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Preparation methods of compound 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate and febuxostat

A technology of isobutoxyphenyl and isobutoxybenzonitrile, which is applied in the field of compound preparation, can solve problems such as low safety, many by-products, and difficult conditions to control, and achieve high safety, high yield, and easy operation. simple effect

Active Publication Date: 2014-06-25
ZHEJIANG AUSUN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this synthesis method, the expensive and corrosive Br 2 For bromination reaction, the conditions are not easy to control, and there are many by-products, which brings difficulties to the purification of the final product, and this method uses cyanide, which is highly toxic and low in safety

Method used

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  • Preparation methods of compound 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate and febuxostat
  • Preparation methods of compound 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate and febuxostat
  • Preparation methods of compound 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate and febuxostat

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preparation example Construction

[0040] The embodiment of the present invention discloses a preparation method of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, comprising the following steps:

[0041] (A) 4-isobutoxybenzonitrile reacts with a chloromethylation reagent under the action of a catalyst to obtain a compound with the structure of formula (III);

[0042]

[0043] (B) reacting the compound with the structure of formula (III) with water under the action of a catalyst to obtain the compound with the structure of formula (IV);

[0044]

[0045] (C) The compound with the structure of formula (IV) undergoes an oxidation reaction under the action of an oxidizing agent to obtain the compound with the structure of formula (V);

[0046]

[0047] (D) reacting the compound with the structure of formula (V) with sodium hydrosulfide to obtain the compound with the structure of formula (VI);

[0048]

[0049] (E) The compound with the structure of formula (VI) is reacted with et...

Embodiment 1

[0074] Add 59.6g (0.5mol) of p-hydroxybenzonitrile and 1000mL of DMF to a 3000mL four-necked round-bottom flask in sequence, add 276.4g (2.0mol) of anhydrous potassium carbonate, 33.2g (0.2mol) of potassium iodide and 274.0g of (2.0mol) isobutane bromide, slowly warm up to 80°C, stir for 6 hours, stabilize the reaction at this temperature, track with TLC during the reaction, until the raw material is completely converted, after the reaction is completed, suction filter, filter cake with 30mLN, Wash with N-dimethylformamide, add 400 mL of water to the combined filtrate, and extract with methyl tert-butyl ether. The filtrate was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, desolvated and refined with 5-7% ethyl acetate / n-hexane to obtain 84.6g of 4-isobutoxybenzonitrile with a yield of 98.5%, HPLC purity is 98.87%.

[0075] Add 13.9g of 4-isobutoxybenzonitrile, 9.45g of methoxyacetyl chloride and 200mL of nitromethane sequentially into a f...

Embodiment 2

[0081] Add 59.6g (0.5mol) of p-hydroxybenzonitrile and 1000mL of DMF to a 3000mL four-necked round-bottom flask in sequence, add 276.4g (2.0mol) of anhydrous potassium carbonate, 33.2g (0.2mol) of potassium iodide and 274.0g of (2.0mol) isobutane bromide, slowly warm up to 80°C, stir for 6 hours, stabilize the reaction at this temperature, track with TLC during the reaction, until the raw material is completely converted, after the reaction is completed, suction filter, filter cake with 30mLN, Wash with N-dimethylformamide, add 400 mL of water to the combined filtrate, and extract with methyl tert-butyl ether. The filtrate was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, desolvated and refined with 5-7% ethyl acetate / n-hexane to obtain 84.6g of 4-isobutoxybenzonitrile with a yield of 98.5%, HPLC purity is 98.87%.

[0082] Add 13.9g of 4-isobutoxybenzonitrile, 3.0g of paraformaldehyde and 50mL of nitromethane in sequence into a 100mL thre...

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Abstract

The invention provides a preparation method of 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate which is obtained by using 4-isobutoxy cyanophenyl as an initial raw material and through a series of reactions. The invention also provides a preparation method of febuxostat, which comprises the following steps: reacting 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate with hydroxylamine hydrochloride under the action of a catalyst to obtain a compound with a structure as shown in formula (VIII); hydrolyzing the compound with the structure as shown in formula (VIII) under an alkaline condition, and performing acidification to obtain febuxostat. The preparation method of the invention prepares febuxostat without using cyanides, and is high in safety. The preparation methods of the invention are simple in operation and high in yield. Experiment results show that the yield of step (A) is up to 90%, the yield of step (B) is up to 85%, the yield of step (C) is up to 90%, the yield of step (D) is up to 90%, and the yield of step (E) is up to 97%.

Description

technical field [0001] The invention relates to the field of compound preparation, in particular to a preparation method of the compound 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester and febuxostat. Background technique [0002] The chemical name of febuxostat is 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid, and its chemical structure is shown in formula (IX): [0003] [0004] Febuxostat is a non-purine xanthine oxidase selective inhibitor for the treatment of hyperuricemia in gout patients. Febuxostat inhibits the activity of xanthine oxidase, prevents and reduces the synthesis of uric acid from hypoxanthine or xanthine, so as to achieve the purpose of reducing blood uric acid. Compared with allopurine drugs for the treatment of gout, febuxostat has obvious advantages: first, it has a significant inhibitory effect on xanthine oxidase, and the effect of lowering uric acid is stronger and more durable; second, it will n...

Claims

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Application Information

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IPC IPC(8): C07D277/56C07C255/54
CPCC07C255/54C07D277/56
Inventor 黄庆云黄欢
Owner ZHEJIANG AUSUN PHARMA
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