A method for preparing etorizine hydrochloride and its intermediates
By controlling the preparation temperature of p-ethylphenylacetone and optimizing the reaction conditions, combined with the Mannich reaction and hydrochloric acidification steps, the problem of high content of impurity compound III in etoricosanol hydrochloride was solved, and high-purity and high-yield etoricosanol hydrochloride was prepared, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- AOBO BIOMEDICAL TECHNOLOGY (HUBEI) CO LTD
- Filing Date
- 2025-12-30
- Publication Date
- 2026-06-30
AI Technical Summary
Existing technologies are insufficient to effectively reduce the content of impurity compound III in etorizine hydrochloride, and traditional purification methods are complex and have low yields, failing to meet drug quality control requirements.
The reaction was carried out by controlling the preparation temperature of p-ethylphenylacetone within the range of -80 to -50 °C, optimizing the molar ratio of propionyl chloride to ethylbenzene and the reaction conditions, combining the Mannich reaction and hydrochlorination steps, using specific solvents and temperature control, and finally purifying by recrystallization of acetonitrile.
It significantly reduced the content of impurity compound III in etorizine hydrochloride to below 0.1%, simplified the operation process, improved the yield, and met the drug quality standards, making it suitable for industrial production.
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Figure CN122301657A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for preparing etorizine hydrochloride and its intermediates. Background Technology
[0002] Eperisone hydrochloride is a centrally acting muscle relaxant used to improve muscle tension in cervicobrachial syndrome, frozen shoulder, and low back pain, as well as to treat spastic paralysis caused by cerebrovascular disorders, spastic spinal cord paralysis, cervical spondylosis, postoperative sequelae (including brain and spinal cord tumors), post-traumatic sequelae (spinal cord injury, head injury), amyotrophic lateral sclerosis, infantile cerebral palsy, spinocerebellar degeneration, spinal vascular disorders, subacute neuromyelopathy optica (SMON), or other cerebrospinal disorders.
[0003] The chemical name of etorizine hydrochloride is 4'-ethyl-2-methyl-3-piperidinephenylacetone hydrochloride, and its structure is shown in Formula I:
[0004]
[0005] The Chinese Pharmacopoeia 2020 edition specifies that the impurity limit for etorizine hydrochloride raw material is that the area of a single impurity peak must not exceed the area of the main peak in the control solution (0.2%).
[0006] The synthesis method of etorizine hydrochloride was disclosed in the "Synthesis of Eperizine Hydrochloride" published in the "Chinese Pharmaceutical Industry Magazine" in 1994: propionyl chloride and ethylbenzene were reacted by Friedel-Crafts acylation to obtain p-ethylphenylacetone, which was then reacted with piperidine hydrochloride by Mannich reaction to form salt to obtain etorizine hydrochloride.
[0007] Japanese Patent JP1998182544 discloses a method for preparing p-ethylphenylacetone. The method involves adding 260g of ethylbenzene and 50g of propionyl chloride to aluminum trichloride under stirring at -20°C, maintaining the temperature below -15°C and continuing stirring for 30 minutes, quenching with water, keeping the reactants below 25°C, continuing stirring for 30 minutes, separating the layers, washing the organic layer with water until the aqueous layer is neutral, and concentrating under reduced pressure. The m-isomer content in p-ethylphenylacetone is 1.87%.
[0008] In the Friedel-Crafts acylation reaction, impurity compound II, with a meta-propionylated benzene ring, is generated. This impurity, after undergoing the Mannich reaction and salt formation, yields the corresponding impurity compound III. Because impurity compound III is structurally very similar to etorizine hydrochloride and has essentially the same physicochemical properties, it is difficult to remove using conventional recrystallization methods. For example, as disclosed in CN117209455B, the content of compound III in pharmaceutical-grade etorizine hydrochloride raw material prepared according to the purification methods disclosed in CN201310163189 and CN201611145468 is 0.2%–0.3%, which fails to meet impurity control requirements and requires further purification to obtain a product that meets quality control standards. The structural formulas of compounds II and III are shown below:
[0009]
[0010] CN117209455B discloses a method for purifying etorizine hydrochloride. The method involves reacting p-ethylphenylacetone with piperidine hydrochloride in the presence of paraformaldehyde via a Mannich reaction. After the reaction, acetone is directly added to obtain crude etorizine hydrochloride, containing 0.27% compound III. Alternatively, a lower alcohol is added to the crude etorizine hydrochloride, heated to dissolve, and then a lower fatty acid ester is slowly added dropwise to precipitate it. The mixture is then hot-pulsed, cooled, filtered, and dried to obtain the final product, etorizine hydrochloride, reducing the compound III content from 0.27% to below 0.05%. While this method yields a product with a low compound III content, it is complex, prone to product loss, and results in a low yield.
