Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups
AssigneeFlorida State University
InventorsRobert A. Holton, Seokchan Kim
Life of this patent
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Abstract
Process for the preparation of a derivative or analog of baccatin III or 10-desacetyl baccatin III having a C2 substituent other than benzoate and/or a C4 substituent other than acetate in which the C2 benzoate substituent and/or the C4 acetate substituent of a derivative of baccatin III or 10-desacetyl baccatin III is/are selectively reduced to the corresponding hydroxy group(s) and converted to R.sub.7 COO- and/or R.sub.8 COO-, respectively, wherein R.sub.7 and R.sub.8 are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, moncyclic aryl, or monocyclic heteroaryl.
Claims13
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.sub.7 COO-- and/or convert the C4 hydroxy substituent to R.sub.8 COO-- wherein R.sub.7 and R.sub.8 are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, monocyclic aryl, or monocyclic heteroaryl.
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.sub.7 COO-- and/or convert the C4 hydroxy substituent to R.sub.8 COO-- wherein R.sub.7 and R.sub.8 are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, moncyclic aryl, or monocyclic heteroaryl.
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.sub.7 COO-- wherein R.sub.7 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, moncyclic aryl, or monocyclic heteroaryl and the 1,2 carbonate is a compound having the formula ##STR38## wherein R.sub.1 is H, --OH, protected hydroxy, or --OCOR.sub.6,
- R.sub.2 is H or a hydroxy protecting group, or ##STR39## R.sub.4 is H or R.sub.8 CO--, R.sub.5 is protected hydroxy,
- R.sub.6 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, moncyclic aryl, or monocyclic heteroaryl;
- R.sub.8 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, moncyclic aryl, or monocyclic heteroaryl;
- R.sub.9 is --OR.sub.14, --SR.sub.15, or --NR.sub.16 R.sub.17 ;
- R.sub.10 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
- R.sub.11 and R.sub.12 are independently hydrogen, alkyl, or alkenyl, alkynyl, aryl, acyl or heteroaryl, provided R.sub.11 and R.sub.12 are not both acyl;
- R.sub.13 is --COR.sub.18, --COOR.sub.18, --COSR.sub.18, --CONR.sub.12 R.sub.18, or --SO.sub.2 R.sub.19,
- R.sub.14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group,
- R.sub.15 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group,
- R.sub.16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- R.sub.17 is an amino protecting group;
- R.sub.18 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, and
- R.sub.19 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR.sub.15, or --NR.sub.12 R.sub.16.
Dependencies are inferred from the claim text.