Preparation method of eperisone hydrochloride

Abstract

The invention belongs to the technical field of chemical medicine synthesis and purification, and particularly relates to a preparation method of eperisone hydrochloride, which comprises the following steps: mixing an eperisone hydrochloride crude product with alkali to obtain eperisone; the method comprises the following steps: mixing eperisone and oxalic acid to obtain eperisone oxalate; the method comprises the following steps: mixing eperisone oxalate with alkali to obtain eperisone; introducing hydrogen chloride gas into eperisone, filtering and drying to obtain eperisone hydrochloride; according to the method, impurities can be effectively removed, and the purity and the yield are improved.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical drug synthesis and purification, and particularly relates to a method for preparing eperisone hydrochloride. Background Art

[0002] Eperisone Hydrochloride, whose chemical name is 1-(4-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-propanone hydrochloride, is a new drug that can act on the central nervous system and vascular smooth muscle at the same time, relieve skeletal muscle tension and improve blood flow, and improve various muscle tension symptoms. It can be used to treat cervical shoulder-arm syndrome, frozen shoulder, low back pain, spastic paralysis, cerebrovascular disorder, spastic spinal cord paralysis, cervical spondylosis, postoperative sequelae, amyotrophic sclerosis, and is a central skeletal muscle relaxant that acts on smooth muscle and has the efficacy and function of relaxing blood vessels and improving blood flow.

[0003] According to literature research, the reported synthetic routes are mainly the following: Route 1: Using ethylbenzene as the starting material, it reacts with propionyl chloride to produce p-ethylpropiophenone through a Friedel-Crafts acylation reaction under the action of aluminum chloride. p-ethylpropiophenone reacts with paraformaldehyde and piperidine hydrochloride to produce a crude product of eperisone hydrochloride. The crude product of eperisone hydrochloride is purified by recrystallization to obtain eperisone hydrochloride. The reaction route is as follows: .

[0004] Route 2: p-Ethylbenzoic acid is condensed with piperidine under the action of a chlorination reagent to generate (4-ethylphenyl)(piperidin-1-yl)methanone, (4-ethylphenyl)(piperidin-1-yl)methanone reacts with a Grignard reagent isopropenylmagnesium bromide to synthesize ethidone, and then salified with hydrogen chloride to obtain ethidone hydrochloride. The reaction route is as follows: .

[0005] In step 1 of the synthetic route of route 1, the Friedel-Crafts acylation reaction will produce impurities with substituent isomers such as 2-ethylpropiophenone and 3-ethylpropiophenone, and the corresponding ortho- and meta-isomer impurities will be produced in the subsequent Mannich reaction process. According to the method provided in an article entitled "Determination of organic impurities in ethylperisone hydrochloride by high performance liquid chromatography" published by Long Huiling and Liu Zhao in the impurities of "Central South Pharmacy" in 2019, meta-impurities appear in multiple batches of raw materials. This type of impurity has a similar chemical structure to the finished product and basically the same physical and chemical properties. It is difficult to remove it using the existing recrystallization method, and this route cannot produce high-quality raw materials.

[0006] Route 2 uses a format reagent, which has harsh reaction conditions, high requirements for equipment, and is somewhat dangerous, making it unsuitable for industrial production. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a preparation method of eperisone hydrochloride, which can effectively remove impurities and improve purity and yield.

[0008] The embodiment of the present invention provides a method for preparing eperisone hydrochloride, comprising mixing a crude product of eperisone hydrochloride with a base to obtain eperisone; mixing eperisone with oxalic acid to obtain eperisone oxalate; mixing eperisone oxalate with a base to obtain eperisone; and introducing hydrogen chloride gas into the eperisone, filtering, and drying to obtain eperisone hydrochloride.

[0009] Preferably, when the crude product of eperisone hydrochloride is mixed with a base, the base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, preferably sodium hydroxide.

[0010] Preferably, when the crude product of eperisone hydrochloride is mixed with a base to obtain eperisone, the molar ratio of eperisone hydrochloride to the base is 1:1-1.5, the reaction temperature is 20-30°C, and the aqueous phase after the reaction is extracted with ethyl acetate to obtain an ethyl acetate solution of eperisone.

