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Methods of preparing and purifying 9-nitro-20-camptothecin

a technology of nitro-20-camptothecin and purification method, which is applied in the field of preparing and purifying 9nitro-20-camptothecin, can solve the problems of further decrease of 9nc yield and 60% yield, and achieve the effect of increasing the yield of 9-nitrocamptothecin

Inactive Publication Date: 2004-01-27
THE STEHLIN FOUND FOR CANCER RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

A feature of the present invention is to provide a method for the preparation of 9-nitrocamptothecin which preferably provides an increase in the yield of 9-nitrocamptothecin.

Problems solved by technology

Further, this procedure results in unwanted byproducts such as the inactive isomer, 12-nitrocamptothecin (12NC), in a ratio of about 1 to 3 of 9NC to 12NC.
The unwanted 12NC, unfortunately, is the major product and accounts for about 60% of the yield.
Because of the low yield of the 9NC and the numerous byproducts, the process of separating and purifying the 9NC is time consuming and costly and leads to a further decrease in the yield of 9NC.

Method used

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  • Methods of preparing and purifying 9-nitro-20-camptothecin
  • Methods of preparing and purifying 9-nitro-20-camptothecin
  • Methods of preparing and purifying 9-nitro-20-camptothecin

Examples

Experimental program
Comparison scheme
Effect test

example 1

Reaction of Camptothecin With KNO.sub.3 in Acetic Acid

To 30 ml acetic acid in a 100 ml round-bottomed flask equipped with a magnetic stirrer were added 0.50 g (0.0014 mol) 20(S)-camptothecin and 0.50 g KNO.sub.3 (0.0050 mol). The mixture was stirred at room temperature for 24 hours and poured onto 500 ml ice-water in several portions while stirring. The suspension was extracted three times with 200 ml methylene chloride each time (200 ml.times.3). The combined extracts were dried over 200 g anhydrous sodium sulfate for 6 hours. After removal of methylene chloride by a rotary evaporator, the residue was refluxed in petroleum ether for 4 hours. After filtration and drying in air for 4 hours the product obtained was a gray white powder. HPLC analysis showed no nitration indicative of camptothecin with KNO.sub.3 in acetic acid. The starting camptothecin was recovered 100% (Table 1).

example 2

Reaction of Camptothecin With KNO.sub.3 in Acetic Anhydride

Camptothecin was nitrated and worked-up in the same manner as the reaction in Example 1. The HPLC analysis of the reaction product showed 100% recovery of the starting camptothecin (Table 1).

example 3

Reaction of Camptothecin With KNO.sub.3 in Trifluoroacetic Anhydride

Camptothecin was nitrated and work-up in the same manner as in Example 1. The HPLC analysis data for the reaction mixture is shown in Table 1.

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Abstract

A method is disclosed for the preparation of 9-nitrocamptothecin which involves reacting 20-camptothecin with at least one inorganic nitrate salt and at least one acid effective in catalyzing the formation of a nitronium ion, where the reaction occurs at a temperature and for a time sufficient to form the 9-nitrocamptothecin. Also, methods of further purifying the 9-nitrocamptothecin by column chromatography or by reprecipitation is also disclosed.

Description

BACKGROUND OF THE INVENTION1. Field of the InventionThe present invention relates to method of preparing and purifying 9-nitro-20-camptothecin (9NC).2. Description of Related Art9-nitro-20(S)-camptothecin has shown great promise in treating certain types of cancer. The water-insoluble 9-nitro-20(S)-camptothecin has been studied both in vitro and in vivo and 9-nitro-20(S)-camptothecin is in clinical trials for certain types of cancer.Japanese Kokai Patent Application No. 59-51288 provides one method of making 9-nitro-camptothecin by treating camptothecin with a slight excess of concentrated nitric acid in concentrated sulfuric acid. However, when following this procedure, a yield of about 3% to about 7% of the 9NC product which is capable for medicinal use is obtained. Further, this procedure results in unwanted byproducts such as the inactive isomer, 12-nitrocamptothecin (12NC), in a ratio of about 1 to 3 of 9NC to 12NC. The following scheme shows the reaction from the use of nitric...

Claims

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Application Information

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IPC IPC(8): C07D491/22C07D491/00
CPCC07D491/22
Inventor CAO, ZHISONG
Owner THE STEHLIN FOUND FOR CANCER RES
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