Process for the synthesis of chlorzoxazone

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...

Examples

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.

[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...

Examples

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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