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Preparation and purification method of everolimus intermediate

A purification method, the technology of everolimus, is applied in chemical instruments and methods, compounds of Group 4/14 elements of the periodic table, organic chemistry, etc., and can solve the problems of high equipment requirements, high operational risks, and high costs. Achieving the effect of simple operation and overcoming complex operation

Inactive Publication Date: 2018-05-18
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Patent 201010017955.X discloses a method for the preparation and purification of everolimus intermediates. In this method, rapamycin, diisopropylethylamine and 2-(tert-butyldiphenylsilyl)oxyethyltris The fluoromethanesulfonate was reacted in toluene at 50-60°C, and the intermediate was separated by column chromatography with a low yield of only 32%.
In addition, the post-processing of the patented intermediate is cumbersome and inconvenient in actual production, and the petroleum ether used in the column chromatography separation process has complex components, and there are no limit regulations and related detection methods. There are many inconveniences in the control and detection of residual solvents in production
[0006] In the prior art, some methods for preparing everolimus intermediates [Liu Mingxia and Ji Honghai, The improvement of the synthesis of everolimus. China Pharmaceutical Industry Journal, 2016 (02): pp. 140-157.], the yield Although it is relatively high, trifluoromethanesulfonic anhydride needs to be used, which is not only expensive, but also a highly corrosive and flammable compound, with high operational risk and high equipment requirements
[0007] Therefore, there is an urgent need for a reaction solution treatment and purification method of an everolimus intermediate, which solves the cumbersome post-treatment of the intermediate reaction solution and simultaneously avoids the problem that petroleum ether is required for column chromatography

Method used

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  • Preparation and purification method of everolimus intermediate
  • Preparation and purification method of everolimus intermediate
  • Preparation and purification method of everolimus intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0027] In a 100ml single-necked flask, add 5.00g of rapamycin and 14.18g of 2-(tert-butyldiphenylsilyl)oxyethyl trifluoromethanesulfonate, then add 40ml of toluene solvent, room temperature Stirring, the solution is a milky white suspension. Then add 3.53g of 2,6-lutidine, heat up and stir, control the temperature between 60°C and 70°C, and react for 6 hours. After cooling to room temperature, the reaction solution was a light yellow suspension solution. The solid residue in the reaction solution was removed by filtration to obtain a pale yellow clear toluene solution. Wet loading column chromatography, eluted in three gradients: first use n-hexane as the eluent until the eluent TLC has no toluene absorption point, the volume of the eluent n-hexane used in this gradient and the raw material rapamycin The weight ratio is 100-250mL / g; then the mixed liquid C 1 As the eluent, collect the TLC eluate containing only everolimus intermediate 1 to obtain the intermediate component,...

Embodiment 2

[0033] In a 100ml single-necked flask, add 5.00g of rapamycin and 14.18g of 2-(tert-butyldiphenylsilyl)oxyethyl trifluoromethanesulfonate, then add 40ml of toluene solvent, room temperature Stirring, the solution is a milky white suspension. Then add 3.53g of 2,6-lutidine, heat up and stir, control the temperature between 60°C and 70°C, and react for 6 hours. After cooling to room temperature, the reaction solution was a light yellow suspension solution. The solid residue in the reaction solution was removed by filtration to obtain a pale yellow clear toluene solution. Wet loading column chromatography, as the elution conditions shown in Table 2, first separate and elute toluene with eluent n-heptane, and then use eluent n-heptane and ethyl acetate (volume ratio 4:1) , separate and collect the intermediate components, and then use ethyl acetate as the eluent to recover unreacted rapamycin raw material components. The specific elution conditions are shown in Table 2.

[003...

Embodiment 3

[0039] In a 100ml single-necked flask, respectively add 5.00g of rapamycin and 14.18g of 2-(tert-butyldiphenylsilyl)oxyethyl trifluoromethanesulfonate, then add 40ml of toluene solvent, Stirring at room temperature, the solution was a milky white suspension. Then add 3.53g of 2,6-lutidine, heat up and stir, control the temperature between 60°C and 70°C, and react for 6 hours. After cooling to room temperature, the reaction solution was a light yellow suspension solution. The solid residue in the reaction solution was removed by filtration to obtain a pale yellow clear toluene solution. Wet loading column chromatography, first use the eluent as methyl tert-butyl ether to separate and elute toluene, then use the eluent methyl tert-butyl ether and ethyl acetate (volume ratio 15:1), separate and collect Intermediate components, and then use ethyl acetate as the eluent to recover unreacted rapamycin raw material components. The specific elution conditions are shown in Table 3. ...

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Abstract

The invention discloses a purification method of an everolimus intermediate. The method specifically includes: (1) reacting rapamycin with 2-(tert-butyl diphenylsilyl)oxyethyl trifluoromethanesulfonate to obtain a reaction solution containing an everolimus intermediate shown as formula I; and (2) filtering the everolimus intermediate reaction solution and conducting column chromatography. Specifically, the eluant for column chromatography is successively a small polar organic solvent and a mixed solvent of small polar organic solvent and ethyl acetate, wherein the small polar organic solvent is n-hexane, n-heptane, cyclohexane or methyl tert-butyl ether. After elution by the method of step (2), the mixture of ethyl acetate and small polar organic solvent is adopted as the eluant, and separation is carried out to obtain unreacted rapamycin. The method provided by the invention solves the problems of tedious post-treatment of the everolimus intermediate reaction solution and the need ofcolumn chromatography for petroleum ether.

Description

technical field [0001] The invention relates to a method for preparing and purifying an everolimus intermediate, belonging to the field of medicine and chemical industry. Background technique [0002] Everolimus is also known as ivermectin. Everolimus is mainly used clinically to prevent rejection after kidney transplantation and heart transplantation. Its mechanism of action mainly includes immunosuppressive effect, antitumor effect, antiviral effect and vascular protection effect. It is often used in combination with other immunosuppressants such as cyclosporine to reduce toxicity. Everolimus is also being studied in neuroendocrine tumors, lymphoma, other cancers, and tuberous sclerosis, either as a single agent or in combination with existing cancer treatments. As an investigational drug, the safety and efficacy of everolimus has not been fully established in the field of oncology, and it is now in the stage of clinical trials under strict control and monitoring. Ever...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18C07F7/20
CPCC07F7/1892C07F7/20
Inventor 匡通滔谭杰阳
Owner HINOVA PHARM INC
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