Process for the manufacture of chroman derivatives, especially alpha-tocopherol and alkanoates thereof

Abstract

The present invention relates to novel processes for the manufacture of chroman derivatives such as α-tocopherol (TCP) and alkanoates thereof, especially α-tocopheryl acetate (TCPA), whereby at least one step of the processes is carried out in the presence of a Lewis acid or a mixture of a Lewis acid with a Bronsted acid as the catalyst under pressure, preferably at an absolute pressure of at least 1.1 bar. As starting materials for the manufacture of TCP and its alkanoates either a mixture of 2,3,5-trimethylhydroquinone (TMHQ) or 2,3,6-trimethylhydroquinone-1-alkanoate (TMHQA) and a compound selected from the group consisting of phytol (pH), isophytol (IP) and (iso)phytol derivatives or 2-phytyl-3,5,6-trimethyl-hydroquinone (PTMHQ)/3-phytyl-2,5,6-trimethylhydroquinone-1-alkanoate (PTMHQA) and/or an isomer thereof are used. Suitable Lewis acids are indium(III) salts and scandium(III) salts. Suitable acid mixtures are iron/iron(II) chloride/hydrogen chloride and zinc(II) chloride/hydrogen chloride.

1 . A process for the alkenylation of phenols comprising 0 to 4 methyl groups, a total of 1 to 3 hydroxy groups and at least one unsubstituted position, whereby the unsubstituted position is ortho to a hydroxy group, with a compound of the formula III and/or IV  
       
         
           
           
               
               
           
         
       
       with R 2  being hydroxy, acetyloxy, benzoyloxy or halogen, 
 n being an integer from 0 to 3, and  
 whereby the reaction is carried out in an organic solvent in the presence of a Lewis acid or a mixture of a Lewis acid with a Bronsted acid as the catalyst under pressure.  
 
     
     
         2 . The process as claimed in  claim 1 , wherein the phenol has the formula IIa  
       
         
           
           
               
               
           
         
       
       with X 1 , X 2  and X 3  being independently from each other hydrogen or methyl and R 3  being hydrogen, acetyl, propionyl, pivaloyl, HO 2 C—CH 2 —CH 2 —CO, nicotinoyl or benzoyl, with the proviso that R 3  is only acetyl, propionyl, pivaloyl, HO 2 C—CH 2 —CH 2 —CO, nicotinoyl or benzoyl, if X 1 , X 2  and X 3  are all methyl.  
     
     
         3 . The process as claimed in  claim 1 , wherein the phenol has the formula II  
       
         
           
           
               
               
           
         
       
       with R 1  being hydrogen, acetyl, propionyl, pivaloyl, HO 2 C—CH 2 —CH 2 —CO, nicotinoyl or benzoyl.  
     
     
         4 . A process for the manufacture of compounds of the formula VIIa by  
       
         
           
           
               
               
           
         
         a) (STEP a) optionally reacting a compound of the formula IIa  
         
           
             
             
                 
                 
             
           
         
         with a compound of the formula III and/or IV in an organic solvent  
         
           
             
             
                 
                 
             
           
         
         b) (STEP b) submitting in an organic solvent a compound of the formula Ia  
         
           
             
             
                 
                 
             
           
         
         and optionally one or more double bond isomers thereof, all obtainable by step a), to ring closure to form chroman derivatives VIIa,  
         with R 2  being hydroxy, acetyloxy, benzoyloxy or halogen,  
         R 3  being hydrogen, acetyl, propionyl, pivaloyl, HO 2 C—CH 2 —CH 2 —CO, nicotinoyl or benzoyl,  
         X 1 , X 2  and X 3  being independently from each other hydrogen or methyl, with the proviso that R 3  is only acetyl, propionyl, pivaloyl, HO 2 C—CH 2 —CH 2 —CO, nicotinoyl or benzoyl, if X 1 , X 2  and X 3  are all methyl, and  
         n being an integer from 0 to 3,  
         whereby at least one of the steps a) and b) is carried out in the presence of a Lewis acid or a mixture of a Lewis acid with a Bronsted acid as the catalyst under pressure.  
       
     
     
         5 . A process for the manufacture of chroman derivatives VIIa  
       
         
           
           
               
               
           
         
       
       by reacting of phenols comprising 0 to 4 methyl groups, a total of 1 to 3 hydroxy groups and at least one unsubstituted position, whereby the unsubstituted position is ortho to a hydroxy group, with a compound of the formula III and/or IV  
       
         
           
           
               
               
           
         
       
       with R 2  being hydroxy, acetyloxy, benzoyloxy or halogen, and 
 n being an integer from 0 to 3,  
 whereby the reaction is carried out in an organic solvent in the presence of a Lewis acid or a mixture of a Lewis acid with a Bronsted acid as the catalyst under pressure.  
 
