Semi-synthetic conversion of paclitaxel to docetaxel

Abstract

A process is provided for the semi-synthesis of taxane derivatives useful in the preparation of docetaxel, in particular, the semi-synthesis of protected taxane derivatives in a one pot reaction of protecting the C-2′, C-7 and C-10 and introducing a t-Boc group at the nitrogen of the amide group at the C-3′ position in paclitaxel and subsequently conversion to docetaxel, and derivatives used therein.

1 . A process for converting paclitaxel or paclitaxel containing material to docetaxel by protecting a compound of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein, R 1  is alkyl, alkenyl or aryl; and X, Y and Z are the same or different and independently hydroxy or protected hydroxy, the process comprising: 
 protecting one or more hydroxy groups at the C-2′, C-7 and C-10 positions of the taxane; and  
 introducing a t-Boc group at the nitrogen of the amide group at the C-3′ position of the taxane to provide a C-2′, C-7, C-10 and N-t-Boc protected paclitaxel derivative,  
 wherein the steps of protecting one or more hydroxy groups and introducing the t-Boc group comprises combining, in a one pot reaction, the taxane with a hydroxy protecting group and a t-Boc agent.  
 
     
     
         2 . The process of  claim 1  wherein the hydroxy protecting groups at the C-2′, C-7 and C-10 positions are the same.  
     
     
         3 . The process of  claim 1  wherein the hydroxy protecting groups at the C-2′, C-7 and C-10 positions are different.  
     
     
         4 . The process of  claim 1  wherein the step of protecting one or more hydroxy groups at the C-2′, C-7 and C-10 positions of the taxane is carried out in the presence of a base.  
     
     
         5 . The process of  claim 4  wherein the base is DMAP, pyridine, TEA, LiOH, n-BuLi, LiH, LiHMDS, KHMDS, NaH, NaHMDS, or a mixture thereof  
     
     
         6 . The process of  claim 5  wherein the base further comprises a metal alkoxide, wherein the metal is a Group I, II, III or transition metal.  
     
     
         7 . The process of  claim 6  wherein the metal alkoxide is Li-t-OBu, Na-t-OBu or K-t-OBu.  
     
     
         8 . The process of  claim 4  wherein the step of protecting one or more hydroxy groups at the C-2′, C-7 and C-10 positions of the taxane comprises combining the taxane with a base and a hydroxy-protecting group in an organic solvent, and wherein the base is DMAP, pyridine, TEA, LiOH, Li-t-OBu, n-BuLi, K-t-OBu or a mixture thereof, and the hydroxy-protecting group is an alkylating agent, silylating agent or acylating agent.  
     
     
         9 . The process of  claim 8  wherein the hydroxy-protecting group is tert-butoxycarbonyl (t-Boc), benzyloxycarbonyl (CBZ), 2,2,2-trichloroethoxycarbonyl (Troc), 9-fluorenyl methoxycarbonyl (Fmoc), 2,2,2-trichloroethoxymethyl, trimethyl silyl, triethyl silyl, dimethyl(t-butyl) silyl, diethylmethylsilyl, dimethyl phenylsilyl, diphenylmethylsilyl, acetyl, acetoxyacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl.  
     
     
         10 . The process of  claim 9  wherein the base is DMAP or n-BuLi and the hydroxy-protecting group is t-Boc, triethylsilyl or dichloroacetyl.  
     
     
         11 . The process of  claim 1  wherein the step of protecting one or more hydroxy groups at the C-2′, C-7 and C-10 positions of the taxane is carried out in the presence of an acid.  
     
     
         12 . The process of  claim 11  wherein the acid is p-toluenesulfonic acid and the hydroxy protecting group is ethoxyethyl or methoxymethyl.  
     
     
         13 . The process of  claim 1  wherein the t-Boc agent is Boc 2 O.  
     
     
         14 . The process of  claim 1  wherein the taxane is paclitaxel or paclitaxel containing material.  
     
     
         15 . A process for preparing docetaxel from a taxane of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein, R 1  is alkyl, alkenyl or aryl; and X, Y and Z are the same or different and independently hydroxy or protected hydroxy, the process comprising: 
 protecting one or more hydroxy groups at the C-2′, C-7 and C-10 positions of the taxane;  
 introducing a t-Boc group at the nitrogen of the amide group at the C-3′ position of the taxane to provide a protected paclitaxel derivative having an urea linkage at the C-3′ position;  
 selectively removing the —C(O)R 1  group from the urea linkage to provide a protected docetaxel; and  
 converting the protected docetaxel to docetaxel by removing the hydroxy-protecting groups at the C-2′, C-7 and C-10 positions,  
 wherein the step of protecting one or more hydroxy groups at C-2′, C-7 and C-10 positions, and introducing the t-Boc group at the nitrogen site of the amide group of the taxane comprises combining, in a one pot reaction, the taxane of Formula (I) with a hydroxy protecting agent and a t-Boc agent, and wherein the step of selectively removing the —C(O)R 1  group comprises subjecting the protected paclitaxel derivative having the urea linkage to a first base.  
 