[0011] Preferably, when edipirone and oxalic acid are mixed to obtain edipirone oxalate, the molar ratio of edipirone to oxalic acid is 0.9~1:1~1.5 (preferably 1:1.1), the reaction temperature is 40~70°C (preferably 60°C), and after the reaction, edipirone oxalate solid is precipitated, methanol is added, the temperature is raised to 70~80°C for slurrying, and after the slurrying is completed, the temperature is lowered to 0~30°C (preferably 10~20°C), crystallized, and filtered to obtain edipirone oxalate.

[0012] Preferably, when eperisone oxalate and a base are mixed to obtain eperisone, the base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate; the reaction temperature is 20-30° C.; after the reaction is completed, dichloromethane is added, filtered, rinsed, and concentrated under reduced pressure to obtain eperisone.

[0013] Preferably, before the hydrogen chloride gas is introduced into the eperisone, the eperisone is first dissolved in a solvent, and the solvent is one or more of methanol, ethanol, acetone, and ethyl acetate (preferably acetone).

[0014] Preferably, the method for preparing the crude product of eperisone hydrochloride is to mix p-ethylpropiophenone, piperidine hydrochloride and paraformaldehyde, and react them to obtain the crude product of eperisone hydrochloride.

[0015] Preferably, the solvent for mixing p-ethylpropiophenone, piperidine hydrochloride and paraformaldehyde is one or more of isopropanol, toluene and ethanol; the molar ratio of p-ethylpropiophenone to piperidine hydrochloride is 0.8-1:1-1.2, and the reaction temperature is 80-100°C.

[0016] Preferably, the preparation method of p-ethylpropiophenone is that ethylbenzene reacts with propionyl chloride under the action of aluminum chloride to obtain p-ethylpropiophenone.

[0017] Preferably, in the preparation method of p-ethylpropiophenone, the reaction temperature is -10 to 5°C, the reaction time is 0.5 to 2 hours, and the molar ratio of ethylbenzene to propionyl chloride is 1:1 to 1.5.

[0018] The overall reaction scheme of the present invention is as follows: .

[0019] The beneficial effect of the present invention is that the inventors used the method provided in the above-mentioned article "Determination of organic impurities in epidermisone hydrochloride by high performance liquid chromatography" to detect multiple batches of original imported reference preparation samples of epidermisone hydrochloride and found that the content of the meta-impurity 1-(3-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-propanone hydrochloride was greater than 0.1%, which is higher than the limit requirement of 0.1% of impurities in raw materials set by ICH. In the existing process route, the Friedel-Crafts acyl method is used to prepare the intermediate I p-ethylpropiophenone, and positionally isomeric meta-ethylpropiophenone and o-ethylpropiophenone will be produced. In the subsequent reaction, positionally isomeric impurities 1-(3-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-propanone hydrochloride and 1-(2-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-propanone hydrochloride will inevitably be produced. This type of impurity has a similar chemical structure to the finished product and basically the same physical and chemical properties, and is difficult to remove using the existing recrystallization method.

[0020] The invention overcomes the shortcomings of the existing preparation method and preparation technology of eperisone hydrochloride. The greatest innovation lies in that oxalic acid is used for salt formation. Oxalate pulping can well remove positional isomerism impurities (especially controlling the intermediate impurity 1-(3-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-acetone hydrochloride of the finished product to be less than 0.05%), thus avoiding the failure of multiple recrystallizations in the traditional process to remove the meta-isomerism impurities. The yield and purity of eperisone hydrochloride can be greatly improved without using dangerous Grignard reagents (the overall yield reaches about 60%, and the purity is greater than or equal to 99.95%).

