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, which process comprises the following steps: (a) reacting a mixture comprising (i) a methyl ketone of formula IV and (ii) a compound of formula: H 2 N—R 2   V and/or an addition salt of proton acid, and (iii) formaldehyde or a source of formaldehyde, in the presence of a solvent, and optionally a proton acid, to afford a β-amino ketone of formula II, and/or an addition salt of a proton acid, and (b) reducing the carbonyl group of said β-amino acid, 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  and R 2  independently represent alkyl, cycloalkyl, aryl or aralkyl, each aryl or aralkyl being optionally further substituted with alkyl, alkoxy and/or halogen, which 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 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 . 
     
     
         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, more preferably in the range of 1.5 to 10 bar and more particularly preferred in the range of 1.5 to 5 bar. 
     
     
         9 . A compound of formula 
       
         
           
           
               
               
           
         
         and its addition salts of proton acids, wherein R 1  represents furanyl, benzofuranyl, isobenzofuranyl, thienyl or benzo[b]thienyl, each 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 ; and 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  with the exception of the compound wherein R 1  represents thienyl and R 2  represents benzyl. 
       
     
     
         10 . A compound of formula 
       
         
           
           
               
               
           
         
         and its addition salts of proton acids, wherein R 4  represents methyl, ethyl, isobutyl or tert-butyl. 
       
     
     
         11 . A compound of formula 
       
         
           
           
               
               
           
         
         and its addition salts of proton acids. 
       
     
     
         12 . A compound of formula 
       
         
           
           
               
               
           
         
         and its addition salts of proton acids. 
       
     
     
         13 . 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 being optionally further substituted with alkyl, alkoxy and/or halogen, which process comprises reacting (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 a 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, wherein R 1  and R 2  are as defined above, and wherein the reaction is carried out at a pressure above 1.5 bar. 
       
     
     
         14 . The process of  claim 13  wherein R 1  is as defined in  claim 2 . 
     
     
         15 . The process of  claim 13  wherein R 2  is as defined in  claim 3 . 
     
     
         16 . The process of  claim 13 , wherein the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV. 
     
     
         17 . The process of  claim 13 , wherein the proton acid is a carboxylic or an inorganic acid, preferably the acid is 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. 
     
     
         18 . The process of  claim 16 , wherein aliphatic and cycloaliphatic alcohols are selected from the group consisting of linear or branched aliphatic C 1-12  alcohols, cycloaliphatic C 5-8  alcohols, di-triethylene glycols and mono C 1-4  alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups. 
     
     
         19 . The process of  claim 18 , 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-propanetriol, 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. 
     
     
         20 . The process of  claim 13 , wherein the pressure during the reaction is above 1.5 bar, more preferably in the range of 1.5 to 10 bar and more particularly preferred in the range of 1.5 to 5 bar. 
     
     
         21 . 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 . 
     
     
         22 . 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. 
     
     
         23 . 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. 
     
     
         24 . 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. 
     
     
         25 . The process of  claim 7 , wherein the pressure during reaction step a) is above 1.5 bar, more preferably in the range of 1.5 to 10 bar and more particularly preferred in the range of 1.5 to 5 bar. 
     
     
         26 . The process of  claim 14  wherein R 2  is as defined in  claim 3 . 
     
     
         27 . The process of  claim 15 , wherein the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV. 
     
     
         28 . The process of  claim 16 , wherein the proton acid is a carboxylic or an inorganic acid, preferably the acid is 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. 
     
     
         29 . The process of  claim 17 , wherein aliphatic and cycloaliphatic alcohols are selected from the group consisting of linear or branched aliphatic C 1-12  alcohols, cycloaliphatic C 5-8  alcohols, di-triethylene glycols and mono C 1-4  alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups. 
     
     
         30 . The process of  claim 19 , wherein the pressure during the reaction is above 1.5 bar, more preferably in the range of 1.5 to 10 bar and more particularly preferred in the range of 1.5 to 5 bar.