Process for the preparation of N-monosubstituted beta-amino alcohols

Abstract

A process for the preparation of a compound of formula: and/or an addition salt of a proton acid, wherein R 1 and R 2 independently represent alkyl, cycloalkyl, aryl or aralkyl, each aryl or aralkyl being optionally further substituted with alkyl, alkoxy and/or halogen. The process includes the following steps: (a) reacting a mixture of (i) a methyl ketone of formula and wherein R 1 is as defined above, and (ii) a compound of formula: H 2 N—R 2   (V) and/or an addition of salt of proton acid, wherein R 2 is as defined above, and (iii) formaldehyde or a source of formaldehyde selected from formaldehyde in aqueous solution 1,3, 5-trioxane, paraformaldehyde and mixtures thereof, in the presence of a solvent selected from the group consisting of water or aliphatic alcohols, cycloaliphatic alcohols and mixtures thereof, and optionally a proton acid, to afford a β-amino ketone of formula: and/or an addition salt of a proton acid, and (b) reducing the carbonyl group said β-amino ketone to provide a compound of formula I, and/or an addition salt of a proton acid, wherein the first step is carried out at a pressure above 1.5 bar.

1 : A process for the preparation of a compound of formula:  
       
         
           
           
               
               
           
         
       
       and/or an addition salt of a proton acid, wherein R 1  represents furanyl or thienyl and R 2  represents alkyl, cycloalkyl, aryl or aralkyl, each aryl or aralkyl is optionally further substituted with alkyl, alkoxy and/or halogen, said process comprises the following steps: 
 a) reacting a mixture comprising: 
 (i) a methyl ketone of formula:  
                     
 wherein R 1  is as defined above, and  
 (ii) a compound of formula:  
   H 2 N—R 2   (V)  
 and/or an addition salt of proton acid, wherein R 2  is as defined above, and  
 (iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of  
 a solvent selected from the group consisting of water, aliphatic alcohols, cycloaliphatic alcohols and mixtures thereof, and  
 optionally a proton acid,  
 
 to afford a β-amino ketone of formula:  
                     
 and/or an addition salt of a proton acid, and  
 b) reducing the carbonyl group of said β-amino ketone to afford a compound of formula I, and/or an addition salt of a proton acid,  
 wherein the first step is carried out at a pressure above 1.5 bar.  
 
     
     
         2 : The process of  claim 1  wherein R 1  is thienyl.  
     
     
         3 : The process of  claim 1  wherein R 2  is selected from the group consisting of linear or branched C 1-8  alkyl, C 3-8  cycloalkyl, phenyl, naphthyl, furanyl, benzofuranyl, thienyl, benzo[b]thienyl and aralkyl, wherein the alkyl moiety of the aralkyl residue is linear C 1-4  alkyl, and the aryl moiety is selected from the group consisting of phenyl, naphthyl, furanyl, benzofuranyl, thienyl and benzo[b]thienyl, each aryl or aralkyl being optionally substituted with halogen, linear or branched C 1-4  alkyl, linear or branched C 1-4  alkoxy, C 3-6  cycloalkyl, CF 3 , C 2 F 5 , OCF 3  or OC 2 F 5 .  
     
     
         4 : The process of  claim 1 , wherein the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV.  
     
     
         5 : The process of  claim 1 , wherein the proton acid is a carboxylic or an inorganic acid, the acid being preferably selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H 2 SO 4 , H 3 PO 4 , mono alkali malonate, alkali hydrogensulfates, alkali hydrogenphosphates and alkali hydrogencarbonates.  
     
     
         6 : The process of  claim 1 , wherein aliphatic and cycloaliphatic alcohols are selected from the group selected of linear or branched aliphatic C 1-12  alcohols, cycloaliphatic C 5-8  alcohols, di- and/or triethylene glycols and mono C 1-4  alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups.  
     
     
         7 : The process of  claim 6 , wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol, cyclohexanol, 1,2-ethanediol, 1,2-propanediol, 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2,3-pro-panetriol, 1,2,6-hexanetriol, diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoacetate, triethylene glycol, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether and triethylene glycol monoacetate.  
     
     
         8 : The process of  claim 1 , wherein the pressure during reaction step a) is above 1.5 bar.  
     
     
         9 - 20 . (canceled)  
     
     
         21 : The process of  claim 1 , wherein R 1  is furanyl.  
     
     
         22 . The process of  claim 2 , wherein R 2  is selected from the group consisting of linear or branched C 1-8  alkyl, C 3-8  cycloalkyl, phenyl, naphthyl, furanyl, benzofuranyl, thienyl, benzo[b]thienyl and aralkyl, wherein the alkyl moiety of the aralkyl residue is linear C 1-4  alkyl, and the aryl moiety is selected from the group consisting of phenyl, naphthyl, furanyl, benzofuranyl, thienyl and benzo[b]thienyl, each aryl or aralkyl being optionally substituted with halogen, linear or branched C 1-4  alkyl, linear or branched C 1-4  alkoxy, C 3-6  cycloalkyl, CF 3 , C 2 F 5 , OCF 3  or OC 2 F 5 .  
     
     
         23 : The process of  claim 3 , wherein the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV.  
     
     
         24 : The process of  claim 4 , wherein the proton acid is a carboxylic or an inorganic acid, the acid being preferably selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H 2 SO 4 , H 3 PO 4 , mono alkali malonate, alkali hydrogensulfates, alkali hydrogenphosphates and alkali hydrogencarbonates.  
     
     
         25 : The process of  claim 5 , wherein aliphatic and cycloaliphatic alcohols are selected from the group selected of linear or branched aliphatic C 1-12  alcohols, cycloaliphatic C 5-8  alcohols, di- and/or triethylene glycols and mono C 1-4  alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups.  
     
     
         26 : The process of  claim 7 , wherein the pressure during reaction step a) is above 1.5 bar.  
     
     
         27 : The process of  claim 1 , wherein the pressure during reaction step a) is in the range of 1.5 to 10 bar.  
     
     
         28 : The process of  claim 1 , wherein the pressure during reaction step a) is in the range of 1.5 to 5 bar.