Novel synthesis of intermediates for the preparation of alpha-tocopherol

Abstract

The present invention relates to a novel synthetic pathway for alpha-tocopherol. The invention discloses different reactions yielding some new intermediates in a very high yield and stereoselectivity.

1 . A process of manufacturing a compound of formula (I) from a compound of formula (II) 
       
         
           
           
               
               
           
         
         using an oxidizing agent which is capable of oxidizing a secondary hydroxyl group in the presence of an olefinic C—C double bond to a keto group without modifying said olefinic C—C group; 
         wherein the wavy line represents a carbon-carbon bond which is linked to the adjacent carbon-carbon double bond so as to have said carbon-carbon double bond either in the Z- or in the E-configuration and 
         * represents a chiral center. 
       
     
     
         2 . The process according to  claim 1 , wherein the oxidizing agent is MnO 2 . 
     
     
         3 . A process of manufacturing a compound of formula (III) from a compound of formula (I) 
       
         
           
           
               
               
           
         
         by an oxidative demethylation using a Ce(IV) salt or a Fe(III) salt, preferably selected from the group consisting of Ce(NH 4 ) 2 (NO 3 ) 6 , Ce(SO 4 ) 2 , FeCl 3  and their respective hydrates, most preferably Ce(NH 4 ) 2 (NO 3 ) 6 ; 
         wherein the wavy line represents a carbon-carbon bond which is linked to the adjacent carbon-carbon double bond so as to have said carbon-carbon double bond either in the Z- or in the E-configuration and 
         * represents a chiral center. 
       
     
     
         4 . The process according to  claim 3 , wherein the compound of formula (I) is prepared by subjecting the compound of formula (II) to an oxidizing agent which is capable of oxidizing a secondary hydroxyl group in the presence of an olefinic C—C double bond to a keto group without modifying said olefinic C—C group. 
     
     
         5 . A process of manufacturing a compound of formula (IV) from a compound of formula (III) 
       
         
           
           
               
               
           
         
         by a dithionite anion or a dithionite salt, particularly by sodium dithionite or an aqueous solution thereof; 
         wherein the wavy line represents a carbon-carbon bond which is linked to the adjacent carbon-carbon double bond so as to have said carbon-carbon double bond either in the Z- or in the E-configuration 
         and * represents a chiral center. 
       
     
     
         6 . The process according to  claim 5 , wherein the compound of formula (III) is prepared by subjecting a compound of formula (I) to an oxidative demethylation using a Ce(IV) salt or a Fe(III) salt, preferably selected from the group consisting of Ce(NH 4 ) 2 (NO 3 ) 6 , Ce(SO 4 ) 2 , FeCl 3  and their respective hydrates, most preferably Ce(NH 4 ) 2 (NO 3 ) 6 . 
     
     
         7 . A process of manufacturing a compound of formula (IV) from a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       using BBR 3  
 wherein the wavy line represents a carbon-carbon bond which is linked to the adjacent carbon-carbon double bond so as to have said carbon-carbon double bond either in the Z- or in the E-configuration and 
 * represents a chiral center. 
 
     
     
         8 . A process of manufacturing a compound of formula (V) from a compound of formula (IV) 
       
         
           
           
               
               
           
         
         in a cyclization reaction using pyrrolidine or a 2-substituted pyrrolidine compound; 
         wherein the wavy line represents a carbon-carbon bond which is linked to the adjacent carbon-carbon double bond so as to have said carbon-carbon double bond either in the Z- or in the E-configuration and 
         * represents a chiral center. 
       
     
     
         9 . The process according to  claim 8 , wherein the compound of formula (IV) is prepared by contacting a compound of formula (III) to a dithionite anion or a dithionite salt, particularly by sodium dithionite or an aqueous solution thereof. 
     
