The invention relates to the synthesis of C-4 methylcarbonate analog of paclitaxel having the formula ##STR1##
and intermediates useful for the preparation of novel antitumor agents starting from 10-desacetylbaccatin (10-DAB).
The compound of formula I is superior to paclitaxel in four distal site tumor models: M109 murine lung carcinoma; HCT/pk human colon carcinoma xenograft (multidrug resistant tumor model); L2987 human lung carcinoma xenograft; and HOC79, a clinically derived Taxol.RTM. unresponsive ovarian carcinoma xenograft. In the tubulin polymerization assay, compound I is about twice as potent as paclitaxel. Crystals of the compound of formula I display moderately increased solubility relative to paclitaxel in typical taxane vehicles and thus offers the potential for administration of less cremophor per dose than that currently administered with paclitaxel.
Previously, the original synthesis of the C-4 methyl carbonate analog of paclitaxel (I) required protections of C-2' and C-7 hydroxyl groups as silyl ethers; hydrolysis of C-2 benzoate and C-4 acetate; protection of C-1 and C-2 hydroxyl groups as cyclic carbonate; formation of C-4 methylcarbonate; regioselective opening of the carbonate to install C-2 benzoate; and removal of protecting groups to prepare I as indicated in Scheme 1. ##STR2## ##STR3##
Conditions: (i) TBDMSCl, imidazole, DMF, 4 h, 90%; (ii) diisopropyidichlorosilane, imidazole, 12 h, MeOH quench, 80%, crystallization from IPA; (iii) Triton-B, DCM, -70.degree. C..fwdarw.0.degree. C., 4 h, chromatography, 40-50%; (iv) carbonyldiimidazole, THF, reflux, 4 h, chromatography, 75%; (v) LHMDS, ClCOOMe, THF, -78.degree. C..fwdarw.0.degree. C., chromatography, 85%; (vi) PhLi, -78.degree. C., THF, 45 min, chromatography, 85%; (vii) TEA.multidot.3HF, THF, ambient temp, chromatography, 80%.
This original synthesis, however, although suitable for the preparation of small batches (&lt;20 g) of I, is not scalable to prepare large GLP and GMP batches of I for the following reasons:
(a) Triton B hydrolysis of compound 4 afforded compound 5 in 40% yield after chromatographic purification. Attempts to improve this reaction were unsuccessful. Furthermore, a variety of impurities 9-12 were identified and were difficult to remove by crystallization or chromatography. PA1 (b) Synthesis of the cyclic carbonate of compound 6 generated 5-10% of an N-acyl impurity 14 which was difficult to remove by crystallization. PA1 (c) Treatment of phenyllithium with compound 7 produced approximately 10% of C-10 deacetate 15. The compound co-crystallized with the product. PA1 (d) Purification of most of the intermediates required the additional step of column chromatography.
USPTO Backgrounds
USPTO Backgrounds