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Industrial tegafur synthesizing method

A technology of tegafur and inert gas, which is applied in the field of medicine, can solve problems such as complex process conditions, poor thermal stability, and cost reduction, and achieve the effects of being suitable for industrial production, increasing yield, and reducing the generation of by-products

Active Publication Date: 2013-06-19
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In view of the ubiquitous technical problems in the prior art that require group protection, poor thermal stability of 2-substituted tetrahydrofuran, easy decomposition and reaction at low temperature, resulting in complicated and harsh conditions for the process, the inventors have developed a method for 5-fluoro-uracil drug To provide a method for preparing tegafur that is suitable for industrial production, the method is simple and easy to operate, and has the characteristics of high yield, less side reactions, and mild reaction conditions. The reaction product only needs simple purification. Meet the requirements of Pharmacopoeia standards. After process optimization, the product yield is greatly improved, the cost is reduced, the purity is above 99.7%, the related substances are below 0.3%, and the single impurity is below 0.1%.

Method used

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  • Industrial tegafur synthesizing method

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Experimental program
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Effect test

Embodiment 1

[0028] Add 50.0kg of 5-fluorouracil, 75.0kg of 2,3-dihydrofuran, 90.0kg of pyridine, and 5.0kg of anhydrous calcium chloride into the 600L hydrogenation reaction kettle in sequence, replace with nitrogen three times after vacuuming, and pass nitrogen to a pressure of 0.68MPa , then raise the temperature to 120°C, increase the pressure to 1.4MPa and keep it under pressure for 11 to 13 hours. After the reaction, cool down to below 55°C, then press filter the insoluble matter, transfer it to a 300L stainless steel reaction tank to evaporate pyridine under reduced pressure, and obtain an oil thing;

[0029] Add 40kg of methanol to the oil to completely dissolve it, transfer it to a 300L glass-lined reaction tank, control the temperature at 35-45°C, slowly add concentrated hydrochloric acid, adjust the pH to about 1, and after the concentrated hydrochloric acid is added dropwise, control the temperature at 30-40°C , continue to stir the reaction for about 6-7 hours, the stirring re...

Embodiment 2

[0032] Add 50.0kg of 5-fluorouracil, 75.0kg of 2,3-dihydrofuran, 83kg of N,N-dimethylformamide, and 4.3kg of anhydrous aluminum chloride to a 600L hydrogenation reactor in sequence, and replace it with argon three times after vacuuming , pass argon gas to a pressure of 0.75MPa, then raise the temperature to 113°C, increase the pressure to 1.5MPa and keep the pressure for 11-13 hours. After the reaction, cool down to below 55°C, then press filter the insoluble matter, and transfer it to a 300L stainless steel reaction tank Pyridine was evaporated under reduced pressure to obtain an oil;

[0033] Add 40kg of methanol to the oil to completely dissolve it, transfer it to a 300L glass-lined reaction tank, control the temperature at 35-45°C, slowly add concentrated hydrochloric acid, adjust the pH value to about 2, and after the concentrated hydrochloric acid is added dropwise, control the temperature at 30-40°C , continue to stir the reaction for about 6-7 hours, the stirring react...

Embodiment 3

[0036] Add 50.0kg of 5-fluorouracil, 75.0kg of 2,3-dihydrofuran, 105kg of dimethyl sulfoxide, and 4.6kg of anhydrous calcium chloride to the 600L hydrogenation reaction kettle in sequence. The pressure is 0.58MPa, then the temperature is raised to 120°C, the pressure is increased to 1.2MPa, and the heat preservation and pressure reaction is carried out for 11 to 13 hours. After the reaction is completed, the temperature is lowered to below 55°C, and then the insoluble matter is filtered, and transferred to a 300L stainless steel reaction tank to evaporate pyridine under reduced pressure. , to get oil;

[0037] Add 40kg of methanol to the oil to completely dissolve it, transfer it to a 300L glass-lined reaction tank, control the temperature at 35-45°C, slowly add concentrated hydrochloric acid, adjust the pH value to about 2.5, and after the concentrated hydrochloric acid is added dropwise, control the temperature at 30-40°C , continue to stir the reaction for about 6-7 hours, ...

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Abstract

The invention belongs to the technical field of medicine, and specifically relates to an industrial tegafur synthesizing method comprising the steps that: under inert gas pressure control and the effects of a Lewis acid catalyst, 5-fluorouracil and 2,3-dihydrofuran are subjected to a substitution reaction in an aprotic polar solvent; and acidification and refining are carried out, such that tegafur is obtained. The method has the advantages of simple reaction process, high yield, less side reactions, mild reaction conditions, and the like. Pharmacopoeia standards can be satisfied with simple refining, and purity is higher than 99.7%.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing tegafur through an industrial method. Background technique [0002] Tegafur (Tegafur, Ftorafur, FT 207), chemical name: 1-(tetrahydro-2-furyl)-5-fluoro-2,4(1H,3H)-pyrimidinedione, is a pyrimidine anticancer drug One, it is the prodrug of 5-fluorouracil (5-FU), which has inhibitory effect on most solid tumors, and its structural formula is as follows: [0003] [0004] When Tegafur is taken orally into the body, it is first converted into 5-FU under the catalysis of liver P450 activating enzyme, and then about 10% enters the intestinal tract and is phosphorylated under the catalysis of orotate ribosyltransferase (ORTC). , and the remaining 90% of 5-FU is catalyzed by dihydropyrimidine dehydrogenase (DPD) in the liver, and is transformed into fluorouridine triphosphate (FUTP) and deoxyfluridine monophosphate ( FdUMP) two active products c...

Claims

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Application Information

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IPC IPC(8): C07D405/04
Inventor 赵志全
Owner SHANDONG NEWTIME PHARMA
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