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Preparation method of docetaxel chiral side chain intermediate

A technology of docetaxel and chiral side chain, applied in the field of drug synthesis, can solve the problems of long route, harsh reaction conditions, low total yield and the like, and achieves the effects of convenient route operation, good stereoselectivity, and simple separation and purification

Inactive Publication Date: 2021-11-12
SHENZHEN ELDERLY MEDICAL RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] In summary, the current literature reports the preparation of (2R,3S)-N-tert-butoxycarbonyl-3-phenylisoserine methyl ester and (2S,3S)-N-tert-butoxycarbonyl-3-phenylisoserine The methods of methyl esters, although these methods have their own characteristics, have many shortcomings: such as expensive reagents, poor stereoselectivity, inconvenient experimental operations, harsh reaction conditions, long routes resulting in low overall yields, etc.

Method used

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  • Preparation method of docetaxel chiral side chain intermediate
  • Preparation method of docetaxel chiral side chain intermediate
  • Preparation method of docetaxel chiral side chain intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Preparation of Compound 4

[0048] Dissolve 10.0g of compound I in 200mL of methanol solvent, slowly add 23.79g of thionyl chloride dropwise in an ice-water bath at 0°C, heat up to reflux for 3h after dropping for 30 minutes, and concentrate under reduced pressure after the reaction; add 400mL of tetrahydrofuran to the concentrated solution- Water (1:1, V / V) mixed solvent, add 16.80g of solid sodium bicarbonate, add 14.40g of Boc anhydride, react at room temperature for 10h, concentrate under reduced pressure after the reaction, add 300mL of purified water, add 250mL*3 ethyl acetate The ester was extracted 3 times, the organic phase was combined, washed with 200 mL of saturated brine, left to separate the liquid, the organic phase was dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the concentrated solution was added with 600 mL of tetrahydrofuran-ethanol (1:1, V / V) Mixed solvent, add 7.57g of sodium borohydride an...

Embodiment 2

[0050] Example 2 Preparation of Compound 4

[0051] Dissolve 10.0g of compound I in 200mL of methanol solvent, slowly add 31.41g of thionyl chloride dropwise in an ice-water bath at 0°C, heat up to reflux for 3h after the drop is completed, and concentrate under reduced pressure after the reaction is complete; add 400mL of tetrahydrofuran to the concentrated solution- Water (1:1, V / V) mixed solvent, add 22.18g of solid sodium bicarbonate, add 14.69g of Boc anhydride, react at room temperature for 10h, concentrate under reduced pressure after the reaction, add 300mL of purified water, add 250mL*3 ethyl acetate The ester was extracted 3 times, the organic phase was combined, washed with 200 mL of saturated brine, left to separate the liquid, the organic phase was dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the concentrated solution was added with 600 mL of tetrahydrofuran-ethanol (1:1, V / V) Mixed solvent, add 4.99g of sodium boro...

Embodiment 3

[0052] Example 3 Preparation of compound 4

[0053] Dissolve 10.0g of compound I in 200mL of methanol solvent, slowly add 39.26g of thionyl chloride dropwise in an ice-water bath at 0°C, heat up to reflux for 3h after the drop is completed, and concentrate under reduced pressure after the reaction is completed; add 400mL of tetrahydrofuran to the concentrated solution- Water (1:1, V / V) mixed solvent, add 27.72g of solid sodium bicarbonate, add 14.40g of Boc anhydride, react at room temperature for 10h, concentrate under reduced pressure after the reaction, add 300mL of purified water, add 250mL*3 ethyl acetate The ester was extracted 3 times, the organic phase was combined, washed with 200 mL of saturated brine, left to separate the liquid, the organic phase was dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the concentrated solution was added with 600 mL of tetrahydrofuran-ethanol (1:1, V / V) Mixed solvent, add 9.99g of sodium bor...

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Abstract

The invention discloses a preparation method of a docetaxel chiral side chain intermediate. The method takes cheap and easily available L-phenylglycine 1 as a raw material, and the route is convenient to operate, good in stereoselectivity, mild in reaction condition, simple to separate and purify and relatively high in total yield, and can be used for large-scale preparation. The adopted raw materials are non-toxic, the production process is pollution-free and environment-friendly, and good conditions are created for industrial large-scale production and commercialization of the product.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of a chiral side chain intermediate of docetaxel. Background technique [0002] Paclitaxel is a diterpene compound extracted from the bark of Taxus genus Taxus (for the structural formula, see formula 1). It is a new type of microtubule stabilizer with unique anticancer activity. It is considered by the National Cancer Institute of the United States to be the most important progress in tumor chemotherapy in the past 15 to 20 years. As a second-line treatment drug for advanced ovarian cancer, it has been approved for marketing in more than 40 countries so far, and has shown encouraging curative effects in the treatment of breast cancer, lung cancer, leukemia, gastrointestinal cancer and vascular restenosis after interventional therapy. . Paclitaxel has limited its clinical application due to the lack of resources and low water solubility. [0003] ...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/22
CPCC07C269/06C07C269/04C07D263/26C07C271/22C07C271/16
Inventor 吴正治龙伯华姜倩倩汪梦霞李利民李子雯
Owner SHENZHEN ELDERLY MEDICAL RES INST
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