Process for selective derivatization of taxanes

Details Process for selective derivatization of taxanes Process for selective derivatization of taxanes

1999-06-17

2001-02-20

Trinh, Ba K. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S510000, C549S511000

Reexamination Certificate

active

06191287

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is directed, in general, to a process for the preparation of taxol and other taxanes, and in particular, to such a process in which the C(7) or C(10) hydroxyl group of a taxane is selectively derivatized.
10-DAB (1), which is extracted from the needles of taxus baccata L., the English yew, has become a key starting material in the production of taxol and Taxotere, both of which are potent anticancer agents. Conversion of 10-DAB to taxol, Taxotere® and other taxanes having antitumor activity requires protection or derivatization of the C(7) and C(10) hydroxyl groups followed by esterification of the C(13) hydroxyl group to attach an appropriate side chain at that position.
Until now, strategies for the preparation of taxol and taxol analogs were based upon the observation of Senilh et al. (
C.R. Acad. Sci. Paris, IT
, 1981, 293, 501) that the relative reactivity of the four hydroxyl groups of 10-DAB toward acetic anhydride in pyridine is C(7)—OH>C(10)—OH>C(13)—OH>C(1)—OH. Denis, et. al. reported (
J. Am. Chem. Soc
., 1988, 110, 5917) selective silylation of the C(7) hydroxyl group of 10-DAB with triethylsilyl chloride in pyridine to give 7-triethylsilyl-10-deacetyl baccatin (III) (2) in 85% yield. Based upon these reports, in those processes in which differentiation of the C(7) and C(10) hydroxyl groups is required (e.g., preparation of taxol from 10-DAB), the C(7) hydroxyl group must be protected (or derivatized) before the C(10) hydroxyl group is protected or derivatized. For example, taxol may be prepared by treating 10-DAB with triethylsilyl chloride to protect the C(7) hydroxyl group, acetylating the C(10) hydroxyl group, attaching the side chain by esterification of the C(13) hydroxyl group, and, finally, removal of protecting groups.
It is known that taxanes having various substituents bonded to either the C(10) or the C(7) oxygens show anticancer activity. To provide for more efficient synthesis of these materials, it would be useful to have methods which permit more efficient and more highly selective protection or derivatization of the C(10) and the C(7) hydroxyl groups.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of highly efficient processes for the preparation of taxol and other taxanes through selective derivatization of the C(7) group or the C(10) hydroxyl group of 10-DAB and other taxanes, particularly a process in which the C(10) hydroxyl group is protected or derivatized prior to the C(7) hydroxyl group; and the provision of C(7) or C(10) derivatized taxanes.
Briefly, therefore, the present invention is directed to a process for the acylation of the C(10) hydroxy group of a taxane. The process comprises forming a reaction mixture containing the taxane and an acylating agent which contains less than one equivalent of an amine base for each equivalent of taxane, and allowing the taxane to react with the acylating agent to form a C(10) acylated taxane.
The present invention is further directed to a process for the silylation of the C(10) hydroxy group of a taxane having a C(10) hydroxy group. The process comprises treating the taxane with a silylamide or a bissilylamide to form a C(10) silylated taxane.
The present invention is further directed to a process for converting the C(7) hydroxy group of a 10-acyloxy-7-hydroxytaxane to an acetal or ketal. The process comprises treating the 10-acyloxy-7-hydroxytaxane with a ketalizing agent in the presence of an acid catalyst to form a C(10) ketalized taxane.
The present invention is further directed to a taxane having the structure:
wherein
M is a metal or comprises ammonium:
R
1
is hydrogen, hydroxy, protected hydroxy, or together with R
14
or R
2
forms a carbonate;
R
2
is keto, —OT
2
