Photochemical process for producing artemisinin

Abstract

Provided is a new photochemical process for preparing artemisinin. Also provided are certain dihydroartemisinic acid derivatives useful for preparing artemisinin.

1 . A process for preparing artemisinin, comprising the steps of:
 preparing a mixture comprising (i) a dihydroartemisinic acid derivative of formula (I)   
       
         
           
           
               
               
           
         
         wherein 
         X is O, S, NH or NO 
         Y is a group selected from formulae (II), (III) and (IV) 
       
       
         
           
           
               
               
           
         
         or, when, X is O, Y can represent OR 4    
         R 1  and R 2 , independently from each other, are hydrogen; a C 1 -C 12  alkyl group which is linear or branched or a C 3 -C 10  cycloalkyl group, said alkyl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6 , alkyl group and a halogen; a trifluoromethyl group; a cycloalkylalkyl group where cycloalkyl and alkyl are as defined above; a C 2 -C 12  alkenyl group which is linear or branched, said alkenyl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; a C 5 -C 14  aryl or heteroaryl group, said aryl or heteroaryl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; an arylalkyl group where aryl and alkyl are as defined above; or a heteroarylalkyl group where heteroaryl and alkyl are as defined above; 
         R 3  is R 1 , OR 1 , NHR 1  or NR 1 R 2 , where R 1  and R 2  are as defined above; 
         R 4  is identical to R 1 , except that R 4  cannot represent hydrogen or else R 4  represents a silyl group; 
         (ii) at least one organic solvent and (iii) a photosensitizer, 
         subjecting said mixture to photooxidation by means of a light source, and 
         recovering the artemisinin thus obtained. 
       
     
     
         2 . The process of  claim 1 , characterized in that the dihydroartemisinic acid derivative has the formula (Ia) 
       
         
           
           
               
               
           
         
         in which X and Y are as defined in  claim 1 . 
       
     
     
         3 . The process according to  claim 1  or  2 , characterized in that the at least one organic solvent is selected from the group consisting of alcohols, chlorinated solvents, ketones, sulfoxides, nitriles, N,N-disubstituted amines, esters, nitrogenated heterocycles, ethers, alkanes, aromatic solvents, and mixtures thereof. 
     
     
         4 . The process according to any one of  claims 1  to  3 , characterized in that the at least one organic solvent is dichloromethane. 
     
     
         5 . The process according to any one of  claims 1  to  4 , characterized in that the polar solvent is used in a ratio of about 4 to 20 volumes with respect to the dihydroartemisinic acid derivative of formula (I) or (Ia). 
     
     
         6 . The process according to any one of  claims 1  to  5 , characterized in that the photosensitizer is selected from Rose bengal, tetraphenylporphyrin, tetraphenylporphyrin derivatives, tetramethylthionine chloride (methylene blue) and toluidine blue. 
     
     
         7 . The process according to any one of  claims 1  to  6 , characterized in that the photosensitizer is used in a molar ratio of about 0.000001 to 1 equivalent with respect to the dihydroartemisinic acid derivative of formula (I) or (Ia). 
     
     
         8 . The process according to any one of  claims 1  to  7 , characterized in that the mixture comprises an acid catalyst. 
     
     
         9 . The process according to any one of  claims 1  to  8 , characterized in that the acid catalyst is present in an amount of 0.5 equivalent per equivalent of compound of formula (I) or (Ia). 
     
     
         10 . The process according to any one of  claims 1  to  9 , characterized in the acid catalyst is a protic acid. 
     
     
         11 . The process according to any one of  claims 1  to  9 , characterized in that the acid catalyst is trifluoroacetic acid. 
     
     
         12 . The process according to any one of  claims 1  to  11 , characterized in that it comprises the steps of:
 preparing a mixture comprising (i) a dihydroartemisinic acid derivative of formula (I) or (Ia) as defined in  claim 1  or  2 , (ii) at least one organic solvent, and (iii) a photosensitizer at ambient temperature, 
 cooling the reaction mixture to a temperature in the range of about −78° C. to ambient temperature with air or oxygen bubbling into it, 
 adding a catalytic amount of an acid catalyst, 
 switching the light source on, 
 maintaining the reaction mixture at the same temperature for 3 h to 24 h, 
 warming up the reaction mixture to a temperature in the range of about 5 to 15° C. for 2 to 4 hours, and then to a higher temperature in the range of about 15 to 25° C. for 1 to 3 hours, 
 stopping the reaction by means such as sequentially, in either sequence, or concurrently switching the light source off and stopping the air or oxygen bubbling, followed by adding a quencher at ambient temperatures, 
 maintaining the reaction mixture at a temperature in the range of about 15° C. to 25° C. for 1 to 3 hours, and 
 recovering the artemisinin thus obtained. 
 