[0021] The preparation and feeding method of intermediate I adopts the method of dripping ethylbenzene and propionyl chloride mixture, which can significantly reduce the generation of positional isomeric impurity m-ethylpropiophenone compared with the one-pot method or the method of dripping propionyl chloride, thereby reducing the content of the subsequent product m-isomerization impurity 1-(3-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-propanone hydrochloride, and improving the purity of the finished product eperizone hydrochloride. DETAILED DESCRIPTION

[0022] The following examples are only for further illustrating the present invention and are not intended to limit the scope of the present invention in any form.

[0023] Example 1 Step 1): Preparation of intermediate Ⅰ (p-ethylpropiophenone) Add 200 ml of dichloromethane and 45 g of aluminum chloride (0.337 mol) into the reaction flask, mix well, cool to 0°C, and add a mixed solution of 30 g of ethylbenzene (0.285 mol) and 29.05 g of propionyl chloride (0.314 mol) dropwise with stirring. The temperature during the addition process does not exceed 0°C. After the addition is completed, react at 0°C for 0.5 h. Add the reaction solution into 200 g of ice water for quenching, separate the liquids, wash twice with 200 ml*2 saturated brine, dry with sodium sulfate, and concentrate under reduced pressure to obtain 44.27 g of yellow-brown liquid intermediate I (p-ethylpropiophenone). The yield of intermediate I is 96.50%, the purity is 97.8%, and the main impurities are meta-isomer: 0.7% and ortho-isomer 1.4%.

[0024] Step 2): Preparation of crude eperisone hydrochloride Add 40g of intermediate I (0.247mol) and 40ml of isopropanol to the reaction bottle, stir until dissolved, then add 8.88g of paraformaldehyde (0.296mol) and 30.04g of piperidine hydrochloride (0.247mol), heat to 95℃ for reaction for 5 hours, add 400ml of acetone after the reaction is complete, cool to 5℃ for crystallization for 2h, filter and dry to obtain 54.31g of crude white solid epirizone hydrochloride, with a yield of 74.32% and a purity of 98.1%.

[0025] Step 3): Preparation of Eperisone Add 250 ml of water, 50 g of crude epidermisone hydrochloride (0.169 mol), and 8.12 g of sodium hydroxide (0.203 mol) into the reaction flask, stir at 20°C for 30 min, extract the aqueous phase twice with 250 ml*2 of ethyl acetate to obtain an ethyl acetate solution of epidermisone, and directly proceed to the next step.

[0026] Step 4): Preparation of Eperisone Oxalate To a reaction flask containing 500 ml of ethyl acetate solution of eperisone was added 15.21 g of oxalic acid (0.169 mol), the temperature was raised to 60 ° C and stirred for 1 h. A large amount of solid eperisone oxalate salt was precipitated in the reaction solution. 50 ml of methanol was added, the temperature was raised to 70 ° C and slurried for 2 hours, then cooled to 10 ° C, kept warm for crystallization for 0.5 h, and then filtered to obtain 48.77 g of white solid eperisone oxalate (0.140 mol). The yield of steps 3 and 4 was 82.60%, and the purity was 99.62%.

[0027] Step 5): Preparation of Eperisone Hydrochloride 225 ml of water and 12.92 g of sodium hydroxide (0.323 mol) were added to the reaction flask, stirred to dissolve, cooled to 20°C, 45 g of eperisone oxalate (0.129 mol) was added, stirred at 20°C for 1 hour, 200 ml of dichloromethane was added and stirred for 10 min, the insoluble sodium oxalate was removed by filtration, the filter cake was rinsed with 50 ml of dichloromethane, the filtrate was layered, the aqueous phase was discarded, and the dichloromethane in the organic phase was recovered by vacuum concentration to obtain eperisone. 200 ml of acetone was added to eperisone and stirred to dissolve, and then hydrogen chloride gas was introduced to precipitate a large amount of white solid, which was filtered and dried to obtain 36.49 g of eperisone hydrochloride, with a yield of 95.62%, a purity of 99.75%, and a maximum single impurity of 0.04%.

[0028] The total yield is 56.6%, the purity is 99.75%, and the maximum single impurity (i.e., meta-impurity) is 0.04%.

