Process for preparation of substituted p-aminophenol

Abstract

The present invention is related to a process of preparing substituted p-aminophenol compound of formula (I) or a salt thereof,

1 . A process of preparing a compound of formula (I) or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is (C 1-6 )alkyl, or (C 3-12 )cycloalkyl; 
         R 2 , R 3 , and R 4  are each independently selected from H, F, Cl, CF 3 , CN, —OH, —NH 2 , (C 1-6 )alkyl, (C 3-12 )cycloalkyl, —O—(C 1-6 )alkyl, —NH(C 1-6 )alkyl, —NH(C 3-12 )cycloalkyl, —N((C 1-6 )alkyl(C 3-12 )cycloalkyl) and —N((C 1-6 )alkyl) 2 ; wherein each of R 1  to R 4  is optionally substituted by one or more substituents selected from H, F, Cl, CF 3 , OXO, CF 3 , CN, (C 1-6 )alkyl, (C 3-12 )cycloalkyl, —OH, —SH, —O(C 1-6 )alkyl, —S(C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl, aryl and heteroaryl; 
       
       comprising:
 Step A: converting a compound of formula (II) to a compound of formula (III) according to reaction scheme 1: 
 
       
         
           
           
               
               
           
         
         wherein the compound of Formula (I) is reacted with a suitable amount of potassium trimethylsilanolate (TMSOK) in the presence of a suitable solvent at a suitable reaction temperature for a suitable reaction time to provide the compound of formula (III), wherein said compound of formula (III) is obtained via a suitable isolation procedure; 
         Step B: converting the compound of formula (III) to a compound of formula (IV) according to reaction scheme 2: 
       
       
         
           
           
               
               
           
         
         wherein the compound of formula (III) is reacted with a suitable amount of oxalyl chloride in the presence of a suitable solvent and at a suitable reaction temperature for a suitable reaction time to form an acid chloride intermediate; and then said acid chloride intermediate is reacted with a suitable amount of alcohol at a suitable reaction temperature for a suitable reaction time to provide the compound of formula (IV), wherein said compound of formula (IV) is obtained via a suitable isolation procedure; and 
         Step C: converting the compound for formula (IV) to a compound of formula (I) according to reaction scheme 3: 
       
       
         
           
           
               
               
           
         
         wherein the compound of formula (IV) is hydrogenated in the presence of a suitable amount of a suitable catalyst, a suitable solvent and at a suitable reaction temperature to provide a compound of formula (I), wherein said compound of formula (I) is obtained via a suitable isolation procedure. 
       
     
     
         2 . The process of  claim 1 , wherein the suitable solvent in scheme 1 of Step A is 2-methyltetrahydrofuran (MeTHF). 
     
     
         3 . The process of  claim 1 , wherein the isolation procedure of Step A comprise cooling the reaction mixture to room temperature after the reaction is complete, quenching the reaction by adding water, adjusting the pH of the reaction mixture to be acidic, separating the organic layer from the aqueous layer of the reaction mixture, washing the organic layer with water, reducing the volume of organic layer to form a residue of the crude product, stirring the residue of the crude product in a solvent to form a slurry suspension, filtering the slurry suspension, and drying the solid to provide the compound of formula (III). 
     
     
         4 . The process of  claim 1 , wherein the suitable solvent to form the acid chloride intermediate in scheme 2 of Step B is 2-methyltetrahydrofuran (MeTHF). 
     
     
         5 . The process of  claim 1 , wherein the suitable amount of oxalyl chloride in Step B is 1-1.5 equivalents compared to the amount of the compound of formula (III). 
     
     
         6 . The process of  claim 1 , wherein the alcohol of Step B is anhydrous methanol, or ethanol. 
     
     
         7 . The process of  claim 1 , wherein yield of the Step B is at least about 92%. 
     
     
         8 . The process of  claim 1 , wherein the isolation procedure of Step B comprises adjusting the pH of the reaction mixture to be neutral by adding basic reagents into the reaction mixture after the reaction is complete, separating the organic layer from the aqueous layer of the reaction mixture, reducing the volume of organic layer to form a residue of the crude product, stirring the residue of the crude product in a solvent to form a slurry suspension, filtering the slurry suspension, and drying the solid to provide the compound of formula (IV). 
     
     
         9 . The process of  claim 1 , wherein the catalyst of Step C comprises palladium on carbon. 
     
     
         10 . The process of  claim 1 , wherein the solvent of Step C comprises methanol, ethanol, water, acetic acid or mixture of two or more of the solvents. 
     
     
         11 . The process of  claim 1 , wherein the isolation procedure of Step C comprises diluting the reaction mixture with tetrahydrofuran (THF) after the reaction is complete, filtering the resulting mixture through a Celite pad, concentrating the filtrate and drying the filtrate to provide the compound of formula (I). 
     
     
         12 . The process of  claim 1 , wherein the compound of formula (I) is further converted to a salt thereof, comprises adding a solvent to the compound of formula (I) obtained from Step C to form a suspension, adding a suitable acid into the suspension at a rate where the temperature of the suspension is maintained below a suitable temperature, and stirring the suspension at a suitable temperature for a suitable reaction time to provided the salt of the compound of formula (I), wherein said salt of the compound of formula (I) is obtained via a suitable isolation procedure. 
     
