Unlock instant, AI-driven research and patent intelligence for your innovation.

Preparation method of everolimus and intermediate of everolimus

An intermediate and system technology, applied in the field of pharmaceutical synthesis, can solve the problems of difficult column chromatography of crude products, unfavorable industrial production, and many deprotection by-products, etc., and achieves the effects of high yield, convenient operation and simple purification.

Inactive Publication Date: 2015-04-01
连云港恒运药业有限公司
View PDF8 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patents WO9409010, WO2012103959A1 and CN102127092A report that the preparation method of everolimus uses hydrochloric acid as a deprotection reagent, see the following reaction formula, this method needs to add hydrochloric acid at 0°C, there are many deprotection by-products, and the crude product is difficult to chromatographically. Disadvantages such as low yield
Patent CN103848849A reports that using low-concentration hydrochloric acid or sulfuric acid as a deprotecting agent can obtain everolimus with a higher yield and purity, but the intermediate compound (II) needs to be purified, and the operation is complicated, which is not conducive to industrial production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of everolimus and intermediate of everolimus
  • Preparation method of everolimus and intermediate of everolimus
  • Preparation method of everolimus and intermediate of everolimus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Dissolve 17.5g of rapamycin and 0.8g of sodium hydroxide in acetonitrile (150ml), heat to 80°C, and add 28.27g of 2-(tert-butyldimethylsilyloxy)ethyl trifluoromethanesulfonate with stirring , reacted for 3 hours, concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain intermediate compound II with a yield of 89.3%.

Embodiment 2

[0030] Dissolve 18.3g of rapamycin and 0.8g of sodium hydroxide in N,N-dimethylformamide (150ml), heat to 80°C, stir and add 2-(tert-butyldimethyl 29.56 g of silyloxy)ethyl ester was reacted for 3 hours, concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain intermediate compound II with a yield of 81.2%.

Embodiment 3

[0032]

[0033] Add compound II (5.36g, 5mmol) into acetonitrile (100ml), keep the temperature at -10-5°C, add triethylamine trihydrogen trifluoride (11ml) to react for 7-8h, TLC detects that the reaction is basically complete, add bicarbonate Adjust the pH to 7-8 with sodium solution, extract with dichloromethane (100ml×3), combine the organic layers, wash with sodium chloride solution (300ml×2), dry the organic layer with anhydrous sodium sulfate, filter and concentrate, and concentrate the solid through Purified by preparative liquid chromatography to obtain compound I (white solid, 4.43 g), with a molar yield of 92.5%. HPLC: 99.56%. LC / MS(m / c)980.68(M+Na + ), after NMR structure analysis, it is determined that the product is compound I, and its collection of spectra is as follows figure 1 , figure 2 shown.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses preparation method of everolimus and an intermediate of everolimus and particularly relates to a preparation method of the medicine everolimus and the intermediate of the everolimus. The preparation method comprises the following step of carrying out reaction on a compound (II) in an organic solvent to prepare a target product in the presence of a deprotection system. The preparation method disclosed by the invention is safe, low in cost, high in yield and easy to purify and industrialize. The formula is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a low-cost, green and environment-friendly synthesis method of everolimus and its intermediates. Background technique [0002] 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. [0003] The pharmacokinetics of everolimus are superior to those of sirolimus. [0004] Everolimus was first developed by Novartis, Switzerland, and has dosage forms such as tablets and dispersible tablets. The trade name is Certican. It was launched in Sweden for the first time in 2003 and has fully occupied the European market in 2006. [0005] In addition, in addition to renal cell ca...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18C07F7/18
CPCC07D498/18C07F7/1804
Inventor 刘学良徐士伟仇伟强乔智涛王珍珍
Owner 连云港恒运药业有限公司