Preparation method of high purity trifluridine

A high-purity technology of trifluridine, which is applied in the field of medicine, can solve the problems of high operating cost, low purity, and low yield, and achieve the effects of simplifying the process flow, clear route, and improving purity and yield

Inactive Publication Date: 2016-12-14
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The above-mentioned methods are different, but there are still some shortcomings such as low yield, low purity and high operating cost, and some better preparation methods are still needed

Method used

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  • Preparation method of high purity trifluridine
  • Preparation method of high purity trifluridine

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Experimental program
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Effect test

Embodiment 1

[0037] Preparation of Compound 3: At room temperature, add 90ml of HMDS and 2ml of TMSCl into the reactor, add 18g of Compound 2 (5-trifluoromethyluracil) under stirring, raise the temperature to 125°C, stir for 2h, and cool to 60°C , and concentrated under reduced pressure at 70-80°C until no liquid flowed out to obtain 30 g of light yellow liquid with a yield of 92.5%, HPLC: 96%.

[0038] Preparation of Compound 5: At room temperature, add 16.4g of Compound 3 to 200ml of chloroform, and add 21.4g of Compound 4 (1-chloro-3,5-di-p-chlorobenzoyl-2-deoxy-D-ribose) under stirring With 0.5g copper difluoride, react at 20-30°C for 24 hours after the addition, add 60ml 1mol / L hydrochloric acid solution to the system after the reaction, stir for 10min, separate the liquid, wash the organic phase twice with 100ml water / time, concentrate The organic phase flows out until there is no solvent, and the residue is recrystallized by adding 300ml of ethanol, the crystals are filtered out, ri...

Embodiment 2

[0041] Preparation of Compound 5: At room temperature, add 19.7g of Compound 3 to 200ml of chloroform, and add 21.4g of Compound 4 (1-chloro-3,5-di-p-chlorobenzoyl-2-deoxy-D-ribose) under stirring With 2.5g copper difluoride, react at 20-30°C for 24 hours after the addition, add 60ml 1mol / L hydrochloric acid solution to the system after the reaction, stir for 10min, separate the liquid, wash the organic phase twice with 100ml water / time, concentrate The organic phase flows out until there is no solvent, the residue is recrystallized by adding 320ml of ethanol, the crystals are filtered out, rinsed with an appropriate amount of ethanol, and the filter cake is vacuum-dried at 45°C for 6h to obtain 23.0g of a white solid, with a yield of 80.2%, HPLC: 96.5% .

[0042] Preparation of Compound 1: Add 11.5g of Compound 5 to 80ml of methanol at room temperature, add 3.3g of sodium methoxide under stirring, stir and react at 20-30°C for 4h, add 4.2g of strong acidic cationic resin and ...

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Abstract

The invention provides a preparation method of high purity trifluridine. The method is as below: reacting a raw material of a compound 2 with HMDS under the action of trimethylchlorosilane to obtain a compound 3; subjecting the compound 3 and a compound 4 to condensation in the presence of a catalyst copper difluoride; conducting ethanol recrystallization to obtain a compound 5; and finally conducting deprotection on the compound 5 under the effect of sodium methylate; and recrystallizing by a mixed solvent of ethanol and acetone (1:1) to obtain the high purity object compound 1. The method has the advantages of high purity of the product, simpleness, easy purification and less industrial pollution.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of high-purity trifluridine. Background technique [0002] Trifluridine, chemical name: 5-trifluoromethyl-2-deoxyuridine, has the strongest effect on herpes simplex virus (HSV-1 and HSV-2), and has the strongest effect on adenovirus, vaccinia virus, cytomegalovirus, Herpes zoster virus also has a certain effect, and it is effective against acyclovir-resistant herpes virus. Its triphosphate derivatives can be incorporated into DNA and compete with thymidine triphosphate to inhibit DNA polymerase. No selectivity for viral DNA and host cell DNA. It is suitable for herpes simplex keratitis, conjunctivitis and other herpetic eye diseases. There are many specific preparation methods, and the main methods of preparation are as follows: [0003] 1) Use trifluorouracil as the starting material, protect it with hexamethylsilazane, and then dock with 1-chloro-2-d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00
CPCC07H19/073C07H1/00
Inventor 袁金桥代永智刘虎蔡剑
Owner HARVEST PHARMA HUNAN CO LTD
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