Method for synthesizing chlorzoxazone

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for synthesizing chlorzoxazone. According to the method, (5-chloro-2-hydroxyphenyl) tert-butyl carbamate is used as a starting material, phenolic hydroxyl of the tert-butyl carbamate is activated by methanesulfonic anhydride and then is cyclized to prepare the target product chlorzoxazone, an oxazolidinone ring is constructed by Boc carbonyl oxygen replacement reaction, use of carbonylation reagents with high toxicity, such as diphosgene, carbon tetrabromide and ethyl chloroformate, is avoided, and the method is suitable for industrial production. Meanwhile, the generation of toxic gas ammonia gas when urea participates in reaction in the prior art can be avoided, and the method is more suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing chlorzoxazone. Background Art

[0002] Chlorzoxazone (Chlorhydroxybenzamide, Chlorzoxazon), CAS No.: 95-25-0, chemical name 5-chloro-2 (3H) -benzoxazolone, is an oral strong muscle relaxant, developed by McNeil Pharmaceuticals in the United States and launched in the mid-1960s. Chlorzoxazone has been mass-produced in the United States and Japan, and is included in the United States Pharmacopeia 24th Edition and the Japanese Pharmacopoeia 13th Edition respectively. This product is one of the 100 commonly used drugs in the United States in recent years, and is listed in the "National Basic Medical Insurance Drug List" and "National Over-the-Counter Drug List" in my country. This product is a central muscle relaxant, which mainly acts on the spinal cord and subcortical centers of the cerebral cortex, inhibits the multi-synaptic nerve reflex arc related to muscle spasms, and relieves muscle spasms to achieve the effect of eliminating pain and increasing the activity of diseased muscles. It is clinically used to treat back pain, neuralgia, rheumatoid arthritis, acute and chronic soft tissue (muscle, ligament, fascia) sprains and contusions, and can also be used to treat muscle spasms, spasticity and chronic fasciitis caused by central nervous system diseases. The total effective rate is as high as 98.59%, which is better than ibuprofen and 4 times that of mefenamic acid. In addition, it also has a certain effect on children's brain dysfunction. Its chemical structure is:

[0003]

[0004] There are many reported preparation methods of chlorzoxazone, such as Wang Shaoyin et al., "Study on the synthesis process of the muscle relaxant chlorzoxazone" [J]. Pharmaceutical Industry, 1987, 18(2): 49-50, Jiao Jianyu et al., "Synthesis of the muscle relaxant chlorzoxazone" [J]. Pharmaceutical Industry, 1988, 19(9): 417-418, Wang Youhai, "Synthesis of the muscle relaxant chlorzoxazone" [J]. Modern Applied Pharmacy, 1991, 8(2): 21-22, He Haoming et al., "Synthesis of chlorzoxazone" [J]. Journal of Chinese Pharmaceutical Industry, 1992, 23(11): 489, Han Baolai et al., "Synthesis of chlorzoxazone" [J]. Journal of Kaifeng Medical College, 2000, 19(3): 53-61. , Zhang Jishi et al., "Study on New Process for the Synthesis of Chlorzoxazone" [J]. Liaoning Chemical Industry, 2004, 33(1): 21-33, Zhang Xiaoyan, "Improvement of New Process for the Synthesis of Chlorzoxazone" [J]. Fine Chemical Raw Materials and Intermediates, 2006, (1): 25-26, Li Yongshu et al., "Synthesis of Central Relaxant Chlorzoxazone from Diphosgene" [J]. Journal of High Efficiency Chemical Engineering, 2006, 20(2): 254-257, Feng Lei et al., "Synthesis of Benzoxazolone Derivatives" [J]. Journal of Wuhan University of Technology, 2011, 33(5): 12-14, as well as CN1560040A, CN106167471A, US2017022172A1 and other documents and patents have all been publicly reported.

