Process of synthesis of 3′,4′-anhydrovinblastine, vinblastine and vincristine

Abstract

The present invention relates to the synthesis of dimer alkaloid compounds, particularly those of the Catharantus (Vinca) family, from an indole unit, such as cantharanthine, and a dihydroindole unit, such as vindoline. A multi-step process is disclosed including the steps of (1) of 1,4-reduction of a first dimeric iminium intermediate to an enamine compound by reaction with a 1,4-dihydropyridine compound; (2) oxidative transformation of the resulting enamine to a second iminium intermediate under controlled aeration; (3) reduction of the second iminium intermediate to form the target dimer alkaloid compounds. The entire process can be conducted in a one-pot operation to obtain the target compounds without isolation of the intermediates.

What is claimed is:  
     
       1. A process for the production of dimer alkaloid compounds comprising the steps of: 
       (a) oxidizing an indole unit having a bridge nitrogen and being represented by the following formula:                    
        wherein R represents hydrogen or COO-alkyl and R 1 , R 2 , R 3  and R 4  independently represent H, OH, O-alkyl, OCO-alkyl, alkyl or aryl groups, said oxidation being carried out in the cold, at a temperature from about −77° C. to about +40° C, thereby oxidizing the bridge nitrogen of said indole unit and forming an N-oxide derivative as represented by the following formula:                    
        wherein R 1 , R 2 , R 3 , and R 4  are the same as above, and without isolating said derivative;  
       (b) treating said N-oxide derivative in the presence at least of one member selected from of the group consisting of acetic anhydride, halogenated acetic anhydride, and acetyl chloride, to effect a Polonovski-type fragmentation reaction;  
       (c) without isolating the product of step (b), stereoscopically coupling said product of step (b) with a dihydroindole unit represented by the formula:                    
        said coupling being conducted in the presence of at least one member selected from the group consisting of acetic anhydride, halogenated acetic anhydride, and acetyl chloride at a low temperature of about −70° to about +40° C., under inert conditions, to form a first iminium intermediate, represented by the formula:                    
        wherein R═COOCH 3  and R 1 , R 2 , R 3 , and R 4  are the same as defined above;  
       (d) reducing said first iminium intermediate by reaction with a 1,4-dihydropyridine compound, thereby forming an enamine intermediate, represented by the following formula:                    
        wherein R═COOCH, and R 1 , R 2 , R 3 , and R 4  are the same as defined in step (c);  
       (e) transforming said enamine intermediate obtained in step (d) by oxidation under controlled aeration conditions to a second iminium intermediate, as represented by the following formula:                    
        wherein R═COOCH 3  and R 1 , R 2 , R 3 , and R 4  are the same as defined in step (c), R 5  is OOH or C 2 H 5  and R 6  is OOH or C 2 H 5 , with the proviso that R 5  and R 6  cannot be the same; and  
       (f) reducing the second iminium intermediate obtained in step (e) to form said dimer alkaloid compounds, represented by the formula:                    
        wherein R, R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are the same as defined in step(e) and R′ 5  and R′ 6  are OH or C 2 H 5 , with the proviso that R′ 5  and R′ 6  cannot be the same.  
     
     
       2. The process according to claim  1 , further including the step of diluting said enamine obtained in step (d) by a factor of 5 to 50 with a solvent fold prior to performing step (e). 
     
     
       3. The process according to claim  1 , wherein the 1,4-dihydropyridine compound that is used in step (d) to reduce said first iminium intermediate is represented by the following formula:                    
       wherein R 11  is H, alkyl, arylalkyl, diarylalkyl, alkoxy, alkoxy, alkoxycarbonylalkyl, dialkoxycarbonylalkyl, alkali metal salts thereof, aryl, and sugar units;  
       R 12 , R 14  and R 16 , independently, are H, alkyl or aryl;  
       R 13  is H, alkyl, carboxylate and salts thereof, aryl, cyano, CONR 17 R 18  wherein R 17  and R 18  independently may be H, alkyl, aryl, or taken together, R 17  and R 18  can form a ring structure containing up to four carbon atoms, said ring structure may further be substituted by CONR 19 R 20 , wherein R 19  and R 20  are H or alkyl; and  
       R 15  may be H, alkyl, carboxylate and salts thereof, and aryl.  
     