[0011] Therefore, there is still a need for a simple preparation method that can reduce the content of compound III in the finished product of etorizine hydrochloride. Summary of the Invention
[0012] The first aspect of the present invention provides a method for preparing p-ethylphenylacetone, comprising reacting propionyl chloride and ethylbenzene in the presence of an acid at a temperature A to obtain p-ethylphenylacetone, wherein the temperature A is -80 to -50°C.
[0013] In some embodiments, the temperature A is -75 to -65°C, and the reaction time is 1 to 10 hours, preferably 3 to 8 hours.
[0014] In some embodiments, the molar ratio of propionyl chloride to ethylbenzene is 1:1 to 2.5, preferably 1:1 to 2;
[0015] In some typical embodiments, the molar ratio of propionyl chloride to ethylbenzene is 1:1.4 to 1.6.
[0016] In some embodiments, the acid is a Lewis acid or a protic acid, selected from aluminum trichloride, ferric chloride, tin tetrachloride, boron trifluoride, titanium tetrachloride, zinc chloride, hydrofluoric acid, sulfuric acid, or phosphoric acid, preferably aluminum trichloride, ferric chloride, or tin tetrachloride;
[0017] In some typical implementations, the acid is anhydrous aluminum trichloride.
[0018] In some embodiments, when the acid is a Lewis acid, the molar ratio of propionyl chloride to the acid is 1:0.9 to 1.5, preferably 1:1 to 1.2.
[0019] In some embodiments, the reaction is carried out in an organic solvent A, which is dichloromethane, dichloroethane, nitromethane, nitrobenzene, or carbon disulfide, preferably dichloromethane or dichloroethane.
[0020] In some embodiments, the mass-to-volume ratio of propionyl chloride to organic solvent A is 1:0 to 15 g / mL, preferably 1:8 to 12 g / mL.
[0021] In some embodiments, the reaction is carried out by adding propionyl chloride dropwise to an acidic organic solvent, followed by the addition of ethylbenzene.
[0022] In some embodiments, the reaction is carried out under nitrogen protection.
[0023] The second aspect of the present invention provides a method for preparing etorizine hydrochloride, wherein after obtaining p-ethylphenylacetone by the method of the present invention, it is reacted with piperidine in a Mannich reaction to form a salt to obtain etorizine hydrochloride.
[0024] In some embodiments, a method for preparing etorizine hydrochloride includes the following steps:
[0025] (b) Ethylphenylacetone was reacted with piperidine and paraformaldehyde in organic solvent B by the Mannich reaction to obtain ethylpermethrin;
[0026] (c) The product from step (b) reacts with hydrogen chloride in organic solvent C to form a salt to obtain etorizine hydrochloride.
[0027] In some embodiments, in step (b), the organic solvent B is one or more of isopropanol, ethanol, n-butanol, or 1,3-dioxolane, preferably isopropanol, ethanol, or 1,3-dioxolane; the piperidine is reacted to form piperidine hydrochloride in situ; and in step (c), the organic solvent C is dichloromethane, ethyl acetate, toluene, or n-heptane, preferably dichloromethane or ethyl acetate.
[0028] In some embodiments, the molar ratio of p-ethyl acetone, piperidine and paraformaldehyde in step (b) is 1:1 to 2:1 to 2; preferably 1:1.1 to 1.5:1:1.1 to 1.8.
[0029] In some embodiments, the reaction temperature in step (b) is 50–100°C, more preferably 70–90°C; and the reaction time is 1–30 h, preferably 15–25 h.
[0030] The reaction temperature in step (c) is -20 to 20°C, and more preferably 0 to 10°C.
[0031] In some embodiments, the etorizine hydrochloride is purified by recrystallization in acetonitrile.