     
         13 . The process of  claim 1 , wherein said acid is hydrochloric acid. 
     
     
         14 . The process of  claim 1 , wherein the compound of formula (I) is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The process of  claim 1 , wherein the compound of Formula (III) synthesized according to scheme 1 is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The process of  claim 1 , wherein the compound of Formula (IV) synthesized according to scheme 2 is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A process of preparing a compound of formula (I) or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is (C 1-6 )alkyl, or (C 3-12 )cycloalkyl; 
         R 2 , R 3 , and R 4  are each independently selected from H, F, Cl, CF 3 , CN, —OH, —NH 2 , (C 1-6 )alkyl, (C 3-12 )cycloalkyl, —O—(C 1-6 )alkyl, —NH(C 1-6 )alkyl, —NH(C 3-12 )cycloalkyl, —N((C 1-6 )alkyl(C 3-12 )cycloalkyl) and —N((C 1-6 )alkyl) 2 ; wherein each of R 1  to R 4  is optionally substituted by one or more substituents selected from H, F, Cl, CF 3 , OXO, CF 3 , CN, (C 1-6 )alkyl, (C 3-12 )cycloalkyl, —OH, —SH, —O(C 1-6 )alkyl, —S(C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl, aryl and heteroaryl; 
       
       comprising:
 Step A: converting a compound of formula (II) to a compound of formula (III) according to reaction scheme 1: 
 
       
         
           
           
               
               
           
         
         wherein the compound of Formula (II) is reacted with a suitable amount of KOH, or NaOH in the presence of a suitable solvent at a suitable reaction temperature for a suitable reaction time to provide the compound of formula (III), wherein said compound of formula (III) is obtained via a suitable isolation procedure; 
         Step B: converting the compound of formula (III) to a compound of formula (IV) according to reaction scheme 2: 
       
       
         
           
           
               
               
           
         
         wherein the compound of formula (III) is reacted with a suitable amount of H 2 SO 4  in the presence of a suitable solvent and at a suitable reaction temperature for a suitable reaction time to form a compound of formula (IV), wherein said compound of formula (IV) is obtained via a suitable isolation procedure; and 
         Step C: converting the compound for formula (IV) to a compound of formula (I) according to reaction scheme 3: 
       
       
         
           
           
               
               
           
         
         wherein the compound of formula (IV) is hydrogenated in the presence of a suitable amount of a suitable catalyst, a suitable solvent and at a suitable reaction temperature to provide a compound of formula (I), wherein said compound of formula (I) is obtained via a suitable isolation procedure. 
       
     
     
         18 . The process of  claim 17  wherein the suitable solvent of Step A comprises water and the reaction temperature is about 85 to 95°. 
     
     
         19 . The process of  claim 17  wherein the the reaction time of Step A is 10 to 30 minutes. 
     
     
         20 . The process of  claim 17  where the suitable amount of KOH or NaOH is about 3-4 eq. 
     
     
         21 . The process of  claim 17  wherein the yield is about 85%. 
     
     
         22 . The process of  claim 17  wherein the isolation procedure of Step A comprises cooling down to room temperature, and extracting with 2-methyltetrahydrofuran and separating the layers; washing the organic layer with water and distilling under vacuum to minimum volume; stirring the residue with a solvent of toluene/methylcyclohexanet to give a suspension; and filtering the product to provide a compound of formula III. 
     
     
         23 . The process of  claim 17  wherein the compound of formula III is reacted with H 2 SO 4  to provide a compound of formula IV. 
     
     
         24 . The process of  claim 17  wherein the reaction temperature is 65-75°. 
     
     
         25 . The process of  claim 17  wherein the yield is about 85%. 
     
     
         26 . The process of  claim 17 , wherein the suitable solvent in scheme 2 of Step B is MeOH or EtOH. 
     
     
         27 . The process of  claim 17 , wherein the suitable amount of sulfuric acid is 1-4 equivalents to the amount of the compound of formula (III). 
     
     
         28 . The process of  claim 17  wherein the catalyst of step C comprises palladium on carbon. 
     
     
         29 . The process of  claim 17  wherein the suitable amount of the catalyst of Step C is from 0.001 to 0.05 equivalent compared to the amount of the compound of formula (IV). 
     
     
         30 . The process of  claim 17 , wherein the solvent of Step C comprises methanol, ethanol, water, acetic acid or mixture of two or more of the solvents. 
     
     
         31 . The process of  claim 17 , wherein the solvent of Step C comprises methanol. 
     
     
         32 . The process of  claim 17 , wherein the isolation procedure of Step C comprises diluting the reaction mixture with tetrahydrofuran (THF) after the reaction is complete, filtering the resulting mixture through a Celite pad, concentrating the filtrate and drying the filtrate to provide the compound of formula (I). 
     
     
         33 . The process of  claim 17 , wherein the compound of formula (I) is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         34 . The process of  claim 17 , wherein the compound of Formula (III) synthesized according to scheme 1 is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The process of  claim 17 , wherein the compound of Formula (IV) synthesized according to scheme 2 is selected from the group consisting of: