Refining method of chlorzoxazone

Abstract

The invention relates to the technical field of medicine preparation, in particular to a refining method of chlorzoxazone. The method comprises the following steps: S1, adding a solvent and a chlorzoxazone crude product into a reaction flask I, heating until reflux dissolution, adding activated carbon, continuously carrying out heat preservation and stirring, and filtering to obtain a filtrate; and S2, adding the filtrate prepared in S1 into a reaction flask II, adding nitrogen for protection, heating and refluxing, then adding an aqueous solution of an antioxidant, carrying out heat-preservation stirring, cooling and stirring for crystallization, filtering, washing a filter cake, and carrying out forced air drying to obtain a chlorzoxazone refined product. The active carbon is added into the chlorzoxazone crude product for decoloration, and the antioxidant is added at the same time, so that the brown crude product can be refined to obtain a white solid, the obtained solid is not easy to oxidize and discolor, and the refining effect on the color of the crude product is good; the color problem of a finished product can be solved only through one-time decoloration operation, filtering operation is reduced, and the method is simpler and more convenient.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation, and more specifically, to a method for refining chlorzoxazone. Background Art

[0002] Chlorzoxazone is a central muscle relaxant that mainly acts on the spinal cord and subcortical areas of the brain to produce muscle relaxation effects. This product is suitable for various acute and chronic soft tissue (muscle, ligament, fascia) sprains, contusions, muscle soreness after exercise, pain caused by muscle strain, muscle spasms caused by central nervous system diseases, and chronic fasciitis. Formula (1) Chlorzoxazone, chemical name 5-chloro-2-benzoxazolone, molecular formula: C 7 H 4 ClNO 2 , molecular weight: 169.57, structural formula: .

[0003] The Chinese invention patent publication number is CN106167471A, and its name is a method for refining chlorzoxazone. It discloses a synthesis method for generating chlorzoxazone through a two-step reaction, which first involves hydrolysis, then hydrogenation reduction, and cyclization. The method mainly involves heating and hydrolyzing the raw material 2,5-dichloronitrobenzene in a strong alkaline aqueous solution to obtain a hydrolysis product. After filtration and drying, 4-chloro-2-nitrophenol with a purity of >99% can be obtained. The entire synthesis route of the present invention has two steps. Step 2 combines the reduction reaction and the cyclization reaction into one step, which not only effectively improves the overall yield, but also shortens the reaction cycle. The residence time of 2-amino-4-chlorophenol is reduced to avoid oxidation and deterioration of the separated compound. However, it uses ethanol / water to recrystallize the brown crude product, and the resulting product is a light yellow to yellow solid, which does not meet the requirements of the pharmacopoeia; Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, one aspect of the present invention is to provide a method for refining chlorzoxazone. The specific steps of the preparation method are as follows: S1. Add the solvent and the crude chlorzoxazone to the reaction bottle I, heat to reflux to dissolve, add activated carbon, continue to keep warm and stir, and filter to obtain a filtrate; S2. Add the filtrate prepared in S1 into reaction bottle II, add nitrogen protection and heat to reflux, then add the aqueous solution of antioxidant, keep warm and stir, cool and stir to crystallize, filter, wash the filter cake, and dry with air to obtain the fine product of chlorzoxazone.

[0005] Preferably, the solvent in S1 is methanol, ethanol or isopropanol.

[0006] Preferably, the crude chlorzoxazone in S1 is a brown crystalline solid with a purity of 96.9%.

[0007] Preferably, the volume ratio of the solvent to the crude chlorzoxazone in S1 is 5-10:1.

[0008] Preferably, the amount of activated carbon in S1 is 3%-10% of the quality of the crude chlorzoxazone.

[0009] Preferably, the reflux temperature in S1 is 65° C.-75° C., and the stirring is maintained at this temperature for 0.5 h-1 h.

[0010] Preferably, the antioxidant in S2 is sodium pyrosulfite, sodium bisulfite or sodium dithionite.

[0011] Preferably, the amount of antioxidant in S2 is 5%-20% of the quality of crude chlorzoxazone.

[0012] Preferably, the reflux temperature in S2 is 65°C-75°C, and the mixture is kept warm and stirred for 10min-30min; the temperature is lowered to 0°C-10°C and stirred for crystallization for 1h-2h, and the filter cake is washed with purified water and dried with air at 50°C.

[0013] Preferably, the chemical purity of the chlorzoxazone fine product in S2 is ≥99.9%, the property is off-white to white crystalline powder, and the yield is 85%-95%.

[0014] The beneficial effects of the present invention are as follows: The present invention adds activated carbon to the chlorzoxazone crude product for decolorization and simultaneously adds an antioxidant, so that the crude product with brown color can be refined to obtain a white solid. The obtained solid is not easy to be oxidized and discolored, and the refining effect on the color of the crude product is good. The present invention can solve the color problem of the finished product through only one decolorization operation, reduces filtering operations, and is more convenient.

[0015] The chlorzoxazone prepared by the invention has a chemical purity of ≥99.9%, is in the form of off-white to white crystalline powder, meets the pharmacopoeia standard, solves the product color problem, has a simple process, is easy to operate, has a good yield, and is suitable for industrial production.

[0016] Additional aspects and advantages of the invention will become apparent from the following description, or may be learned by practice of the invention. DETAILED DESCRIPTION

[0017] In order to more clearly understand the above-mentioned purpose, features and advantages of the present invention, the present invention is further described in detail below in conjunction with specific embodiments. It should be noted that the embodiments of the present application and the features in the embodiments can be combined with each other without conflict.

[0018] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from the description. Therefore, the protection scope of the present invention is not limited to the specific embodiments disclosed below.

[0019] Embodiment 1 Step 1: Add ethanol (500 mL, 10 vol) and 50.0 g of crude chlorzoxazone to a 1 L reaction bottle, start stirring, heat to 70 °C and reflux to dissolve, add activated carbon (5.0 g, 10% w / w), keep warm and stir for 0.5 h, filter while hot, and add the filtrate to a 2 L reaction bottle.

[0020] Step 2: Protect with nitrogen, raise the temperature to 68°C and reflux, slowly add sodium dithionite solution (500mL, 10vol), after addition, keep warm and stir for 10min, cool to 5°C for crystallization for 1.5h, filter, and dry the filter cake at 50°C to constant weight to obtain 43.2g of off-white to white crystalline powder with a chemical purity of 99.99% and a yield of 86.4%. Before purification, the crude chlorzoxazone is a brown solid with a purity of 95.45%.

[0021] Embodiment 2 Step 1: Add ethanol (250 mL, 5 vol) and 50.0 g of crude chlorzoxazone to a 500 mL reaction bottle, start stirring, heat to 68 °C and reflux to dissolve, add activated carbon (1.5 g, 3% w / w), keep warm and stir for 45 min, filter while hot, and add the filtrate to a 1 L reaction bottle.

[0022] Step 2: Protect with nitrogen, raise the temperature to 66°C and reflux, slowly add sodium dithionite solution (500mL, 10vol), after addition, keep warm and stir for 10min, cool to 10°C for crystallization for 2h, filter, and air dry the filter cake at 50°C to constant weight to obtain 46.3g of off-white to white crystalline powder, with a chemical purity of 100% and a yield of 92.6%. Before purification, the crude chlorzoxazone is a brown solid with a purity of 96.87%.

[0023] Comparative Example Step 1: Add ethanol (200 mL, 5 vol) and 40.0 g of crude chlorzoxazone to a 500 mL reaction bottle, start stirring, heat to 72 °C and reflux to dissolve, add activated carbon (4.0 g, 10% w / w), keep warm and stir for 30 min, filter while hot, and add the filtrate to a 1 L reaction bottle.

[0024] Step 2: Heat to 73°C and reflux to dissolve, slowly add purified water (200 mL, 5 vol), after addition, keep warm and stir for 10 min, cool to 5°C for crystallization for 2 h, filter, and air dry the filter cake at 50°C to constant weight to obtain 35.0 g of off-white to white crystalline powder with a chemical purity of 99% and a yield of 87.5%. Before purification, the crude chlorzoxazone is a brown solid with a purity of 96.42%.

[0025] Test experiment The samples prepared in the embodiment were compared with the prior art samples, and the results are shown in Table 1 below: Table 1 Compared with the prior art, the purification method of the present invention can effectively obtain chlorzoxazone whose properties and purity meet the pharmacopoeia standards and meet the use requirements.

[0026] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may also have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for refining chlorzoxazone, characterized in that: The specific steps of the preparation method are as follows: S1. Add the solvent and the crude chlorzoxazone to the reaction bottle I, heat to reflux to dissolve, add activated carbon, continue to keep warm and stir, and filter to obtain a filtrate; S2. Add the filtrate prepared in S1 into reaction bottle II, add nitrogen protection and heat to reflux, then add the aqueous solution of antioxidant, keep warm and stir, cool and stir to crystallize, filter, wash the filter cake, and dry with air to obtain the fine product of chlorzoxazone.

2. A method for refining chlorzoxazone according to claim 1, characterized in that: The solvent in S1 is methanol, ethanol or isopropanol.

3. A method for refining chlorzoxazone according to claim 1, characterized in that: The crude chlorzoxazone in S1 is a brown crystalline solid with a purity of 96.9%.

4. A method for refining chlorzoxazone according to claim 1, characterized in that: The volume ratio of the solvent to the crude chlorzoxazone in S1 is 5-10:

1.

5. The method for refining chlorzoxazone according to claim 1, characterized in that: The amount of activated carbon in S1 is 3%-10% of the quality of the crude chlorzoxazone.

6. The method for refining chlorzoxazone according to claim 1, characterized in that: The heating reflux temperature in S1 is 65° C.-75° C., and the mixture is stirred for 0.5 h-1 h.

7. The method for refining chlorzoxazone according to claim 1, characterized in that: The antioxidant in S2 is sodium pyrosulfite, sodium bisulfite or sodium dithionite.

8. The method for refining chlorzoxazone according to claim 1, characterized in that: The amount of the antioxidant in S2 is 5%-20% of the quality of the crude chlorzoxazone.

9. The method for refining chlorzoxazone according to claim 1, characterized in that: The reflux temperature in S2 is 65-75°C, and the mixture is kept warm and stirred for 10-30 minutes; the mixture is cooled to 0-10°C and stirred for crystallization for 1-2 hours, and the filter cake is washed with purified water and dried with air at 50°C.

10. The method for refining chlorzoxazone according to claim 1, characterized in that: The chemical purity of the chlorzoxazone in S2 is ≥99.9%, and its properties are off-white to white crystalline powder, with a yield of 85%-95%.

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