A kind of synthetic method of everolimus

A synthesis method and intermediate technology, which are applied in the field of medicinal chemistry synthesis, can solve the problems of low product yield and the like, and achieve the effect of improving the overall yield

Active Publication Date: 2011-12-07
四川摩尔生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to overcome the shortcomings of the low product yield existing in the existing everolimus synthesis preparation, and to provide an improved everolimus synthesis method

Method used

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  • A kind of synthetic method of everolimus
  • A kind of synthetic method of everolimus
  • A kind of synthetic method of everolimus

Examples

Experimental program
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Effect test

Embodiment 1

[0052] The synthetic method of the everolimus of the present embodiment comprises the following steps:

[0053] (1) Preparation of everolimus intermediate 02:

[0054] In a 300mL multi-necked flask, weigh 10g of rapamycin under the condition of dryness and nitrogen protection, add it into 80mL of dichloromethane organic solvent, stir to dissolve, and then add 2,6-lutidine 10g, lower the temperature to -20°C, add 14g of trifluoromethanesulfonic anhydride dropwise and stir, after the dropwise addition, keep the reaction for 3h. HPLC detects reaction, when raw material reaction completes. 100 mL of saturated brine was added dropwise, the layers were extracted, and the organic layer was washed several times with 100 mL of saturated brine until nearly neutral, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10 g of everolimus intermediate 02. The yield of intermediate 02 was 87.4%.

[0055] (2) Preparation of everolimus intermediate 03:

...

Embodiment 2

[0061] The 31-hydroxyl of the raw material rapamycin in this embodiment is protected with dimethyl tert-butyl silyl ether, that is, the raw material is a kind of rapamycin derivative (31-TBDMS-pamycin). The synthetic method of everolimus comprises the following steps:

[0062] (1) Preparation of everolimus intermediate 02

[0063] In a 300mL multi-necked flask, under the condition of dry anhydrous and nitrogen protection, dissolve 11.25g of 31-TBDMS-pamycin in 80mL of dichloromethane, add 10g of 2,6-lutidine, and cool down to -20℃ , Add 14 g of trifluoromethanesulfonic anhydride dropwise, after the addition, keep the temperature for 3 h. HPLC detects that the reaction is complete. 100 mL of saturated brine was added dropwise, and the layers were extracted. The organic layer was washed with 100 mL of saturated brine several times until nearly neutral, and dried over anhydrous sodium sulfate. Concentration under reduced pressure yielded 12.1 g of everolimus intermediate 02. ...

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Abstract

The invention discloses a synthesis method of everolimus. The synthesis method of the everolimus comprises the following steps: based on rapamycin or a rapamycin derivative the 31-hydroxy of which is protected as a raw material, firstly carrying out a reaction on the raw material with triflic anhydride so as to obtain an intermediate 02; then carrying out a reaction on the intermediate 02 with mono-protected glycol so as to obtain an intermediate 03; and de-protecting the intermediate 03 so as to obtain the everolimus. In the process in the invention, the raw material can be fully converted into the intermediate 02 through reacting with triflic anhydride, and the intermediate 02 can be fully converted into the intermediate 03 through reacting with mono-protected glycol; and each step reaction can be fully carried out, and the total yield is greatly improved to above 50%.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a synthesis method of everolimus. Background technique [0002] Everolimus (trade name: Afinitor, structural formula I) is a new generation of macrolide rapamycin derivative drugs. The drug was developed by Novartis Corp. and first launched in Germany in 2004. It is now in clinical use in many countries. It is mainly used for 1) advanced renal cancer that is ineffective for other drugs; 2) it can supplement nerve calcium The immunosuppressive effect of protein inhibitor cyclosporine is used to prevent the rejection of heart or kidney transplantation; 3) drug stent administration is one of the most commonly used drugs for drug-eluting stents. [0003] [0004] WO9409010 first reported the use of rapamycin (Rapamycin, structural formula II, R 1 =H) A method for synthetically preparing everolimus as a raw material; the document J.labelled Compd Radioph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18
Inventor 蔡泽贵
Owner 四川摩尔生物制药有限公司
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