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A kind of "one pot method" synthetic method of febuxostat intermediate

A synthesis method and a febuxostat technology, applied in the field of pharmaceutical technology, can solve the problems of high production cost and operational risk, and achieve the effects of easy industrial application, good quality and improved production efficiency

Active Publication Date: 2020-09-25
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This route uses noble metals to catalyze hydrogenation and diazotization reactions, uses highly toxic cyanide, and has relatively high production costs and operational risks.

Method used

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  • A kind of "one pot method" synthetic method of febuxostat intermediate
  • A kind of "one pot method" synthetic method of febuxostat intermediate
  • A kind of "one pot method" synthetic method of febuxostat intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Add compound II (2-(4-hydroxyphenyl)-4-methylthiazole-5-ethyl carboxylate) 10g, anhydrous potassium carbonate 13.2g (2.6eqv) into a 100ml reaction kettle, and then add N,N - Dimethylformamide 40ml and bromoisobutane 13g (2.6eqv), start stirring. Raise the temperature to 75-80°C, and keep the reaction at this temperature for 5 hours; TLC is carried out in the middle control (developer: PE:EA=4:1), TLC shows that the reaction is complete, then cool down to 25°C, and remove potassium carbonate by suction filtration.

[0048] The filtrate was transferred to a 500mL reaction kettle and continued cooling and stirring. Phosphorus oxychloride 4.2mL (1.2eqv) was added dropwise at 0°C, then heated to 60°C and stirred for 2h. Cool down to 10°C, add ammonia water (25%, 57.2ml) dropwise, then add elemental iodine 10.6g, control the reaction temperature and stir at 20°C for 2h. TLC was carried out in the middle control (developer: PE:EA=4:1), after the reaction was complete, 50 mL ...

Embodiment 2

[0050] Add 50g of compound II, 66g of anhydrous potassium carbonate, 200ml of N,N-dimethylformamide and 65g of bromoisobutane into a 500ml reaction kettle, and start stirring. Raise the temperature to 90-95°C, and keep the reaction at this temperature for 2-3 hours; conduct intermediate control by TLC (developing agent: PE:EA=4:1), TLC shows that the reaction is complete, then cool down to 40-45°C, and remove carbonic acid by suction filtration potassium.

[0051] The filtrate was transferred to a 1000mL reaction kettle and continued cooling and stirring. At 0°C, 21 mL of phosphorus oxychloride was added dropwise, then the temperature was raised to 60°C and stirred for 2 hours. Cool down to 10°C, add ammonia water (25%, 286ml) dropwise, then add 53g of elemental iodine, control the reaction temperature at 20°C and stir for 2-3 hours. TLC was carried out in the middle control (developer: PE:EA=4:1), after the reaction was complete, 50 mL of saturated aqueous sodium sulfite so...

Embodiment 3

[0053] Compared with Example 2, the main difference is that adding POCl 3 After the reaction temperature is reduced, specifically as follows:

[0054] Add 10g of Compound II, 13.2g of anhydrous potassium carbonate, 40ml of N,N-dimethylformamide and 13g of bromoisobutane into a 100ml reaction kettle, and start stirring. Raise the temperature to 90-95°C, and keep the reaction at this temperature for 2-3 hours; conduct intermediate control by TLC (developer: PE:EA=4:1), TLC shows that the reaction is complete, then cool down to 25°C, and remove potassium carbonate by suction filtration.

[0055] The filtrate was transferred to a 500mL reaction kettle and continued cooling and stirring. At 0°C, 4.2 mL of phosphorus oxychloride was added dropwise, then the temperature was raised to 40°C and stirred for 2 hours. Cool down to 10°C, add ammonia water (25%, 57.2ml) dropwise, then add elemental iodine 10.6g, control the reaction temperature and stir at 20°C for 2h. TLC was carried ou...

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Abstract

The invention belongs to the field of medicine synthesis and in particular relates to a 'one pot method' synthesis method for a Febuxostat intermediate 2-(3-cyan-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate. The method comprises the following steps: by taking 2-(4-hydroxy phenyl)-4-methyl thiazole-5-ethyl formate as an initial raw material, carrying out an etherification reaction on the compound with bromo-iso-butane under catalysis of an alkali, and carrying out solid-liquid separation so as to obtain filtrate; dropping phosphorus oxychloride into the filtrate, carrying out a stirring reaction, continuously stirring with ammonia water and elementary iodine, carrying out a quenching reaction after the reaction is completed, and carrying out extraction and organic phase concentration, thereby obtaining the Febuxostat intermediate. By adopting the method provided by the invention, the key intermediate of Febuxostat can be synthesized through serial operation of a one-pot method,purity requirements can be met without multiple times of purification in the process, in addition, a good yield is achieved, and the method is applicable to industrial large-scale production.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical technology, in particular to a febuxostat intermediate 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl carboxylate method of preparation. Background technique [0002] Febuxostat, molecular formula C16H16N2O3S; molecular weight: 316.37 [0003] Structural formula: [0004] Febuxostat is a new generation drug for the treatment of gout. It is used to inhibit uric acid production and reduce blood uric acid concentration. It is the second uric acid production-inhibiting drug after allopurinol. Developed by Japan's Teijin Pharmaceuticals (Teijin Company), it was first approved for marketing in France on May 5, 2008, under the trade name Adenuric, and is used for the treatment of gout. On February 16, 2009, it was approved by the FDA and launched in the United States under the trade name Uloric. In recent years, a lot of research has been done on the synthesis of febuxostat a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 晏瑾懿宋率华刘虎袁金桥
Owner HARVEST PHARMA HUNAN CO LTD