Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-10
2001-06-19
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06248908
ABSTRACT:
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to the synthesis of a paclitaxel C-4 methylcarbonate analog from 10-deacetylbaccatin III.
BACKGROUND AND SUMMARY OF THE INVENTION
The invention relates to the synthesis of C-4 methylcarbonate analog of paclitaxel having the formula
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® 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.
Conditions: (i) TBDMSCl, imidazole, DMF, 4 h, 90%; (ii) diisopropyidichlorosilane, imidazole, 12 h, MeOH quench, 80%, crystallization from IPA; (iii) Triton-B, DCM, −70° C.→0° C., 4 h, chromatography, 40-50%; (iv) carbonyldiimidazole, THF, reflux, 4 h, chromatography, 75%; (v) LHMDS, ClCOOMe, THF, −78° C.→0° C., chromatography, 85%; (vi) PhLi, −78° C., THF, 45 min, chromatography, 85%; (vii) TEA·3HF, THF, ambient temp, chromatography, 80%.
This original synthesis, however, although suitable for the preparation of small batches (<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.
Impurities
(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.
(c) Treatment of phenyllithium with compound 7 produced approximately 10% of C-10 deacetate 15. The compound co-crystallized with the product.
(d) Purification of most of the intermediates required the additional step of column chromatography.
Synthetic routes for the preparation of compound I have been previously disclosed. See WO94/14787; Chen et al., “First Synthesis of Novel Paclitaxel (Taxol) Analogs Modified at the C4-Position”, J. Org. Chem. 59 (21). pp. 6156-6158 (1994); Chen et al., “Novel C-4 Paclitaxel (Taxol®) Analogs: Potent Antitumor Agents”, Bioorg. Med. Chem. Lett. 5 (22), pp. 2471-2476 (1995). However, none of these processes disclose the preparation of the compound of formula I starting from 10-DAB. Furthermore, the synthesis of the present invention provides a process wherein the acetate group at the C-4 position of 10-DAB is reductively removed using Red-Al prior to C-10 acetylation. As such, C-10 deacetylation side products are avoided.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
In an effort to overcome these disadvantages, a more expedient synthesis of I was developed. This novel synthesis provides for the synthesis of I from readily available paclitaxel precursor 10-deacetylbaccatin (“10-DAB”) 16 and is described in detail in Scheme 2.
In this novel process, the C-4 carbonate analog of 10-DAB 21 is viewed as the key intermediate in the synthesis of I. The key reaction in this novel synthesis is the chemoselective reduction of the C-4 acetate using Red-Al. The paclitaxel phenylisoserine side chain at C-13 is appended via the &bgr;-lactam route or oxazole based coupling chemistry, described in U.S. Pat. No. 5,274,124 (Holton) and U.S. patent application Ser. No. 07/995,443 respectively, and incorporated herein by reference, to provide the compound of formula I.
Alternate coupling via oxazole acid and its conversion to I
Use of the novel synthesis of this invention is advantageous since 10-DAB is significantly less expensive to use as a starting compound than paclitaxel itself. Furthermore, the chemistry of the novel synthesis of the present invention is amenable to scale-up and synthesis of new antitumor agents in the C-4 carbonate series with modified side chain.
The present invention is further described by reference to the working Examples. The Examples are provided for the purpose of illustrating the present invention and should not be construed as being a limitation on the scope or spirit of the invention. It should be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto.
REFERENCES:
patent: Re. 34277 (1993-06-01), Denis et al.
patent: 5274124 (1993-12-01), Holton
patent: 6025385 (2000-02-01), Shimizu et al.
patent: 6147234 (2000-11-01), Holton et al.
patent: WO 94/14787 (1994-07-01), None
Chen et al., J. Org. Chem., vol. 59, pp. 6156-6158 (1994).
Chen et al., Biorg. Med. Chem. Lett., vol. 5, No. 22, pp. 2741-2746 (1995).
Babcock Timothy J.
Bristol--Myers Squibb Company
Lambkin Deborah C.
Lopez Gabriel
Wright Sonya N.
LandOfFree
Process for the preparation of a paclitaxel C-4 methyl... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of a paclitaxel C-4 methyl..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of a paclitaxel C-4 methyl... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2501823