CN113816920A

CN113816920A - Synthetic method of chlorzoxazone

Info

Publication number: CN113816920A
Application number: CN202010556992.1A
Authority: CN
Inventors: 费凡; 张乃华; 刘忠
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2020-06-18
Filing date: 2020-06-18
Publication date: 2021-12-21
Anticipated expiration: 2040-06-18
Also published as: CN113816920B

Abstract

The invention belongs to the technical field of drug synthesis, and provides a novel synthesis method of chlorzoxazone, which performs ring expansion reaction on a raw material SM-1 under the action of peroxyacid and alkali; after-treatment, the chlorzoxazone is obtained. Avoids the problems that the 2-amino-4-chlorophenol is adopted as the starting material to generate polymeric impurities which are difficult to refine and remove and influence the purity of the product. Compared with the prior art, the method has higher product yield and purity, and is more suitable for industrial production.

Description

Synthetic method of chlorzoxazone

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of chlorzoxazone.

Background

Chlorzoxazone (chlorhydroxybenzazole, Chlorzoxazon), chemically named 5-chloro-2 (3H) -benzoxazolone, is an oral potent muscle relaxant, developed by McNeil pharmaceutical works in the united states and marketed in the mid-sixties of the twentieth century. Chlorzoxazone has been mass-produced in the united states and japan and is separately collected in the united states pharmacopeia 24 edition and the japan bureau of medicine 13 edition. The product is one of the commonly used medicines in the United states in recent 100 years, and is listed in the national basic medical insurance medicine catalogue and the national non-prescription medicine catalogue in China. The product is a central muscle relaxant, and mainly acts on spinal cord and subcortical center of brain to inhibit multi-synaptic nerve reflex arc related to muscle spasm generation, and relieve muscle spasm to relieve pain and increase activity of pathological muscle. The traditional Chinese medicine composition is clinically used for treating low back pain, neuralgia, rheumatoid arthritis, sprain and contusion of acute and chronic soft tissues (muscles, ligaments and fascia), and can also be used for treating muscle spasm, ankylosis, chronic fasciitis and the like caused by central neuropathy, the total effective rate is up to 98.59%, the curative effect is better than that of ibuprofen, and is 4 times that of mefenacin. In addition, it has certain curative effect on children's brain dysfunction. The chemical structural formula is as follows:

more methods for preparing chlorzoxazone are reported at present, for example, the research on the synthesis process of chlorzoxazone in muscle relaxant, such as Shaoxing et al [ J ]. in the pharmaceutical industry, 1987,18(2):49-50, the research on the synthesis process of chlorzoxazone in muscle relaxant, such as Shaoyang et al [ J ]. in the pharmaceutical industry, 1988,19(9): 417. 418, the research on the synthesis of chlorzoxazone in muscle relaxant, such as Youhayai (J ]. in the modern applied pharmacology, 1991,8(2):21-22, the research on the synthesis of chlorzoxazone, such as [ J ]. in the Chinese pharmaceutical industry, 1992,23(11):489, the research on the synthesis of chlorzoxazone, such as Korea (J ]. in 2004 medical science, 2000,19(3):53-61, the research on the synthesis process of chlorzoxazone, such as Shuyao et al [ J ]. in the New Process, such as Yongyao (33, J ]. in Yongshi et al (33), New process improvement of chlorzoxazone synthesis (J), fine chemical raw materials and intermediates (2006, (1):25-26, Liyongxue and the like) in Bingqi synthesis center relaxant chlorzoxazone (J), high efficiency chemical engineering bulletin (2006, 20(2):254-257, Von-Lei and the like synthesis of benzoxazolone derivatives (J), Wuhan university of engineering university bulletin (2011, 33(5):12-14, CN1560040A, CN106167471A, US2017022172A1 and the like are published and reported in patents by Zhang Yan.

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

the first method has high requirements on equipment, and needs to prepare chlorzoxazone under high pressure with carbon monoxide under the condition of taking noble metal as a catalyst, and the method has high cost and large difficulty in process operation. The second method adopts Hofmann rearrangement reaction for preparation, although the reaction conditions are mild, 5-chlorosalicylamide is not easy to obtain, and is only limited to laboratory level research, and the industrial production is difficult. The third method adopts urea to carry out cyclization to prepare chlorzoxazone, which is more suitable for industrial scale-up production, and is also the main method for preparation and production at home and abroad at present, and only adopts different solvents and catalysts in the cyclization process. A 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., all of which can be used as the cyclization reagent of oxazolidinone.

