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Preparation method of tipiracil

A technology for tipiramidine and pyrimidinedione is applied in the field of preparation of tipiramidine, which can solve the problems of low yield and poor purity, and achieve the effects of high yield, improved selectivity and reduced risk.

Active Publication Date: 2017-05-31
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Aiming at the problems of low yield and poor purity in the preparation of tipiracil in existing industrial production, the invention provides a preparation method of tipiracil

Method used

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  • Preparation method of tipiracil
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  • Preparation method of tipiracil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1) Dissolve 10.0g of 6-chloromethyluracil in 100ml of dimethyl sulfoxide, add 17.0g of chlorosuccinimide with stirring at room temperature, raise the temperature to 60°C after the addition, and carry out the heat preservation reaction for 4h . The reacted system was added to 400ml of water to precipitate a light yellow solid. After suction filtration and drying, 11.0g of intermediate A was obtained, with a yield of 90.7%.

[0033] 2) Add 33.6ml of n-butyllithium n-hexane solution (2mol / L) into the reaction flask, add 50ml of tetrahydrofuran, slowly add 5.9g of α-pyrrolidone into the reaction flask, and control the temperature at 0-5°C for reaction. After completion, add dropwise to 9.0g of intermediate A in 50ml of tetrahydrofuran solution, then control the temperature to 5°C for 3 hours of reaction, after the reaction is completed, warm up to room temperature, filter with suction, add water to beat the solid, wash with water, filter with suction, and dry to obtain 10.2...

Embodiment 2

[0036] 1) Dissolve 10.0g of 6-chloromethyluracil in 100ml of N,N-dimethylformamide, add 16.5g of chlorosuccinimide with stirring at room temperature, heat up to 60°C after addition, and Insulation reaction was carried out for 3h. The reacted system was added to 400ml of water to precipitate a light yellow solid. After suction filtration and drying, 11.4g of intermediate A was obtained, with a yield of 94.0%.

[0037] 2) Add 37.5ml of lithium diisopropylamide THF solution (2.0mol / L) into the reaction flask, add 50ml of methanol, slowly drop 6.6g of α-pyrrolidone into the reaction flask, and control the temperature at 0-5°C for reaction After the reaction is complete, add it dropwise to 10 g of intermediate A in methanol solution, then control the temperature to 0 ° C for 3 hours, after the reaction is completed, warm up to room temperature, filter with suction, add water to beat, wash with water, filter with suction, and dry to obtain 11.3 g Intermediate B, yield 90.0%.

[00...

Embodiment 3

[0040] 1) Dissolve 10.0g of 6-chloromethyluracil in 100ml of N,N-dimethylformamide, add 16.8g of chlorosuccinimide with stirring at room temperature, raise the temperature to 60°C after the addition, and carry out Insulation reaction 4h. The reacted system was added to 400ml of water to precipitate a light yellow solid. After suction filtration and drying, 11.2g of intermediate A was obtained, with a yield of 92.3%.

[0041] 2) Add 38.2ml of n-butyllithium n-hexane solution (2mol / L) into the reaction flask, add 50ml of methanol, slowly drop 6.5g of α-pyrrolidone into the reaction flask, and control the temperature at 0-5°C for reaction. After completion, add dropwise to 10g of intermediate A in methanol solution, then control the temperature to 0°C for 2 hours of reaction, after the reaction is completed, warm up to room temperature, filter with suction, add water to beat, wash with water, filter with suction, and dry to obtain 11.2g of intermediate B , yield 89.2%.

[0042]...

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Abstract

The invention discloses a preparation method of tipiracil. The method comprises the following steps: by using 6-chloromethyl uracil as the initial raw material, carrying out chlorination reaction to obtain an intermediate A, carrying out condensation reaction on the intermediate A and alpha-pyrrolidone in the presence of strong alkali to enhance the reaction selectivity, and finally, carrying out ammonolysis reaction on the intermediate B to obtain the tipiracil. The preparation method is simple, has the advantages of mild reaction conditions and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically relates to a preparation method of tipiracil. Background technique [0002] Tipiracil hydrochloride (TPI) is one of the main components of fluoropyrimidine tablets, and fluoropyrimidine tablets are a compound preparation developed by Japan Dapeng Pharmaceutical Industry Co., Ltd. In March 2014, the drug was approved by Japanese PMDA For unresectable advanced or recurrent colorectal cancer refractory to standard regimens. The components in fluridine tablets contain tipiracil hydrochloride (TPI), and tipiracil hydrochloride can inhibit thymidine phosphorylase involved in the degradation of trifluorothymidine, so as to maintain the effective blood level of trifluorothymidine. At the same time, it can inhibit the adverse reaction of trifluorothymidine alone, thereby enhancing the safety of medication. The structural formula of Tipiracil Hydrochloride is shown below. [0003]...

Claims

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Application Information

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IPC IPC(8): C07D403/06
CPCC07D403/06
Inventor 高大龙杨庆坤周学文李保勇吴柯张兆珍董廷华杨波勇
Owner 山东安信制药有限公司
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