, acyloxy, or together with R
1
forms a carbonate;
R
4
is —OT
4
or acyloxy;
R
7
is —OSiR
J
R
K
R
L
;
R
9
is hydrogen, keto, —OT
9
, or acyloxy;
R
10
is hydrogen, keto, —OT
10
, or acyloxy;
R
13
is hydroxy, protected hydroxy, keto, or MO—;
R
14
is hydrogen, —OT
14
, acyloxy, or together with R
1
forms a carbonate;
R
J
, R
K
R
L
are independently hydrocarbyl, substituted hydrocarbyl, or heteroaryl, provided, however, if each of R
J
, R
K
and R
L
are alkyl, at least one of R
J
, R
K
and R
L
comprises a carbon skeleton having at least four carbon atoms; and
T
2
, T
4
, T
9
, T
10
, and T
14
are independently hydrogen or hydroxy protecting group.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Among other things, the present invention enables the selective derivatization of the C(10) hydroxyl group of a taxane without first protecting the C(7) hydroxyl group. Stated another way, it has been discovered that the reactivities previously reported for the C(7) and C(10) hydroxyl groups can be reversed, that is, the reactivity of the C(10) hydroxyl group becomes greater than the reactivity of the C(7) hydroxyl group under certain conditions.
Although the present invention may be used to selectively derivatize a taxane having a hydroxy group at C(7) or C(10), it offers particular advantages in the selective derivatization of taxanes having hydroxy groups at C(7) and C(10), i.e., 7,10-dihydroxy taxanes. In general, 7,10-dihydroxytaxanes which may be selectively derivatized in accordance with the present invention correspond to the following structure:
wherein
R
1
is hydrogen, hydroxy, protected hydroxy, or together with R
14
or R
2
forms a carbonate;
R
2
is keto, —OT
2
, acyloxy, or together with R
1
forms a carbonate;
R
4
is —OT
4
or acyloxy;
R
9
is hydrogen, keto, —OT
9
, or acyloxy;
R
13
is hydroxy, protected hydroxy, keto, or
R
14
is hydrogen, —OT
14
, acyloxy or together with R
1
forms a carbonate;
T
2
, T
4
, T
9
, and T
14
are independently hydrogen or hydroxy protecting group;
X
1
is —OX
6
, —SX
7
, or —NX
8
X
9
;
X
2
is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl;
X
3
and X
4
are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl;
X
5
is —X
10
, —OX
10
, —SX
10
, —NX
8
X
10
or —SO
2
X
11
;
X
6
is hydrocarbyl, substituted hydrocarbyl, heteroaryl, hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
X
7
is hydrocarbyl, substituted hydrocarbyl, heteroaryl, or sulfhydryl protecting group;
X
8
is hydrogen, hydrocarbyl, or substituted hydrocarbyl;
X
9
is an amino protecting group;
X
10
is hydrocarbyl, substituted hydrocarbyl, or heteroaryl;
X
11
is hydrocarbyl, substituted hydrocarbyl, heteroaryl, —OX
10
, or —NX
8
X
14
; and
X
14
is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl.
Selective C(10) Derivatization
In accordance with the process of the present invention, it has been discovered that the C(10) hydroxyl group of a taxane can be selectively acylated in the absence of an amine base. Preferably, therefore, amine bases such as pyridine, triethylamine, dimethylaminopyridine and 2,6-lutidine, if present at all, are present in the reaction mixture in relatively low concentration. Stated another way, if an amine base is present in the reaction mixture, the molar ratio of the amine base to the taxane is preferably less than 1:1, more preferably less than 10:1, and most preferably less than 100:1.
Acylating agents which may be used for the selective acylation of the C(10) hydroxyl group of a taxane include anhydrides, dicarbonates, thiodicarbonates, and isocyanates. In general, the anhydrides, dicarbonates, and thiodicarbonates correspond to structure 4 and the isocyanates correspond to structure 5:
wherein R
1
is —OR
a
, —SR
a
, or R
a
; R
2
is —OC(O)R
b
, —OC(O)OR
b
, —OC(O)SR
b
, —OPOR
b
R
c
, or —OS(O)
2
R
b
; R
3
is hydrocarbyl, substituted hydrocarbyl, or heteroaryl; and R
a
, R
b
, R
c
are independently hydrocarbyl, substituted hydrocarbyl, or heteroaryl. For example, suitable carboxylic acid anhydride acylating agents include acetic anhydride, chloroacetic a

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