Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups

Claim 2

A process for the preparation of a derivative or analog of baccatin III or 10-desacetyl baccatin III from a derivative or analog of baccatin III or 10-desacetyl baccatin III which comprises a C2 benzoate and/or a C4 acetate substituent, the process comprising selectively reducing the C2 benzoate substituent and/or the C4 acetate substituent with an aluminate to the corresponding hydroxy group(s) and acylatingthe C2 hydroxy substituent and/or the C4 hydroxy substituent to convert the C2 hydroxy substituent to R 7 COO-- and/or convert the C4 hydroxy substituent to R 8 COO-- wherein R 7 and R 8 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, monocyclic aryl, or monocyclic heteroaryl.

Claim 3

The process of claim 1 wherein the derivative or analog of baccatin III or 10-desacetyl derivative has the formula ##STR36## wherein R 1 is H, --OH, protected hydroxy, or --OCOR 6 , R 2 is H or a hydroxy protecting group, or ##STR37## R 3 is H or R 7 CO--, R 4 is H or R 8 CO--, R 5 is --OH or protected hydroxy, R 6 , R 7 , and R 8 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, moncyclic aryl, or monocyclic heteroaryl; R 9 is --OR 14 , --SR 15 , or --NR 16 R 17 ; R 10 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R 11 and R 12 are independently hydrogen, alkyl, or alkenyl, alkynyl, aryl, acyl or heteroaryl, provided R 11 and R 12 are not both acyl; R 13 is --COR 18 , --COOR 18 , --COSR 18 , --CONR 12 R 18 , or --SO 2 R 19 , R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group, R 15 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group, R 16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 17 is an amino protecting group; R 18 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, and R 19 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 15 , or --NR 12 R 16 .

Claim 4

The process of claim 1 wherein the C2 benzoate substituent and/or the C4 acetate substituent of the derivative of baccatin III or 10-desacetyl baccatin III are selectively reduced with lithium aluminum hydride or sodium bis(2-methoxyethoxy) aluminum hydride.

Claim 5

The process of claim 1 wherein R 7 is p-fluoro-phenyl.

Claim 6

The process of claim 2 wherein the C2 benzoate substituent and/or the C4 acetate substituent of the derivative of baccatin III or 10-desacetyl baccatin III are selectively reduced with lithium aluminum hydride or sodium bis(2methoxyethoxy) aluminum hydride.

Claim 7

The process of claim 1 wherein R 7 is monocyclic aryl.

Claim 8

The process of claim 1 wherein R 7 is C 1 -C 6 alkyl, C 1 -C 6 alkanoxy or halogen substituted monocyclic aryl.

Claim 9

The process of claim 1 wherein the derivative or analog of baccatin III or 10-desacetyl baccatin III is prepared from a C1 hydroxy C2 benzoate derivative of baccatin III or 10-desacetyl baccatin III, the C1 hydroxy C2 benzoate derivative is reduced with sodium bis(2-methoxyethoxy) aluminum hydride to form a 1,2-diol derivative, the 1,2-diol is reacted with Cl 2 CO to form a 1,2-carbonate, and the 1,2-carbonate is reacted with a nucleophilic reagent to convert the C2 substituent to R 7 COO-- wherein R 7 is as defined in claim 1.

Claim 10

A process for the preparation of a derivative or analog of baccatin III or 10-desacetyl baccatin III from a derivative or analog of baccatin III or 10-desacetyl baccatin III which comprises a C2 benzoate and/or a C4 acetate group, the process comprising selectively reducing the C2 benzoate substituent and/or the C4 acetate substituent of a derivative of baccatin III or 10-desacetyl baccatin III with lithium aluminum hydride or sodium bis(2-methoxyethoxy) aluminum hydride to the corresponding hydroxy group(s) and reacting the corresponding hydroxy group(s) with an acylating agent to convert the C2 hydroxy substituent to R 7 COO-- and/or convert the C4 hydroxy substituent to R 8 COO-- wherein R 7 and R 8 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, moncyclic aryl, or monocyclic heteroaryl.

