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Afloqualone preparation method

A technology for fluoroquinone and naphthoquinone, which is applied in the field of preparation of fluoroquinone, can solve the problems of low total yield, increase fluorine exchange reaction, increase upper protection and deprotection reaction, etc., and achieves reduction of production cost, The effect of increasing conversion rates

Active Publication Date: 2014-03-05
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The total yield of this process is 28%. This method also replaces fluoroacetyl chloride with chloroacetyl chloride, but not only increases the fluorine exchange reaction but also increases the protection and deprotection reactions. The reaction steps are many, the total yield is low, and the cost is high.
During the verification process of this process, it was found that dechlorination phenomenon was found in the process of hydrogen reduction of Pd-C, resulting in a very low yield of this step reaction

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0034] Synthesis of 5-Nitroisatoic Anhydride 2

[0035] Add concentrated sulfuric acid (100mL) into a 250mL three-necked flask, slowly add isatoic anhydride 1 (30.0g, 0.18mol) under mechanical stirring at 0-10°C, stir and dissolve, then add 65% concentrated nitric acid (21.4g, 0.22 mol), maintain the temperature at 0-10°C, drop the addition for 1 hour, keep warm and continue the reaction for 1 hour, stop stirring, slowly pour the reaction solution into 300mL ice-water mixture, stir for 20 minutes, the solid is fully separated out, filtered, washed with water, and dried to obtain 5-nitroisatoic anhydride 2 (37.5 g, yield: 97.9%). m.p.264.8-265.5°C; the purity measured by HPLC is 98.4% (the mobile phase is acetonitrile: 20mmol / L KH 2 PO 4 Aqueous solution (pH3.25)=30:70, V / V).

Embodiment 2

[0037] Synthesis of 5-Nitroisatoic Anhydride 2

[0038] Add concentrated sulfuric acid (100mL) into a 250mL three-necked flask, slowly add isatoic anhydride 1 (30.0g, 0.18mol) at 0-10°C under mechanical stirring, stir and dissolve, then add dropwise 98% fuming nitric acid (14.2g, 0.22mol), maintain the temperature at 0-5°C, add dropwise for 1h, keep warm and continue to react for 1h, stop stirring, slowly pour the reaction solution into 300mL ice-water mixture, stir for 20min, the solid is fully separated out, filtered, washed with water, and dried 5-nitroisatoic anhydride 2 (37.0 g, yield: 96.6%) was obtained. m.p.263.8-265.3°C; the purity measured by HPLC is 97.2% (the mobile phase is acetonitrile: 20mmol / L KH 2 PO 4 Aqueous solution (pH3.25)=30:70, V / V).

Embodiment 3

[0040] Synthesis of 5-Acetamidoisatoic Anhydride 3

[0041] In a 500mL autoclave, add 5-nitroisatoic anhydride 2 (20.0g, 96.0mmol), tetrahydrofuran (200mL), Raney nickel (1.00g, purchased from Aladdin Reagents (Shanghai) Co., Ltd., product number R111435, The specification is 500g, 20-40 mesh, and the Raney nickel used in other examples of this specification is the same), first replace the air with nitrogen three times, check the air tightness, then replace the nitrogen with hydrogen three times, and maintain the pressure at 2.0Mpa with hydrogen , react at 60°C for 2h, stop the reaction, filter out Raney nickel, add acetic anhydride (9.79g, 96.0mmol) to the filtrate at room temperature, stir and react for 1h, then concentrate under reduced pressure and dry to obtain 5-acetamido Isatoic anhydride 3 (20.1 g, yield: 95.0%). m.p.215.1-216.0°C; the purity measured by HPLC is 98.0% (the mobile phase is acetonitrile: 20mmol / L KH 2 PO 4 Aqueous solution (pH3.25)=50:50, V / V).

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Abstract

The present invention discloses a afloqualone preparation method, which comprises: adopting an isatin anhydride as a starting raw material, carrying out nitration, reduction and acetylation to synthesize a key intermediate N-(2-amino-5-acetylaminobenzoyl)o-toluidine, and then carrying out aminolysis, cyclization, fluorine exchange and deprotection to obtain the target product afloqualone. The afloqualone preparation method has characteristics of cheap and easily-available raw materials, production cost reduction, elimination of use of highly-toxic and highly-harmful reagent fluoroacetyl chloride in the existing literature method, safety and environmental protection. In addition, tetrabutyl ammonium bromide is adopted as the phase transfer catalyst of the fluorine exchange reaction so as to substantially improve the conversion rate of the fluorine exchange reaction, and the total yield of the target product afloqualone prepared from the starting raw material isatin anhydride can be more than 60.0%.

Description

(1) Technical field [0001] The present invention relates to a preparation method of 6-amino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-phthalazinone (fluoroquinone for short), In particular, it relates to a method for preparing fluoroquinone by using isatoic anhydride as a starting material. (2) Background technology [0002] Fluoroquinone was first listed in Japan in 1983 and was developed by Japan Tanabe Co., Ltd. After more than 20 years of clinical application, it has been proved to be a relaxant with good curative effect on facial and neck muscle spasm. As a muscle relaxant, fluoroquinone mainly acts on a wider area of ​​the supraspinal center to relieve the hypertonic state of the muscles. Its central muscle relaxation activity is about 22-29 times that of toluene propanol and 8-10 times that of clomezaldone. Compared with known muscle relaxants, fluoroquinone has less side effects and toxicity, and has good safety. [0003] Before the present invention provides, t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/91
CPCC07D239/91
Inventor 陈志卫苏为科徐盼云袁其亮王超陈寅镐
Owner ZHEJIANG UNIV OF TECH
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