[0032] In some embodiments, the etorizine hydrochloride is purified to obtain crystal form A, which exhibits characteristic peaks at the following diffraction angles 2θ by X-ray powder diffraction: 6.8±0.2°, 13.5±0.2°, 17.0±0.2°, 18.6±0.2°, 20.4±0.2°, 20.7±0.2°, 27.3±0.2°, 29.1±0.2°, 29.5±0.2°, wherein etorizine hydrochloride crystal form A contains ≤0.2% of compound III, preferably, the content of compound III is ≤0.1%;
[0033]
[0034] Compared with the prior art, the positive technical effects achieved by the present invention are as follows:
[0035] 1. The method for preparing p-ethylphenylacetone provided by the present invention reduces the formation of compound II by controlling the reaction temperature and optimizing the reaction conditions, resulting in high purity and improved yield of the finished product.
[0036] 2. The method for preparing etorizine hydrochloride provided by the present invention uses p-ethylphenylacetone prepared by the method of the present invention as raw material, which reduces the content of compound III, simplifies the post-processing, increases the yield, and the content of impurity A in the obtained etorizine hydrochloride crystal form meets the requirements of pharmaceutical regulatory authorities, making it suitable for industrial production. Attached Figure Description
[0037] Figure 1 The image shows the X-ray powder diffraction pattern of ethperisone hydrochloride crystal form A prepared in Example 1-B of this invention. Detailed Implementation
[0038] The present invention will be further illustrated by specific embodiments below, but these are not intended to limit the scope of protection of the present invention. Any modifications or alterations made to the present invention that are easily achievable by those skilled in the art without departing from the concept of the present invention will fall within the scope of the present invention.
[0039] Unless otherwise specified, the terminology used in this invention has the following meanings:
[0040] DCM refers to dichloromethane;
[0041] EA refers to ethyl acetate;
[0042] M refers to mmol / L;
[0043] % is a percentage of weight / weight (w / w);
[0044] Concentrated hydrochloric acid refers to a 30-38% hydrochloric acid aqueous solution, such as a 36-38% hydrochloric acid aqueous solution.
[0045] In this invention, the relative molecular mass of the polymer is calculated based on its monomer, for example, the relative molecular mass of paraformaldehyde is calculated based on formaldehyde.
[0046] In this invention, the detection conditions for the content of etorizine hydrochloride and compound III are as follows:
[0047] Table 1 Chromatographic conditions 1
[0048]
[0049]
[0050] In this invention, the detection conditions for the content of ethyl phenylacetone and compound II are as follows:
[0051] Table 2 Chromatographic conditions 2
[0052]
[0053] X-ray powder diffraction detection method:
[0054] Instrument Model: Bruker D8 ADVANCE
[0055] Testing basis: Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0451, Method II
[0056] Test conditions:
[0057] Anode target: Cu; Voltage and current: 40kV 40mA; Diverging slit 0.6mm, Solar slit 2.5°;
[0058] Continuous scanning; Scan range: 3°-40°; Step size: 0.02°; Scan speed: 0.2s / step; Detector: LynxEye.
[0059] Sample preparation: Place 2-5 mg of sample in the middle of a background-free sample holder or a regular sample holder and flatten it with a spatula.
[0060] Example 1-A: Synthesis of p-Ethylphenylacetone
[0061] Under N2 protection, DCM (1330 g) and anhydrous AlCl3 (158.4 g) were added to the reaction flask, stirred, and cooled to -75 to -65 °C. Propionyl chloride (100 g) and ethylbenzene (172 g) were added dropwise, and the reaction was carried out at -75 to -65 °C for 5 hours. After the reaction was complete, the reaction solution was quenched dropwise in purified water at 0–10 °C, and then concentrated hydrochloric acid was added dropwise. After the addition was complete, the mixture was kept at 0–10 °C with stirring. The mixture was separated, and the organic phase was washed with 2M hydrochloric acid, washed with water, and concentrated to obtain 165 g of a brown oily substance with a purity of 99.1%, containing 0.18% compound II.
