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Improved method for semi-synthesizing docetaxel

A technology for docetaxel and a synthesis method, which is applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of unstable intermediates, harsh conditions, and high product costs, and achieve the effects of overcoming many reaction steps and improving yields

Inactive Publication Date: 2013-01-23
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, the route widely adopted for synthesizing docetaxel is to prepare docetaxel by docking with the mother nucleus with the side chain of straight-chain isoserine and the four-membered ring azetidinone, but there are various disadvantages, such as: Many steps, harsh conditions, difficult experimental operation, difficult chiral resolution, high product cost, unstable intermediates, difficult separation, purification and storage of products, etc., are difficult to meet the needs of industrial production

Method used

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  • Improved method for semi-synthesizing docetaxel
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  • Improved method for semi-synthesizing docetaxel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025]

[0026] In a 25 mL round bottom flask, (2R,3S)-3-phenylisoserine methyl ester (1.0 g, 5.1 mmol) was dissolved in toluene, tribromoacetaldehyde (1.57 g, 5.6 mmol) and a catalytic amount of Pyridinium p-toluenesulfonate, oil bath 120 ° C, stirred for 2 hours, TLC detection, raw materials disappeared, stop the reaction, remove toluene under reduced pressure, column chromatography purification (petroleum ether: ethyl acetate = 5: 1) to obtain product 2 : 2.29g, yield 98%.

[0027] (4S,5R)-2-Trichloromethyl-4-phenyl-5-carboxy-1,3-oxazolane: ESI-MS m / z: 455.8454[M+H] + ; 1 H-NMR (400MHz, CDCl 3 ): δ7.52 (d, 2H), 7.51-7.32 (m, 3H), 5.47 (d, 1H), 4.71 (s, 1H), 4.70 (d, 1H), 3.76 (s, 3H).

Embodiment 2

[0029]

[0030] Dissolve compound 2 (457.9mg, 1.0mmol) in 4.5mL ethanol-water (8:1), add lithium hydroxide (71.8mg, 3.0mmol), stir at room temperature for 3h, remove the methanol solvent under reduced pressure, acidify with 2N hydrochloric acid , extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain compound 3: 403.9 mg, yield 91%.

[0031](4S,5R)-2-Trichloromethyl-4-phenyl-5-carboxy-1,3-oxazolane: ESI-MS m / z: 441.8309[M+H] + ; 1 H-NMR (400MHz, DMSO): δ7.60(d, 2H), 7.36-7.25(m, 3H), 5.42(s, 1H), 5.39(s, 1H), 4.94-4.90(m, 1H), 4.63-4.59 (m, 2H), 4.34 (d, 1H).

Embodiment 3

[0033]

[0034] Dissolve 10-DAB (544.6 mg, 1 mmol) in 5 mL of anhydrous pyridine, under nitrogen protection, under ice-salt bath conditions, slowly add trichloroacetyl chloride (600.0 mg, 3.3 mmol) dropwise, the temperature is controlled at minus 5 degrees, three After the dropwise addition of chloroacetyl chloride was completed, it was naturally raised to room temperature and detected by TLC. After 1.5 hours, the raw material disappeared. Stir and drop in deionized water under ice bath conditions, extract with ethyl acetate, dry with anhydrous sodium sulfate, filter, and reduce pressure The solvent was distilled off, and compound 5 was obtained by column chromatography: 1.08 g, with a yield of 96%.

[0035] 1 H-NMR (400MHz, CDCl 3 ): δ7.67(t, 2H), 7.60(t, 1H), 7.47(t, 2H), 6.27(s, 1H), 5.66-5.60(m, 2H), 4.99(d, 1H), 4.92( d, 1H), 4.60(d, 1H), 4.32(d, 1H), 4.15(d, 1H), 3.98(d, 1H), 2.64-2.62(m, 1H), 2.30(s, 3H), 2.16 (s, 3H), 2.15-1.86(m, 2H), 1.84(s, 3H), 1.14(s, 3H), 1...

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Abstract

The invention discloses an improved method for semi-synthesizing docetaxel. The method comprises the following steps of: protecting hydroxyl radicals at the 7th position and the 10th position of 10-deacetyl baccatin III which is taken as an initial raw material, introducing an optical rotation side chain at the 13th position of the 10-deacetyl baccatin III to synthesize an intermediate, and finally, hydrolyzing to obtain a target product, namely the docetaxel. The side chain is synthesized by reacting (2R,3S)-3-phenylpropionate with tribromoacetaldehyde to obtain an oxazoline intermediate, and hydrolyzing the oxazoline intermediate. The preparation method is simple, few side reactions are performed, the yield and the purity are high, isomer byproducts are avoided, the content of impurities is low, and the cost is greatly reduced, so the commercial preparation of the docetaxel can be promoted. The method has an important significance and a huge economic benefit for protecting the species and resource of Taxus chinensis plants, reducing the treatment cost of tumor and the like.

Description

technical field [0001] The present invention relates to an improved semi-synthetic method of docetaxel, in particular to the synthesis of a docetaxel side chain and the modification of the parent ring 10-deacetylbaccatin III (10-DAB), The parent ring is then condensed with the side chain to give docetaxel. Background technique [0002] Paclitaxel (Taxol) is a natural organic compound extracted from the bark or needles of the yew plant. ) crude extracts of paclitaxel were isolated from bark and wood. In the screening experiment, Wani and Wall found that the crude extract of paclitaxel had high activity on mouse tumor cells cultured in vitro, and began to isolate this active ingredient. In 1969, paclitaxel was identified as the active ingredient. Due to the extremely low content of this active ingredient in plants, they did not work with Andre T., a chemistry professor at Duke University, until 1971 (J. .McPhail), determined the chemical structure of the active ingredient-t...

Claims

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Application Information

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IPC IPC(8): C07D305/14
CPCY02P20/55
Inventor 陈艳君高坤
Owner NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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