Efficient preparation method of chlorzoxazone

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to an efficient preparation method of chlorzoxazone. The target product chlorzoxazone is prepared by taking (5-chloro-2-hydroxyphenyl) tert-butyl carbamate as a starting material to react with N, N-diethylaminosulfur trifluoride for self-cyclization, an oxazolidinone ring is constructed by Boc carbonyl oxygen replacement reaction in the process, the reaction condition is mild, the operation is safer and more convenient, 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 high-efficiency preparation method of 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 the degradation of urea. In addition, the reaction is carried out at a high temperature of more than 100 degrees Celsius, which places high requirements on the reaction equipment.

[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 current chlorzoxazone preparation technology, the present invention provides a novel chlorzoxazone preparation 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 preparing chlorzoxazone as shown in formula I specifically comprises the following operations:

[0014] The temperature is controlled at T, and the compound N,N-diethylaminosulfur trifluoride is added to the reaction solvent of the compound (5-chloro-2-hydroxyphenyl)carbamic acid tert-butyl ester. The temperature is controlled at T for reaction. After the reaction is completed, the target product I is obtained by post-treatment.

[0015] In a preferred embodiment, the reaction solvent is selected from one of dichloromethane, chloroform, 1,2-dichloroethane, toluene or a combination thereof, among which dichloromethane is particularly preferred.

[0016] In a preferred embodiment, the molar ratio of the compound SM to N,N-diethylaminosulfur trifluoride is 1:1.0-1.2, with 1:1.05 being particularly preferred.

[0017] In a preferred embodiment, the temperature T is -10 to 25°C, with 0 to 5°C being particularly preferred.

[0018] In a preferred embodiment, the post-treatment step is as follows: quenching the reaction solution with a saturated sodium bicarbonate solution, cooling to room temperature, separating the organic phase, extracting the aqueous phase with dichloromethane, combining the organic phases, washing with saturated brine, concentrating the organic phase to dryness under reduced pressure, and then recrystallizing from an ethanol / purified water system to obtain the target product I.

[0019] In a preferred embodiment, the volume ratio of the refined solvent ethanol to purified water is 1:1-7, mL / mL, with 1:5, mL / mL being particularly preferred.

[0020] Beneficial effects of the present invention:

[0021] 1. The present invention provides a novel method for preparing chlorzoxazone, which uses tert-butyl (5-chloro-2-hydroxyphenyl)carbamate as a starting material and reacts with N,N-diethylaminosulfur trifluoride to undergo self-cyclization to prepare the target product chlorzoxazone.

[0022] 2. This process uses the Boc carbonyl oxygen replacement reaction to construct the oxazolidinone ring. The reaction conditions are mild and the operation is safer and more convenient.

[0023] 3. The chlorzoxazone prepared by this process has a high yield and purity, and is suitable for industrial scale-up production. DETAILED DESCRIPTION

[0024] 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.

[0025] The present invention adopts HPLC to measure the purity of chlorzoxazone, and the chromatographic conditions are as follows:

[0026] Chromatographic column: YMC Triart-C 18 Column (4.6 mm × 250 mm, 5 μm) or chromatographic column with equivalent performance;

[0027] 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;

[0028] Column temperature: 30°C;

[0029] Detection wavelength: 280nm;

[0030] Flow rate: 1.0ml / min;

[0031] Injection volume: 10 μL;

[0032] The elution gradient is shown in Table 1:

[0033] Table 1 Elution gradient table

[0034]

[0035] In the following embodiments, various processes and methods not described in detail are conventional methods well known in the art.

[0036] Example 1

[0037] The temperature was controlled at 0-5°C, a solution of N,N-diethylaminosulfur trifluoride (16.92 g, 0.105 mol) in dichloromethane (50 mL) was added to tert-butyl (5-chloro-2-hydroxyphenyl)carbamate (SM, 24.37 g, 0.10 mol) in dichloromethane (10 mL), and the reaction was controlled at 0-5°C. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (400 mL) solution, cooled to room temperature, separated and the organic phase was taken, the aqueous phase was extracted with dichloromethane (100 mL × 2), the organic phases were combined, washed with saturated brine (150 mL), 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, 300 mL) system was recrystallized to obtain the target product I with a yield of 98.6% and a purity of 99.92%.

[0038] Example 2

[0039] The temperature was controlled at -10 to -5°C, a solution of N,N-diethylaminosulfur trifluoride (16.12 g, 0.10 mol) in chloroform (50 mL) was added to a solution of (5-chloro-2-hydroxyphenyl)carbamic acid tert-butyl ester (SM, 24.37 g, 0.10 mol) in chloroform (10 mL), and the temperature was controlled at -10 to -5°C for reaction. After the reaction was completed, the reaction solution was quenched with a saturated sodium bicarbonate solution (400 mL), cooled to room temperature, separated and the organic phase was taken, the aqueous phase was extracted with dichloromethane (100 mL × 2), the organic phases were combined, washed with saturated brine (150 mL), 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, 500mL) system was recrystallized to obtain the target product I with a yield of 94.3% and a purity of 99.70%.

[0040] Example 3

[0041] The temperature was controlled at 20-25°C, a solution of N,N-diethylaminosulfur trifluoride (19.34 g, 0.12 mol) in 1,2-dichloroethane (50 mL) was added to tert-butyl (5-chloro-2-hydroxyphenyl)carbamate (SM, 24.37 g, 0.10 mol) in 1,2-dichloroethane (10 mL), and the temperature was controlled at 20-25°C for reaction. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (400 mL) solution, cooled to room temperature, separated and the organic phase was taken, the aqueous phase was extracted with dichloromethane (100 mL × 2), the organic phases were combined, washed with saturated brine (150 mL), 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, 250 mL) system was recrystallized to obtain the target product I with a yield of 95.6% and a purity of 99.60%.

[0042] Example 4

[0043] The temperature was controlled at 25-30°C, a solution of N,N-diethylaminosulfur trifluoride (22.57 g, 0.14 mol) in toluene (50 mL) was added to a solution of (5-chloro-2-hydroxyphenyl)carbamic acid tert-butyl ester (SM, 24.37 g, 0.10 mol) in toluene (10 mL), and the temperature was controlled at 25-30°C for reaction. After the reaction was completed, the reaction solution was quenched with a saturated sodium bicarbonate solution (400 mL), cooled to room temperature, separated and the organic phase was taken, the aqueous phase was extracted with dichloromethane (100 mL × 2), the organic phases were combined, washed with saturated brine (150 mL), the organic phase was concentrated to dryness under reduced pressure and then purified by ethanol / purified water (V 乙醇 :V 纯化水 =1:9, 200 mL) system was recrystallized to obtain the target product I with a yield of 88.8% and a purity of 98.85%.

Claims

1. An efficient preparation method of chlorzoxazone, characterized in that: The preparation method comprises the following steps: Controlling the temperature T, adding the compound N,N-diethylaminosulfur trifluoride to the reaction solvent of the compound (5-chloro-2-hydroxyphenyl)carbamic acid tert-butyl ester, controlling the temperature T for reaction, and after the reaction is completed after detection, obtaining the target product I through post-treatment; The reaction route is as follows:

2. The preparation method according to claim 1, characterized in that: The reaction solvent is selected from one of dichloromethane, chloroform, 1,2-dichloroethane and toluene.

3. The preparation method according to claim 1, characterized in that: The feeding molar ratio of the compound SM to N,N-diethylaminosulfur trifluoride is 1:1.0-1.

2.

4. The preparation method according to claim 1, characterized in that: The temperature T is -10 to 25°C.

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