Process for preparing paclitaxel

Details Process for preparing paclitaxel Process for preparing paclitaxel

1999-02-23

2000-10-10

Lambkin, Deborah C.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549510, C07D26302, C07D30500

Patent

active

061303364

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel process for preparing paclitaxel represented by the following formula (I): ##STR2## in which Ph represents phenyl,
The present invention also relates to novel intermediates which may be used in the process for preparing paclitaxel of formula 1; and to processes for preparing them.


BACKGROUND ART

Paclitaxel of formula1, a terpene taxane derivative, is a potent anti-tumor chemotherapeutics having a broad spectrum of anti-leukemia and anti-tumor activity. Accordingly, many concerns have been focused on this compound in both area of biology and chemistry. Paclitaxel has also been allowed to be commercially marketed as an anti-tumor agent against ovarian cancer and breast cancer in several countries including the United States.
Hitherto, paclitaxel has been provided by separation from the bark of Taxus brevifolia which is a kind of western yew tree. However, since the separation and purification procedures are very burdensome and further only small amount of paclitaxel is contained in the bark of that evergreen tree, the amount of paclitaxel thus provided can hardly meet the more and more increasing commercial need.
Recently, the chemists have extensively studied about semi-syntheses which are applicable for preparing paclitaxel and about new synthetic methods for the same compound including processes for preparing the intermediates. However, a lot of synthetic methods reported heretofore have not shown a satisfactory result.
For example, WO 93/06094 discloses a process for preparing paclitaxel by reacting a beta-lactam compound and 7-triethylsilyl-baccatin III, then by deprotecting, as depicted in the following reaction scheme 1. Now, this is recognized as the shortest procedure to obtain the desired paclitaxel compound. ##STR3## in which TES represents triethylsilyl, and hereinafter has the same meaning.
Although this method has a merit that the coupling reaction can be readily carried out by using the beta-lactam compound, it also has many disadvantages such that the synthesis of the beta-lactam compound itself is very difficult, the coupling reaction should be proceeded at a low temperature of -45.degree. C. under an anhydrous condition, a toxic acid having a strong corrosive action against glass products as well as properties hard to treat (i.e.,48% HF) should be used during the process for removing the triethylsilyl (TES) group used as a protecting group for a taxane derivative, etc.
In addition, as depicted in the following reaction scheme 2, a process wherein an oxazolidine compound instead of the beta-lactam is coupled with a 7-Troc-baccatin III in the presence of dicyclohexylcarbodiimide or 2-dipyridylcarbonate is described in Commercon et al., Tetrahedron Letters, pp5185-5188, 1992. ##STR4## in which Boc represents t-butoxycarbonyl, meaning.
In the above process for preparing paclitaxel, a new protecting group for the taxane derivative (-Troc) which is different from that used in the prior process of reaction scheme 1 (-TES) has been used. However, according to the use of this novel protecting group, more reaction steps should be carried out to obtain the desired product, vigorous reaction conditions are required for the protection as well as deprotection reaction, and as a result the total yield becomes low. Therefore, the process of reaction scheme 2 is understood inferior to that of reaction scheme 1.
In the process of reaction scheme 2, an oxazolidine derivative is coupled with a taxane derivative to prepare paclitaxel. As the known oxazolidine derivatives which have been used for such a purpose, a compound represented by the following formula 6 (see, WO 94/10169) and a compound represented by the following formula 7 (see, Korean Patent Appln. No. 95-703548) can be mentioned. ##STR5## in which R.sub.a represents phenyl or R.sub.f O, wherein R.sub.f represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl or heterocyclic compound containing nitrogen atom, phenylalkyl, phenyl, alkoxyphenyl or dialkoxyphenyl, or ##STR6## in whi

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