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New taxane derivative and preparation method thereof

A compound, the technology of triethylsilyl, is applied in the field of preparing the anti-tumor drug cabazitaxel, which can solve the problems of high cost, low yield, and many steps

Active Publication Date: 2012-04-11
SHANGHAI BIOMAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] It can be seen that according to the existing synthesis of cabazitaxel, there are many steps, the yield is low, and the cost is high

Method used

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  • New taxane derivative and preparation method thereof
  • New taxane derivative and preparation method thereof
  • New taxane derivative and preparation method thereof

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preparation example Construction

[0084] III. Preparation method of compound IV.

[0085] Compound IV can use compound V as a raw material (see Bioorganic & Medicinal Chemistry Letters, Volume 13, No. 11, 2419-2482.1993 for the synthesis method of compound V), and the trichloroethoxycarbonyl group in compound V can be selectively removed by zinc powder reduction. (Troc) Obtained.

[0086]

[0087] In the formula, R1 is a hydroxyl protecting group or hydrogen.

[0088] In existing literature reports, trichloroethoxycarbonyl (Troc) can be deprotected in the presence of zinc powder and acetic acid as a solvent. In the present invention, when R1 is stable under acetic acid conditions, this condition can be used to selectively remove the trichloroethoxycarbonyl (Troc), such as R1 is triethylsilyl, tert-butyldimethylsilyl (TBS) and tert-butyldiphenylsilyl. However, due to the presence of strong acid acetic acid, R1 will be removed in a small amount and partly, which will affect the yield of the reaction, and post-treatm...

Embodiment 1

[0121] Add 80ml of acetic acid and 12g of active zinc powder to a 100ml reaction flask, stir evenly, and after heating to 60-70°C, add 5g of 2'-TBS-7, 10-Troc-Docetaxel. After stirring the reaction for 5 hours, TLC showed that the reaction was complete. After the reaction, filter, add 80ml ethyl acetate and 80ml water to the filtrate. After separation, the organic phase is washed with water (50ml), saturated sodium bicarbonate (50ml×2), saturated sodium chloride (50ml), anhydrous sulfuric acid Sodium is dry. After filtering out the anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure to obtain a white solid, namely 2.5 g of 2'-TBS-docetaxel, with a yield of 81%.

[0122] MS (m / z): 972 (M+Na). 1 HNMR (500MHz) δ 0.31 (6H, m), 0.92 (9H, m), 1.13 (3H, s), 1.30 (12H, m), 1.72 (7H, m), 1.92 (4H, m), 2.18 ( 1H, m), 2.35 (1H, m), 2.61 (4H, m), 3.95 (1H, d), 4.21 (3H, m), 4.28 (1H, d), 4.54 (1H, s), 4.97 (1H) , D), 5.21 (1H, s), 5.27 (1H, m), 5.50 (1H, m), 5....

Embodiment 2

[0124] At 35~40℃, add 50ml methanol, 10g active zinc powder, 50ml water and 10g ammonium chloride into a 100ml reaction flask, stir well, add 5g 2'-TES-7, 10-Troc-Docetaxel . After stirring the reaction for 4 hours, TLC showed that the reaction was complete. After the reaction, filter, add 80ml ethyl acetate and 80ml water to the filtrate. After separation, the organic phase is washed with water (50ml), saturated sodium bicarbonate (50ml×2), saturated sodium chloride (50ml), anhydrous sulfuric acid Sodium is dry. After filtering out the anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure to obtain a white solid, namely 2.8 g of 2'-TES-docetaxel, with a yield of 90%.

[0125] MS (m / z): 972 (M+Na). 1 HNMR (500MHz) δ 0.39 (6H, m), 0.78 (9H, m), 1.13 (3H, s), 1.30 (12H, m), 1.72 (7H, m), 1.92 (4H, m), 2.18 ( 1H, m), 2.35 (1H, m), 2.61 (4H, m), 3.95 (1H, d), 4.21 (3H, m), 4.28 (1H, d), 4.54 (1H, s), 4.97 (1H) , D), 5.21 (1H, s), 5.27 (1H, m), 5.50 (1H, ...

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Abstract

The invention provides a new taxane derivative and a preparation method thereof as well as a method of preparing antitumor medicaments (cabazitaxel, docetaxel and taxol) by utilizing new taxane isoserine ester.

Description

Technical field [0001] The invention relates to the field of chemical synthesis and medicine. Specifically, the present invention relates to a new taxane isoserine ester and a preparation method thereof, and a method for further preparing the antitumor drug cabazitaxel. Background technique [0002] Cabazitaxel (cabazitaxel) is an anti-tumor drug, belonging to the taxanes, prepared semi-synthetically from the precursor extracted from yew. Cabazitaxel is a microtubule inhibitor that binds to microtubules and tubulin to promote the formation of microtubules while inhibiting their assembly and disassembly. This leads to the stabilization of microtubules, which is the result of cell function and inhibition during the intermittent phase. Cabazitaxel is suitable for use in combination with prednisone to treat patients with metastatic prostate cancer who have been refractory to treatments containing docetaxel. [0003] The chemical name of cabazitaxel: (2α, 5β, 7β, 10β, 13α)-4-acetoxy-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14
CPCC07D305/14
Inventor 郑云满许天惠
Owner SHANGHAI BIOMAN PHARMA
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