Claim 11

A process for the preparation of a derivative or analog of baccatin III or 10-desacetyl baccatin III from a derivative or analog of baccatin III or 10-desacetyl baccatin III which comprises a C2 benzoate and/or a C4 acetate group, the process comprising selectively reducing the C2 benzoate substituent and/or the C4 acetate substituent of a derivative of baccatin III or 10-desacetyl baccatin III with lithium aluminum hydride or sodium bis(2-methoxyethoxy) aluminum hydride to the corresponding hydroxy group(s) and reacting the corresponding hydroxy group(s) with an acylating agent to convert the C2 hydroxy substituent to R 7 COO-- and/or convert the C4 hydroxy substituent to R 8 COO-- wherein R 7 and R 8 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, moncyclic aryl, or monocyclic heteroaryl.

Claim 12

The process of claim 9 wherein the acylating agent is anhydride or an acid chloride.

Claim 13

The process of claim 9 wherein R 7 is C 1 -C 6 alkyl, C 1 -C 6 alkanoxy or halogen substituted monocyclic aryl.

Claim 14

A process for the preparation of a derivative or analog of baccatin III or 10-desacetyl baccatin III from a 1,2 carbonate derivative of baccatin III or 10-desacetyl baccatin III, the process comprising reacting the 1,2 carbonate with a nucleophilic reagent to convert the C2 substituent to R 7 COO-- wherein R 7 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, moncyclic aryl, or monocyclic heteroaryl and the 1,2 carbonate is a compound having the formula ##STR38## wherein R 1 is H, --OH, protected hydroxy, or --OCOR 6 , R 2 is H or a hydroxy protecting group, or ##STR39## R 4 is H or R 8 CO--, R 5 is protected hydroxy, R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, moncyclic aryl, or monocyclic heteroaryl; R 8 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, moncyclic aryl, or monocyclic heteroaryl; R 9 is --OR 14 , --SR 15 , or --NR 16 R 17 ; R 10 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R 11 and R 12 are independently hydrogen, alkyl, or alkenyl, alkynyl, aryl, acyl or heteroaryl, provided R 11 and R 12 are not both acyl; R 13 is --COR 18 , --COOR 18 , --COSR 18 , --CONR 12 R 18 , or --SO 2 R 19 , R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group, R 15 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group, R 16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 17 is an amino protecting group; R 18 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, and R 19 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 15 , or --NR 12 R 16 .

Claim 15

A process for the preparation of a derivative or analog of baccatin III or 10-desacetyl baccatin III from a 1,2 carbonate derivative of baccatin III or 10-desacetyl baccatin III, the process comprising reacting the 1,2 carbonate with a nucleophilic reagent to convert the C2 substituent to R 7 COO-- wherein R 7 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, moncyclic aryl, or monocyclic heteroaryl and the 1,2 carbonate is a compound having the formula ##STR38## wherein R 1 is H, --OH, protected hydroxy, or --OCOR 6 , R 2 is H or a hydroxy protecting group, or ##STR39## R 4 is H or R 8 CO--, R 5 is protected hydroxy, R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, moncyclic aryl, or monocyclic heteroaryl; R 8 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, moncyclic aryl, or monocyclic heteroaryl; R 9 is --OR 14 , --SR 15 , or --NR 16 R 17 ; R 10 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R 11 and R 12 are independently hydrogen, alkyl, or alkenyl, alkynyl, aryl, acyl or heteroaryl, provided R 11 and R 12 are not both acyl; R 13 is --COR 18 , --COOR 18 , --COSR 18 , --CONR 12 R 18 , or --SO 2 R 19 , R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group, R 15 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group, R 16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 17 is an amino protecting group; R 18 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, and R 19 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 15 , or --NR 12 R 16 .

Claim 16

The process of claim 12 wherein the nucleophilic reagent is a Grignard reagent or an alkyllithium reagent.