[0005] The processes disclosed in the above documents are finally combined into the following materials to synthesize the target product:

[0006]

[0007] The first method has high requirements for equipment and needs to be prepared under high pressure with carbon monoxide under the condition of precious metals as catalysts. This method is costly and difficult to operate. The second method uses the Hofmann rearrangement reaction for preparation. Although the reaction conditions are mild, 5-chlorosalicylamide is not easy to obtain and is limited to laboratory research, making industrial production difficult. The third method uses urea for cyclization to prepare chlorzoxazone, which is more in line with industrial scale-up production and is also the main method for preparation and production at home and abroad. The only difference is the solvent and catalyst used in the cyclization process. The fourth method is to prepare chlorzoxazone by replacing other cyclization reagents, such as phosgene, N,N'-carbonyldiimidazole, diphosgene, carbon tetrabromide, N,N'-disuccinimidyl carbonate, ethyl chloroformate, etc., which can be used as cyclization reagents for oxazolidinone.

[0008] The above processes all use substituted chlorophenols to prepare chlorzoxazone. In the preparation process using urea as a cyclization reagent in method 3, the cyclization is initially carried out in a strong acid environment, but a large amount of toxic and irritating ammonia will be produced in the later stage of the reaction due to urea degradation. In addition, the reaction is carried out at a high temperature greater than 100 degrees Celsius, which places high demands on the reaction equipment. Diphosgene, carbon tetrabromide and ethyl chloroformate used in method 4 are all highly toxic and have low operational safety.

[0009] In view of the above-mentioned deficiencies in the current process for preparing chlorzoxazone, it is still a problem to be solved to study and find a process suitable for industrial production of chlorzoxazone with mild reaction conditions, simple operation process, high product yield and high purity. Summary of the invention

[0010] In view of the problems existing in the existing chlorzoxazone synthesis technology, the present invention provides a novel chlorzoxazone synthesis method. The method has mild reaction conditions, a simple operation process, and the obtained target product has high purity and yield.

[0011] The specific technical solutions of the present invention are as follows:

[0012]

[0013] A method for synthesizing chlorzoxazone as shown in formula I specifically comprises the following operations:

[0014] At room temperature, compound SM, i.e. tert-butyl (5-chloro-2-hydroxyphenyl)carbamate, methanesulfonic anhydride and a base are added to a reaction solvent and reacted under controlled temperature T. After the reaction is completed, the target product I is obtained by post-treatment.

[0015] Preferably, the base is selected from one of N,N-diisopropylethylamine, triethylamine, N-methylmorpholine or a combination thereof, wherein N,N-diisopropylethylamine is particularly preferred.

[0016] Preferably, the reaction solvent is selected from one or a combination of 1,2-dichloroethane, toluene, chlorobenzene, and bromobenzene, among which toluene is particularly preferred.

[0017] Preferably, the molar ratio of the compound SM to methanesulfonic anhydride and the base is 1:1.05-1.4:2.5-5.0, with 1:1.1:3.0 being particularly preferred.

[0018] Preferably, the reaction temperature T is 60-100°C, particularly preferably 80-85°C.

[0019] In a preferred embodiment, the post-treatment step is as follows: cooling the reaction solution to room temperature, diluting it with dichloromethane and then adding it to a 1 mol / L NaOH solution, separating the organic phase, washing it with saturated brine, concentrating the organic phase to dryness under reduced pressure and then recrystallizing it from an ethanol / purified water system to obtain the target product I.

[0020] In a preferred embodiment, the volume ratio of the refined solvent ethanol to purified water is 1:1-5, mL / mL, with 1:3, mL / mL being particularly preferred.

[0021] Beneficial effects of the present invention:

[0022] 1. The present invention provides a novel method for synthesizing chlorzoxazone, which uses tert-butyl (5-chloro-2-hydroxyphenyl)carbamate as a starting material, activates the phenolic hydroxyl group thereof with methanesulfonic anhydride, and then undergoes self-cyclization to prepare the target product chlorzoxazone.

