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A kind of simple and convenient refining method of capecitabine intermediate

A capecitabine and refining method technology, applied in the field of organic or drug synthesis, can solve the problems of rising refining costs, high solvent consumption rate, yield discount, etc., and achieve the effect of simple process, high separation efficiency and low cost

Active Publication Date: 2015-11-18
HEFEI LIFEON PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a production process, this inefficient purification method not only has a long cycle, but also has a high solvent consumption rate. In addition, the yield discount in each refining process makes the refining cost rise step by step.

Method used

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  • A kind of simple and convenient refining method of capecitabine intermediate
  • A kind of simple and convenient refining method of capecitabine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] 1. Preparation of 2,3-dibenzoyl-5-deoxy-5-fluorocytidine: Suspend 44.5g (0.363mol) of dimethylaminopyridine in 280ml of acetonitrile and 29.5ml (0.364mol) of pyridine, in 8 33.7 g (0.22 mol) of phosphorus oxychloride was added dropwise under the condition of ℃. After the addition is completed, continue to stir and react at 23°C to 25°C for 65 minutes, then drop to 2°C, and slowly add 33.07g (purity 0.073mol) of 2,3-dibenzoyl-5-deoxy-5-fluorouridine ( The solution made of compound 2) and 187ml of acetonitrile was added dropwise, the temperature was raised to 23°C-25°C, and the stirring reaction was continued for 3.5h. The temperature was then lowered to 5°C-7°C, and 176ml of concentrated ammonia water was added dropwise to the solution, stirred and reacted at 23°C-25°C for about 70 minutes, and the end point of the reaction was indicated by TLC. Developing solvent: ethyl acetate:petroleum ether=7.5:2.5; stationary phase: GF254.

[0020] 2. Extraction and washing: After...

Embodiment 2

[0027] Embodiment 2 (comparative embodiment of low concentration extract)

[0028] In this example, the dry ethyl acetate solution was diluted with the same solvent and adjusted to 500 ml before precipitation and impurity removal, and the concentration of the intermediate in the solution was measured to be 52.2 mg / ml. Then perform the operation according to the precipitation and impurity removal process of Example 1 and the subsequent crystallization conditions. 7.20 g of impurity precipitates were obtained, wherein the content of intermediates was reduced to 1.03%. Yield of one-step crystallization: 24.35, of which, intermediate content: 92.48%.

Embodiment 3

[0029] Embodiment 3 (comparative embodiment of high-concentration extract)

[0030] In this example, the dry ethyl acetate solution was adjusted to 400ml with a small amount of the same solvent before precipitation and impurity removal, and the concentration of the intermediate in the solution was measured to be 64.8mg / ml. Then, the operation was carried out according to the precipitation removal and subsequent crystallization conditions of Example 1, and 12.13 g of total impurity precipitates were obtained, wherein the content of intermediates soared to 29.80%. Yield of one-step crystallized product: 19.67g (compared with Example 1, yield decreased by 16.6.%), melting point 198.2°C-198.9°C, content 99.63%.

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Abstract

The invention discloses a method for simply and conveniently decontaminating and crystallizing synthetic reaction liquid of 2,3-di-benzoyl-5-deoxidizing-5-gemcitabine, the intermediate of capecitabine, as an antineoplastic drug. The method is characterized by including the following steps: performing one-time precipitation and decontamination under specified conditions to an ethyl acetate extracting solution obtained after the chlorination of 2,3-di-benzoyl-5-deoxidizing-5-gemcitabine and the amination are performed; moderately concentrating the filtrate of the extracting solution and then further performing cooling crystallization in the original solvent, and obtaining the high-purity target object through one step. Besides, the precipitate impurities can be recycled and reused as chlorination and amination reaction raw materials. According to the method, the complicated steps that the crude product concentrated residues in the prior art are subjected to multiple recrystallization through a mixed solvent are eliminated, besides, the yield is remarkably improved, the preparation cost is greatly reduced, and the method is particularly suitable for industrial production.

Description

technical field [0001] The invention relates to a simple and convenient method for refining a synthetic crude product of an antineoplastic drug capecitabine intermediate, 2,3-dibenzoyl-5-deoxy-5-fluorocytidine, and belongs to the field of organic or pharmaceutical synthesis. Background technique [0002] Capecitabine is currently an effective drug widely used in the treatment of advanced primary or metastatic breast cancer and metastatic colorectal cancer that are ineffective to drugs such as paclitaxel and doxorubicin. Therefore, the research and improvement of its various synthesis processes have become a current hot topic. [0003] There are several routes for the chemical synthesis of capecitabine. Among them, the synthesis process using 5-deoxy-5-fluorouridine as a raw material is still widely used due to the advantages of cheap protective group reagents and easy control of process conditions. Its synthetic route is as follows: [0004] [0005] In the above synth...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/067C07H1/00C07H1/06
Inventor 季俊虬高美华李孝常陈军
Owner HEFEI LIFEON PHARMA