     
       4. The process according to claim  3 , wherein R 13  and R 15  are carboxylate. 
     
     
       5. The process according to claim  3 , wherein R 13  is CONR 17 R 18  wherein R 17  and R 18  independently may be H, alkyl, aryl, or taken together, R 17  and R 18  can form a ring structure containing up to four carbon atoms, said ring structure may further be substituted by CONR 15 R 20 , wherein R 19  and R 20  are H or alkyl. 
     
     
       6. The process according to claim  5 , wherein R 11  is an electron-donating substituent selected from the group consisting of alkyl, aryl, carboxy, carboxylate and salts thereof, and sugar units. 
     
     
       7. The process according to claim  6 , wherein R 1  is selected from the group consisting of carboxylic esters and carboxylate salts. 
     
     
       8. The process according to claim  7 , wherein R 1  is 1′,2′-di (methoxy carbonyl) ethyl. 
     
     
       9. The process according to claim  7 , wherein R 1  is sodium-isobutyl-1-carboxylate. 
     
     
       10. The process of claim  1 , wherein the reduction of step (d) is conducted in an inert atmosphere at a temperature in the range from about −60° to about +60° C. in the presence of at least one solvent selected from the group consisting of lower alkyl alkanols, acetonitrile, dimethyl sulfoxide, dimethylformamide, dioxane, tetrahydrofuran, and chlorinated lower hydrocarbons. 
     
     
       11. The process according to claim  10 , wherein the reduction of step (d) is conducted at a temperature in the range of about −20° to about −60° C. 
     
     
       12. The process according to claim  1  wherein the oxidative transformation step (e) is selected from the group consisting of: 
       (1) controlled aeration/oxygenation in which a solution of said enamine is stirred in open air or with a stream of air/oxygen bubbled through the solution;  
       (2) controlled aeration/oxygenation in which a solution of said enamine and a metal ion, selected from the group consisting of ferric ion (Fe +3 ), cupric ion (Cu +2 ), cuprous ion (Cu +1 ), mercuric ion (Hg 2   +2 ) and silver ion (Ag +1 ) is stirred in open air or with a stream of air/oxygen bubbled through the solution;  
       (3) controlled aeration/oxygenation in which a solution of said enamine and a flavin coenzyme is stirred in open air or with a stream of air/oxygen bubbled through the solution;  
       (4) controlled aeration/oxygenation in which a solution of said enamine and a flavin coenzyme is stirred in open air or with a stream of air/oxygen bubbled through the solution, wherein the flavin coenzyme generates, in situ, the corresponding 1,5-dihydroflavin coenzyme;  
       (5) controlled aeration/oxygenation in which a solution of said enamine and a member selected from the group consisting of hydrogen peroxide and hydroperoxides represented by the Formula R—OOH, where R is alkyl or aryl and mixtures thereof is stirred in open air or with a stream of air/oxygen bubbled through the solution (G) said aeration/oxidation being conducted in an organic solvent at a pH of 5-9 and a reaction temperature of about −60° to about +60° C.  
     
     
       13. The process according to claim  12 , wherein the oxidative transformation step (e) is conducted at a pH in the range of 6-8. 
     
     
       14. The process according to claim  12 , wherein about two equivalents of ferric chloride are employed in step (e) (2). 
     
     
       15. The process according to claim  12 , wherein the time of aeration in the oxidative transformation step (e) is from bout five to about twenty minutes. 
     
     
       16. The process according to claim  12 , wherein the oxidative transformation step (e) is conducted at a temperature in the range from about 0° to about 20° C. 
     
