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Preparation method of everolimus

A technology of everolimus and compounds, applied in the field of preparation of everolimus, can solve the problems of unsuitability for actual production and application, low yield, poor repeatability, etc., achieve stable reaction, high yield, and short synthetic route Effect

Inactive Publication Date: 2012-11-21
SHANGHAI SHYNDEC PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The disadvantage of this synthetic method is that the repeatability of the reaction is poor, the yield is low, only about 5%, and it is not suitable for actual production and application.

Method used

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  • Preparation method of everolimus
  • Preparation method of everolimus
  • Preparation method of everolimus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add tert-butyldimethylhydroxyethoxysilane (1.00g, 5.67mmol) and 2,6-lutidine (0.90g, 8.40mmol) into 15.00ml of dichloromethane, at 0°C under nitrogen protection Next, trifluoromethanesulfonic anhydride (1.76g, 6.23mmol) was added and reacted for 3 hours to obtain compound II-1 (1.50g).

[0023]

[0024] MS (m / z): 309.28 [M+H] + , 1 HNMR (CDCl 3 ): δ4.53(m,2H);3.92(m,2H);0.90(s,9H);0.09(s,6H).

Embodiment 2

[0026] Add tert-butyldimethylhydroxyethoxysilane (1.00g, 5.67mmol) and 2,6-lutidine (0.90g, 8.40mmol) into 15.00ml of dichloromethane, at -10°C under nitrogen protection In this case, trifluoromethanesulfonic anhydride (1.76 g, 6.23 mmol) was added, and compound II-1 (1.50 g) was obtained after 4 hours of reaction.

Embodiment 3

[0028] Add rapamycin (1.00g, 1.09mmol) and potassium carbonate (1.20g, 8.68mmol) into 10.00ml acetone and stir, then add compound Ⅱ-1 (2.70g, 8.76mmol) and react at room temperature for 6 hours to obtain the compound B-1 (0.35g).

[0029]

[0030] MS (m / z): 1094.75 [M+Na] + , 1 HNMR was identical to the product described in Example 8-a of US5665772.

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Abstract

The invention belongs to the technical field of the preparation method of everolimus. The preparation method of everolimus provided by the invention comprises the steps as follows: 1) adding Trifluoromethanesulfonic anhydride into an alkaline organic solution of tert butyl dimethyl hydroxyl ethoxy silane under the protection of nitrogen to obtain a compound II through a reaction; 2) adding the compound II into an alkaline organic solution of a compound A to obtain a compound B through a reaction; and 3) reacting the compound B in a solvent with an acid to obtain the everolimus. The synthesis method provided by the invention has advantages of short synthetic route, high yield, simple operation, stable reaction and low cost, and is suitable for application to industrialized production.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of everolimus. Background technique [0002] Everolimus is a water-soluble derivative of rapamycin developed by Novartis, Switzerland, which can be administered orally. It is mainly used as an antineoplastic drug, immunomodulator, and immunosuppressant. The in vitro immunosuppressive activity of everolimus is 1 / 3 of that of rapamycin, but it is equivalent to rapamycin in vivo. It has been approved by the European EMEA and the US FDA in August 2008 and March 2009, respectively , for the treatment of patients with advanced renal cell carcinoma. At the same time, everolimus has the effect of inhibiting the proliferation of vascular endothelial cells, and has been approved as a coating drug for drug stents. The XINECEV stent developed by Abbott Company with everolimus as a coating drug has been used as a drug for coronary artery disease in 2006. The treatment is marketed in Europe and As...

Claims

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Application Information

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IPC IPC(8): C07D498/18
CPCY02P20/55
Inventor 杨智亮王国平侯建
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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