The processes all adopt substituted chlorophenol to prepare chlorzoxazone, wherein in the third method, in the preparation process taking urea as a cyclization reagent, cyclization is carried out in a strong acid environment, but in the later reaction period, a large amount of ammonia gas is generated due to urea degradation, so that the whole reaction system is neutral to alkalescent, the nucleophilicity of amino in the system is obviously enhanced compared with that in an acid environment, and the reaction is carried out at high temperature, so that a small amount of polymers (crude products and crude products, crude products and initial materials, initial materials and crude products, initial materials and initial materials) are generated in the synthesis process, and are difficult to refine and remove, and the purity of the product is influenced.

In view of the above-mentioned disadvantages of the current processes for the preparation of chlorzoxazone. Therefore, the research and search of a process which has mild reaction conditions, simple and convenient operation process, high product yield and high purity and is suitable for the industrial production of chlorzoxazone still needs to solve the problem at present.

Disclosure of Invention

Aiming at the problems of the existing preparation technology of chlorzoxazone, the invention provides a novel synthesis method of chlorzoxazone. The method has mild reaction conditions and simple and convenient operation process, and the prepared target product has higher purity and yield.

The specific technical scheme of the invention is as follows:

a synthetic method of chlorzoxazone specifically comprises the following steps:

adding SM-1, peroxy acid and alkali into a reaction solvent at room temperature, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain chlorzoxazone.

Preferably, the peroxy acid includes, but is not limited to, one or a combination of trifluoro peroxyacetic acid, monoperoxymaleic acid, monoperoxyphthalic acid, 3, 5-dinitroperoxybenzoic acid, para-nitro peroxybenzoic acid, meta-chloroperoxybenzoic acid (mCPBA), peroxybenzoic acid, peroxyacetic acid, wherein mCPBA is particularly preferred.

Preferably, the alkali includes but is not limited to one or a combination of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, wherein potassium bicarbonate is particularly preferred.

Preferably, the reaction solvent includes but is not limited to one or a combination of dichloromethane and chloroform.

Preferably, the feeding molar ratio of SM-1 to peroxy acid and base is 1: 1.05-2.0: 1.2 to 4.0, wherein a ratio of 1: 1.4: 2.0.

in a preferable scheme, the reaction temperature is-5-30 ℃.

Preferably, the post-treatment step is as follows: and adding a sodium hydroxide solution into the reaction solution, separating the solution, adding the sodium hydroxide solution into the organic phase, separating the solution, combining the water layers, adjusting the pH value to 6-7 by using dilute hydrochloric acid, filtering to obtain a crude product, and recrystallizing the crude product by using an ethanol/purified water system to obtain the chlorzoxazone.

In a preferred scheme, the mass fraction of the sodium hydroxide solution is 5-20%.

In a preferable scheme, the concentration of the dilute hydrochloric acid is 0.5-3 mol/L.

Preferably, the volume ratio of the refined solvent ethanol to the purified water is 1: 2 to 4.

The invention has the beneficial effects that:

the invention provides a novel synthesis method of chlorzoxazone, which is prepared by Baeyer-Villiger oxidation rearrangement reaction with SM-1 as a starting material, and solves the problems of the prior art that a plurality of polymerization impurities are generated, the purification is difficult to remove, and the purity of the product is influenced. The preparation process of chlorzoxazone has the advantages of high yield and purity of the obtained product, mild reaction conditions and suitability for industrial production.

Drawings

FIG. 1 is a liquid phase analytical profile of the purity of crude chlorzoxazone of example 1.

FIG. 2 is a liquid phase analysis spectrum of purity of a refined product of chlorzoxazone of example 1.

Detailed Description

The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.

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

a chromatographic column: YMC Triart-C₁₈A column (4.6mm x 250mm, 5 μm) or a chromatography column of comparable performance;

mobile phase: mobile phase A: (monoammonium phosphate 1.15g, dissolved in water and diluted to 1000ml, adjusted to pH 6.0. + -. 0.2 with ammonia) -acetonitrile (75: 25), mobile phase B: acetonitrile, gradient elution;

column temperature: 30 ℃;

detection wavelength: 280 nm;

flow rate: 1.0 ml/min;

sample introduction amount: 10 mu l of the mixture;

the elution gradient is shown in table 1:

TABLE 1 elution gradiometer

In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.

Example 1

Adding SM-1(15.36g, 0.10mol), m-chloroperoxybenzoic acid (24.16g, 0.14mol) and potassium bicarbonate (10.02g, 0.20mol) into dichloromethane (400ml) at room temperature, controlling the temperature to be 10-15 ℃ until the reaction is finished, adding a sodium hydroxide solution (400ml) with the mass fraction of 10% into the reaction solution, stirring for 0.5h, and separating liquid to obtain an aqueous phaseAdding 10% sodium hydroxide solution (250ml) into the organic phase, stirring for 0.5h, separating liquid, taking the water phase, combining the water layers, adjusting the pH value to 6-7 with 2mol/L hydrochloric acid, filtering to obtain a crude product, and purifying the crude product with ethanol/purified water (V)_Ethanol:V_{Purified water}2: 3, 240ml) to obtain chlorzoxazone with the total yield of 93.4% and the purity of 99.950%.

