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The synthetic method of cabazitaxel

A technology of cabazitaxel and isoborneol, which is applied in the field of drug synthesis, can solve problems such as no description of the synthesis method of cabazitaxel, and achieve the effect of short steps and mild conditions

Active Publication Date: 2011-12-21
江苏宁录科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

To the best of our knowledge, there is no specific description of the synthetic method of cabazitaxel in the published literature

Method used

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  • The synthetic method of cabazitaxel
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  • The synthetic method of cabazitaxel

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preparation example Construction

[0024] The preparation method of cabazitaxel of the present invention, its synthetic theoretical analysis is as follows:

[0025]

[0026] Reaction scheme 2. Retrosynthesis analysis of cabazitaxel

[0027]From the retrosynthetic analysis (reaction formula 2), it can be seen that chiral β-lactam and 7,10-dimethoxy-10-baccatin III (7,10-dimethoxy-10-deacetylbaccatin III) are the most suitable for the synthesis of carbastatin Two key intermediates of race. Referring to literature method (Tetrahedron, 1992, 48, 6985-7012; 1996, 52, 209-224), we use Oppolzer reagent 1 As a chiral source, after five steps of reaction, (3R,4S)-β-lactam with 98% ee was obtained 5 (reaction formula 1). Oppolzer reagent 1 Can be recycled and reused.

Embodiment 1

[0030] one, (3R,4S)-1-(tert-butoxycarbonate group)-3-(tert-butyldimethylsilyloxy)-4-phenylazetidin-2-one ( 6 ) preparation:

[0031] Step 1: Isoborneol 1 (7.5g, 18.9 mmol), anhydrous pyridine (1.53 mL, 18.9 mmol) and DMAP (50 mg) were dissolved in anhydrous tetrahydrofuran (80 mL), cooled to 0°C in an ice-water bath, and chlorinated Acetyl chloride (1.50 mL, 18.9 mmol). The ice-water bath was removed and the reaction mixture was stirred at reflux for 16 hours. When the reaction mixture was cooled to room temperature, it was slowly poured into ice-cold saturated sodium bicarbonate solution (150 mL), and extracted with diethyl ether (4×100 mL). The combined ether extracts were washed with saturated copper sulfate solution (3×50 mL) and saturated brine (2×50 mL), respectively, and dried over anhydrous sodium sulfate. The crude product was separated by flash silica gel column chromatography (eluted with 10% ethyl acetate / n-hexane) to give isobornyl chloroacetate as a whi...

Embodiment 2

[0043] one, (3R,4S)-1-(tert-butoxycarbonate group)-3-(tert-butyldimethylsilyloxy)-4-phenylazetidin-2-one ( 6 ) preparation:

[0044] Step 1: Isoborneol 1 (7.5g, 18.9 mmol), anhydrous pyridine (1.53 mL, 18.9 mmol) and DMAP (50 mg) were dissolved in anhydrous tetrahydrofuran (80 mL), cooled to 0°C in an ice-water bath, and chlorinated Acetyl chloride (3.0 mL, 38 mmol). The ice-water bath was removed, and the reaction mixture was stirred at reflux for 15 hours. When the reaction mixture was cooled to room temperature, it was slowly poured into ice-cold saturated sodium bicarbonate solution (150 mL), and extracted with diethyl ether (4×100 mL). The combined ether extracts were washed with saturated copper sulfate solution (3×50 mL) and saturated brine (2×50 mL), respectively, and dried over anhydrous sodium sulfate. The crude product was separated by flash silica gel column chromatography (eluted with 10% ethyl acetate / n-hexane) to give isobornyl chloroacetate as a wh...

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Abstract

The invention discloses a method for synthesizing cabazitaxel, and belongs to the field of medicine synthesis. In the method, oppolzer reagent is used as a chiral source, and (3R,4S)-beta-lactam with optical purity ee of 98 percent is obtained by five steps. Under the action of a proper alkali, hydroxyls on C-7 and C-10 in 10-baccatine III are methylated selectively to form 7,10-dimethoxy-10-baccatine III in one step. Then beta-lactam is used to esterify the 7,10-dimethoxy-10-baccatine III under an alkaline condition, and then cabazitaxel with a purity of 99 percent can be obtained by a step of removing protective groups. In the synthesis method, the steps are short and the conditions are mild.

Description

Technical field: [0001] The invention relates to a method for synthesizing prostate cancer drug cabazitaxel, which belongs to the field of drug synthesis. Background technique: [0002] According to statistics from the American Cancer Society, prostate cancer accounts for a quarter of newly diagnosed cancer cases in the United States each year, and is the second leading cause of cancer death in American men, second only to lung cancer. About 220,000 prostate cancer patients were diagnosed in 2010, and more than 32,000 patients died from the disease. In Europe, the annual death toll is 27,000, but the global prostate cancer death toll far exceeds this figure. Because prostate cancer is usually diagnosed at a later age, the patient population is aging. Prostate cancer drug market prospects are very broad. Market research firm Decision Resources predicts that the market value of prostate cancer drugs will grow from nearly $4 billion in 2009 to $5.7 billion in 2014, and wil...

Claims

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Application Information

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IPC IPC(8): C07D305/14
CPCY02P20/55Y02P20/582
Inventor 孙小强陈新杨海涛缪春宝
Owner 江苏宁录科技股份有限公司
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