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Compound and preparation method thereof and midbody compound prepared with same and preparation method thereof

A technology for compounds and intermediates, applied in the field of compounds and their preparation, can solve the problems of low synthesis yield, harsh conditions, unfavorable industrial operation, etc., and achieves soft reaction conditions, convenient industrial production, and superior chemical selectivity and yield. Effect

Inactive Publication Date: 2010-10-13
CHONGQING TAIHAO PHARM CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] (1) COLIN, US4924012 is composed of (2R, 3S) 2-ethoxyethoxy-3-tert-butoxycarbonylamino-3-phenylpropionic acid and protected 10-deacetylbaccatin III in DCC and DMAP In the presence of condensation to prepare docetaxel, the reaction temperature is 70 ° C, lower synthesis yield
[0008] (2) OJIMA, WO94 / 18164, HOLTON, WO93 / 06079 by (3R, 4S)-1-tert-butoxycarbonyl-3-EEO-4-phenylazetidine-2-ketone and 10-deacetyl Bacatine III is the main raw material to synthesize docetaxel through a three-step reaction; it must be at -78°C, LiN(TMS) 2 Under the action of ring-opening condensation, the conditions are harsh, which is not conducive to industrial operation

Method used

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  • Compound and preparation method thereof and midbody compound prepared with same and preparation method thereof
  • Compound and preparation method thereof and midbody compound prepared with same and preparation method thereof
  • Compound and preparation method thereof and midbody compound prepared with same and preparation method thereof

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Embodiment 1

[0022] Synthesis of Compound (Ⅶ)

[0023] Synthesis of compound ②: under nitrogen protection, 4.9 g (30 mmol) of compound ① was dissolved in 60 ml of methanol, 12 ml of 6N hydrochloric acid aqueous solution was added to the reaction solution, and reflux reaction was carried out at 65° C. for 20 hours, and the reaction solution was cooled to room temperature. In a water bath at 40°C, concentrate under reduced pressure to completely remove methanol, add 30ml of deionized water, adjust the pH to 7 with 5N aqueous sodium hydroxide solution, and then extract the water layer 3 times with 40ml of 1:1 mixed solvent of ethyl tetrahydrofuran acetate , combined the organic layers, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure at 40°C to obtain 4.9 g of white crystals. 60ml (volume ratio 7 / 3) mixed solution of isopropyl ether and ethyl acetate was used for recrystallization to obtain 3.7g of white crystals of compound 2, Mp101°C.

[...

Embodiment 2

[0027] Embodiment 2: the synthesis of compound (Ⅳ)

[0028] Under nitrogen protection, 8g (14.6mmol) 10-deacetylbaccatin III (II) was added in 100ml of anhydrous chloroform, stirred and dissolved, then added 2.86g (16.0mmol) N, N'-thiocarbonyldiimidazole ( III), stirring reaction at room temperature, the reaction system is bright yellow and transparent, continue to react for 1 hour, the reaction solution is washed with water and saturated sodium chloride, MgSO 4 Dry, filter, concentrate to dryness under reduced pressure at 55°C, and crystallize with ethyl acetate / n-hexane to obtain 8.6 g of white solid compound (IV). Mp145-148℃

Embodiment 3

[0029] Embodiment 3: the synthesis of compound (Ⅵ)

[0030] Under the protection of nitrogen, put 8.6g (13.1mmol) of the obtained compound (IV) into a three-necked flask, add 100ml of anhydrous pyridine and stir to dissolve, cool down to 10°C, and add trichloroethoxycarbonyl chloride (Ⅴ) dropwise under stirring 3.2g (15mmol) was diluted with 5ml of toluene, naturally warmed to room temperature, then stirred and reacted at room temperature for 1 hour, cooled, 100ml of n-hexane was added to the reaction solution, left overnight, and filtered to obtain 9.2g of white crystalline compound (VI).

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Abstract

The invention discloses a novel phenylisoserine derivative: (2R, 3S)-3-(tert-butoxycarbonylamino)-2(2-ethoxypropene-2-oxo)-3-phenylpropionic acid as a side chain for the synthesis of docetaxel, and a preparation method for the compound. The preparation method includes the following steps that: (2R, 3S)2-hydroxy-3-amino phenylalanine methylester is prepared with (3R, 4S)3-hydroxy-4-phenylazetidine-2-ketone ring-opening product, the amino group is protected by the tert-butoxycarbonyl group, the hydroxyl group is protected by the 2-ethoxypropene group, the methyl ester is unshackled, and thereby the novel phenylisoserine derivative is obtained. The invention also discloses a midbody compound which is prepared with the compound and used for synthesizing docetaxel, and a preparation method for the midbody compound. The novel synthesis route for synthesizing docetaxel has the advantages of mild reaction conditions and high condensation efficiency, can be used for industrialized production, and can be widely popularized.

Description

technical field [0001] The invention relates to a compound and a preparation method thereof, an intermediate compound prepared from the compound and used for synthesizing docetaxel, and a preparation method of the intermediate compound. Background technique [0002] Docetaxel (I) belongs to the taxane class of antineoplastic drugs and is a microtubule depolymerization inhibitor. It was developed by the French company Rhône-Planc Leon, and Docetaxel was launched in Mexico in April 1995. , and then listed in Britain, the United States, France, Italy, Germany, Japan and other countries, and is currently listed in more than 80 countries. [0003] [0004] Docetaxel is approved for the treatment of advanced breast cancer and non-small cell lung cancer. It has a significant effect on solid tumors such as prostate cancer, pancreatic cancer, soft tissue tumors, head and neck cancer, gastric cancer, and esophageal cancer. Platinum-failed patients with advanced ovarian cancer have...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/22C07C269/06C07D405/12C07D305/14
Inventor 徐少军应振培李靖
Owner CHONGQING TAIHAO PHARM CO LTD
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