Method of making asymmetric DE ring intermediates for the synthesis of camptothecin and camptothecin analogs
AssigneeNorth Carolina State University
InventorDaniel L. Comins
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Abstract
The present invention is directed towards new methods of making DE ring intermediates of Formula (III), ##STR1## wherein Y is H or halogen and R is loweralkyl, which in turn are useful in methods of making camptothecin and camptothecin analogs. The present invention also provides new compounds useful in the methods of making compounds of Formula (III).
Claims22
A method of making a compound of Formula (III) ##STR16## wherein R is loweralkyl, and Y is H or halogen;
- by hydrolyzing a compound of Formula (X) ##STR17## wherein R.sub.7 is loweralkoxy, R.sub.8 is loweralkoxy and the R.sub.9 moiety has a configuration that forces R and the --OH group of the compound (X) to take a first stereochemical orientation about the chiral carbon at position 7 by sterically hindering the formation of an opposite, second stereochemical orientation about the chiral carbon at position 7;
- in an aqueous solution under heat with an inorganic acid to yield the compound of Formula (III).
A method of making a compound of Formula (X) ##STR24## wherein Y is H or halogen, R is loweralkyl, R.sub.7 is loweralkoxy, R.sub.8 is loweralkoxy, and the R.sub.9 moiety has a configuration that forces R and the --OH group of the compound (X) to take a first stereochemical orientation about the chiral carbon at position 7 by sterically hindering the formation of an opposite, second stereochemical orientation about the chiral carbon at position 7;
- comprising reacting a compound of Formula (VIII) ##STR25## wherein Hal is halogen;
- with a base of the Formula A.sup.+ B.sup.-, wherein A.sup.+ is an inorganic cation, and B.sup.- is an organic anion, to form a first intermediate, then stereospecifically adding to the first intermediate, an .alpha.-ketoester of Formula (IX) ##STR26## at a temperature below 0.degree. C. to yield the compound of Formula (X).
A compound of Formula (X) ##STR29## wherein Y is H or halogen, R is loweralkyl, R.sub.7 is loweralkoxy, R.sub.8 is loweralkoxy, and the R.sub.9 moiety has a configuration that forces R and the --OH group of the compound (X) to take a first stereochemical orientation about the chiral carbon at position 7 by sterically hindering the formation of an opposite, second stereochemical orientation about the chiral carbon at position 7.
Dependencies are inferred from the claim text.