Intermediates in pharmaceutical camptothecin preparation

#The present invention relates to novel chemical compounds that are useful as intermediates in the preparation of camptothecin and camptothecin-like compounds and to processes for their preparation.

#Useful camptothecin and camptothecin-like compounds that can be produced using intermediates and processes of the present Invention include compounds 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 Beckman 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 Honsha, 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. 5,180,722 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-like compounds 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 enantioselectively install the chiral center.

#The term "alkyl" as used herein means, a linear or branched alkyl group with from 1 to about 8 carbon atoms, such as, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, hexyl and octyl. The terms "halo" and "halogen" as used herein refers to a substituent which may be fluoro, chloro, bromo, or iodo. The term "triflate" as used herein refers to trifluoromethanesulphonate. The designation "C" as used herein means centigrade. The term "ambient temperature" as used herein means from about 20.degree. C. to about 30.degree. C.

#Compounds of the present Invention have 1 or more asymmetric carbon atoms that form enantiomeric arrangements, i.e., "R" and "S" configurations. The present Invention includes all enantiomeric forms and any combinations of these forms. For simplicity, where no specific configuration is depicted in the structural formulas, it is to be understood that both enantiomeric forms and mixtures thereof are represented. Unless noted otherwise, the nomenclature convention, "(R)" and "(S)" denote essentially optically pure R and S enantiomers respectively. Also included in the present Invention are other forms of the compounds including: solvates, hydrates, various polymorphs and the like.

#Acceptable salts include, but are not limited to salts with inorganic acids and bases such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or salts with organic acids such as acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, palmoate, salicylate, oxalic and stearate. For further examples of acceptable salts see, "Pharmaceutical Salts," J. Pharm. Sci., 66(1), 1 (1977).