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Process for preparing 17-allyl amino geldanamycin (17-AAG) and other ansamycins

A technology of 17-AAG and angiomycin is applied in the field of preparing 17-allylaminogeldanamycin (17-AAG) and other ansamycins, and can solve the problems of instability, low yield, Low purity, etc.

Inactive Publication Date: 2008-07-30
CONFORMAL THERAPEUTICS CORP (US)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The purpose of the present invention is to improve one or more deficiencies in the prior art, for example, to improve one or more of the following problems, namely, low yield, low purity, instability, problems associated with the use of halogenated organic solvents Environmental toxicity, and additional incidental costs such as time, expense, waste disposal, and health risks, etc.

Method used

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  • Process for preparing 17-allyl amino geldanamycin (17-AAG) and other ansamycins
  • Process for preparing 17-allyl amino geldanamycin (17-AAG) and other ansamycins
  • Process for preparing 17-allyl amino geldanamycin (17-AAG) and other ansamycins

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Synthesis of 17-allylaminogeldanamycin (17-AAG)

[0082] Put 45.0g (80.4mmol) of Geldanamycin in a 2L dry flask with 1.45L of dry THF, add 36.0mL (470mmol) of allylamine dropwise to it for more than 30 minutes, wherein the allylamine Place in 50 mL of dry THF. The reaction mixture was stirred at room temperature under nitrogen protection for 4 hours until TLC analysis showed that the reaction was complete [(GDM: bright yellow: Rf=0.40; (5%MeOH-95%CHCl 3 ); 17-AAG: purple: Rf = 0.42 (5% MeOH-95% CHCl 3 )]. The solvent was removed by rotary evaporation, and the crude product was mixed with 420 mL H at 25 °C 2 O:EtOH (90:10) was mixed, then filtered, and dried at 45 °C for 24 hours to obtain 40.9 g (66.4 mmol) of purple crystal 17-AAG (82.6% yield, purity >98% at 254 nm by HPLC monitoring) . MP 206-212°C. 1 The results obtained by H NMR and HPLC were consistent with that of the desired product.

Embodiment 2

[0084] 17-AAG crystallized in isopropanol

[0085] An alternative method of purification is instead crystallization in ethanol, but dissolving the crude product 17-AAG from Example 1 in 800 mL of 2-propanol (isopropanol) at 80°C or at reflux (about 82.2°C), and then Cool to room temperature. Filtration, followed by drying at 45° C. for 24 hours gave 44.6 g (72.36 mmol) of purple crystals of 17-AAG (90% yield, purity >99% at 254 nm by HPLC monitoring). MP 147-153°C. 1 The results obtained by H NMR and HPLC were consistent with that of the desired product.

Embodiment 3

[0087] Ethanol Washing of the 17-AAG Polymorph of Example 2

[0088] An optional method of purification is in 400 mL of H 2 The product 17-AAG in Example 2 was mixed in O:EtOH (90:10) at 25°C, filtered, and dried at 45°C for 24 hours to obtain 42.4 g (68.6 mmol) of purple crystals of 17-AAG (95% Yield, purity >99% at 254 nm monitored by HPLC). MP 147-153°C. 1 The results obtained by H NMR and HPLC were consistent with that of the desired product.

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Abstract

Efficient chemical processes for preparing high yields, purities, and different polymorphic forms of 17-allyl amino geldanamycin (17-AAG) and other ansamycins are described and claimed.

Description

[0001] This application is a divisional case of the invention patent application No. 02818718.0 filed on September 18, 2002, entitled "Methods for the Preparation of 17-allylaminogeldanamycin (17-AAG) and Other Hapnomycins" Application. [0002] related application [0003] This application claims priority to U.S. Provisional Application No. 60 / 331,893, filed September 21, 2001 by Zhang et al., and U.S. Provisional Application No. 60 / 326,639, filed September 24, 2001 by Zhang et al. Both headings are "Methods for the Preparation of 17-Allylaminogeldanamycin (17-AAG) and Other Hapnomycins," which are hereby incorporated by reference in their entirety, including all figures and diagrams. technical field [0004] The present invention relates to the application of chemical preparation methods to the preparation of haptomycin compounds which are useful as antibiotics and in the treatment of various proliferative diseases such as cancer. Background technique [0005] Included i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D225/06C07D225/04A61K31/395A61P31/00A61P35/00
Inventor 张琳马库斯·F·贝姆西埃德·塞加
Owner CONFORMAL THERAPEUTICS CORP (US)
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