[0029] Comparative Example 1 Step 1) Preparation of Intermediate I (p-ethylpropiophenone) and step 2) Preparation of crude eperisone hydrochloride were the same as in Example 1. The amount of each raw material was adjusted simultaneously to obtain 100 g of crude eperisone hydrochloride.

[0030] Step 3): Preparation of finished product of eperisone hydrochloride Add 100 ml of methanol and 500 ml of acetone to the reaction flask, stir, add 100 g of crude ethylperisone hydrochloride, raise the temperature to reflux after the materials are added, continue stirring for 0.5 h after the system is dissolved, then slowly cool down, start timing when the temperature drops to 5 ° C, control the temperature at 5 ° C and stir for 0.5 h, crystallization is completed, filter, rinse the filter cake with 100 ml of cold acetone, and dry the wet product at 50 ° C in vacuum to constant weight to obtain 61.2 g of ethylperisone hydrochloride finished product, yield: 61.20%, purity 99.12%, maximum single impurity 0.36%,

[0031] The total yield is 59.1%, the purity is 99.12%, and the maximum single impurity (i.e., meta-impurity) is 0.36%.

[0032] Comparative Example 2 Step 1): Preparation of intermediate Ⅰ (p-ethylpropiophenone) 400 ml of dichloromethane, 60 g of ethylbenzene (0.570 mol) and 58.10 g of propionyl chloride (0.628 mol) were added to the reaction flask, the reaction solution was cooled to 0°C, 90 g of aluminum chloride (0.674 mol) was added, the reaction solution was cooled to 0°C and reacted for 0.5 h, the reaction solution was added to 400 g of ice water for quenching, the solution was separated, washed twice with 400 ml*2 saturated brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain 84.38 g of yellow-brown liquid intermediate I (p-ethylpropiophenone), the yield of intermediate I was 91.25%, the purity was 95.6%, and the main impurities were meta-isomer: 1.5% and ortho-isomer 2.1%.

[0033] Steps 2, 3, 4 and 5 are the same as those in Example 1, except that the yield of step 5) of this example is 94.53%, the purity is 99.52%, and the maximum single impurity is 0.15%.

[0034] The total yield was 53.0%, the purity was 99.52%, and the maximum single impurity (i.e., meta-impurity) was 0.15%.

[0035] Through the above examples, it is found that the purification of ethylperisone oxalate after salt formation can improve the purity of the product and reduce the maximum single impurity; the preparation of ethylpropiophenone in step 1) using the method of dripping ethylbenzene and propionyl chloride can reduce the content of difficult-to-remove impurities, so the most preferred conditions for the preparation method of the present invention are that in step 1), the reaction temperature is -5~0°C, the reaction time is 0.5~1 hour, the molar ratio of the starting material I to propionyl chloride is 1:1.1, the feeding method is to mix ethylbenzene and propionyl chloride and then drip the mixed solution of ethylbenzene and propionyl chloride, the solvent used in step 2) is isopropanol, the intermediate I and the starting material The molar ratio of Ⅱ is 1:1.0; the reaction temperature is 95-100°C, the base used in step 3) is sodium hydroxide, the molar ratio of eperisone to oxalic acid in step 4) is 1:1.1, the reaction temperature is 60°C, the crystallization temperature is 10-20°C, the solvent used for eperisone salt formation in step 5) is acetone, the final yield of intermediate I is 96.50%, the yield of crude eperisone hydrochloride is 74.32%, the yield of eperisone oxalate is 82.60%, the yield of finished eperisone hydrochloride is 95.62%, the purity is 99.75%, and the maximum single impurity (i.e., meta-impurity) is 0.04%.

[0036] Comparative Example 3 Compared with Example 1, steps 1) to 3) are the same as in Example 1, except that step 4) is the preparation of eperisone acetate, and step 4) is: To a reaction flask containing 500 ml of ethyl acetate solution of epidermisone, 10.14 g of acetic acid (0.169 mol) was added, the temperature was raised to 60 ° C and stirred for 1 h. A large amount of epidermisone acetate solid was precipitated in the reaction solution. 50 ml of methanol was added, the temperature was raised to 70 ° C and slurried for 2 hours, then cooled to 10 ° C, kept warm for crystallization for 0.5 h, and then filtered to obtain 36.27 g of white solid epidermisone acetate (0.114 mol). The yield of steps 3 and 4 was 67.20%, and the purity of epidermisone acetate was 98.1%.

