Preparation method and detection method of febuxostat raw material

A kind of technology of febuxostat and detection method, applied in the field of preparation of febuxostat raw materials

Inactive Publication Date: 2013-04-10
GUIZHOU XINBANG PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] In addition, there is currently no set of strict and reliable quality testing standards for febuxostat raw materials

Method used

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  • Preparation method and detection method of febuxostat raw material
  • Preparation method and detection method of febuxostat raw material
  • Preparation method and detection method of febuxostat raw material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0333] Embodiment 1: the synthesis of intermediate III

[0334] Add 500g and 4.2mol of p-hydroxybenzonitrile II and 2000mL of HCl-saturated DMF to the reaction flask in sequence, add 565g and 7.5mol of thioacetamide under stirring, raise the temperature to 100°C, and stir for 5 hours; monitor the reaction by TLC , where R f II = 0.7, R f III=0.5, developer: ethyl acetate:petroleum ether=1:1, GF254 silica gel plate; stop heating, recover DMF under reduced pressure, add 1.5L water to the residue, extract twice with ethyl acetate, 4500mL each time, combine The organic phase was depressurized until the solvent was exhausted to obtain a viscous solid, which was added with 4000 mL of dichloromethane, stirred and dispersed for 30 min, filtered to obtain a tan solid, dried at 60°C, and weighed to obtain 421 g of Intermediate III, with a yield of 65.5%. TLC detected as a single spot.

Embodiment 2

[0335] Embodiment 2: the synthesis of intermediate IV

[0336] In the reaction bottle, add 420g, 2.74mol of intermediate III, 7.8L of absolute ethanol and 546g, 3.36mol of ethyl 2-chloroacetoacetate in sequence, stir to form a suspension, and heat to reflux for 5h; monitor the reaction by TLC , where, RfIII=0.5, RfⅣ=0.8, developing agent: ethyl acetate:petroleum ether=1:1, GF254 silica gel plate; stop heating, after a little cooling, recover ethanol under reduced pressure until exhausted, add ethyl acetate 2500mL to the residue , stirred for 20 min, filtered, washed with 200 mL of ethyl acetate, and dried to obtain a tan solid, which was dried under reduced pressure at 50°C overnight, and weighed to obtain 650 g of intermediate IV with a yield of 90.0%, which was detected as a single spot by TLC.

Embodiment 3

[0337] Embodiment 3: the synthesis of intermediate V

[0338] Under stirring, 650g, 2.46mol of intermediate IV and 357g, 2.55mol of hexamethylenetetramine were added to a reaction flask containing 3.57kg of polyphosphoric acid, heated to 100°C, and reacted for 2 hours; the reaction was monitored by TLC, Among them, R f IV=0.4,R f Ⅴ=0.55, developer: ethyl acetate:petroleum ether=1:3, GF254 silica gel plate; stop heating, add ice water 1100mL after cooling slightly, stir, extract with ethyl acetate 3 times, 1200mL each time, combine the organic phases, Wash twice with saturated brine, 1000 mL each time, dry over anhydrous sodium sulfate, filter, and recover ethyl acetate from the filtrate under reduced pressure to obtain 368 g of yellow solid, namely intermediate V, with a yield of 51.2%, and its TLC detection is basically a single spot.

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Abstract

The invention discloses a preparation method and a detection method of febuxostat raw material. The preparation method comprises Cyanophenol, DMF (Dimethyl Formamide) saturated with HCl, and thioacetamide are mixed and react to obtain an intermediateIII; the intermediate III, anhydrous ethyl alcohol, 2-chlorination acetoacetic ester are mixed and react to obtain an intermediate IV; the intermediate IV, hexamethylene tetramine and polyphosphoric acid are mixed and react to obtain an intermediate V; the intermediate V, DMF, anhydrous potassium carbonate and bromo-2-methylpropane are mixed and react to obtain an intermediate VI; the intermediate VI, anhydrous formic acid, oxammonium hydrochloride and sodium formate are mixed and react to obtain an intermediate VII; the intermediate VII, anhydrous ethyl alcohol and sodium hydroxide are mixed and react to obtain a febuxostat crude product; and refining and crystal transformation are performed to the febuxostat crude product to obtain the febuxostat raw material. Aiming at avoiding defects in the prior art, the preparation technology of the febuxostat raw material is optimized, and a systematic, complete and effective component identifying and content measuring method is established.

Description

technical field [0001] The invention relates to a preparation method and detection method of febuxostat raw material, belonging to the technical field of medicinal chemistry. Background technique [0002] Gout is a group of heterogeneous diseases with increased blood uric acid caused by purine metabolism disorders and (or) acid excretion disorders. Gout has been a common disease in developed countries such as Europe and the United States since ancient times. In the past 20 years, the prevalence of hyperuricemia and gout in Asia has been significantly increasing. [0003] Allopurinol is the only drug used to inhibit the production of uric acid clinically, and it is widely used clinically as a gold drug for gout. Maintain a high drug level, many patients are allergic to allopurinol, ineffective or intolerable. [0004] Febuxostat (febuxostat) is a specific xanthine oxidase inhibitor, English name: febuxostat, chemical name: 2-[3-cyano-4-(2-methylpropoxy)phenyl ]-4-methylth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56G01N30/02
CPCG01N21/35G01N30/02G01N2030/025G01N2030/027
Inventor 张观福
Owner GUIZHOU XINBANG PHARMACEUTICAL CO LTD
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