     
     
         16 . The process of  claim 15  wherein the hydroxy protecting groups at the C-2′, C-7 and C-10 positions are the same.  
     
     
         17 . The process of  claim 15  wherein the hydroxy protecting groups at the C-2′, C-7 and C-10 positions are different.  
     
     
         18 . The process of  claim 15  wherein the step of protecting one or more hydroxy groups at the C-2′, C-7 and C-10 positions of the taxane is carried out in the presence of a second base.  
     
     
         19 . The process of  claim 18  wherein the second base is DMAP, pyridine, TEA, LiOH, n-BuLi, LiH, LiHMDS, KHMDS, NaH, NaHMDS, or a mixture thereof.  
     
     
         20 . The process of  claim 19  wherein the second base further comprises a metal alkoxide, wherein the metal is a Group I, II, III or transition metal.  
     
     
         21 . The process of  claim 20  wherein the metal alkoxide is Li-t-OBu, Na-t-OBu or K-t-OBu.  
     
     
         22 . The process of  claim 18  wherein the step of protecting one or more hydroxy groups at the C-2′, C-7 and C-10 positions of the taxane comprises combining the taxane with a base and a hydroxy-protecting group in an organic solvent, and wherein the base is DMAP, pyridine, TEA, LiOH, Li-t-OBu, n-BuLi, K-t-OBu or a mixture thereof, and the hydroxy-protecting group is an alkylating agent, silylating agent or acylating agent.  
     
     
         23 . The process of  claim 22  wherein the hydroxy-protecting group is tert-butoxycarbonyl (t-Boc), benzyloxycarbonyl (CBZ), 2,2,2-trichloroethoxycarbonyl (Troc), 9-fluorenyl methoxycarbonyl (Fmoc), 2,2,2-trichloroethoxymethyl, trimethyl silyl, triethyl silyl, dimethyl(t-butyl) silyl, diethylmethylsilyl, dimethyl phenylsilyl, diphenylmethylsilyl, acetyl, acetoxyacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl.  
     
     
         24 . The process of  claim 23  wherein the base is DMAP or n-BuLi and the hydroxy-protecting group is t-Boc, triethylsilyl or dichloroacetyl.  
     
     
         25 . The process of  claim 15  wherein the step of protecting one or more hydroxy groups at the C-2′, C-7 and C-10 positions of the taxane is carried out in the presence of an acid.  
     
     
         26 . The process of  claim 25  wherein the acid is p-toluenesulfonic acid and the hydroxy protecting group is ethoxyethyl or methoxymethyl.  
     
     
         27 . The process of  claim 15  wherein the t-Boc agent is Boc 2 O.  
     
     
         28 . The process of  claim 15  wherein the taxane is paclitaxel or paclitaxel containing material.  
     
     
         29 . The process of  claim 15  wherein the first base is a metal hydroxide or a metal alkoxide.  
     
     
         30 . The process of  claim 29  wherein the metal hydroxide is LiOH, NaOH or KOH.  
     
     
         31 . The process of  claim 29  wherein the metal alkoxide is calcium methoxide, sodium methoxide, lithium methoxide or potassium methoxide.  
     
     
         32 . The process of  claim 29  wherein the first base is used in conjunction with a peroxide.  
     
     
         33 . The process of  claim 32  wherein the peroxide is H 2 O 2 , t-butyl hydroperoxide (TBHB) or m-chloroperoxybenzoic acid (mCPBA).  
     
     
         34 . The process of  claim 33  wherein LiOH is used in conjunction with H 2 O 2 .  
     
