Unlock instant, AI-driven research and patent intelligence for your innovation.

New preparation method of febuxostat

A febuxostat and new process technology, which is applied in the field of febuxostat's new process preparation method, can solve the problems of high factory equipment requirements, difficult wastewater treatment, high risk, shorten production cycle, increase cost, The effect of short reaction time

Inactive Publication Date: 2013-02-20
葛长乐
View PDF8 Cites 9 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] This route has many deficiencies in the process of preparing febuxostat: the raw material 3-nitro-4-hydroxybenzaldehyde is difficult to purchase in China; it needs to use the hydrogenation reaction under the catalysis of palladium carbon, which is harmful to the factory equipment. The requirements are high, and there is a certain risk; in the preparation of cyanide, sodium nitrite needs to be used for diazotization reaction, which is easy to cause corrosion of equipment; in the preparation of cyanide, it is necessary to use highly toxic cuprous cyanide, Potassium cyanide, high pollution and high risk
[0013] In the process of synthesizing febuxostat in this route, since potassium cyanide is used to introduce cyano groups, there are problems of high toxicity, high risk, and difficult wastewater treatment

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • New preparation method of febuxostat
  • New preparation method of febuxostat
  • New preparation method of febuxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The preparation of embodiment 1 3-formyl-4-hydroxyl thiobenzamide

[0042] Sodium hydrosulfide (67g, content 70%, 0.84mol) and magnesium chloride hexahydrate (85g, 0.42mol) were added to a 2L three-necked flask, and DMF (420ml) was added to dissolve under stirring. Then 2-hydroxy-5-cyano-benzaldehyde (61.80 g, 0.42 mol) was added, heated and heated for 1 h under stirring according to the conditions in Table 1, and detected by TLC. When the reaction was almost complete, 800 mL of purified water was added. Under stirring, the pH was adjusted to 3 with concentrated hydrochloric acid. Then extract with ethyl acetate, 400ml ethyl acetate each time, extract 3 times. Separate the layers and combine the organic layers. The organic layer was washed 3 times with saturated brine, 200ml each time. The organic layer was washed with purified water three times, 2000 ml each time. After the organic layer was separated, it was dried over anhydrous magnesium sulfate (100 g). After ...

Embodiment 2

[0048] Example 2 Preparation of 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-ethoxycarbonylthiazole

[0049] Add the product of step 1 (63.96, 0.35mol) into a 1L three-necked flask, add 600mL of absolute ethanol, and dissolve completely under stirring. Added ethyl 2-chloroacetoacetate (61.02g, 0.37mol) and then added 1g of KI, and heated to reflux for 6h. After the reaction was completed, the heating was removed, and the temperature was naturally cooled to room temperature, and solids were precipitated. Filter and dry the filter cake to obtain 64.24 g of light yellow-green solid with a yield of 63.0%.

[0050] MS (m / z): 292.0 [M+H]

[0051] HPLC purity: 99.0%.

Embodiment 3

[0052] Example 3 Preparation of 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-ethoxycarbonylthiazole

[0053] The product of step 2 (37.87g, 0.13mol) was added to a 500mL three-necked flask, formic acid (88%, 200ml) was added, and then hydroxylamine hydrochloride (10.51g, 0.15mol) and sodium formate dihydrate (21.0g, 0.20mol) were added. Stirring and heating, warming to reflux. Insulation and reflux reaction for 6h. TLC followed the reaction. After the reaction was finished, cool and crystallize naturally, and filter. The filter cake was dispersed with water, and the pH was adjusted to 9 with 10% potassium hydroxide. Then adjust the pH to 3 with 10% dilute hydrochloric acid. A pale yellow solid precipitated out. Dry to obtain 31.90 g of light yellow powder solid, yield 85.1%.

[0054] MS (m / z): 289.1 [M+H]

[0055] HPLC purity: 97.5%.

[0056] TLC detection reaction. Developing agent: petroleum ether / ethyl acetate=3:1

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
Melting pointaaaaaaaaaa
Login to View More

Abstract

The invention relates to a new preparation method of febuxostat. The new preparation method includes subjecting 2-hydroxyl-5- cyan-benzaldehyde and NaSH to reaction in solvent to obtain 3- aldehyde-4-hydroxybenzothioamide; subjecting 3-aldehyde-4-hydroxybenzothioamide and 2-halogenoacetyl ethyl acetate to reaction to obtain 2-(3-aldehyde-4-hydroxycyclohexyl phenyl)-4-methyl-5-ethoxy thiazolecarboxylate in a closed loop manner; subjecting the 2-(3- aldehyde-4-hydroxycyclohexyl phenyl)-4-methyl-5- ethoxy thiazolecarboxylate and hydroxylamine to reaction in formic acid solution to obtain 2-(3-cyan-4- hydroxycyclohexyl phenyl)-4-methyl-5- ethoxy thiazolecarboxylate; subjecting the product and halogenated isobutene to reaction under effect of potassium carbonate to obtain 2-(3- aldehyde-4- isobutoxyphenyl)-4-methyl-5- ethoxy thiazolecarboxylate; and finally removing ester group by hydrolysis through sodium hydroxide to obtain the febuxostat. The preparation method is simple in process and good in reproducibility, free of use of cyanide, few in byproducts, low in pollution, high in yield, low in cost, short in production cycle, and suitable for industrial production; raw materials and reagents used in the preparation method are easy to obtain and low in toxicity; and quality of products is easy to control.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a new process for preparing febuxostat. Background technique [0002] The occurrence of gout is due to the excessive production of uric acid in the body and the decline in the ability of the kidneys to clear it. The accumulation of uric acid in the body leads to the deposition of urate crystals in the joints and various organs. Therefore, the usual means of treatment for gout is to promote uric acid excretion and inhibit uric acid production, and take appropriate measures to improve related symptoms. The generation of uric acid in the body is related to purine metabolism. In the last step of purine metabolism, hypoxanthine generates xanthine under the action of xanthine oxidoreductase (XOR), and then further generates uric acid. Inhibiting the activity of this enzyme can effectively reduce Production of uric acid. Febuxostat is the latest XOR inhibitor developed in the wor...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D277/56
Inventor 葛长乐
Owner 葛长乐