[0023] 2. This process uses the Boc carbonyl oxygen replacement reaction to construct the oxazolidinone ring, avoiding the use of highly toxic carbonylation reagents such as diphosgene, carbon tetrabromide and ethyl chloroformate, and also avoiding the production of toxic ammonia gas when urea is used in the prior art to participate in the reaction; in addition, the reaction temperature can also be reduced to conventional heating below 100 degrees Celsius, making the operation safer and more convenient.

[0024] 3. The chlorzoxazone prepared by this process has a high yield and purity, and is suitable for industrial scale-up production. DETAILED DESCRIPTION

[0025] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention all fall within the scope of protection claimed by the present invention.

[0026] The present invention adopts HPLC to measure the purity of chlorzoxazone, and the chromatographic conditions are as follows:

[0027] Chromatographic column: YMC Triart-C 18 Column (4.6 mm × 250 mm, 5 μm) or chromatographic column with equivalent performance;

[0028] Mobile phase: Mobile phase A: (1.15 g of ammonium dihydrogen phosphate, dissolved in water and diluted to 1000 mL, pH adjusted to 6.0 ± 0.2 with ammonia)-acetonitrile (75:25), mobile phase B: acetonitrile, gradient elution;

[0029] Column temperature: 30°C;

[0030] Detection wavelength: 280nm;

[0031] Flow rate: 1.0ml / min;

[0032] Injection volume: 10 μL;

[0033] The elution gradient is shown in Table 1:

[0034] Table 1 Elution gradient table

[0035]

[0036] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0037] Example 1

[0038] At room temperature, tert-butyl (5-chloro-2-hydroxyphenyl)carbamate (SM, 24.37 g, 0.10 mol), methanesulfonic anhydride (19.16 g, 0.11 mol), and N,N-diisopropylethylamine (38.77 g, 0.30 mol) were added to toluene (250 mL), and the temperature was controlled at 80-85°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with dichloromethane (1000 mL), and added to 1 mol / L NaOH solution (500 mL). The organic phase was separated and washed with saturated brine (400 mL×2). The organic phase was concentrated to dryness under reduced pressure and then purified by ethanol / purified water (V 乙醇 :V 纯化水 =1:3, 300mL) system was recrystallized to obtain the target product I with a yield of 98.5% and a purity of 99.98%.

[0039] Example 2

[0040] At room temperature, tert-butyl (5-chloro-2-hydroxyphenyl)carbamate (SM, 24.37 g, 0.10 mol), methanesulfonic anhydride (18.29 g, 0.105 mol), and triethylamine (30.36 g, 0.30 mol) were added to toluene (250 mL), and the temperature was controlled at 80-85°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with dichloromethane (1000 mL), and added to 1 mol / L NaOH solution (500 mL). The organic phase was separated and washed with saturated brine (400 mL×2). The organic phase was concentrated to dryness under reduced pressure and then purified by ethanol / purified water (V 乙醇 :V 纯化水 =1:3, 300mL) system was recrystallized to obtain the target product I with a yield of 94.3% and a purity of 99.75%.

[0041] Example 3

[0042] At room temperature, tert-butyl (5-chloro-2-hydroxyphenyl)carbamate (SM, 24.37 g, 0.10 mol), methanesulfonic anhydride (24.39 g, 0.14 mol), and N-methylmorpholine (30.35 g, 0.30 mol) were added to toluene (250 mL), and the temperature was controlled at 80-85°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with dichloromethane (1000 mL), and added to 1 mol / L NaOH solution (500 mL). The organic phase was separated and washed with saturated brine (400 mL×2). The organic phase was concentrated to dryness under reduced pressure and then purified by ethanol / purified water (V 乙醇 :V 纯化水 =1:3, 300mL) system was recrystallized to obtain the target product I with a yield of 95.1% and a purity of 99.62%.

