Claims
- 1. A process for the asymmetric synthesis of camptothecin analogues comprising:
- a) forming a chiral cis dioxolanone having a diester function, of the absolute configuration desired in the camptothecin analogue;
- b) converting said cis dioxolanone to form a compound of Formula (I) ##STR38## wherein X is selected from a group consisting of a good leaving group, a cyano group, a carboxylic acid, and an N-aryl carboxylic amide derivative of Formula (A); ##STR39## c) converting said compound of Formula (I) into a compound of Formula (II) ##STR40## wherein: R is propargyl or substituted propargyl of Formula (B) ##STR41## and Y is selected from a group consisting of a good leaving group, a cyano group, carboxylic acid, and N-aryl carboxylic amide derivative of Formula (A); and
- d) converting said compound of Formula (II) into a camptothecin analogue.
- 2. A process according to claim 1 wherein step a) further comprises the step of Michael addition of an enolate of a dioxolanone to diethyl glutonate to form said cis dioxolanone having a diester function.
- 3. A process according to claim 1 wherein step b) further comprises the following steps:
- 1) hydrolysis of said diester function of said cis dioxolanone followed by ring closure to form a corresponding glutarimide; and
- 2) treatment of said glutarimide with an excess of a thionyl halide in dimethylformamide; followed by workup in aqueous base to form a compound of Formula (I) wherein X is bromide or iodide.
- 4. A process according to claim 3 wherein said thionyl halide is thionyl bromide and said compound of Formula (I) is the compound wherein X is bromide.
- 5. A process according to claim 1 wherein step b) further comprises the steps of:
- 1) hydrolysis of said diester function of said cis dioxolanone followed by ring closure to form a corresponding glutarimide; and
- 2) treatment of said glutarimide with an excess of a sulfonylating agent in dimethylformamide to give a compound of Formula (I) wherein X is a sulfonate.
- 6. A process according to claim 5 wherein said compound of Formula (I) is a compound wherein X is selected from the group consisting of p-fluorobenzenesulfonate, trifluoromethanesulfonate and fluorosulfonate.
- 7. A process according to claim 6 wherein said compound of Formula (I) is the compound wherein X is trifluoromethanesulfonate.
- 8. A process according to claim 1 wherein said step c) further comprises the steps of:
- 1) formation of a compound of Formula (I) wherein X is cyano;
- 2) alkylation of the pyridone ring nitrogen of said compound in step 1 ) with propargyl bromide followed by hydrolysis to form a compound of Formula (II) wherein R is propargyl and Y is a carboxylic acid; and
- 3) coupling said carboxylic acid function of said compound of Formula (II) in step 2) with p-aniside to from a compound of Formula (II) wherein Y is an N-aryl carboxylic amide derivative of Formula (A).
Parent Case Info
This is a divisional of application Ser. No. 08/075,063, filed Jun. 10, 1993 now U.S. Pat. No. 5,405,963.
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5258516 |
Comins et al. |
Nov 1993 |
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Divisions (1)
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Number |
Date |
Country |
Parent |
75063 |
Jun 1993 |
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