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A kind of preparation method of trifluridine

A compound and selected technology, applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of viscosity of the reaction system, difficult to stir, and unsuitable for industrial production.

Active Publication Date: 2021-12-24
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Secondly, the literature suggests solvent-free or solvent-less reactions, wherein solvent-free reactions are not suitable for industrial production, and the reaction system with less solvents is viscous and difficult to stir.

Method used

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  • A kind of preparation method of trifluridine
  • A kind of preparation method of trifluridine
  • A kind of preparation method of trifluridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] The preparation of embodiment 1 formula III-1 compound

[0079]

[0080] Under the protection of nitrogen, add pre-dried acetonitrile (42kg), 5-trifluoromethyluracil (18kg), HMDS (19.8kg) and ammonium sulfate (796g) into a 200L reactor, and control the temperature of the feed liquid at 75°C to 85°C. ℃, stirring the reaction for 4h, and stopping the reaction. The feed solution is first controlled at 45-55°C and concentrated under reduced pressure to remove acetonitrile, and then heated to 65-75°C to continue to concentrate under reduced pressure to remove excess HMDS. After concentrating, 13.1 kg of anisole was added to the residue for dissolving, filtered, and the filtrate was collected to obtain 44.3 kg of anisole solution containing the compound of formula III-1 (wherein, the quality of the compound of formula III-1 was 31.2 kg, and the amount of benzyl The mass of ether is 13.1 kg).

Embodiment 2

[0081] The preparation of embodiment 2 formula II-1 compound

[0082]

[0083] Under the protection of nitrogen, add acetic anhydride (1.96kg) to the anisole solution containing the compound of formula III-1 prepared in Example 1, heat the system to 40°C-50°C, and add the formula IV-1 in 5 batches under stirring. 1 compound (9.5kg*5, α / β is about 60:40), add a batch every 0.5h, after the compound of formula IV-1 is added, control the temperature at 40°C-50°C and continue to stir for 2-3h, TLC monitors that the compound of formula III-1 has reacted completely, and the reaction is stopped, and the reaction system is syrupy and easy to stir.

[0084] Add 74 kg of absolute ethanol to the reaction system, stir to disperse the solid evenly, crystallize the system at -5-5°C for 7h-10h, and dry the filter cake at 45°C-55°C for 14-18h to obtain the crude compound of formula II-1 46.72 kg. (α:β=1:14.1)

[0085] Pump 654kg of absolute ethanol into a 1000L glass-lined reactor, add 4...

Embodiment 3

[0086] Example 3 Preparation of Trifluridine

[0087]

[0088] Under the protection of nitrogen, add 160kg of anhydrous methanol and 23.2kg of the refined compound of formula II-1 into a 300L reaction kettle, stir, cool down with chilled water, control the temperature of the system at -20°C to -10°C, and add the pre-prepared sodium methoxide dropwise Methanol (5.57kg sodium methoxide, 26kg methanol) solution, dropwise, continue to control the temperature and stir for 2h, after the reaction of the refined product of the compound of formula II-1 is monitored by TLC, control the temperature at -20°C to -10°C, and add acetic acid dropwise to adjust System pH to neutral.

[0089] Concentrate the reaction solution thus obtained to dryness under reduced pressure at 35°C-45°C, add 150 kg of acetone to the concentrate with stirring, stir for 1 hour, filter, and concentrate the filtrate to dryness at 30°C-40°C. The residue was beaten twice with 50 kg of ethyl acetate, filtered, and ...

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Abstract

The present application relates to a preparation method of trifluridine, comprising reacting a compound of formula III and a compound of formula IV in a first solvent in the presence of an acid to obtain a compound of formula II, and further reacting to obtain trifluridine.

Description

[0001] References to related applications [0002] This application claims the rights and interests of the Chinese patent application No. 201810817373.6 submitted to the State Intellectual Property Office of the People's Republic of China on July 24, 2018, the entire contents of which are hereby incorporated herein by reference. technical field [0003] The application relates to the fields of organic chemistry and medicinal chemistry, in particular, the application relates to a preparation method of trifluridine. Background technique [0004] Trifluridine, molecular formula: C 10 h 11 f 3 N 2 o 5 , molecular weight: 296.2, full name: 1-(2-deoxy-β-D-erythrofuranose)-5-trifluoromethyl-2,4-dihydroxypyrimidine, English name: Trifluridine, its chemical structure is as follows: [0005] [0006] Trifluridine has the strongest effect on herpes simplex virus (HSV-1 and HSV-2), and also has a certain effect on adenovirus, vaccinia virus, cytomegalovirus, and herpes zoster vi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H1/00
CPCC07H1/00C07H19/073Y02P20/55C07H19/06
Inventor 刘林赵瑞桑光明周兴健郭晓鹏张爱明吴刚夏春光张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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