     
     
         13 . The process according to  claim 12 , characterized in that the acid catalyst is chosen amongst protic acids and/or Lewis acids, such as amongst protic acids, such as trifluoroacetic acid. 
     
     
         14 . The process according to any one of  claims 12  to  13 , characterized in that:
 the first cooling step is carried out at a temperature between −5° C. and −20° C., for example −10° C.; 
 during the warming up step, the reaction mixture is warmed up to 10° C. for 2 h, and then to ambient temperature, such as 20° C. for 1 hour, and/or 
 after stopping the reaction, the reaction mixture is maintained at ambient temperature, such as 20° C. for 2 h. 
 
     
     
         15 . The process according to any one of  claims 12  to  14 , characterized in that it comprises an additional purification step of the recovered artemisinin. 
     
     
         16 . The process according to any one of  claims 1  to  14  characterized in that the artemisinin is recovered by precipitation and isolation in an alkane/alcohol mixture. 
     
     
         17 . The process according to  claim 16 , wherein the alkane is selected from n-heptane, n-hexane, cyclohexane, n-pentane, and CMC; and the alcohol is selected from ethanol and isopropanol 
     
     
         18 . Compounds of formula (I) 
       
         
           
           
               
               
           
         
         wherein
 X is O, S, NH or NO 
 Y is a group selected from formulae (II), (III) and (IV) 
 
       
       
         
           
           
               
               
           
         
         
           R 1  and R 2 , independently from each other, are hydrogen; a C 1 -C 12  alkyl group which is linear or branched or a C 3 -C 10  cycloalkyl group; said alkyl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; a trifluoromethyl group; a cycloalkylalkyl group where cycloalkyl and alkyl are as defined above; a C 2 -C 12  alkenyl group which is linear or branched, said alkenyl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; a C 5 -C 14  aryl or heteroaryl group, said aryl or heteroaryl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; an arylalkyl group where aryl and alkyl are as defined above; or a heteroarylalkyl group where heteroaryl and alkyl are as defined above; and 
           R 3  is R 1 , OR 1 , NHR 1  or NR 1 R 2 , where R 1  and R 2  are as defined above. 
         
       
     
     
         19 . A compound of formula (I) according to  claim 18 , which is the diastereoisomer of formula (Ia) 
       
         
           
           
               
               
           
         
         wherein X and Y are as defined in  claim 16 . 
       
     
     
         20 . A compound of formula (I) or (Ia) according to  claim 18  or  19 , wherein X is O. 
     
     
         21 . A compound of formula (I) or (Ia) according to any one of  claims 18  to  20 , wherein
 X is O; 
 Y is a group selected from formulae (II), (III) or (IV) 
 
       
         
           
           
               
               
           
         
         R 1  and R 2 , independently from each other, are hydrogen; a C 1 -C 12  alkyl group which is linear or branched or a C 3 -C 10  cycloalkyl group, said alkyl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; a C 2 -C 12  alkenyl group which is linear or branched, said alkenyl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; a trifluoromethyl group; or a C 5 -C 14  aryl or heteroaryl group, said aryl or heteroaryl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; and 
         R 3  is R 1 , OR 1  or NR 1 R 2 , where R 1  and R 2  are as defined above. 
       
     
     
         22 . A compound of formula (I) or (Ia) according to any one of  claims 18  to  21 , wherein
 X is O; 
 Y represents a group of formula (II) 
 
       
         
           
           
               
               
           
         
         where R 3  is OR 1  and R 1  is a C 1 -C 12  alkyl group which is linear or branched or a C 3 -C 10  cycloalkyl group, said alkyl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen, or a C 6 -C 14  aryl or heteroaryl group, said aryl or heteroaryl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen. 
       
     
     
         23 . The use of a compound of formula (I) or (Ia) 
       
         
           
           
               
               
           
         
         wherein
 X is O, S, NH or NO 
 Y is a group selected from formulae (II), (III) or (IV) 
 
       
       
         
           
           
               
               
           
         
         
           R 1  and R 2 , independently from each other, are hydrogen; a C 1 -C 12  alkyl group which is linear or branched or a C 3 -C 10  cycloalkyl group, said alkyl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; a trifluoromethyl group; a cycloalkylalkyl group where cycloalkyl and alkyl are as defined above; a C 2 -C 12  alkenyl group which is linear or branched, said alkenyl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; a C 5 -C 14  aryl or heteroaryl group, said aryl or heteroaryl group being unsubstituted or substituted by one or more substituent(s) selected from a C 1 -C 6  alkyl group and a halogen; an arylalkyl group where aryl and alkyl are as defined above; or a heteroarylalkyl group where heteroaryl and alkyl are as defined above; and 
         
         R 3  is R 1 , OR 1 , NHR 1  or NR 1 R 2 , where R 1  and R 2  are as defined above, for preparing artemisinin.