A kind of purification method of everolimus

A purification method, everolimus technology, applied in the field of organic synthesis, can solve the problems of high cost and unfavorable industrial production

Active Publication Date: 2022-05-20
CHIA TAI TIANQING PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the crude product of everolimus prepared by the prior art, the raw material rapamycin and the 7-ring isomer of everolimus (the following structural formula) are the main impurities and silica gel column chromatography is also difficult to remove these two impurities. Most of the technology uses the method of preparative liquid phase for purification, and the product needs to be purified through multiple preparative liquid phases, and the cost of multiple preparative liquid phase purification is high, which is not conducive to industrial production

Method used

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  • A kind of purification method of everolimus
  • A kind of purification method of everolimus
  • A kind of purification method of everolimus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Embodiment 1: the preparation of compound 2

[0067]

[0068] Ethyl acetate (1.7 L) and rapamycin (140 g, compound 1) were sequentially added into the reaction flask and stirred to dissolve. Add imidazole (47g), lower the temperature to 0-5°C, start to add TMS-Cl (66.5g) dropwise, after dropping, control the reaction at 0-5°C for 0.5h, monitor by TLC until the reaction of raw materials is complete. Adjust dilute sulfuric acid to pH = 1, continue the reaction for 2.5 h, adjust to pH = 7 with imidazole, wash with saline, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and the concentrate is subjected to silica gel column chromatography (mobile phase conditions: ethyl acetate Ester / n-hexane gradient elution) to obtain off-white compound 2 (yield: 91%).

Embodiment 2

[0069] Embodiment 2: the preparation of compound 6

[0070]

[0071] 2,6-lutidine (72g), dichloromethane (320ml) and compound 3 (98.7g) were added to the reaction flask in sequence, and stirred evenly. Control temperature at -5~5℃ and add Tf dropwise 2 O / dichloromethane solution (174g / 95ml), dropwise until compound 3 reacts completely. Washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, the concentrate (compound 4, 172.6g) was dissolved in n-hexane (690ml), and 2,6-di-tert-butyl-4-methylpyridine (115g) and Compound 5 (138g), stirred at 50-60°C, reacted for 22h, and the reaction was complete. Purified by flash silica gel column and concentrated to obtain off-white compound 6 (yield 70%).

[0072] 13 C-NMR (CDCl 3 ,500MHz)δ:209.1,207.1,198.6,169.1,166.9,139.0,137.8,136.3,132.2,130.3,125.4,126.9,126.8,98.9,85.0,82.6,77.5,73.6,70.7,66.1,96.5, ,55.3,50.9,44.9,43.5,40.6,40.2,40.1,39.0,37.9,35.8,35.0,34.7,33.5,32.4,32.3,31.1,29.7,26.3,26.2,25.7,24...

Embodiment 3

[0074] Embodiment 3: Preparation of Everolimus 7

[0075]

[0076] Acetonitrile (220 mL) and compound 6 (22 g) were sequentially added into a 500 mL reaction flask, and stirred to dissolve. Slowly add 0.2mol / L hydrochloric acid (19.2ml) under temperature control at -10-0°C, and react for 0.5h after addition, and monitor by TLC until the reaction is complete. Add dichloromethane / purified water (220mL / 220mL) while controlling the temperature at -10-0°C, stir and separate the layers, and extract the aqueous phase with dichloromethane (106mL). The organic phases were combined, washed with purified water (220 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain solid everolimus 7 (20.4 g).

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Abstract

The present invention provides a purification method of everolimus. Everolimus is derivatized, separated, and then hydrolyzed, and the content of impurity rapamycin in the treated everolimus is greatly reduced. Further, the product with higher purity can be obtained at a higher yield through one-time preparation of liquid phase purification, thereby reducing the industrial cost of the purification step; the application further provides a preparation method of everolimus, which has a high yield and is easy to operate. Simple and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a derivatization method for purifying everolimus. Background technique [0002] Everolimus (trade name: afinitor) is a new generation of macrolide rapamycin derivative drug, developed by Novartis, for advanced renal cell carcinoma that has failed treatment with sunitinib or sorafenib ; It can supplement the immunosuppressive effect of the calcineurin inhibitor cyclosporine, and is used to prevent the rejection of heart or kidney transplantation; it is also one of the most commonly used drugs for drug-eluting stents at present, and has the following structural formula: [0003] [0004] In the crude product of everolimus prepared by the prior art, the raw material rapamycin and the 7-ring isomer of everolimus (structural formula is as follows) are the main impurities and silica gel column chromatography is also difficult to remove these two impurities. Most of the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/18C07F7/18
CPCC07D498/18
Inventor 张家松郭猛吴杨全陈克涛谭永华
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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