.  
 
   
   
       4 . Process according to  claim 1  wherein the substituted or unsubstituted 1-naphthols is 1-naphthol  
   
   
       5 . Process according to  claim 1  wherein the reactive alkyl compounds is of the general formula (IIIa) or (IIIb) represented by  
       R 1 —Y  (IIIa), or  (R 1 —O) 2 SO 2   (IIIb)  
     where 
 R 1  is C 3 -C 12 -alkyl, C 2 -C 8 -haloalkyl, C 7 -C 13 -arylalkyl or substituents of the general formula (IV),  
   A-B  (IV)  
 where  
 A is C 2 -C 8 -alkylene, C 2 -C 8 -haloalkylene and  
 B is NR 6 R 7 , SR 6  or OR 6    
 where  
 R 6  and R 7  are each independently substituted or unsubstituted C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 7 -C 12 -arylalkyl or C 6 -C 10 -aryl or NR 6 R 7  together is a 5- to 8-membered heterocycle and  
 Y is chlorine, bromine, iodine or sulphonate.  
 
   
   
       6 . Process according to  claim 1  wherein the reactive alkyl compounds are of the general formula (IIIa)  
     where 
 R 1  is a substituent of the general formula (IV) where  
 A is C 2 -C 4 -alkylene or C 2 -C 4 -haloalkylene and  
 B is NR 6 R 7  or OR 6  and  
 where  
 R 6  and R 7  are each independently substituted or unsubstituted C 1 -C 4 -alkyl or  
 NR 6 R 7  together is a 5- or 6-membered heterocycle and  
 Y is chlorine, bromine, iodine, methanesulphonate, tosylate or trifluoromethanesulphonate.  
 
   
   
       7 . Process according to  claim 1  wherein the reactive alkyl compound is 2-(N-morpholinyl)ethyl chloride, 2-(N-morpholinyl)ethyl bromide or 2-(N-morpholinyl)ethylmethanesulphonate, or ammonium salts thereof.  
   
   
       8 . Process according to  claim 7  wherein the reactive alkyl compound is N-(2-chloroethyl)morpholine hydrochloride.  
   
   
       9 . Process according to  claim 1  wherein step a) is effected in the presence of a base.  
   
   
       10 . Process according  claim 9  wherein step a) is effected in the presence of an aqueous solution of sodium hydroxide having a concentration of from 30 to 70% by weight.  
   
   
       11 . Process according to  claim 1  wherein step a) is carried out in ethanol.  
   
   
       12 . Process according to  claim 1  wherein step a) is carried out at a temperature of from 0 to 120° C.  
   
   
       13 . Process according to  claim 1  wherein step b) is carried out in the presence of polyphosphoric acid.  
   
   
       14 . Process according to  claim 13  wherein the molar ratio of polyphosphoric acid to 1-naphthol ether is from 5.0 to 12.0.  
   
   
       15 . Process according to  claim 1  wherein the hydroxylammonium salt is hydroxylamine hydrochloride.  
   
   
       16 . Process according to  claim 1  wherein the carboxylic acid is acetic acid, propionic acid or trifluoroacetic acid.  
   
   
       17 . Process according to  claim 1  wherein the reaction temperature in step b) is from 50 to 130° C.  
   
   
       18 . Process according to  claim 1  wherein the 4-acylamino-1-naphthol ethers are converted by acid hydrolysis to the ammonium salts of 4-amino-1-naphthol ethers in step c).  
   
   
       19 . Process according to  claim 18  wherein the acid hydrolysis is carried out in the presence of acids having a pKa of 2 or less in step c).  
   
   
       20 . Process according to  claim 19  wherein the acid hydrolysis is carried out in the presence of concentrated hydrochloric acid.  
   
   
       21 - 25 . (canceled)  
   
   
       26 . Compounds of the general formulae (VIIIa) and (VIIIb),  
     
       
         
         
             
             
         
       
     
     where 
 R 1 , R 2 , R 3 , R 4  and n are as defined under formula (VII) and X is the anion of an acid.  
 
   
   
       27 . The compound of formula (VIIIa) or (VIIIb) which is 4-(2-([1]-napthyloxy-[4]-amino)ethyl)morpholine dihydrochloride or the ammonium salt thereof.  
   
   
       28 . A process for preparing pharmaceutical compounds comprising providing compounds of the general formulae (VIIIa) and (VIIIb),  
     
       
         
         
             
             
         
       
     
     where 
 R 1 , R 2 , R 3 , R 4  and n are as defined under formula (VII) and X is the anion of an acid.