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A kind of preparation method of everolimus

A technology of everolimus and intermediates, applied in the field of preparation of everolimus, which can solve the problems of insufficient reaction, low total product yield, unstable properties, etc.

Active Publication Date: 2019-07-26
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Due to the large number of rapamycin reaction sites and unstable properties, in the above-mentioned preparation method of using rapamycin as a raw material to synthesize and prepare everolimus, the reaction needs to be controlled under milder conditions, usually the temperature is controlled at 50-60°C, if the temperature is too low, the reaction cannot be fully carried out; if the temperature is too high, rapamycin and its intermediates will easily degrade or generate other unknown impurities. If the reaction temperature is too low or too high, the total yield of the product will be lower Low
When the reaction temperature of the existing literature report scheme is effectively controlled at 50-60°C, more than 50% of rapamycin cannot effectively participate in the reaction

Method used

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  • A kind of preparation method of everolimus
  • A kind of preparation method of everolimus
  • A kind of preparation method of everolimus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: Preparation of Everolimus Intermediate 1:

[0029] Add 9g of rapamycin, 4.5g of 2,6-lutidine, and 100ml of tetrahydrofuran into a 250ml three-neck flask, cool down in an ice-salt water bath, stir to dissolve, and start to drop 7ml of (CH 3 ) 3 SiCl, heat preservation reaction, after 3 hours of reaction, TLC detects the reaction process, if there is no rapamycin spot, then the double protection reaction is completed, then add 5ml HCl dropwise, after 5 hours of reaction, TLC detection, if there is no double protection rapamycin spot, then The hydrolysis reaction is complete. The reaction solution was extracted with 200ml of ethyl acetate, and the ethyl acetate layer was extracted with 50ml of water, NaHCO 3 Wash with 50ml of saturated solution, then wash with 50ml of salt water, extract the aqueous layer twice with ethyl acetate, combine the organic layers, and anhydrous Na 2 SO 4 Drying; Ethyl acetate was evaporated under reduced pressure to obtain 9.6 ...

Embodiment 2

[0030] Embodiment 2: Preparation of Everolimus Intermediate 2

[0031] At 0-10°C, add 500ml of toluene to a 1L three-necked round-bottomed flask, then add 4.4g of ethylene oxide, after cooling down, add 9.6g of rapamycin intermediate 1 into the reaction solution, and add a small amount of hydrochloric acid at the same time, Continue to react for 6 hours, TLC monitors until the reaction is complete, water 250ml, NaHCO 3 Wash with 250ml of saturated solution, then wash with 250ml of salt water, extract the aqueous layer twice with toluene, combine the organic layers, and anhydrous Na 2 SO 4 Drying; toluene was evaporated under reduced pressure to obtain 6.8 g of pure everolimus intermediate 2.

Embodiment 3

[0032] Embodiment 3: Preparation of everolimus crude product

[0033] Dissolve 6.8g of the coupled product in 500ml of methanol in a 1L single-necked bottle, cool down in an ice-water bath, add 10ml of HCl dropwise after half an hour, react for 4 hours after the dropwise addition, and track and detect with TLC. After the reaction is completed, evaporate under reduced pressure Dry, then dissolve the residue with 500ml ethyl acetate, wash with saturated brine, extract the aqueous layer 3 times with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, evaporate to dryness under reduced pressure to obtain a yellow oil, and separate through the column to obtain the crude product 5.6g.

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Abstract

The invention discloses a method for preparing everolimus. The method includes the following steps that rapamycin and trimethylchlorosilane react so as to achieve double protection of hydroxyl groups in positions 31 and 40, and acidic hydrolysis is conducted to obtain an intermediate 1 with the protected hydroxyl group in the position 31; the intermediate 1 and ethylene oxide have a condensation reaction to obtain an intermediate 2, the intermediate 2 is subjected to acidic hydrolysis to obtain an everolimus crude product, and the crude product is separated and purified by means of a preparation liquid phase to obtain everolimus.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of everolimus. Background technique [0002] Everolimus (everolimus; trade name: Afinitor) chemical name [40-O-(2-hydroxyethyl)-rapamycin], is a new generation of macrolide rapamycin derivative drugs, structural formula as follows: [0003] [0004] Everolimus is a certain water-soluble derivative of rapamycin developed by Novartis, Switzerland. It can be administered orally. It 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. It is also used to treat advanced kidney cancer. It is also being studied in neuroendocrine tumors, lymphoma, other cancers, and tuberous sc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/18
Inventor 张贵民白文钦黄传青徐勇王增日
Owner SHANDONG NEWTIME PHARMA