Example 2

Adding SM-1(15.36g, 0.10mol), m-chloroperoxybenzoic acid (18.12g, 0.105mol) and sodium carbonate (21.20g, 0.20mol) into dichloromethane (400ml) at room temperature, controlling the temperature to be 20-25 ℃ until the reaction is finished, adding a sodium hydroxide solution (400ml) with the mass fraction of 10% into a reaction solution, stirring for 0.5h, separating liquid, taking an aqueous phase, adding a sodium hydroxide solution (250ml) with the mass fraction of 10% into an organic phase, stirring for 0.5h, separating liquid, taking an aqueous phase, combining aqueous layers, adjusting the pH value to be 6-7 by using 2mol/L hydrochloric acid, filtering to obtain a crude product, and filtering the crude product to obtain an ethanol/purified water (V)_Ethanol:V_{Purified water}1:3, 240ml) to obtain chlorzoxazone, the total yield is 91.3%, and the purity is 99.870%.

Example 3

Adding SM-1(15.36g, 0.10mol), m-chloroperoxybenzoic acid (17.26g, 0.10mol) and potassium carbonate (27.64g, 0.20mol) into dichloromethane (400ml) at room temperature, controlling the temperature to be 25-30 ℃ until the reaction is finished, adding a sodium hydroxide solution (400ml) with the mass fraction of 10% into a reaction solution, stirring for 0.5h, separating liquid, taking an aqueous phase, adding a sodium hydroxide solution (250ml) with the mass fraction of 10% into an organic phase, stirring for 0.5h, separating liquid, taking an aqueous phase, combining aqueous layers, adjusting the pH value to be 6-7 by using 2mol/L hydrochloric acid, filtering to obtain a crude product, and filtering the crude product to obtain an ethanol/purified water (V)_Ethanol:V_{Purified water}1:3, 240ml) to obtain chlorzoxazone, the total yield is 89.2%, and the purity is 99.865%.

Example 4

Adding SM-1(15.36g, 0.10mol), m-chloroperoxybenzoic acid (34.51g, 0.20mol) and sodium bicarbonate (16.80g, 0.20mol) into chloroform (400ml) at room temperature, controlling the temperature to be 5-10 ℃ until the reaction is finished, adding a sodium hydroxide solution (400ml) with the mass fraction of 5% into the reaction solution, stirring for 0.5h, separating liquid, taking out an aqueous phase, and taking an organic phaseAdding 5% sodium hydroxide solution (350ml) by mass fraction, stirring for 0.5h, separating, collecting water phase, mixing water layers, adjusting pH to 6-7 with 2mol/L hydrochloric acid, filtering to obtain crude product, and purifying the crude product with ethanol/purified water (V)_Ethanol:V_{Purified water}2: 3, 240ml) to obtain chlorzoxazone, the total yield is 93.2%, and the purity is 99.910%.

Example 5

Adding SM-1(15.36g, 0.10mol), m-chloroperoxybenzoic acid (36.24g, 0.21mol) and sodium bicarbonate (16.80g, 0.20mol) into dichloromethane (400ml) at room temperature, controlling the temperature to be 0-5 ℃ until the reaction is finished, adding a sodium hydroxide solution (400ml) with the mass fraction of 5% into a reaction solution, stirring for 0.5h, then carrying out liquid separation to obtain an aqueous phase, adding a sodium hydroxide solution (350ml) with the mass fraction of 5% into an organic phase, stirring for 0.5h, then carrying out liquid separation to obtain an aqueous phase, combining the aqueous layers, adjusting the pH value to be 6-7 by using 2mol/L hydrochloric acid, filtering to obtain a crude product, and carrying out ethanol/purified water (V) treatment on the obtained crude product_Ethanol:V_{Purified water}1:3, 240ml) to obtain chlorzoxazone, the total yield is 93.1%, and the purity is 99.887%.

Example 6

Adding SM-1(15.36g, 0.10mol), trifluoro peroxyacetic acid (18.20g, 0.14mol) and potassium bicarbonate (12.01g, 0.12mol) into dichloromethane (400ml) at room temperature, controlling the temperature to be 25-30 ℃ until the reaction is finished, adding a sodium hydroxide solution (400ml) with the mass fraction of 10% into a reaction solution, stirring for 0.5h, separating to obtain an aqueous phase, adding a sodium hydroxide solution (250ml) with the mass fraction of 10% into an organic phase, stirring for 0.5h, separating to obtain the aqueous phase, combining the aqueous layers, adjusting the pH value to 6-7 by using 2mol/L hydrochloric acid, filtering to obtain a crude product, and filtering the crude product to obtain the crude product by using ethanol/purified water (V)_Ethanol:V_{Purified water}2: 3, 240ml) to obtain the chlorzoxazone, the total yield is 92.4 percent, and the purity is 99.867 percent.