     
       17. The process according to claim  2 , wherein said enamine obtained in step (d) is diluted from about 5 to about 20 fold with a solvent, prior to performing step (e). 
     
     
       18. The process according to claim  17 , wherein said enamine is diluted 8 to 12 fold. 
     
     
       19. The process according to claim  1 , wherein said reduction step (f) is conducted at a temperature in the range from about 4° to about −20° C., and at a pH between about 7.5 and about 8.5, and wherein the reaction mixture in step (f) is concentrated in vacuo at a temperature between about 0° and about 10° C. before extraction and isolation of the target compound. 
     
     
       20. The process according to claim  1 , wherein the reducing used in step (f) comprises contacting the reaction product from step (e) with an alkali metal borohydride selected from the group consisting of NaBH 4 , KBH 4  and LiBH 4 . 
     
     
       21. The process according to claim  1 , wherein steps (a)-(f) are conducted in a one-pot operation without isolation of any intermediate products. 
     
     
       22. The process according to claim  1 , wherein at least one of the intermediates formed in steps (c), (d) and (e) is isolated prior to being further reacted. 
     
     
       23. The process according to claim  22 , wherein each of said intermediates formed in steps (c), (d) and (e) isolated prior to being further reacted. 
     
     
       24. A process according to claim  1 , wherein the dimer alkaloid compound is vinblastine. 
     
     
       25. A process according to claim  24 , further comprising the step of oxidizing said vinblastine to obtain the dimer alkaloid compound vincristine. 
     
     
       26. A process according to claim  1 , wherein the dimer alkaloid compound is leurosidine. 
     
     
       27. A process for the production of dimer alkaloid compounds comprising the steps of: 
       (a) forming an N-oxide derivative in the cold, at a temperature from about −77° to about +40° C. from an indole unit having a bridge nitrogen by oxidizing the bridge nitrogen and without isolating said derivative;  
       (b) treating said N-oxide derivative in the presence at least of one member selected from the group consisting of acetic anhydride, halogenated acetic anhydride, and acetyl chloride, to effect a Polonovski-type fragmentation reaction;  
       (c) without isolating the product of step (b), stereospecifically coupling said product of step (b) with a dihydroindole unit in the presence of at least one member selected from the group consisting of acetic anhydride, halogenated acetic anhydride, and acetyl chloride at a low temperature of about −70° to about +40° C., under inert conditions, to form a first iminium intermediate;  
       (d) reducing said first iminium intermediate by reaction with a 1,4-dihydropyridine compound, thereby forming an enamine intermediate;  
       (e) preparing a second iminium intermediate by oxidative transformation of said enamine intermediate obtained in step (d) under controlled aeration conditions; and  
       (f) reducing the product obtained in step (e) to form dimer alkaloid compounds represented by the formula:                    
        wherein:  
       alk=CH 3  or (CH 2 ) n    
       CH 3  where n=1-5;  
       R 1 =CH 3    
       R 2 =H or CO-alk;  
       R 3 =H;  
       R 4 =COO-alk or CONR 13 R 14  wherein R 13  and R 14  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;  
       Z=—CH═CH— or —CH 2 —CH 2 —;  
       R=II or IIa;                    
        and wherein,  
       R 7 =H or COO-alk;  
       R 8 =H, OH, O-alk, OCO-alk or alkyl;  
       R 9 =H, OH, O-alk, OCO-alk or alkyl;  
       R 10 =H, OH, O-alk, OCO-alk;  
       R 11 =H or COO-alk; and  
       R 12 =H or alkyl.  
     
     
       28. The process according to claim  27 , further including the step of diluting said enamine obtained in step (d) by a factor of 5 to 50 with a solvent fold prior to performing step (e). 
     
