Method for preparing taxane natural product

A technology of natural products and taxanes, which is applied in the field of preparation of taxanes natural products, can solve the problems of low yield and achieve the effect of high yield and high availability

Active Publication Date: 2019-11-05
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

[0010] However, when the above scheme I and scheme II carry out the cross-protection of 7,10 and 2' hydroxyl groups, each step reaction has obvious by-products, and the yield is low

Method used

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  • Method for preparing taxane natural product
  • Method for preparing taxane natural product
  • Method for preparing taxane natural product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Step S1: Dissolve 7,10-Di-Troc-docetaxel (2.3g) in 14ml of formic acid and stir the reaction at room temperature (16°C). The sodium solution was neutralized until no bubbles were generated, the liquid was extracted and separated, and the organic phase was collected and concentrated to obtain 1.8 g of product I.

[0041] Step S2: Dissolve the product I (1.8g) in 6ml of DMF, add 2-methylimidazole (0.3g), stir in an ice bath to dissolve, slowly add TesCl (0.3g) dropwise, and continue the reaction for 60min after the dropwise addition , add 5ml of water to quench the reaction, extract with ethyl acetate, wash the organic phase three times with water, and concentrate to obtain 1.8g of product II.

[0042] Step S3: Dissolve the product II (1.8g) in 18ml of dichloromethane, add tigelic acid (0.18g) and DMAP (0.02g), add DIC (0.8ml) dropwise under stirring, and react at room temperature (15°C) 2h. After the reaction, the reaction liquid was suction filtered, the filtrate was ...

Embodiment 2

[0049] Step S1: Dissolve 7,10-Di-Troc-docetaxel (5.0g) in 50ml of formic acid, and stir the reaction at 25°C. After reacting for 1h, add 50ml of dichloromethane to dilute, and dilute with saturated sodium bicarbonate solution And until no bubbles are produced, the liquid is extracted and separated, and the organic phase is collected and concentrated to obtain 3.8g of product I.

[0050] Step S2: Dissolve the product I (3.8g) in 12ml of DMF, add 2-methylimidazole (0.87g), stir in an ice bath to dissolve, slowly add TesCl (1.0g) dropwise, and continue the reaction for 15min after the dropwise addition , add 5ml of water to quench the reaction, extract with ethyl acetate, wash the organic phase three times with water, and concentrate to obtain 3.9g of product II.

[0051] Step S3: Dissolve the product II (3.9g) in 40ml of dichloromethane, add tigelic acid (0.66g) and DMAP (0.19g), add DIC (2.3ml) dropwise under stirring, and react at 25°C for 1.5h. After the reaction, the reacti...

Embodiment 3

[0054] Step S1: Dissolve 7,10-Di-Troc-docetaxel (31.0g) in 240ml of formic acid and stir the reaction at room temperature (18°C). The sodium hydrogen solution was neutralized until no bubbles were generated, the liquid was extracted and separated, and the organic phase was collected and concentrated to obtain 25.3 g of product I.

[0055] Step S2: Dissolve the product I (25.3g) in 75ml DMF, add 2-methylimidazole (5.0g), stir in an ice bath to dissolve, slowly add TesCl (6.0g) dropwise, and continue the reaction for 45min after the dropwise addition , add 100ml of water to quench the reaction, extract with ethyl acetate, wash the organic phase with water three times, and concentrate to obtain 24.6g of product II.

[0056] Step S3: Dissolve the product II (24.6g) in 250ml of dichloromethane, add tigelic acid (3.5g) and DMAP (1.0g), add DIC (12ml) dropwise under stirring, and react at room temperature 20°C for 1h. After the reaction, the reaction liquid was suction filtered, the...

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Abstract

The invention discloses a method for preparing a taxane natural product. The taxane natural product is 10-deacetyl cephalomannine. The method includes the steps that 7,10-Di-Troc-docetaxel is dissolved in formic acid, dichloromethane is added for dilution after a reaction is completed, a sodium bicarbonate solution is adopted for neutralization until no bubbles are formed, extraction and liquid separation are carried out, and an organic phase is collected and concentrated to obtain a product I; the product I is dissolved in DMF, 2-methylimidazole is added, TesCl is added dropwise slowly, aftera reaction is completed, water is added for quenching the reaction, ethyl acetate is adopted for extraction, and the organic phase is washed with water and concentrated to obtain a product II; the product II is dissolved in the dichloromethane, tiglic acid and DMAP are added, DIC is added dropwise, after a reaction is completed, a reaction solution is subjected to suction filtration, and a filtrate is diluted with the dichloromethane, washed with water and then concentrated to obtain a product III; the product III is subjected to a concentration process twice, purified by column chromatography, concentrated and dried to obtain the 10-deacetyl cephalomannin. No obvious by-products are generated in each step, the yield is high, the product purity is high, preparation processes of starting materials are mature, the starting materials are easy to obtain, and massive taxane natural products can be prepared.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation method of a taxane natural product (10-deacetyl cephalomannine). Background technique [0002] The literature Deacetylation of paclitaxel and other taxanes (Zheng Q Y, Darbie LG, Cheng X, et al..Tetrahedron Letters, 1995, 36(12): 2001-2004.) reported that the 10-position was removed using cephalomannine as a raw material. The method for obtaining 10-deacetyl cephalomannine from acetyl group, the raw material cephalomannine of this method is also one of the natural products extracted from Taxus chinensis, and is a characteristic impurity in natural paclitaxel. The content of natural paclitaxel in the branches and leaves of Taxus chinensis is only a few ten-thousandths, and the content of cephalomannine as its characteristic impurity is much lower, and it is difficult to separate cephalomannine and paclitaxel, so this raw material is not easy to obtain in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14
CPCC07D305/14
Inventor 陆叶梦黄春陆蒙晨葛月兰
Owner 无锡紫杉药业股份有限公司
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