[0062] Example 1-B: Synthesis of Eperisone Hydrochloride
[0063] Under nitrogen protection, 177 mL of 5M isopropanol hydrochloride solution was added to the reaction flask, stirred, and cooled to 0–20 °C. Piperidine (62.9 g) was added dropwise, and after the addition was complete, the mixture was kept at 10–20 °C with stirring for 2 h. Then, 100 g of p-ethylacetone and 23.1 g of paraformaldehyde were added, and the mixture was stirred for 30 min. The temperature was then raised to 80–90 °C, and the reaction was maintained for 16 h. After the reaction was complete, purified water was added to the reaction solution, the temperature was lowered, and the aqueous phase was washed with n-heptane to adjust the pH to slightly alkaline. The extracted organic phase was washed with NaH₂PO₄ aqueous solution, followed by washing with water. The organic phase was concentrated until no fraction remained, yielding an oily substance. The oily substance was dissolved in ethyl acetate. The solution was cooled to 0–10 °C, and 193 ml of 5 M hydrogen chloride / ethyl acetate solution was added dropwise. After stirring, the mixture was filtered after crystallization. The solid was recrystallized from acetonitrile to obtain 127.6 g of etorizine hydrochloride crystal form A1, with a purity of 99.8% and a compound III content of 0.11%.
[0064] The obtained ethperisone hydrochloride crystal form A was characterized, and its X-ray powder diffraction pattern is attached. Figure 1 As shown, it has characteristic diffraction peaks at the following 2θ angles: 6.8±0.2°, 13.5±0.2°, 17.0±0.2°, 18.6±0.2°, 20.4±0.2°, 20.7±0.2°, 27.3±0.2°, 29.1±0.2°, and 29.5±0.2°.
[0065] Example 2-A: Synthesis of p-Ethylphenylacetone
[0066] Under N2 protection, dichloromethane (398 kg) was added to a 1500 L reactor. Stirring and cooling were started, and anhydrous AlCl3 (47.4 kg) was added at -75 to -65 °C. After stirring and maintaining this temperature for 30 to 40 minutes, propionyl chloride (30 kg) was added dropwise at -75 to -65 °C. After the addition was complete, stirring and maintaining this temperature for 30 to 40 minutes was continued, followed by the addition of ethylbenzene (50.2 kg). The reaction was then carried out at -75 to -65 °C for 7 hours.
[0067] After the central control is qualified, the reaction solution is added dropwise to a purified water (150 kg) aqueous solution at 0-10℃. After the addition is completed, the mixture is kept at 0-10℃ and stirred for 30-60 min. The liquid is separated, the organic phase is washed with 2M hydrochloric acid solution, washed with water, and concentrated to obtain 51.6 kg of brown oily substance with a purity of 99.5% and a compound II content of 0.23%.
[0068] Example 2-B: Synthesis of Eperisone Hydrochloride
[0069] Under N2 protection, 69 kg of 5M hydrochloric acid / isopropanol solution was added to a 200L reactor. The temperature was lowered to 0–20°C, and piperidine (31 kg) was added dropwise. After the addition was complete, the temperature was maintained at 10–20°C and stirred for 2 hours. Then, 51.6 kg of p-ethylacetone and 11.4 kg of paraformaldehyde were added. After the addition was complete, the mixture was stirred for 30 minutes and then heated to 80–90°C. After reacting for 24 hours, purified water was added to the reaction solution, and the temperature was lowered to 20–30°C. After washing with n-heptane, the pH of the aqueous phase was adjusted to weakly alkaline. The mixture was extracted, and the organic phases were combined. The mixture was washed with NaH2PO4 aqueous solution, washed with water, and concentrated to obtain an oily substance. Ethyl acetate was added to dissolve the substance, and the temperature was lowered to 0–10°C. 95.3 kg of 5M hydrogen chloride / ethyl acetate solution was added dropwise, and the mixture was stirred. After crystallization, the mixture was filtered. The solid was recrystallized with acetonitrile to obtain 65.9 kg of ethylperisone hydrochloride crystal form A with a purity of 99.8% and a compound III content of 0.05%.
[0070] The X-ray powder diffraction pattern of the obtained etorizine hydrochloride crystal form A is basically consistent with that of Example 1.
[0071] Comparative Example 1:
[0072] Under nitrogen protection, dichloromethane (665.0 g, 500 ml) was added to a 1 L jacketed reaction flask. Mechanical stirring was started, and cooling was initiated to maintain the system temperature at -45 to -40 °C. Stirring was stopped, and aluminum trichloride (158.4 g) was added. Propionyl chloride (100.0 g, 74 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 30 to 45 min. The system temperature was maintained at -45 to -40 °C, and ethylbenzene (114.8 g, 132 mL) was slowly added dropwise. After the addition was complete, the mixture was kept at -45 to -40 °C for 8 hours. After the reaction was deemed acceptable, the reaction solution was added dropwise to a 150 kg aqueous solution of purified water at 0 to 10 °C. After the addition was complete, the mixture was kept at 0 to 10 °C and stirred for 30 to 60 min. The mixture was separated, and the organic phase was washed with 2 M hydrochloric acid solution, washed with water, and concentrated to obtain 160 g of a brown oily substance with a purity of 97.92%, containing 0.62% of compound II.