     
       29. The process according to claim  27 , wherein the 1,4-dihydropyridine compound that is used in step (d) to reduce said first iminium intermediate is represented by the following formula:                    
       wherein R 11  is H, alkyl, arylalkyl, diarylalkyl, alkoxy, alkoxy, alkoxycarbonylalkyl, dialkoxycarbonylalkyl, alkali metal salts thereof, aryl, and sugar units; 
       R 12 , R 14  and R 16 , independently, are H, alkyl or aryl;  
       R 13  is H, alkyl, carboxylate and salts thereof, aryl, cyano, CONR 17 R 18  wherein R 17  and R 18  independently may be H, alkyl, aryl, or taken together, R 17  and R 18  can form a ring structure containing up to four carbon atoms, said ring structure may further be substituted by CONR 19 R 20 , wherein R 19 l and  R 20  are H or alkyl;  
       R 15  may be H, alkyl, carboxylate and salts thereof, and aryl.  
     
     
       30. The process according to claim  27 , wherein R 13  and R 15  are carboxylate. 
     
     
       31. The process according to claim  29 , wherein R 13  is CONR 17 R 18  wherein R 17  and R 18  independently may be H, alkyl, aryl, or taken together, R 17  and R 18  can form a ring structure containing up to four carbon atoms, said ring structure may further be substituted by CONR 19  R 20 , wherein R 19  and R 20  are H or alkyl. 
     
     
       32. The process according to claim  31 , wherein R 11  is an electron-donating substituent selected from the group consisting of alkyl-aryl, carboxy, carboxylate and salts thereof, and sugar units. 
     
     
       33. The process according to claim  32 , wherein R 1  is selected from the group consisting of carboxylates and carboxylate salts. 
     
     
       34. The process according to claim  6  wherein the oxidative transformation step (e) is selected from the group consisting of: 
       (1) controlled aeration/oxygenation in which a solution of said enamine is stirred in open air or with a stream of air/oxygen bubbled through the solution;  
       (2) controlled aeration/oxygenation in which a solution of said enamine and a metal ion, selected from the group consisting of ferric ion (Fe +3 ), cupric ion (Cu +2 ), cuprous ion (Cu +1 ), mercuric ion (Hg 2   +2 ) and silver ion (Ag +1 ) is stirred in open air or with a stream of air/oxygen bubbled through the solution;  
       (3) controlled aeration/oxygenation in which a solution of said enamine and a flavin coenzyme is stirred in open air or with a stream of air/oxygen bubbled through the solution;  
       (4) controlled aeration/oxygenation in which a solution of said enamine and a flavin coenzyme is stirred in open air or with a stream of air/oxygen bubbled through the solution, wherein the flavin coenzyme generates, in situ, the corresponding 1,5-dihydroflavin coenzyme;  
       (5) controlled aeration/oxygenation in which a solution of said enamine and a member selected from the group consisting of hydrogen peroxide and hydroperoxides represented by the Formula R—OOH, where R is alkyl or aryl and mixtures thereof is stirred in open air or with a stream of air/oxygen bubbled through the solution (G) said aeration/oxidation being conducted in an organic solvent at a pH of 5-9 and a reaction temperature of about −60° to about +60° C.  
     
     
       35. The process according to claim  27 , wherein the reducing used in step (f) comprises contacting the reaction product from step (e) with an alkali metal borohydride selected from the group consisting of NaBH 4 , KBH 4  and LiBH 4 . 
     
     
       36. The process according to claim  27 , wherein steps (a)-(f) are conducted in a one-pot operation without isolation of any intermediate products. 
     
     
       37. A process according to claim  27 , wherein the dimer alkaloid compound is vinblastine. 
     
     
       38. A process according to claim  37 , further comprising the step of oxidizing said vinblastine to obtain the dimer alkaloid compound vincristine. 
     
     
       39. A process according to claim  27 , wherein the dimer alkaloid compound is leurosidine. 
     
     
       40. The process according to claim  1 , wherein  3 ′, 4 ′- anhydrovinblastine is isolated following any one of steps  ( d ), ( e )  or  ( f ).