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Preparation method of gimeracil intermediate

A technology of gimeracil and intermediates, applied in the field of chemical synthesis, can solve the problems of poor yield and purity, difficult to remove, unfavorable for large-scale industrialization, etc., and achieves the effects of improving purity, improving yield, and saving reaction steps and costs.

Pending Publication Date: 2020-12-22
LUNAN PHARMA GROUP CORPORATION
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

2-Hydroxy-4-methoxy-3-cyanopyridine is used as the starting material to prepare the crude product of gimeracil containing many impurities, which can reach more than 99% after repeated refining, and the single impurity exceeds 0.1%, which is difficult to remove. The patent Although a relatively pure product has been obtained through refining, the refining method requires the use of an elution column, a large amount of solvent, and many steps, which is not conducive to large-scale industrialization
The present inventor found that the yield and purity were very poor when verifying the existing synthetic scheme, which could not meet the requirements of industrial production
And most of the existing disclosed technologies are obtained through cyclization and chlorination of compound III in the above-mentioned route, and its yield and purity have seriously affected the quality of gimeracil, and the means for the current prior art solution are mostly for 5- Purification of chloro-3-cyano-4-methoxy-2(1H)-pyridone or purification of the final product gimeracil

Method used

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  • Preparation method of gimeracil intermediate
  • Preparation method of gimeracil intermediate
  • Preparation method of gimeracil intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0043] In the there-necked flask, add 177.2g (1mol) 1,1-dicyano-2-methoxy-4-(N,N-dimethylamino)-1,3-butadiene (III) under stirring, Mass fraction 80% acetic acid aqueous solution 708.8g, add reflux device, heat reflux reaction, TLC detection, after the reaction is completed, cool down to 20-25°C, add 850.5g of acetic anhydride, continue stirring for 1-1.5 hours; heat up 50-55°C, Then 175.5 g (1.3 mol) of sulfuryl chloride was added dropwise, and after the dropwise addition was completed, the reaction was continued with heat preservation; TLC detection, after the reaction was completed, the solvent was evaporated under reduced pressure, and 886 ml of ice water was added to the residue, and stirred and crystallized at 0-5°C 2 to 3 hours, filter, wash the filter cake with ice water, wash until the filtrate is neutral, and dry; get the off-white gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2(1H)- The yield of pyridone (V) is 96.5%; the HPLC purity is 99.928%, and the maximum ...

Embodiment 2

[0045] In the there-necked flask, add 177.2g (1mol) 1,1-dicyano-2-methoxy-4-(N,N-dimethylamino)-1,3-butadiene (III) under stirring, Mass fraction 80% acetic acid aqueous solution 531.6g, add reflux device, heat reflux reaction, TLC detection, after the completion of the reaction, cool down to 20-25°C, add 611.4g of acetic anhydride, continue to stir for 1-1.5 hours; heat up to 50-55°C, Then sulfonyl chloride 162g (1.2mol) was added dropwise, and after the dropwise addition was completed, the reaction was continued with insulation; TLC detected that after the reaction was completed, the solvent was evaporated under reduced pressure, and 708ml of ice water was added to the residue, and stirred and crystallized at 0-5°C for 2 ~3 hours, filter, wash the filtrate with ice water to neutrality, and dry; to obtain the off-white gemeracil intermediate 5-chloro-3-cyano-4-methoxy-2(1H)-pyridone (V), The yield is 94.38%; the HPLC purity is 99.920%, and the maximum simplex is less than 0.1...

Embodiment 3

[0047] In the there-necked flask, add 177.2g (1mol) 1,1-dicyano-2-methoxy-4-(N,N-dimethylamino)-1,3-butadiene (III) under stirring, Mass fraction 80% acetic acid aqueous solution 886.0g, add reflux device, heat reflux reaction, TLC detection, after the reaction is completed, cool down to 20-25°C, add 1151.8g of acetic anhydride, continue stirring for 1-1.5 hours; heat up 50-55°C, Then 189.0 g (1.4 mol) of sulfuryl chloride was added dropwise. After the dropwise addition was completed, the reaction was continued with heat preservation; TLC detection, after the reaction was completed, the solvent was evaporated under reduced pressure, and 532 ml of ice water was added to the residue, and the crystallization was stirred at 0-5 ° C. 2 to 3 hours, filter, wash the filtrate with ice water to neutrality, and dry; to obtain the off-white gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2(1H)-pyridone (V) , the yield is 95.6%; the HPLC purity is 99.917%, and the maximum single impurit...

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Abstract

The invention belongs to the technical field of chemical synthesis, and provides a method for preparing a gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2(1H)-pyridone, wherein the method comprisesthe steps: by using 1,1-dicyano-2-methoxy-4-(N,N-dimethylamino)-1,3-butadiene as a starting material, carrying out reflux cyclization in an acetic acid aqueous solution with the mass fraction of 80%,cooling the reaction solution, adding acetic anhydride, heating to a required temperature, dropwise adding sulfonyl chloride for chlorination, and treating to obtain a product. The method is good inyield, high in purity, easy to operate, capable of saving production cost and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of a gimeracil intermediate. Background technique [0002] Gimeracil (I), chemical name: 5-chloro-4-hydroxyl-2-(lH)-pyridone, CAS No. 103766-25-2, its structural formula is as follows: [0003] [0004] Gimeracil is one of the components of the new drug S-1 for the treatment of gastric cancer. It can inhibit the catabolism of 5-fluorouracil released from tegafur under the action of dihydropyrimidine dehydrogenase, which helps to maintain blood and tumors for a long time. The effective concentration of 5-fluorouracil in the tissue, so as to achieve the same effect as continuous intravenous infusion of 5-fluorouracil. [0005] S-1 is a fluorouracil derivative oral anticancer agent, which includes tegafur and the following two types of modulators: gimeracil and oteracil. The functions of its three components are as follows: Tegafur is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/85C07D213/69
CPCC07D213/69C07D213/85
Inventor 白文钦朱姚亮
Owner LUNAN PHARMA GROUP CORPORATION
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