Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-03-26
1994-05-10
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549281, 549350, 560183, C07D31178, C07D32300, C07C 6973
Patent
active
053109465
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a new process for preparing cyclic peroxyacetal lactone, lactol or ether compounds.
BACKGROUND OF THE INVENTION
The present invention is particularly important in its application to the preparation of biologically active compounds comprising the cyclic peroxyacetal lactone or lactol functionalities.
One such biologically active compound is qinghaosu (Artemisinin) which has the following formula: ##STR1##
Qinghaosu is a potent antimalarial which has been successfully used to treat patients suffering from malaria. The reemergence of strains of malaria resistant to conventional (chloroquine) therapy is posing a worldwide problem, and indeed, there is no universally acceptable cure at the present time. Qinghaosu occurs to the extent of about 0.1 (dry weight) in an annual shrub, qinghao or (Artemisia annua), which grows in most provinces of China. Unfortunately, the world demand for qinghaosu far exceeds the supply, and there is considerable pressure to develop bioactive analogues, or to develop alternative sources for the compound. The compound has been prepared by total synthesis in the laboratory, but the structural complexity is such that no total laboratory synthesis has been economically feasible.
The Disclosure of the Invention
In one aspect, the invention provides a process for preparing a compound containing:
The process of the present invention can be carried out as a "one-pot" reaction, referred to as the direct method or by a series of steps, referred to as the indirect method.
In particular, the direct method involves oxygenation of a compound of formula ##STR2## in the presence of one or more oxidizing metal catalysts to give a compound of formula ##STR3## wherein n=1, 2 or 3 ##STR4## where R is H, alkyl, aryl or arylalkyl R.sup.1 are independently alkyl, aryl or each R.sup.1 together with the group --O--C--O-- to which they are attached form a cyclic acetal R.sup.2 and R.sup.3 are independently selected from H, optionally substituted alkyl, optionally substituted aryl, the optional substituents being selected from alkyl, aryl, halogen, OR, CF.sub.3, NO.sub.2, COR, NRR', SR, COOR, CONRR', SO.sub.3 R, SO.sub.2 NRR', SR, SOR and SO.sub.2 R, where R and R' are as defined for R above; SR", SOR", SO.sub.2 R" where R" is alkyl or aryl optionally substituted by one or more substitutents selected from alkyl, aryl, halogen, OR, CF.sub.3, NO.sub.2, COR, NRR', SR, COOR, CONRR', SO.sub.3 R, SO.sub.2 NRR', SR, SOR and SO.sub.2 R, where R and R' are as defined for R above; straight chain and X together with a substituent Y can also form a ring; one or more sustituents selected from alkyl, aryl, halogen, OR, CF.sub.3, NO.sub.2, COR, NRR', SR, COOR, CONRR', SO.sub.3 R, SO.sub.2 NRR', SR, SOR and SO.sub.2 R, where R and R' are as defined for R above; Y can be on the same C atom as the hydroperoxy group and any C atom may be disubstituted by Y and includes replacement of H atom(s) in "(CH.sub.2).sub.m " by Y; with the carbon atom to which they are attached form a keto group.
The direct method involves oxygenation of the hydroperoxy compound in the presence of one or more catalysts to undergo a new oxygenation-cleavage-cyclization reaction to give a cyclic peroxyacetal lactone, lactol or ether compound.
According to IUPAC nomenclature, acetals derived from acids, ketones, aldehydes are all called "acetals". However, it is common to name an acetal derived from a ketone, a "ketal". Thus, it is to be understood that the term "acetal" also includes within its scope acetals derived from ketones i.e. ketals.
The skilled addressee would understand that the process of the invention may result in one or more stereogenic (chiral) centres being formed resulting in stereoisomers. Thus, it is to be understood that the present invention includes within its scope the preparation of stereoisomers. The present invention also encompasses any isomers or mixtures thereof when prepared according to the present invention.
The Schematic Diagram (A) illustrates the process for the direct met
REFERENCES:
patent: 4992561 (1991-02-01), Roth et al.
"A simple Conversion of Artesmisinic Acid Into Artemisinin," Roth et al., Journal of Natural Products, vol. 52, pp. 1183-1185, Oct. 1989.
"A Short and Stereospecific Synthesis of (+)-Deoxoartemisinin and (-)-Deoxodesoxyartemisinin," Jung et al., Tetrahedron Ltrs., vol. 30, pp. 5973-5976, Nov. 1989.
"Catalysed Oxygenation of Allylic Hydroperoxides Derived From Qinghao . . . " Haynes et al., J. Chem. Soc. Commun., p. 451 Feb. 1990.
"Stereospecific Synthesis of (+)-Homodeoxoartemisinin," Heterocycles, vol. 29, No. 12, 1989, pp. 2273-2277.
"Artemisinic Acid: A Versatile Chiral Synthon and Bioprecursor to Natural Products," Jung et al., Planta Med. 56(1990), p. 624.
"A Concise and Stereoselective Synthesis of (+)-n-Butyldeoxoartemisinin," Jung et al., Synlett, 1990, pp. 743-744.
"The Development of New Peroxidic Antimalarials," Haynes et al., Chemistry in Australia, Mar. 1991, pp. 64-67.
"A Facile Semi-Synthesis of the Antimlarial Drug Qinghaosu," Roth et al., Journal of Chem. Education, pp. 612-613 Jul. 1991.
"A Concise Synthesis of 12-(3'-Hydroxy-n-Propyl)-Deoxoartemisinin," Jung et al. Bioorganic & Medicinal Chemistry Ltrs., 1991, vol. 1, No. 12, pp. 741-744.
"1,2-Dioxetanes as New Antimalarial Agents," Zaman et al., J. Chem. Soc. Chem. Commun., 1992, p. 329.
"Efficient Preparation of Novel Qinghaosu (Artemisinin) Derivatives," Haynes et al., Synlett, 1992.
"Practical Conversion of Artemisinic Acid into Deoxyartemisinin," Jung et al., J. Org. Chem., 1986, 51, No. 26, 1985, pp. 5417-5419.
"Total Synthesis of Arteanuuin (Qinghaosu) and Related Compounds," Zhou, Pure and Applied Chemistry, 58, No. 5, 1986, pp. 817-824.
Haynes Richard K.
Vonwiller Simone C.
Ivy C. Warren
Owens A. A.
Rhone-Poulenc Rorer S.A.
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