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Synthesis method for transforming impurity 3-formyl febuxostat into febuxostat

A formyl febux and synthesis method technology, applied in the field of pharmaceutical chemical synthesis, can solve problems such as unreasonable utilization, environmental pollution, difficult control of diazotization reaction, etc., and achieve convenient operation, high yield, suitable for large-scale The effect of large-scale industrial production

Inactive Publication Date: 2018-07-20
TIANJIN LISHENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The diazotization reaction of this route is not easy to control, and the cyanation reaction requires metered cuprous cyanide, which is likely to cause environmental pollution; 3) JP 6345724 announced that 4-nitrobenzonitrile was used as the starting material to undergo Dinitrile was obtained, alkylation with isobutyl bromide, thiolation, and cyclization gave 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5 -Ethyl thiazole carboxylate, finally hydrolyzed to obtain febuta; 4) JP 1994329647 announced that 4-hydroxyphenyl thioformamide was used as raw material, after cyclization, formylation, alkylation, dehydration to nitrile group, hydrolysis ended up with febuxostat
[0006] 3-Formyl febuxostat is an impurity that appears during the synthesis of febuxostat. In the past, this impurity was removed during the refining process and has not been rationally utilized.
So far no studies have been reported on the conversion of 3-formyl febuxostat to febuxostat

Method used

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  • Synthesis method for transforming impurity 3-formyl febuxostat into febuxostat
  • Synthesis method for transforming impurity 3-formyl febuxostat into febuxostat
  • Synthesis method for transforming impurity 3-formyl febuxostat into febuxostat

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Experimental program
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Effect test

Embodiment 1

[0026] Add 3.19 g (0.01 mol) 3-formyl febuxostat, 2.3 g (0.02 mol) azidotrimethylsilane, and 50 ml ethyl acetate to a 100 ml three-necked flask equipped with a thermometer and mechanically stirred. , slowly added 6.88 g (0.04mol) of p-toluenesulfonic acid, heated in a water bath, raised the temperature to 40 °C, and kept the temperature for 12 hours. The reaction was monitored by TLC. 2.59 g of febuxostat was obtained by crystallization, with a yield of 82% and a content of 97.9%.

Embodiment 2

[0028] Add 3.19 g (0.01 mol) 3-formyl febuxostat, 3.94 g (0.02 mol) p-toluenesulfonyl azide, 50 ml ethyl acetate, respectively, to a 100 ml three-neck flask equipped with a thermometer and mechanical stirring. Slowly add 6.88 g (0.04mol) of p-toluenesulfonic acid, heat in a water bath, raise the temperature to 40 °C, keep the temperature for 12 hours, and monitor the reaction by TLC. After the reaction, distill off the ethyl acetate in the reaction solution and recrystallize with ethanol 2.56 g of febuxostat was obtained with a yield of 81% and a content of 98.0%.

Embodiment 3

[0030] Add 3.19 g (0.01 mol) 3-formyl febuxostat, 1.3 g (0.02 mol) sodium azide, and 50 ml ethyl acetate to a 100 ml three-necked flask equipped with a thermometer and mechanical stirring, and slowly add 6.88 g (0.04 mol) of p-toluenesulfonic acid, heated in a water bath, raised the temperature to 40 ° C, kept the temperature for 12 hours, and monitored the reaction by TLC. After the reaction, distilled off the ethyl acetate in the reaction solution, and recrystallized with ethanol to obtain non- Buxostat 2.81 g, yield 89%, content 98.5%.

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Abstract

The invention relates a synthesis method for transforming a main impurity 3-formyl febuxostat of febuxostat into the febuxostat. The synthesis method comprises the following steps: taking the 3-formylfebuxostat as a starting raw material, and carrying out chemical reaction in a nitrogen-containing reagent and an organic solvent of Bronsted acid; finishing transformation of a functional group by utilizing Schmidt reaction, so as to transform a formyl group into a cyano group, so as to finally obtain the febuxostat. The invention discloses the novel method for transforming the functional group,i.e., the formyl group, into the cyano group by taking the impurity 3-formyl febuxostat as the starting material to synthesize the febuxostat for the first time. The synthesis method has the characteristic of convenience for operation, simple synthesis technology, high yield and the like.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a synthetic method for converting drug impurities into finished drugs, more specifically, a method for converting febuxostat impurities into febuxostat, that is, converting 3-formyl febuxostat into febuxostat Stata. Background technique [0002] The chemical name of Febuxostat is: 2-(3-cyano-4-isobutoxy)-4-methyl-5-thiazolecarboxylic acid, and its chemical structure is: [0003] [0004] Febuxostat is a selective inhibitor of non-purine xanthine oxidase / xanthine dehydrogenase, which is clinically used to reduce blood uric acid in patients with gout. In April 2008, the European EMEA approved the marketing of febuxostat tablets, and in February 2009, the US FDA approved the marketing of febuxostat tablets. Compared with similar drugs, febuxostat has high selectivity and stronger activity, and its curative effect is better than allopurinol, the current g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 石亮亮张瑜霍志甲宋昆泽姜根华
Owner TIANJIN LISHENG PHARM CO LTD
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