[0037] Step 5) is the same as in Example 1, with the yield of step 5) being 95.31%, the purity being 99.21%, and the maximum single impurity being 0.17%.

[0038] The total yield is 45.9%, the purity is 99.21%, and the maximum single impurity (i.e., meta-impurity) is 0.17%.

[0039] A person skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of protection of the present application is limited to these examples. In line with the concept of the present application, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments of the present application as described above, which are not provided in detail for the sake of simplicity.

[0040] One or more embodiments of the present application are intended to cover all such substitutions, modifications and variations that fall within the broad scope of the present application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of one or more embodiments of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing eperisone hydrochloride, characterized in that: The crude product of eperisone hydrochloride is mixed with a base to obtain eperisone; eperisone is mixed with oxalic acid to obtain eperisone oxalate; eperisone oxalate is mixed with a base to obtain eperisone; hydrogen chloride gas is introduced into eperisone, filtered, and dried to obtain eperisone hydrochloride.

2. The preparation method according to claim 1, characterized in that hydrochloric acid When the crude product of eperisone is mixed with a base, the base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate.

3. The preparation method according to claim 2, characterized in that hydrochloric acid When the crude product of eperisone is mixed with a base to obtain eperisone, the molar ratio of eperisone hydrochloride to the base is 1:1-1.5, the reaction temperature is 20-30°C, and the aqueous phase after the reaction is extracted with ethyl acetate to obtain an ethyl acetate solution of eperisone.

4. The preparation method according to claim 1, characterized in that: When eperisone and oxalic acid are mixed to obtain eperisone oxalate, the molar ratio of eperisone to oxalic acid is 0.9-1:1-1.5, the reaction temperature is 40-70°C, and solid eperisone oxalate is precipitated after the reaction. Methanol is added, and the temperature is raised to 70-80°C for pulping. After the pulping is completed, the temperature is lowered to 0-30°C, crystallized, and filtered to obtain eperisone oxalate.

5. The preparation method according to claim 1, characterized in that: When eperisone oxalate and a base are mixed to obtain eperisone, the base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate; the reaction temperature is 20-30° C. After the reaction is completed, dichloromethane is added, the reaction is filtered, rinsed, and concentrated under reduced pressure to obtain eperisone.

6. The preparation method according to claim 5, characterized in that: Before the hydrogen chloride gas is introduced into the eperisone, the eperisone is first dissolved in a solvent, and the solvent is one or more of methanol, ethanol, acetone, and ethyl acetate.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The preparation method of the crude product of eperisone hydrochloride comprises the following steps: mixing p-ethylpropiophenone, piperidine hydrochloride and paraformaldehyde, and reacting the mixture to obtain the crude product of eperisone hydrochloride.

8. The preparation method according to claim 7, characterized in that: The solvent for mixing p-ethylpropiophenone, piperidine hydrochloride and paraformaldehyde is one or more of isopropanol, toluene and ethanol; the molar ratio of p-ethylpropiophenone to piperidine hydrochloride is 0.8-1:1-1.2, and the reaction temperature is 80-100°C.

9. The preparation method according to claim 7, characterized in that: The preparation method of p-ethylpropiophenone is that ethylbenzene reacts with propionyl chloride under the action of aluminum chloride to obtain p-ethylpropiophenone.

10. The preparation method according to claim 9, characterized in that: In the preparation method of p-ethylpropiophenone, the reaction temperature is -10 to 5°C, and the molar ratio of ethylbenzene to propionyl chloride is 1:1 to 1.5; during the reaction, a mixed solution of ethylbenzene and propionyl chloride is added dropwise to an organic solution of aluminum chloride, and the solvent in the organic solution of aluminum chloride is dichloromethane.