[0073] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.
Claims
1. A method for preparing p-ethylphenylacetone, characterized in that, The method includes reacting propionyl chloride and ethylbenzene in the presence of an acid at a temperature A to obtain p-ethylphenylacetone, wherein the temperature A is -80 to -50°C.
2. The preparation method according to claim 1, characterized in that, The temperature A is -75 to -65°C, and the reaction time is 1 to 10 hours, preferably 3 to 8 hours.
3. The preparation method according to claim 1, characterized in that, The molar ratio of propionyl chloride to ethylbenzene is 1:1 to 2.5, preferably 1:1 to 2, and more preferably 1:1.4 to 1.
6.
4. The preparation method according to claim 1, characterized in that, The acid is a Lewis acid or a protic acid, selected from one or more of aluminum trichloride, ferric chloride, tin tetrachloride, boron trifluoride, titanium tetrachloride, zinc chloride, hydrofluoric acid, sulfuric acid, or phosphoric acid; preferably aluminum trichloride, ferric chloride, or tin tetrachloride; more preferably anhydrous aluminum trichloride; when the acid is a Lewis acid, the molar ratio of propionyl chloride to acid is 1:0.9 to 1.5, preferably 1:1 to 1.
2.
5. The preparation method according to claim 1, characterized in that, The reaction is carried out in organic solvent A, which is selected from one or more of dichloromethane, dichloroethane, nitromethane, nitrobenzene or carbon disulfide; preferably dichloromethane or dichloroethane; the mass-to-volume ratio of propionyl chloride to organic solvent A is 1:0 to 15 g / mL, preferably 1:8 to 12 g / mL.
6. The preparation method according to claim 1, characterized in that, The reaction is carried out by adding propionyl chloride dropwise to an acidic organic solvent, followed by the addition of ethylbenzene.
7. A method for preparing etorizine hydrochloride, characterized in that, The method includes (a) preparing p-ethylacetone by the method according to any one of claims 1-6; and then reacting it with piperidine in a Mannich reaction to form a salt to obtain ethperidone hydrochloride.
8. The preparation method according to claim 7, characterized in that, The method includes the following steps: (b) Ethylphenylacetone was reacted with piperidine and paraformaldehyde in organic solvent B by the Mannich reaction to obtain ethylpermethrin; (c) The product from step (b) reacts with hydrogen chloride in organic solvent C to form a salt to obtain etorizine hydrochloride.
9. The preparation method according to claim 8, characterized in that, The organic solvent B in step (b) is one or more of isopropanol, ethanol, n-butanol, or 1,3-dioxolane, preferably isopropanol, ethanol, or 1,3-dioxolane. The piperidine is reacted to form piperidine hydrochloride in situ; The organic solvent C mentioned in step (c) is dichloromethane, ethyl acetate, toluene, or n-heptane, preferably dichloromethane or ethyl acetate.
10. The preparation method according to claim 8, characterized in that, In step (b), the molar ratio of p-ethyl acetone, piperidine, and paraformaldehyde is 1:1 to 2:1 to 2; preferably 1:1.1 to 1.5:1:1.1 to 1.
8.
11. The preparation method according to claim 8, characterized in that, The reaction temperature in step (b) is 50–100°C, more preferably 70–90°C; the reaction time is 1–30 h, more preferably 15–25 h; the reaction temperature in step (c) is -20–20°C, more preferably 0–10°C.
12. The preparation method according to claim 8, characterized in that, The hydrochloric acid is purified by recrystallization in acetonitrile.
13. A crystal form A of ethperisone hydrochloride obtained by the preparation method according to claim 12, characterized in that, The X-ray powder diffraction of crystal form A has characteristic peaks at the following diffraction angles 2θ: 6.8±0.2°, 10.6±0.2°, 13.5±0.2°, 17.0±0.2°, and 18.5±0.2°. The ethylparaben hydrochloride crystal form A contains ≤0.2% of compound III, preferably, the content of compound III is ≤0.1%;