     
         10 . A process of manufacturing a compound of formula (VII) from a compound of formula (IV) 
       
         
           
           
               
               
           
         
         comprising the step 
         i) manufacturing a compound of formula (V) from a compound of formula (IV) according to a process according to  claim 8   
       
       
         
           
           
               
               
           
         
         followed either by a one-step reaction d3) 
         d3) chemically transforming the compound of formula (V) to the compound of formula (VII) 
         or by a two-step reaction of the sub-steps d1) and d2) 
         d1) chemically transforming the compound of formula (V) to a compound of formula (VI); 
       
       
         
           
           
               
               
           
         
         and 
         d2) chemically transforming the compound of formula (VI) to the compound of formula (VII) 
         wherein * and # represent chiral centers. 
       
     
     
         11 . A process of stereoselectively manufacturing a compound of formula (V-R) 
       
         
           
           
               
               
           
         
         from a compound of formula (IV-E) 
       
       
         
           
           
               
               
           
         
         in a cyclization reaction using a 2-substituted pyrrolidine compound of formula (VIII-a) 
       
       
         
           
           
               
               
           
         
         or from a compound of formula (IV-Z) 
       
       
         
           
           
               
               
           
         
         in a cyclization reaction using a 2-substituted pyrrolidine compound of formula (VIII-b) 
       
       
         
           
           
               
               
           
         
         wherein * represents a chiral center; 
         and Y 1  represents either 
       
       
         
           
           
               
               
           
         
         
           a C 1-6  alkyl group or a group CH 2 Y 2  or 
           or a substituent carrying a Brønsted acid functional group; 
           wherein R 6  represents a linear or branched C 1-12 -alkyl group which optionally further comprises at least one aromatic group and/or C═O and/or NH and/or NH 2  group; 
           Y 2  represents either OH or OR 7  or NHR 7  or NHCOOR 7  or 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 7  represents either
 a linear or branched C 1-12 -alkyl group which optionally further comprises at 
 least one aromatic group and/or C═O and/or NH and/or NH 2  group 
 
           or
 an aryl group or a substituted aryl group or a heteroaryl group or a substituted heteroaryl group. 
 
         
       
     
     
         12 . A process of manufacturing stereoselectively a compound of formula (VII-R) from a compound of formula (IV) 
       
         
           
           
               
               
           
         
         comprising the step 
         ii) manufacturing stereoselectively a compound of formula (V-R) according to a process according to  claim 11   
       
       
         
           
           
               
               
           
         
         followed either by a one-step reaction d3) 
         d3) chemically transforming the compound of formula (V-R) to the compound of formula (VII-R) 
         or by a two-step reaction of the sub-steps d1) and d2) 
         d1) chemically transforming the compound of formula (V-R) to a compound of formula (VI-R); 
       
       
         
           
           
               
               
           
         
         and 
         d2) chemically transforming the compound of formula (VI-R) to the compound of formula (VII-R) 
         wherein * represent chiral centers. 
       
     
     
         13 . A compound of formula (I), particularly of formula (I-E) 
       
         
           
           
               
               
           
         
         wherein the wavy line represents a carbon-carbon bond which is linked to the adjacent carbon-carbon double bond so as to have said carbon-carbon double bond either in the Z- or in the E-configuration and 
         * represents a chiral center. 
       
     
     
         14 . A compound of formula (III), particularly of formula (III-E) 
       
         
           
           
               
               
           
         
         wherein the wavy line represents a carbon-carbon bond which is linked to the adjacent carbon-carbon double bond so as to have said carbon-carbon double bond either in the Z- or in the E-configuration and 
         * represents a chiral center. 
       
     
     
         15 . A compound of formula (IV), particularly of formula (IV-E) 
       
         
           
           
               
               
           
         
         wherein the wavy line represents a carbon-carbon bond which is linked to the adjacent carbon-carbon double bond so as to have said carbon-carbon double bond either in the Z- or in the E-configuration and 
         represents a chiral center. 
       
     
     
         16 . The compound of formula (I) or (III) or (IV) or (IV-E) according to  claim 13 , wherein all chiral centers indicated by * are in the R-configuration.