Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1998-05-14
2000-11-07
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
546 41, 546 48, C07D49122
Patent
active
06143891&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a method of preparing camptothecin and camptothecin analogs employing chemical compounds that are useful as intermediates and to processes for the preparation of the intermediates.
BACKGROUND OF THE INVENTION
Camptothecin is a naturally occurring compound, found in Camptotheca acuminata. Camptothecin and camptothecin analogs have been found to have anti-leukemic and anti-tumor properties.
Camptothecin and camptothecin analogs can be synthesized using processes described in U.S. Pat. No. 4,894,456 to Wall et al. issued Jan. 16, 1990; U.S. Pat. No. 4,399,282 to Miyasaka, et al. issued Aug. 16, 1983; U.S. Pat. No. 4,399,276 to Miyasaka, et al. issued Aug. 16, 1983; U.S. Pat. No. 4,943,579 to Vishnuvajjala, et al. issued Jul. 24, 1990; European Patent Application 0 321 122 A2 filed by SmithKline Becham Corporation, and published Jun. 21, 1989; U.S. Pat. No. 4,473,692 to Miyasaka, et al. issued Sep. 25, 1984; European Patent application No. 0 325 247 A2 filed by Kabushiki Kaisha Yakult Honsh, and published Jul. 26, 1989; European Patent application 0 556 585 A2 filed by Takeda Chemical Industries, and published Aug. 25, 1993; U.S. Pat. No. 4,981,968 to Wall, et al. issued Jan. 1, 1991; U.S. Pat. No. 5,049,668 to Wall, et al. issued Sep. 17, 1991; U.S. Pat. No. 5,162,532 to Comins, et al.; issued Nov. 10, 1992; U.S. Pat. No. 5,180,722 to Wall, et al. issued Jan. 19, 1993 and European Patent application 0 540 099 A1, filed by Glaxo Inc., and published May 5, 1993.
Previous methods used in the preparation of camptothecin and camptothecin analogs employ resolutions or chiral auxiliaries to obtain enantiomerically enriched intermediates. A problem with these methods is that a resolution necessitates discarding half of the racemic material and a chiral auxiliary requires utilizing stoichiometric amounts of a chiral subunit to stereoselectively install the chiral center.
A method which uses a process of catalytic asymmetric induction is described in U.S. patent application Ser. No. 08/237,081 and Fang et al., Journal of Organic Chemistry, 59(21), 6142-6143 (1994). One potential problem with such prior methods is that some of the chirally specific intermediates themselves may exhibit cell toxicity. Furthermore, the final step of the synthesis described in U.S. patent application Ser. No. 08/237,081, now U.S. Pat. No. 5,491,237, requires the use of a palladium catalyst which must subsequently be removed from the final drug substance by multiple recrystallizations. The potent cytotoxicity of camptothecin and some of its analogs requires that stringent safeguards be imposed during all the later steps of manufacturing to protect production personnel and the environment. Such safeguards increase the complexity and cost of manufacturing and handling camptothecin and its analogs.
An object of the present invention is a method for the preparation of camptothecin and its analogs wherein the chirality at the 20 position is not introduced until the penultimate manufacturing step. This would reduce the risk of accidental contamination of the environment and injury to the production worker, and hence, reduces the need for stringent safeguards, since handling and storage of highly biologically active material is minimized.
SUMMARY OF THE INVENTION
The present invention provides a method of preparing compounds of Formula (I) which comprises oxidizing compounds of Formula (II) ##STR2## wherein: R.sub.1 and R.sub.2, which may be the same or different, are independently selected from hydrogen, lower alkyl, (C.sub.3-7)cycloalkyl, (C.sub.3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, or alkoxy alkyl, or (--CH.sub.2 NR.sub.7 R.sub.8), wherein: independently selected from hydrogen, lower alkyl, (C.sub.3-7) cycloalkyl, (C.sub.3-7) cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, or lower alkoxy lower alkyl; or (C.sub.3-7) cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, or lower alkoxy lower alkyl, and R.sub.8 represents --COR.sub.9, )cycloa
REFERENCES:
Krohn et al., Chemical Abstracts, vol. 83, abstract 193573, 1975.
Herzberg, R.P., Journal of Medicinal Chemistry, vol. 32, No. 3, 1989, pp. 715-720, "Modification of the Hydroxy Lactone Ring of Camptothecin".
Chemical Abstracts Registry Handbook Number Section, 1992, pp. 4277ru, "See Compound with rn=143490-55-5".
S. Sawada, et al., Chemical Abstracts, vol. 117, No. 17, 1992, pp. 882, "Preparation of Camptothecin Derivatives as Anti-tumor Agents".
Fang, F.G. et al., Journal of Organic Chemistry, vol. 59, No. 21, 1994, pp. 6142-6143, "Catalytic Ennantioselective Synthesis of 20(S)-Camptothecin: A Practical Application of the Sharpless Asymmetric Dihydroxylation Reaction".
Krohn, K. et al., Chemische Berichte, vol. 108, 1975, pp. 3030-3042, "Alkylierung Von Campothecin-Vorstufen".
Fang Francis Gerard
Xie Shiping
Glaxo Wellcome Inc.
Lemanowicz John L.
Raymond Richard L.
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