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Docetaxel semi-synthesis method

A docetaxel and semi-synthetic technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of harsh reaction conditions and short reaction time

Inactive Publication Date: 2013-06-12
江苏斯威森生物医药工程研究中心有限公司
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0017] The present invention relates to a semi-synthetic method of docetaxel, specifically to solve the problem that the reaction conditions in the synthesis of docetaxel are too harsh, including avoiding the use of strong acid and strong base, etc., optimizing the selection of reaction reagents, thereby abandoning inert gas protection, to simplify the reaction equipment and reduce the synthesis cost. Secondly, the 7- and 10-hydroxyl protection methods of 10-deacetylbaccatin III were further optimized, so that the reaction time was shorter, the conditions were milder, and the yield higher

Method used

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Experimental program
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Effect test

Embodiment 1

[0026] Embodiment 1 (semi-synthetic reaction formula sees figure 2 )

[0027] (1) Hydroxyl protection of side chain precursor

[0028] Dissolve 3.4 g of optically active side chain precursors in 30 ml of tetrahydrofuran (THF), and then slowly add 5.8 g of triethylamine, 76 mg of 4-dimethylaminopyridine (DMAP) and 2.4 g of β-(trimethylsilyl ) ethoxymethyl chloride, and the mixture was stirred at 0°C for 30 minutes. During the spot plate, when it is completely converted into a less polar product, add 30mL ethyl acetate to dilute, then wash with 15ml saturated aqueous sodium bicarbonate solution and 15ml brine, and dry with 5g sodium sulfate, filter, and concentrate the filtrate. Recrystallized from alkane to obtain a white powder. Vacuum-filtered on a Buchner funnel, and vacuum-dried at room temperature to a constant weight of 3.45 g, yield 72%.

[0029] (2) Side chain C 3’ tert-butoxycarbonyl

[0030] Take 0.95 g of the product with optical activity after the previous st...

Embodiment 2

[0036] (1) Hydroxyl protection of side chain precursor

[0037] Dissolve 3.4 g of optically active side chain precursors in 30 ml of tetrahydrofuran, and then slowly add 5.8 g of triethylamine, 76 mg of 4-dimethylaminopyridine (DMAP) and 2.4 g of β-(trimethylsilyl)ethoxy methyl chloride, and the mixture was stirred at 0°C for 30 minutes. During the spot plate, when it is completely converted into a less polar product, add 30mL ethyl acetate to dilute, then wash with 15ml saturated aqueous sodium bicarbonate solution and 15ml brine, and dry with 5g sodium sulfate, filter, and concentrate the filtrate. Recrystallized from alkane to obtain a white powder. Vacuum-filtered on a Buchner funnel, and vacuum-dried at room temperature to a constant weight of 3.45 g, yield 72%.

[0038] (2) Side chain C 3’ tert-butoxycarbonyl

[0039] Take 0.95 g of the product with optical activity after the previous step of purification and dissolve it in 10 ml of tetrahydrofuran, then slowly add 1...

Embodiment 3

[0045] (1) Hydroxyl protection of side chain precursor

[0046] Dissolve 3.4 g of optically active side chain precursors in 30 ml of tetrahydrofuran, and then slowly add 5.8 g of triethylamine, 76 mg of 4-dimethylaminopyridine (DMAP) and 2.4 g of β-(trimethylsilyl)ethoxy methyl chloride, and the mixture was stirred at 0°C for 30 minutes. During the spot plate, when it is completely converted into a less polar product, add 30mL ethyl acetate to dilute, then wash with 15ml saturated aqueous sodium bicarbonate solution and 15ml brine, and dry with 5g sodium sulfate, filter, and concentrate the filtrate. Recrystallized from alkane to obtain a white powder. Vacuum-filtered on a Buchner funnel, and vacuum-dried at room temperature to a constant weight of 3.45 g, yield 72%.

[0047] (2) Side chain C 3’ tert-butoxycarbonyl

[0048] Take 0.95 g of the product with optical activity after the previous step of purification and dissolve it in 10 ml of tetrahydrofuran, then slowly add 1...

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Abstract

The invention relates to a docetaxel semi-synthesis method. Specifically, the docetaxel semi-synthesis method comprises the following steps: (1) performing united protection on 7-hydroxyl and 10-hydroxyl of 10-deacetylbaccatin III by using silane protecting group; (2) under solvent environment, performing condensation on the protected beta-lactam side chain precursor of 2-hydroxyl and the protected 10-deacetylbaccatin III; and (3) deprotecting the condensation product to produce crude docetaxel product, and purifying. In addition, the selection of reaction agents can be optimized, and the protection from strong acid and strong base and inert gas can be avoided, so that reaction equipment is simplified, the yield of the product is improved, and the synthesis cost is lowered.

Description

technical field [0001] The invention relates to a method for semi-synthesizing docetaxel using 10-deacetylbaccatin III as a raw material. Background technique [0002] Cancer is one of the leading causes of death worldwide. WHO estimates that without intervention, 84 million people will die from cancer between 2005 and 2015. Therefore, all mankind has been making unremitting efforts to fight against cancer. In the treatment of cancer, drug treatment is an extremely important link. The use of effective anticancer drugs will give patients a longer survival time and hope for survival. According to statistics, among many anti-tumor drugs, natural plant anti-tumor drugs account for the largest proportion, accounting for more than 27% of the share. Among the top 10 antineoplastic drugs by single product, plant-based antineoplastic drugs occupy two seats, paclitaxel and docetaxel. However, 90% of paclitaxel in the market still comes from plant extraction. Due to the slow growth...

Claims

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Application Information

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IPC IPC(8): C07D305/14
CPCY02P20/55
Inventor 彭学东张梅赵金召王俊杰
Owner 江苏斯威森生物医药工程研究中心有限公司
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