[0043] Example 4

[0044] At room temperature, tert-butyl (5-chloro-2-hydroxyphenyl)carbamate (SM, 24.37 g, 0.10 mol), methanesulfonic anhydride (19.16 g, 0.11 mol), N,N-diisopropylethylamine (32.31 g, 0.25 mol) were added to 1,2-dichloroethane (250 mL), and the temperature was controlled at 60-65 ° C. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with dichloromethane (1000 mL), and added to 1 mol / L NaOH solution (500 mL). The organic phase was separated and washed with saturated brine (400 mL × 2). The organic phase was concentrated to dryness under reduced pressure and then purified by ethanol / purified water (V 乙醇 :V 纯化水 =1:1, 200 mL) system was recrystallized to obtain the target product I with a yield of 94.8% and a purity of 99.68%.

[0045] Example 5

[0046] At room temperature, tert-butyl (5-chloro-2-hydroxyphenyl)carbamate (SM, 24.37 g, 0.10 mol), methanesulfonic anhydride (19.16 g, 0.11 mol), N,N-diisopropylethylamine (64.62 g, 0.5 mol) were added to chlorobenzene (250 mL), and the temperature was controlled at 95-100 ° C. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with dichloromethane (1000 mL), and added to 1 mol / L NaOH solution (500 mL). The organic phase was separated and washed with saturated brine (400 mL × 2). The organic phase was concentrated to dryness under reduced pressure and then purified by ethanol / purified water (V 乙醇 :V 纯化水 =1:5, 400 mL) system was recrystallized to obtain the target product I with a yield of 95.0% and a purity of 99.60%.

[0047] Example 6

[0048] At room temperature, tert-butyl (5-chloro-2-hydroxyphenyl)carbamate (SM, 24.37 g, 0.10 mol), methanesulfonic anhydride (17.42 g, 0.10 mol), N,N-diisopropylethylamine (34.90 g, 0.27 mol) were added to toluene (250 mL), and the temperature was controlled at 55-60 ° C. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with dichloromethane (1000 mL), and added to 1 mol / L NaOH solution (500 mL). The organic phase was separated and washed with saturated brine (400 mL × 2). The organic phase was concentrated to dryness under reduced pressure and then purified by ethanol / purified water (V 乙醇 :V 纯化水 =1:1, 200 mL) system was recrystallized to obtain the target product I with a yield of 87.6% and a purity of 98.98%.

[0049] Example 7

[0050] At room temperature, tert-butyl (5-chloro-2-hydroxyphenyl)carbamate (SM, 24.37 g, 0.10 mol), methanesulfonic anhydride (27.87 g, 0.16 mol), N,N-diisopropylethylamine (67.21 g, 0.52 mol) were added to bromobenzene (250 mL), and the temperature was controlled at 100-105 °C. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with dichloromethane (1000 mL), and added to 1 mol / L NaOH solution (500 mL). The organic phase was separated and washed with saturated brine (400 mL × 2). The organic phase was concentrated to dryness under reduced pressure and then purified by ethanol / purified water (V 乙醇 :V 纯化水 =1:7, 500mL) system was recrystallized to obtain the target product I with a yield of 89.7% and a purity of 98.56%.

Claims

1. A method for synthesizing chlorzoxazone, characterized in that: The synthesis method comprises the following steps: At room temperature, compound SM, i.e. tert-butyl (5-chloro-2-hydroxyphenyl)carbamate, methanesulfonic anhydride and a base are added to a reaction solvent, and the reaction is carried out under controlled temperature T. After the reaction is completed, the target product I is obtained by post-treatment; The reaction route is as follows:

2. The synthesis method according to claim 1, characterized in that The base is selected from one of N,N-diisopropylethylamine, triethylamine and N-methylmorpholine.

3. The synthesis method according to claim 1, characterized in that The reaction solvent is selected from one of 1,2-dichloroethane, toluene, chlorobenzene and bromobenzene.

4. The synthesis method according to claim 1, characterized in that The molar ratio of the compound SM to methanesulfonic anhydride and the base is 1:1.05-1.4:2.5-5.

0.

5. The synthesis method according to claim 1, characterized in that The reaction temperature T is 60-100°C.

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