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Capecitabine preparation method

The technology of capecitabine and step 2, applied in the field of medicine, can solve the problems of consumption of raw and auxiliary materials, danger to operators and the environment, and high cost, and achieve the effects of reducing environmental impact, reducing drug costs, and reducing medical expenses.

Inactive Publication Date: 2016-05-11
SHANGHAI JINHE BIO TECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0008] In comparison, the route I is shorter, but tin tetrachloride is used in large quantities, and tin tetrachloride is easy to absorb water and undergoes chemical changes, so it has higher requirements on production conditions, and tin is a toxic metal. Environmental pollution, high cost, and tin metal ions are easy to remain in the product, causing the toxic metal ions in the drug to exceed the standard, causing hidden dangers to the safety of the drug
Route II is a long route with a low yield, which is very unfavorable for industrial production, reducing the production effectiveness and the actual utilization of raw and auxiliary materials
Triphosgene is used in the route Ⅲ reaction. Triphosgene will slowly decompose during storage due to humidity, heat and other reasons. The phosgene produced by the decomposition is a highly toxic chemical. In large-scale industrial production, the toxicity is relatively high, which is harmful to operators and The environment creates potential dangers, the route is too long, and the consumption of raw and auxiliary materials is relatively large

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preparation example Construction

[0036] The preparation method of capecitabine of the present invention: comprise the following steps:

[0037] Step 1, using 5-FU as the initial raw material, reacting with pentoxyformyl chloride to generate an intermediate; 5-fluorocytosine: pyridine: pentoxyformyl chloride = 1:1.25~1.4:1.1~1.3, preferably 5-fluorocytosine Pyrimidine:pyridine:pentyloxycarbonyl chloride=1:1.33:1.21. The dropwise addition of pentoxycarbonyl chloride is controlled at -10°C to 0°C, preferably -10°C to -5°C. The reaction temperature is controlled at 0°C to 40°C, preferably room temperature. The concentration of hydrochloric acid used in the quenching reaction is controlled at 0.1-1.0N, preferably 0.2N. The amount of hydrochloric acid used in the quenching reaction is controlled at: HCl:5-fluorocytosine=0.25˜0.025:1, preferably HCl:5-fluorocytosine=0.05:1.

[0038] In step 2, the intermediate is coupled with a ribose derivative to generate capecitabine; the product of the first step: sugar deriv...

Embodiment 1

[0047]Add 80ml of dichloromethane into a 1L three-neck reaction flask equipped with a thermometer and a constant pressure dropping funnel, start magnetic stirring, add 3.04g of 5-fluorocytosine to the reaction flask, and then add 7.1g of pyridine. Under nitrogen protection, 11.7 g of n-amyl chloroformate was added to the constant pressure dropping funnel, and then 10 ml of dichloromethane was added. Cool the reaction solution to -10°C, start to add the dichloromethane solution of n-pentyl chloroformate dropwise, control the dropping temperature at -10°C to -5°C, remove the freezing liquid after the addition, and stir the reaction at room temperature for 2 hours. After the reaction, suck in 30ml of 0.2N hydrochloric acid, stir for 15 minutes, collect the lower dichloromethane phase, and wash the dichloromethane phase with 0.2N hydrochloric acid three times (20ml×3). Finally the dichloromethane phase was washed with water (50ml x 1). The dichloromethane phase was dried with anh...

Embodiment 2

[0050] Add 3.8 L of dichloromethane into a 10 L three-neck reaction flask equipped with a thermometer and a constant pressure dropping funnel, start mechanical stirring, add 152 g of 5-fluorocytosine, and then 122 g of pyridine into the reaction flask. Under nitrogen protection, 212 g of n-amyl chloroformate was added to the constant pressure dropping funnel, and then 200 ml of dichloromethane was added. Cool the reaction solution to -10°C, start to add the dichloromethane solution of n-pentyl chloroformate dropwise, control the dropping temperature at -10°C to -5°C, remove the freezing liquid after the addition, and stir the reaction at room temperature for 2 hours. After the reaction, suck in 1.5L of 0.2N hydrochloric acid, stir for 15 minutes, collect the lower dichloromethane phase, and wash the dichloromethane phase with 0.2N hydrochloric acid three times (500ml×3). Finally the dichloromethane phase was washed with water (500ml x 1). The dichloromethane phase was dried w...

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Abstract

The invention discloses a capecitabine preparation method; 5-FU as a raw material is subjected to a reaction with pentyloxy formyl chloride, then an intermediate is generated and then is coupled with a ribose derivative, an ethoxyl protective group of ethoxyl of the ribose derivative is removed in the coupling reaction, and thus the target compound capecitabine is obtained; the method comprises the following steps: step one, the 5-FU as the raw material is subjected to the reaction with pentyloxy formyl chloride, and then the intermediate is generated; and step two, the intermediate is coupled with the ribose derivative to generate the product capecitabine. The production cost can be saved, the medical expense of patients is reduced, the side effect is reduced, and the yield is higher.

Description

technical field [0001] The invention relates to a preparation method of an antineoplastic drug, in particular to a preparation method of capecitabine, and belongs to the technical field of medicine. Background technique [0002] In recent years, the number of cancer patients in the world has increased year by year, especially in emerging developing countries, where China has become the country with the highest new incidence rate. The "2013 China Cancer Registration Annual Report" issued by the National Cancer Registration Center also shows that my country In the past 20 years, cancer has shown a trend of younger age, higher morbidity and mortality. The incidence of tumors is increasing at a rate of 3%-5% per year. In the prevention and treatment of tumors, it is urgent to develop new anti-tumor drugs, and it is also urgent to vigorously develop their performance. Good anti-tumor generic drugs. [0003] Capecitabine is a new type of oral flucytosine pro-nuclear analogue, which...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
CPCY02P20/55C07H19/06C07H1/00
Inventor 张伟中王权勇吴玉娟谢斌冯蕾宇蔡志香
Owner SHANGHAI JINHE BIO TECH
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