     
         35 . A process for preparing docetaxel from an initial mixture of taxanes, wherein the initial mixture comprises paclitaxel and at least one additional taxane selected from the group of 10-deacetylbaccatin III, 9-dihydro-13-acetylbaccatin III, baccatin III, cephalomannine, 10-deacetyl taxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol, the process comprising the steps of: 
 protecting the hydroxy groups at the C-2′ and C-7 positions of paclitaxel;    introducing a t-Boc group at the nitrogen of the amide group at the C-3′ position of paclitaxel to provide a protected paclitaxel derivative having an urea linkage at the C-3′ position;    selectively removing the benzoyl group from the urea linkage to provide a protected docetaxel; and    converting the protected docetaxel to docetaxel by removing the hydroxy-protecting groups at the C-7, C-2′ and C-10 positions,    wherein the step of protecting the hydroxy groups at C-2′ and C-7 positions, and introducing a t-Boc group at the nitrogen site of the amide group of paclitaxel are carried out in a one pot reaction wherein the mixture containing paclitaxel is combined with a hydroxy protecting agent and a t-Boc agent; and wherein the step of selectively removing the benzoyl group comprises subjecting the protected paclitaxel derivative having the urea linkage to a first base.    
     
     
         36 . The process of  claim 35  wherein the hydroxy protecting groups at the C-2′ and C-7 positions are the same.  
     
     
         37 . The process of  claim 35  wherein the hydroxy protecting groups at the C-2′ and C-7 positions are different.  
     
     
         38 . The process of  claim 35  wherein the step of protecting one or more hydroxy groups at the C-2′ and C-7 positions of paclitaxel is carried out in the presence of a second base.  
     
     
         39 . The process of  claim 38  wherein the second base is DMAP, pyridine, TEA, LiOH, n-BuLi, LiH, LiHMDS, KHMDS, NaH, NaHMDS, or a mixture thereof.  
     
     
         40 . The process of  claim 39  wherein the second base further comprises a metal alkoxide, wherein the metal is a Group I, II, III or transition metal.  
     
     
         41 . The process of  claim 40  wherein the metal alkoxide is Li-t-OBu, Na-t-OBu or K-t-OBu.  
     
     
         42 . The process of  claim 38  wherein the step of protecting one or more hydroxy groups at the C-2′ and C-7 positions of the taxane comprises combining the taxane with the second base and a hydroxy-protecting group in an organic solvent, and wherein the second base is DMAP, pyridine, TEA, LiOH, Li-t-OBu, n-BuLi, K-t-OBu or a mixture thereof, and the hydroxy-protecting group is an alkylating agent, silylating agent or acylating agent.  
     
     
         43 . The process of  claim 42  wherein the hydroxy-protecting group is tert-butoxycarbonyl (t-Boc), benzyloxycarbonyl (CBZ), 2,2,2-trichloroethoxycarbonyl (Troc), 9-fluorenyl methoxycarbonyl (Fmoc), 2,2,2-trichloroethoxymethyl, trimethyl silyl, triethyl silyl, dimethyl(t-butyl) silyl, diethylmethylsilyl, dimethyl phenylsilyl, diphenylmethylsilyl, acetyl, acetoxyacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl.  
     
     
         44 . The process of  claim 43  wherein the base is DMAP or n-BuLi and the hydroxy-protecting group is t-Boc, triethylsilyl or dichloroacetyl.  
     
     
         45 . The process of  claim 35  wherein the step of protecting one or more hydroxy groups at the C-2′ and C-7 positions of the taxane is carried out in the presence of an acid.  
     
     
         46 . The process of  claim 45  wherein the acid is p-toluenesulfonic acid and the hydroxy protecting group is ethoxyethyl or methoxymethyl.  
     
     
         47 . The process of  claim 35  wherein the t-Boc agent is Boc 2 O.  
     
     
         48 . The process of  claim 35  wherein the first base is a metal hydroxide or a metal alkoxide.  
     
     
         49 . The process of  claim 48  wherein the metal hydroxide is LiOH, NaOH or KOH.  
     
     
         50 . The process of  claim 48  wherein the metal alkoxide is calcium methoxide, sodium methoxide, lithium methoxide or potassium methoxide.  
     
     
         51 . The process of  claim 48  wherein the first base is used in conjunction with a peroxide.  
     
     
         52 . The process of  claim 51  wherein the peroxide is H 2 O 2 , t-butyl hydroperoxide (TBHB) or m-chloroperoxybenzoic acid (mCPBA).  
     
     
         53 . The process of  claim 52  wherein LiOH is used in conjunction with H 2 O 2 .  
     
     
         54 . The process of  claim 35  wherein the step of protecting the hydroxy group at the C-2′ and C-7 position of paclitaxel further comprises protecting one or more hydroxy groups at the C-2′, C-7 and C-10 positions of each taxane in the initial mixture having a hydroxy group at these positions.  
     