Example 7

Adding SM-1(15.36g, 0.10mol), peroxybenzoic acid (19.34g, 0.14mol) and potassium bicarbonate (11.01g, 0.11mol) into dichloromethane (400ml) at room temperature, controlling the temperature to be 25-30 ℃ until the reaction is finished, adding a sodium hydroxide solution (400ml) with the mass fraction of 10% into a reaction solution, stirring for 0.5h, separating the solution to obtain an aqueous phase, and adding the mass fraction of the aqueous phase into the organic phaseStirring 10% sodium hydroxide solution (250ml) for 0.5h, separating, collecting water phase, mixing water layers, adjusting pH to 6-7 with 2mol/L hydrochloric acid, filtering to obtain crude product, and purifying the crude product with ethanol/purified water (V)_Ethanol:V_{Purified water}2: 3, 240ml) to obtain chlorzoxazone, the total yield is 92.0 percent, and the purity is 99.872 percent.

Example 8

Adding SM-1(15.36g, 0.10mol), peroxyacetic acid (10.65g, 0.14mol) and potassium bicarbonate (40.05g, 0.40mol) into dichloromethane (400ml) at room temperature, controlling the temperature to be 0-5 ℃ until the reaction is finished, adding a sodium hydroxide solution (300ml) with the mass fraction of 20% into a reaction solution, stirring for 0.5h, separating to obtain a water phase, adding a sodium hydroxide solution (250ml) with the mass fraction of 20% into an organic phase, stirring for 0.5h, separating to obtain a water phase, combining the water layers, adjusting the pH value to 6-7 by using 2mol/L hydrochloric acid, filtering to obtain a crude product, and performing ethanol/purified water (V) treatment on the obtained crude product_Ethanol:V_{Purified water}2: 3, 240ml) to obtain the chlorzoxazone, the total yield is 92.8 percent, and the purity is 99.884 percent.

Example 9

Adding SM-1(15.36g, 0.10mol), paranitroperoxybenzoic acid (25.64g, 0.14mol) and potassium bicarbonate (41.05g, 0.41mol) into dichloromethane (400ml) at room temperature, controlling the temperature to be 0-5 ℃ until the reaction is finished, wherein the mass fraction of a sodium hydroxide solution (400ml) in a reaction solution is 10%, stirring for 0.5h, separating liquid to obtain an aqueous phase, adding a sodium hydroxide solution (250ml) with the mass fraction of 10% into an organic phase, stirring for 0.5h, separating liquid to obtain the aqueous phase, combining the aqueous layers, adjusting the pH value to 6-7 by using 2mol/L hydrochloric acid, filtering to obtain a crude product, and purifying the crude product by using ethanol/purified water (V)_Ethanol:V_{Purified water}1:3, 240ml) to obtain chlorzoxazone, the total yield is 91.5%, and the purity is 99.920%.

Claims

1. A synthesis method of chlorzoxazone is characterized in that SM-1 is used as a raw material, and ring expansion reaction is carried out to obtain chlorzoxazone; the route is as follows:

2. the synthetic method according to claim 1, comprising the steps of: adding SM-1, peroxy acid and alkali into a reaction solvent at room temperature, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain chlorzoxazone.

3. The method of claim 2, wherein the peroxyacid is one or a combination of trifluoroperacetic acid, monoperoxymaleic acid, monoperoxyphthalic acid, 3, 5-dinitroperbenzoic acid, paranitroperoxybenzoic acid, m-chloroperoxybenzoic acid, perbenzoic acid, peroxyacetic acid.

4. The synthesis method of claim 2, wherein the base is one or a combination of sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate.

5. The synthesis method according to claim 2, wherein the reaction solvent is one of dichloromethane and chloroform or a combination thereof.

6. The synthesis method according to claim 2, wherein the molar ratio of SM-1 to peroxy acids and bases is 1: 1.05-2.0: 1.2 to 4.0.

7. The synthesis method according to claim 2, wherein the reaction temperature is-5 to 30 ℃.

8. The synthesis method according to claim 2, characterized in that the post-treatment step is: and adding a sodium hydroxide solution into the reaction solution, separating the solution, adding the sodium hydroxide solution into the organic phase, separating the solution, combining the water layers, adjusting the pH value to 6-7 by using dilute hydrochloric acid, filtering to obtain a crude product, and recrystallizing the crude product by using an ethanol/purified water system to obtain the chlorzoxazone.

9. The synthesis method according to claim 8, wherein the mass fraction of the sodium hydroxide solution is 5% to 20%.