Synthesis method of 2-(3-cyan-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid

A technology of isobutoxyphenyl thiocarboxamide and isobutoxybenzonitrile is applied in the field of synthesis of 2-phenyl-4-methyl-5-thiazole formic acid, and can solve the problem of high price and increase production Cost and other issues, to achieve the effect of low cost, easy operation and high yield

Inactive Publication Date: 2010-10-20
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Route 5 is a new route designed by our experimental group on the basis of summarizing the literature. Compared with the above four routes, it has great advantages. The raw materials are easy to obtain, the intermediates do not need to be purified by column chromatography, and the yield is high, but there are also shortcomings: The price of raw material iodine used is higher, which increases the production cost

Method used

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  • Synthesis method of 2-(3-cyan-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid
  • Synthesis method of 2-(3-cyan-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid
  • Synthesis method of 2-(3-cyan-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] (1) Preparation of 3-bromo-4-hydroxybenzonitrile

[0049] Add 10g of 4-hydroxybenzonitrile, 60mL of dichloromethane and 0.5g of iodine into a 250mL three-necked flask, stir at -5°C under temperature control, and slowly add 26.7g of bromine dropwise, after completion of the dropwise reaction, stir at room temperature for 18h . Pour the reaction solution into 110mL of NaHSO with a mass fraction of 16% 3 The solution was stirred for 30 min, filtered with suction, washed with water, and dried to obtain 14.9 g of white solid with a yield of 89.5%. EI-MS: m / z 197.0 [M-H] - . mp: 154-155°C (Document: mp: 155-156°C, J. Org. Chem. 62(13), 4504-4506, 1997).

[0050] (2) Preparation of 3-bromo-4-isobutoxybenzonitrile

[0051] Add 14.9g of 3-bromo-4-hydroxybenzonitrile, 15.0g of triethylamine, and 75mL of acetone into a 250mL round bottom flask, stir, then add 20.6g of bromoisobutane and 0.75g of potassium iodide, at 80°C Reaction 6h. Distillation under reduced pressure gave...

Embodiment 2

[0063] (1) Preparation of 3-bromo-4-hydroxybenzonitrile

[0064] Add 20g of 4-hydroxybenzonitrile, 150mL of dichloromethane and 1g of iodine into a 250mL three-necked flask, stir at 0°C under temperature control, and slowly add 53.4g of bromine dropwise, after the dropwise completion, stir at room temperature for 24h. Pour the reaction solution into 440mL of NaHSO with a mass fraction of 16% 3 solution, stirred for 30 min, filtered with suction, washed with water, and dried to obtain 30.6 g of white solid with a yield of 92.0%.

[0065] (2) Preparation of 3-bromo-4-isobutoxybenzonitrile

[0066] Add 30.6g of 3-bromo-4-hydroxybenzonitrile, 42.3g of anhydrous potassium carbonate, and 150mL of DMF into a 500mL round-bottomed flask, stir, then add 62.4g of bromoisobutane and 1.5g of PEG400, at 60°C Reaction 8h. Suction filtration while hot, wash the filter cake with DMF, and distill the filtrate under reduced pressure to obtain a yellow oil, pour it into water, extract with chl...

Embodiment 3

[0076] (1) Preparation of 3-bromo-4-hydroxybenzonitrile

[0077] Add 60g of 4-hydroxybenzonitrile, 480mL of dichloromethane and 3g of iodine into a 500mL three-necked flask, stir at -5°C under temperature control, and slowly add 160.3g of bromine dropwise. Pour the reaction solution into 660mL of NaHSO with a mass fraction of 16% 3 The solution was stirred for 30 min, filtered with suction, washed with water, and dried to obtain 89.8 g of white solid, with a yield of 90.7%.

[0078] (2) Preparation of 3-bromo-4-isobutoxybenzonitrile

[0079] Add 89.8g of 3-bromo-4-hydroxybenzonitrile, 71.7g of pyridine, and 450mL of ethanol into a 500mL round bottom flask, stir, then add 125.2g of bromoisobutane and 8g of PEG400, and react at 50°C for 8h. Distillation under reduced pressure gave a yellow oil, which was poured into water and extracted with dichloromethane. The combined organic layers were added with anhydrous sodium sulfate and dried. Filter and distill to obtain 118.7 g of ...

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Abstract

The invention belongs to the technical field of medicine, relating to a synthesis method of 2-(3-cyan-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid. The synthesis method is characterized by comprising the following steps of: brominating to obtain 3-bromine-4-hydroxyl cyanobenzene by using 4-hydroxyl cyanobenzene as a raw material, alkylating by using bromo-isobutane to obtain 3-bromine-4-isobutoxy cyanobenzene, and cyaniding with cuprous cyanide to obtain 4-isobutoxy-1,3-benzene dinitrile; carrying out a formylation reaction with sodium bisulfide to prepare 3-cyan-4-isobutoxyphenylthioformamide in the presence of anhydrous magnesium chloride, and cyclizing with 2-chloroacetoacetic acid ethyl ester to prepare 2-(3-cyan-4-isobutoxy) phenyl-4-methyl-5-thiazole ethyl formate; and finally, hydrolyzing to prepare the 2-(3-cyan-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid. The method has the characteristics of easy raw material obtaining, simple and convenient operation, higher yield, lower cost and higher final product purity (the HPLC, High Performance Liquid Chromatography purity is not lower than 99.9 percent) and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a xanthine oxidase inhibitor febuxostat (Febuxostat), the chemical name is 2-(3-cyano-4-isobutoxy)phenyl-4-methyl-5-thiazolecarboxylic acid resolve resolution. Background technique [0002] Gout is a group of heterogeneous metabolic diseases caused by long-term purine metabolism disorder and / or decreased uric acid excretion. Gout is the second most common metabolic disease in humans after diabetes. The clinical features of gout are hyperuricemia, recurrent acute arthritis, tophi deposition, gouty chronic arthritis and joint deformities, often involving the kidneys, causing chronic interstitial nephritis and kidney stones. The prerequisite for the onset of gout is hyperuricemia, which refers to the uric acid content in serum at 37°C (men exceed 70mg / L; women exceed 60mg / L). Due to the high concentration of uric acid, urate crystallization is deposited in the tissue, causing the inflammatory response of gout, and then ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
Inventor 王绍杰施翔
Owner SHENYANG PHARMA UNIVERSITY
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