     
     
         6 . The process as claimed in  claim 1 , wherein n in formulas III and IV is 3.  
     
     
         7 . A process for the manufacture of alkanoates of the formula VIIIa,  
       
         
           
           
               
               
           
         
       
       by reacting compounds of the formula VIIc,  
       
         
           
           
               
               
           
         
       
       with an appropriate acylating agent, 
 wherein n is an integer from 0 to 3, X 1 , X 2  and X 3  are independently from each other hydrogen or methyl, and R is selected from the group consisting of acetyl, propionyl, pivaloyl, HO 2 C—CH 2 —CH 2 —CO, nicotinoyl, and benzoyl,  
 characterized in that the reaction is carried out in the presence of a Lewis acid as the catalyst at reduced pressure or under pressure.  
 
     
     
         8 . The process as claimed in  claim 7 , wherein X 1 , X 2  and X 3  are methyl and n=3.  
     
     
         9 . The process as claimed in  claim 1  characterized in that the Lewis acid used as the catalyst is indium trichloride, indium tribromide, indium triiodide, indium triacetate, indium tris[bis(trifluoromethanesulfonamide)], indium triflate or scandium triflate.  
     
     
         10 . The process as claimed in  claim 1  characterized in that the mixture of a Lewis acid and a Bronsted acid used as the catalyst is a mixture of ZnCl 2  with HCl or Fe and/or FeCl 2  with HCl.  
     
     
         11 . A process for the manufacture of alkanoates of the formula VIIIa,  
       
         
           
           
               
               
           
         
       
       by reacting the reaction mixture obtained by step b) of the process according to  claim 4  with an appropriate acylating agent, wherein n is 3, X 1 , X 2  and X 3  are methyl, and R is selected from the group consisting of acetyl, propionyl, pivaloyl, HO 2 C—CH 2 —CH 2 —CO, nicotinoyl, and benzoyl, characterized in that the reaction is carried out in the presence of a Lewis acid as the catalyst at reduced pressure or under pressure.  
     
     
         12 . The process according to  claim 4  characterized in that all steps are carried out under pressure.  
     
     
         13 . The process according to  claim 1 , characterized in that the organic solvent is a non-polar aprotic organic solvent.  
     
     
         14 . The process according to  claim 13  characterized in that the non-polar aprotic organic solvent is selected from the group consisting of cyclohexane, hexane, heptane, octane, 1,1,1-trichloroethane, 1,2-dichloroethane, methylene chloride, methylene bromide, benzene, toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and 1,4-dichlorobenzene.  
     
     
         15 . A process for the manufacture of alkanoates of α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol, comprising reacting an α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol, respectively, obtained by a process according to  claim 1  with an acylating agent.  
     
     
         16 . A process for the manufacture of alkanoates of α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol by reacting α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol, respectively, with an acylating agent selected from the group consisting of the anhydrides and halides of acetic acid, propionic acid, pivalic acid, succinic acid, nicotinic acid, and benzoic acid, characterized in that the reaction is carried out in the presence of an indium(III) salt as the catalyst.  
     
     
         17 . A process for the manufacture of formulations of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol or their alkanoates, whereby α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol or their alkanoates, respectively, obtained by a process according to  claim 1  is used.  
     
     
         18 . A process for the manufacture of a compound of the formula X  
       
         
           
           
               
               
           
         
       
       by reacting a compound of the formula II  
       
         
           
           
               
               
           
         
       
       with a compound of the formula IX  
       
         
           
           
               
               
           
         
       
       in an organic solvent 
 with R 1  being hydrogen, acetyl, propionyl, pivaloyl, HO 2 C—CH 2 —CH 2 —CO, nicotinoyl or benzoyl,  
 R 2  being hydroxy, acetyloxy, benzoyloxy or halogen,  
 and n being an integer from 0 to 3,  
 whereby the reaction is carried out in the presence of a Lewis acid or a mixture of a Lewis acid with a Bronsted acid as the catalyst under pressure.  
 
     
     
         19 . A process for the manufacture of compounds of the formula X with R 1  being acetyl, propionyl, pivaloyl, HO 2 C—CH 2 —CH 2 —CO, nicotinoyl or benzoyl,  
       
         
           
           
               
               
           
         
       
       by reacting a compound of the formula X with R 1  being hydrogen with an appropriate acylating agent, 
 wherein n is an integer from 0 to 3,  
 characterized in that the reaction is carried out in the presence of a Lewis acid as the catalyst at reduced pressure or under pressure.