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Preparation method of capecitabine impurity (5-fluoro-2-oxo-1,2-dihydropyrimidine-4-yl)amylcarbamate

A technology of amyl carbamate and capecitabine, applied in the field of medicine, can solve problems such as less impurities, and achieve the effects of simple steps, high yield and improved product purity

Inactive Publication Date: 2019-02-15
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To study and control the impurity, the first thing is to carry out the separation and preparation of the impurity, but there are few reports on the preparation of the impurity at present.

Method used

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  • Preparation method of capecitabine impurity (5-fluoro-2-oxo-1,2-dihydropyrimidine-4-yl)amylcarbamate
  • Preparation method of capecitabine impurity (5-fluoro-2-oxo-1,2-dihydropyrimidine-4-yl)amylcarbamate
  • Preparation method of capecitabine impurity (5-fluoro-2-oxo-1,2-dihydropyrimidine-4-yl)amylcarbamate

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Experimental program
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Effect test

Embodiment 1

[0025] Add 30 g of 5-fluorocytosine, 22 g of pyridine, 300 ml of dichloromethane, and 5 g of tetrabutylammonium bromide into a 500 ml three-neck flask, stir well at room temperature, and slowly add 38.5 g of n-pentyl chloroformate dropwise. After the dropwise addition, the reaction was stirred at room temperature for 2 hours to obtain a viscous mixture. Add 20 g of diatomaceous earth into the Buchner funnel, pour the above viscous mixture into suction filtration, and obtain a clear filtrate. Add 150ml of purified water to wash the filtrate, let stand to separate layers, collect the organic phase, control the temperature at 50°C and concentrate to dryness under reduced pressure, add 200ml of n-hexane to the residue, stir well and filter to obtain a solid wet product, and dry at a temperature of 50°C After drying, 53.9 g of white solid was obtained, with a yield of 95.7% and a purity of 99.15%. (HPLC normalization method, chromatographic conditions: chromatographic column is In...

Embodiment 2

[0028] Add 30 g of 5-fluorocytosine, 23 g of pyridine, 300 ml of dichloromethane, and 5 g of tetrabutylammonium bromide into a 500 ml three-necked flask, stir well at room temperature, and slowly add 39 g of n-pentyl chloroformate dropwise. After the dropwise addition, the reaction was stirred at room temperature for 1.5 hours to obtain a viscous mixture. Add 20 g of diatomaceous earth into the Buchner funnel, pour the above viscous mixture into suction filtration, and obtain a clear filtrate. Add 150ml of purified water to wash the filtrate, let stand to separate layers, collect the organic phase, control the temperature at 50°C and concentrate to dryness under reduced pressure, add 200ml of n-hexane to the residue, stir well and filter to obtain a solid wet product, and dry at a temperature of 50°C Dry to get white solid 54.1g, yield 96.0%, purity 99.21% (HPLC normalization method, chromatographic condition: chromatographic column is Inertsil ODS-2 column (4.6mm * 250mm 5 μ ...

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Abstract

The invention discloses a preparation method of a capecitabine impurity (5-fluoro-2-oxo-1,2-dihydropyrimidine-4-yl)amylcarbamate. According to the method, 5-flucytosine and n-amyl chloroformate reactin an organic solvent to produce (5-fluoro-2-oxo-1,2-dihydropyrimidine-4-yl)amylcarbamate with pyridine as an acid binding agent and tetrabutylammonium bromide as a phase transfer catalyst. The preparation method comprises simple steps, the yield (90% or higher) is high, and the prepared product has higher purity (99% or higher) and can be completely used as an impurity reference substance to be used for quality research of capecitabine.

Description

technical field [0001] The invention relates to a preparation method of capecitabine impurity-(5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)amyl carbamate, which belongs to the technical field of medicine. Background technique [0002] Capecitabine (Capecitabine) is an oral chemotherapy drug with selective activity on tumor cells. It is a prodrug of 5-fluorouracil (5-FU). Activation preferentially produces 5-fluorouracil in tumor tissue, inhibits cell division and interferes with RNA and protein synthesis. Capecitabine is suitable for the further treatment of advanced primary or metastatic breast cancer who have not responded to paclitaxel and chemotherapy regimens including anthracyclines. It is mainly used for the treatment of advanced primary or metastatic breast cancer, rectal cancer, colon cancer and gastric cancer. [0003] Based on the significant impact of impurities on drug quality, there are corresponding regulatory requirements for impurity analysis and control rega...

Claims

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Application Information

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IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 赵孝杰苏曼杨上任
Owner SHANDONG BOYUAN PHARM CO LTD