     
         55 . The process of  claim 35  wherein the initial mixture comprises paclitaxel and at least two additional taxanes selected from 10-deacetylbaccatin III, 9-dihydro-13-acetylbaccatin III, baccatin III, cephalomannine, 10-deacetyl taxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol.  
     
     
         56 . The process of  claim 35  wherein the initial mixture comprises paclitaxel and at least three additional taxanes selected from 10-deacetylbaccatin III, 9-dihydro-13-acetylbaccatin III, baccatin III, cephalomannine, 10-deacetyl taxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol.  
     
     
         57 . The process of  claim 35  wherein the initial mixture comprises paclitaxel, 10-deacetylbaccatin III, 9-dihydro-13-acetylbaccatin III, baccatin III, cephalomannine, 10-deacetyl taxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol.  
     
     
         58 . The process of  claim 35  wherein the initial mixture of taxanes is a waste taxane solution comprising one or more of the following: 
 pooled waste stream fractions collected during a chromatographic separation of a crude or partially purified taxane extract; and    pooled waste mother liquors collected during a recrystallization of a crude or partially purified taxane extract.    
     
     
         59 . The process of  claim 58  wherein the waste taxane solution comprises pooled waste stream fractions collected during a chromatographic separation of a crude taxane extract.  
     
     
         60 . The process of  claim 58  wherein the waste taxane solution comprises pooled waste stream fractions collected during chromatographic separations of both crude and partially purified taxane extracts and pooled waste mother liquors collected during recrystallizations of both crude and partially purified taxane extracts.  
     
     
         61 . The process of  claim 60  wherein the crude and partially purified taxane extracts are obtained from taxane-containing materials from the genus  Taxus  or from synthesis.  
     
     
         62 . A process of converting a taxane of Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein, R 1  is alkyl, alkenyl or aryl, and X, Y and Z are the same or different and independently hydroxy or protected hydroxy, to docetaxel, the process comprising: 
 introducing a nitroso group (—NO) at the nitrogen of the amide group at the C-3′ position of the taxane to provide a N-nitrosoamide intermediate;  
 hydrolyzing the N-nitrosoamide intermediate to provide a N-nitrosoamine intermediate;  
 reducing the N-nitrosoamine intermediate to provide a primary amine intermediate; and  
 converting the primary amine derivative to docetaxel.  
 
     
     
         63 . The process of  claim 62  wherein the step of introducing the nitroso group comprises combining the taxane of Formula (I) with a nitrosation agent.  
     
     
         64 . The process of  claim 63  wherein the nitrosation agent is NaNO 2 , LiNO 2 , or KNO 2  in the presence of an acid.  
     
     
         65 . The process of  claim 63  wherein the nitrosation agent is N 2 O 4 .  
     
     
         66 . The process of  claim 62  wherein the step of hydrolyzing the N-nitrosoamide intermediate comprises combining the N-nitrosoamide intermediate with a metal hydroxide and a peroxide.  
     
     
         67 . The process of  claim 66  wherein the metal hydroxide is LiOH and the peroxide is H 2 O 2 .  
     
     
         68 . The process of  claim 62  wherein the step of reducing the N-nitrosoamine intermediate comprises combining the N-nitrosoamine intermediate with a reducing agent selected from Raney Nickel, palladium on carbon in the presence of hydrogen gas and platinum on carbon in the presence of hydrogen gas.  
     
     
         69 . The process of  claim 62  wherein the compound of Formula (I) is paclitaxel or paclitaxel containing material.  
     
     
         70 . The process of  claim 62  wherein the compound of Formula (I) is part of a mixture comprising the compound of Formula (I), and one or more compounds selected from the group consisting of paclitaxel, 9-dihydro-13-acetylbaccatin III, cephalomannine, 10-deacetyl taxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol.  
     
     
         71 . The process of  claim 70  wherein the initial mixture of taxanes is a waste taxane solution comprising one or more of the following: 
 pooled waste stream fractions collected during a chromatographic separation of a crude or partially purified taxane extract; and    pooled waste mother liquors collected during a recrystallization of a crude or partially purified taxane extract.    
     
     
         72 . The process of  claim 71  wherein the waste taxane solution comprises pooled waste stream fractions collected during a chromatographic separation of a crude taxane extract.  
     
     
         73 . The process of  claim 71  wherein the waste taxane solution comprises pooled waste stream fractions collected during chromatographic separations of both crude and partially purified taxane extracts and pooled waste mother liquors collected during recrystallizations of both crude and partially purified taxane extracts.  
     
     
         74 . The process of  claim 73  wherein the crude and partially purified taxane extracts are obtained from taxane-containing materials from the genus  Taxus  or from synthesis.