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Preparation for paclitaxel and derivatives thereof

A derivative, paclitaxel technology, applied in the field of preparation of paclitaxel and its derivatives, can solve problems that are not involved

Active Publication Date: 2008-10-01
ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in its research work, the 2'-O-acetyl-paclitaxel mentioned in the present invention is not involved as a raw material, and the selective hydrolysis of the C (2') acetyl group obtains the problem of paclitaxel

Method used

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  • Preparation for paclitaxel and derivatives thereof
  • Preparation for paclitaxel and derivatives thereof
  • Preparation for paclitaxel and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 Preparation of Paclitaxel by Catalytic Acetylation of 10-Deacetyl-Paclitaxel Using Various IIIB Metal Element Salts

[0054] Weigh 10-deacetyl-paclitaxel (content 62%, LC-MS spectrogram see figure 1 ) sample 100mg was dissolved in 1ml reaction solvent, and the salt of metal elements of group IIIB of catalytic equivalent was added, and after mixing well, about 3 equivalents of acetic anhydride was slowly added dropwise, stirred at room temperature, and TLC detected that 10-deacetyl-paclitaxel was completely converted 2'-O-acetyl-paclitaxel (LC-MS spectrum see figure 2 ), add 1ml saturated NaHCO 3 The solution was extinguished, and then the reaction was moved to an ice-water bath (0° C.), and 1 ml of 30% hydrogen peroxide was slowly added dropwise. After 1.5 h, TLC detected that the reaction was complete. After the reaction, the feed liquid was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and vacuum rotary evaporated to obtain paclitaxel...

Embodiment 2

[0057] Example 2 Preparation of paclitaxel from 10-deacetyl-paclitaxel by various hydrolysis methods

[0058] Weigh 10-deacetyl-paclitaxel (content 62%, LC-MS spectrogram see figure 1 ) sample 100mg was dissolved in 1ml reaction solvent, and catalytic equivalent of cerium chloride was added, after mixing well, about 3 equivalents of acetic anhydride was slowly added dropwise, after stirring at room temperature for 2 hours, 1ml of water was added to extinguish the reaction, and then an appropriate amount of over Oxides and alkaline substances react at room temperature, and TLC detects that the reaction is complete. After the reaction, the feed liquid was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and vacuum rotary evaporated to obtain paclitaxel (see the LC-MS spectrogram image 3 ). Various reaction solvents, peroxides, alkaline substances and their corresponding dosages, reaction time and the yield of the target product paclitaxel are shown in Table ...

Embodiment 3

[0062] Example 3 "One-pot method" to prepare cephalomannine from 10-deacetyl-cephalomannine

[0063] Weigh 10-deacetyl-cephalomannine (content 85%, LC-MS spectrogram see Figure 4 ) sample 500mg, dissolved in 3ml tetrahydrofuran, added 0.05g lanthanum nitrate and mixed thoroughly, slowly added dropwise 0.25ml acetic anhydride, reacted at -78°C (dry ice-ethanol) for 3 hours, after heating to 0°C, added saturated NaHCO3 The reaction was quenched with 2ml of the solution, and then 200mg of mCPBA was added. After 3 hours, TLC detected that the reaction was complete. After the reaction, the feed liquid was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and 0.47g white solid was obtained by rotary evaporation in vacuo, which was purified by silica gel column chromatography to obtain 0.39g cephalomannine (content 90%, yield 78.5 %, LC-MS spectrum see Figure 5 ).

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Abstract

The invention relates to a 'one-pot' method which is suitable for industrial application, which is used for preparing taxol and derivatives thereof. The method adopts 10-deacetyl- taxane compounds simultaneously containing hydroxyls at the sites of C(2') and C(10) as raw material; under the catalytic function of metal element salt, by using acetic oxide, the hydroxyls at the sites C(2') and C(10) are selectively acetylated, and then peroxidate and alkaline matter are added into the reaction system; the acetyl is selectively hydrolyzed at the site of C(2'), thereby obtaining the taxane compounds with acetylated hydroxyl at C(10) site.

Description

Technical field: [0001] The invention relates to a "one-pot method" suitable for industrial application, which is used for preparing paclitaxel and its derivatives. Especially related to 10-deacetyl-taxane compounds as raw materials, the reaction of selective acetylation of C (2') and C (10) hydroxyl groups, the reaction of selective hydrolysis of C (2') acetyl groups, The two-step reaction is placed in the same reaction system, and the "one-pot" synthesis is carried out to obtain the taxane compound with hydroxyacetylation at the C(10) position. Background technique: [0002] Paclitaxel (Formula IV, 1) and Docetaxel (Formula V) are currently used as first-line clinical drugs and are widely used in the treatment of different types of tumors. [0003] [0004] Formula IV paclitaxel and 10-desacetyl-paclitaxel Formula V docetaxel [0005] A large number of 10-deacetyl-taxane compounds, such as 10-deacetyl-taxol (formula IV, 2), can be obtained by means of taxus plant extr...

Claims

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Application Information

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IPC IPC(8): C07D305/14
CPCC07D305/14
Inventor 杨凌张延延葛广波
Owner ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI
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