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Method for preparing paclitaxel by virtue of semi-synthesis

A technology of paclitaxel and compounds, applied in the field of semi-synthetic preparation of paclitaxel, which can solve the problems of long reaction time and many by-products, and achieve the effects of short reaction time, few reaction by-products and high yield

Inactive Publication Date: 2013-12-18
无锡紫杉药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the above-mentioned method of semi-synthesizing paclitaxel, the ring-opening deprotection all uses solvents such as ethyl acetate, methanol or ethanol, the reaction time is long, and there are many by-products

Method used

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  • Method for preparing paclitaxel by virtue of semi-synthesis
  • Method for preparing paclitaxel by virtue of semi-synthesis
  • Method for preparing paclitaxel by virtue of semi-synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] a, preparation of baccatin III (i.e. compound of formula II)

[0059] At room temperature, 300g10-DAB and 30g CeCl 3 .7H 2 O was added to 6L of tetrahydrofuran, and 700mL of acetic anhydride was added dropwise under stirring, and monitored by TLC. After 1.5 hours, the reaction was completed. Pour the reaction solution into ice water and let it stand until no white particles were precipitated, then suction filtered and dried to obtain the compound of formula II 305.1 g, the molar yield is 94.4%; molar yield = (actual molar amount of bacatin III formed / theoretical molar amount of baccatin III formed) × 100%.

[0060] Structural identification of the resulting compound:

[0061] LC-MS(ESI):587.3[M+H] + , elemental analysis: C63.46%, H6.52%, O30.02%

[0062] b. Preparation of 7-TES-baccatin III (i.e. compound of formula III)

[0063] At room temperature, dissolve 305.1g of baccatin III in 1200mL of N,N-dimethylformamide, stir and dissolve, add 152.6g of imidazole and 2...

Embodiment 2

[0075] a, preparation of baccatin III (i.e. compound of formula II)

[0076] At room temperature, 500g10-DAB and 25g CeCl 3 .7H 2 O was added to 6L tetrahydrofuran, 1000mL acetic anhydride was added dropwise under stirring, and monitored by TLC. After 2 hours, the reaction was completed. Pour the reaction solution into ice water and let it stand until no white particles were precipitated. Then, suction filtered and dried to obtain bacatine. III is 495.5g, and the molar yield is 92.0%; molar yield=(actual molar amount of bacatin III formed / theoretical molar amount of baccatin III formed)×100%.

[0077] b. Preparation of 7-TES-baccatin III (i.e. compound of formula III)

[0078] At room temperature, dissolve 495.5g of baccatin III in 1486mL of N,N-dimethylformamide, stir and dissolve, add 148.7g of imidazole and 297.3mL of triethylchlorosilane, monitor by TLC, and the reaction is complete after 3 hours. Add ice water to stop the reaction, extract with dichloromethane, wash th...

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Abstract

The invention discloses a method for preparing paclitaxel by virtue of semi-synthesis, and the method comprises the following steps: firstly, acetylizing the tenth hydroxyl of 10-DAB (Diaminobenzidine) in the presence of CeCl3.7H2O; secondly, protecting the seventh hydroxyl of the 10-DAB by use of triethylchlorosilane, performing condensation reaction on the tenth acetylized hydroxyl, a compound of which the seventh hydroxyl is protected and (4S,5R)-2,4-diphenyl-4,5-dihydrogen oxazole-5-carboxylic acid to obtain a paclitaxel precursor; finally, opening a side chain oxazole ring of the paclitaxel precursor, and synchronously removing the seventh trichloroacetic protecting group to obtain the paclitaxel. The method has high reaction yield and few byproducts, and is moderate in reaction condition, fast in reaction, simple and convenient in post treatment, and suitable for industries for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing paclitaxel by a semi-synthetic method. Background technique [0002] Paclitaxel (trade name Taxol) is a taxane diterpenoid isolated from Taxus plants. Its novel structure, unique anti-cancer mechanism, remarkable anti-cancer effect and broad anti-cancer spectrum are considered to be one of the best anti-cancer drugs discovered so far. After the United States, paclitaxel as a first-line anticancer drug has been approved for marketing in more than 40 countries. However, the lack of paclitaxel supply greatly limits its clinical application. At present, the main source of medicinal paclitaxel is to extract and isolate from the bark of the natural Taxus genus. However, due to the small number of plants in this genus, slow growth, low content, and rather difficult extraction, it is impossible to meet the growing clinical needs in the long run. [0003]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14
CPCY02P20/55
Inventor 龚喜高杰周理洁杨兵梁翩陆叶梦王琼喻琼林
Owner 无锡紫杉药业股份有限公司