Paclitaxel synthesis

Y. Ueda, J. D. Matiskella, A. B. Mikkilineni, V. Farina, J. O. Knipe, W. C. Rose, A. M. Casazza, D. M. Vyas, Novel, Water-Soluble Phosphate Derivatives of 2 -Ethoxycarbo-nylpaclitaxel as Potential Prodrugs of Paclitaxel Synthesis and Antitumor Evaluation , Bioorg. Med. Chem. Lett. 1995, 5, 247 - 252. 

Kang and co-workers prepared the (3-halo amide arrangement required for oxazoline formation from allylic alcohols via a two-step process. For example, treatment of the allylic alcohol 122 with trichloroacetonitrile and base followed by activation of the double bond with iodine monochloride, provides 123. Hydrolysis of 123 gave 124 from which cyclization provided the oxazoline 18a used for paclitaxel synthesis (Scheme 8.36). 

To better appreciate the standard by which inequitable conduct is measured, let s review an actual recent court opinion, Bristol-Myers Squibb Company v. Rhone-Poulenc Rorer, Inc.,1% where this issue was heard. This case serves to explain how materiality and intent are inextricably related. Perhaps less abstractly, it will also show why it is important for the scientists to pay close attention to what they publish as well as to documents that they are asked to review.79 This decision arose from an appeal from theU.S. District Court for the Southern District of New York (D-SDNY), which held the Rhone-Poulenc Rorer (RPR) patent relating to methods of preparing Taxol (hereinafter referred to by its generic name paclitaxel) as well as claiming key intermediates in the paclitaxel synthesis to be unenforceable due to inequitable conduct. A brief review of the facts of the case is presented next. 

Saravanakumar G, Min KH et al (2009) Hydrotropic oligomer-conjugated glycol chitosan as a carrier of paclitaxel Synthesis, characterization, and in vivo biodistribution. J Control Release 140 210-217... 

By the so-called metal alkoxide paclitaxel synthesis, the yield via these stages was increased to 92%. [326] BMS obtained a hcence and started producing pach-taxel along this route at their plant in Swords, Ireland. 

Seligson AL, Terry RC, Bressi JC, Douglass JG III, Sovak M (2001) A New Prodrug of Paclitaxel Synthesis of Protaxel. Anti-Cancer Drugs 12 305... 

Scheme 2.15 On the formation of 3-azido-2-hydroxy-3-phenylpropionic acid ethyl ester as intermediate in the Paclitaxel synthesis ...

Synthesis of paclitaxel and resiniferatoxin analogs, diterpenoids with oxetane fragments 97G461. 

T. C. Boge, G. I. Georg, The medicinal chemistry of / -amino acids paclitaxel as an illustrative example in Enantioselective Synthesis of /3-amino acids, E. Juaristi (Ed.), Wiley-VCH, New York, 1997. 

Figure 4.48 Synthesis map showing starting materials used for the synthesis of paclitaxel (taxol).

Table 4.21 Summary of reaction metrics and synthesis tree parameters for paclitaxel (taxol) synthesis plans ranked according to overall kernel (maximum) RME. ...

Kanazawa, A.M., Denis, J.N., Greene, A.E. (1994) Direct, Stereoselective Synthesis ofthe Protected Paclitaxel (Taxol) Side Chain and High-Yield Transformation to Paclitaxel. Chemical Communications, 2591-2592. 

Takahashi and coworkers have used INOC for synthesis of the chiral CD rings paclitaxel, which is an antitumor agent. Synthetic strategy starting from 2-deoxy-D-ribose is demonstrated in Scheme 8.22.110 The precursor of INOC was prepared by 1,2-addition of a,(3-unsaturated ester to ketone. INOC and subsequent reductive cleavage by H2/Raney Ni afford the desired CD ring structure. 

V-bromo-benzamide is a useful method for the synthesis of the side chain of paclitaxel (taxol) from isopropyl cinnamate.219... 

Zakharian, T.Y., Seryshev, A., Sitharaman, B., Gilbert, B.E., Knight, V., and Wilson, L.J. (2005) A fullerene-paclitaxel chemotherapeutic synthesis, characterization, and study of biological activity in tissue culture./. Am. Chem. Soc. 127, 12508-12509. 

A fine example of such a semi-synthesis is the preparation of the anti-cancer drug paclitaxel (Taxol ), a relatively scarce compound from Taxus brevifolia. Here, the natural and better accessible 10-deacetylbaccatin III, isolated from the leaves of Taxus baccata, provides the complicated ring system of paclitaxel, including all substituents with the right stereostructure (Scheme 5.1). In just four reaction steps [5] paclitaxel is obtained from 10-deacetylbaccatin III. 

Many groups have employed a Diels-Alder strategy toward the synthesis of the well-known antitumor compound paclitaxel, which has a tetracyclic core containing two... 

---