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Process for the synthesis of chlorzoxazone

a chlorzoxazone and process technology, applied in the field of chlorzoxazone synthesis, can solve the problems of increasing work volume, inefficient industrial scale, and not particularly economical synthesis in terms of energy

Inactive Publication Date: 2017-01-26
PROCOS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a method for synthesizing the muscle relaxant chlorzoxazone using different starting materials and chemicals. The methods described in the text involve the use of urea or phosgene, which are toxic and require special precautions for use and disposal. The technical effects of the patent text are to provide alternative methods for synthesizing chlorzoxazone that do not require the use of urea or phosgene, which are more efficient and safe for industrial scale production.

Problems solved by technology

The patent does not report the degree of purity of the product obtained and, despite the high yield of the process, this synthesis is not particularly economical in terms of energy because very high temperatures are used.
Moreover, the required work-up considerably increases the volumes of work, making it inefficient on an industrial scale.
The procedure does not provide any data relating to the yield or purity of the chlorzoxazone (1) obtained, but even if they were excellent, the process presents the significant drawback of the manageability of phosgene, a particularly reactive, toxic reagent which requires special precautions for both use and disposal.
The procedure described therein also appears unsatisfactory in terms of yields.
The use of CO is problematic; said gas is highly poisonous, and insidious because it is odourless, colourless and tasteless.
Its extremely hazardous nature requires particular precautions which make its industrial use extremely complicated.

Method used

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  • Process for the synthesis of chlorzoxazone
  • Process for the synthesis of chlorzoxazone
  • Process for the synthesis of chlorzoxazone

Examples

Experimental program
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Effect test

example 1

[0036]Ethyl chloroformate (9.8 g, 90.5 mmol) is dripped into a suspension of potassium carbonate (27.9 g, 201.8 mol) and 4-chloro-2-aminophenol (10.0 g, 69.6 mmol) in ethyl acetate (70 mL), heated to 60° C., in 4 hours. After completion of the reaction, the mixture is cooled at 5° C. for 1.5 hours, and the reaction mixture is filtered and re-washed with ethyl acetate (15 mL). The crude product is reduced to a pulp in water for 1.5 hours, filtered under vacuum and washed with water (10 mL); chlorzoxazone (1) (11.1 g), with a purity exceeding 98%, is obtained. Molar yield from 4-chloro-2-aminophenol to chlorzoxazone: 94%.

example 2

[0037]Ethyl chloroformate (2.9 g, 26.3 mmol) is dripped into a solution of 4-chloro-2-aminophenol (3.0 g, 20.9 mmol) and triethylamine (2.7 g, 26.3 mmol) in acetonitrile (20.9 mL), cooled to 0° C. The mixture is left under stirring at 0° C. for one hour, and potassium carbonate (8.4 g, 60.8 mmol) is then added. The resulting mixture is left under stirring at 60° C. for 18 h. After completion of the reaction, the mixture is cooled at 5° C. for 1.5 hours, and the reaction mixture is filtered and re-washed with acetonitrile (5 mL). The crude product is reduced to a pulp in water for 1.5 hours, filtered under vacuum and washed with water (10 mL); chlorzoxazone (1), with a purity exceeding 96%, is obtained. Molar yield from 4-chloro-2-aminophenol to chlorzoxazone: 92%.

example 3

[0038]Ethyl chloroformate (1.96 g, 18.1 mmol) is dripped into a suspension of sodium bicarbonate (5.8 g, 69.0 mmol) and 4-chloro-2-aminophenol (2.0 g, 13.9 mmol) in water (11 ml) at 0° C. The mixture is left to stand at room temperature for about half an hour, after which potassium carbonate is added and the reaction mixture is heated to 55-60° C. The reaction is finished after 2 hours. The reaction mixture is filtered and re-washed with water (10 mL) to obtain chlorzoxazone (1) (2.3 g, 13.6 mol) with a purity exceeding 95%. Molar yield from 4-chloro-2-aminophenol to chlorzoxazone: 98%.

[0039]UPLC-MS [M-H]−=168 m / z

[0040]1H-NMR (in DMSO) (chemical shifts expressed in ppm relative to the TMS signal): 11.82 (1H, s), 7.31 (1H, d), 7.15 (1H, dd), 7.13-7.11 (1H, m). 13C-NMR: 154.7, 142.6, 132.2, 128.2, 121.9, 111.2, 110.3.

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Abstract

Disclosed is a process for the synthesis of chlorzoxazone (1) from 4-chloro-2-aminophenol and ethyl chloroformate in the presence of a base.The process is particularly advantageous because it uses ethyl chloroformate instead of triphosgene, a highly dangerous reagent that releases phosgene and must be handled with extremely strict procedures to guarantee the safety of operators in industrial facilities.Ethyl chloroformate allows the possibility of working with a number of solvents, including water.The yield and purity of the product obtained are very high.

Description

[0001]This application claims priority to and the benefit of Italian Patent Application No. 102015000037594 filed on Jul. 23, 2015, incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Chlorzoxazone, 5-chlorobenzo[d]oxazol-2(3H)-one, is a muscle relaxant which acts at central level and is used in the treatment of muscle spasms and the resulting pain. Chlorzoxazone acts on the spinal cord, by depressing / suppressing the reflexes.[0003]A number of examples of synthesis of chlorzoxazone (1) from 4-chloro-2-aminophenol, into which an acyl group, usually from urea or phosgene, is inserted, are described in the literature. Cases in which the carbonyl group inserted is directly gaseous CO are also reported.[0004]A representative example of the use of urea for the synthesis of chlorzoxazone (1) is reported in U.S. Pat. No. 3,812,138 (DE2131366), which discloses the formation of dibenzothiazolones from various aminophenols / aminothiols in the presence of urea and m...

Claims

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Application Information

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IPC IPC(8): C07D263/58
CPCC07D263/58
Inventor BOGOGNA, LUIGICICIONE, LAVINIABAROZZA, ALESSANDROROLETTO, JACOPOPAISSONI, PAOLO
Owner PROCOS
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