A process for the preparation of ethoheptazine hydrochloride

Abstract

The application provides a preparation method of ethperidol hydrochloride. First, p-ethylbenzoic acid is condensed with piperidine under the action of a chlorinating reagent to obtain (4-ethylphenyl)(piperidin-1-yl)methanone, and then ethperidol is synthesized by one-pot reaction of (4-ethylphenyl)(piperidin-1-yl)methanone and isopropenylmagnesium bromide. The reaction steps are few, and ethperidol hydrochloride can be obtained without column chromatography, the purity of ethperidol hydrochloride reaches 99.9%, and the content of isomer impurities in ethperidol raw medicine is reduced.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, and more specifically, relates to a method for preparing etorizine hydrochloride. Background Technology

[0002] Eperisone hydrochloride, also known as Myona or Eperisone, has the chemical name 1-(4-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-propanone hydrochloride, with the structural formula shown in Formula (I). It is a centrally acting muscle relaxant used to improve muscle tension in cervicobrachial syndrome, frozen shoulder, and low back pain. It also improves cerebrovascular disorders, cervical spondylosis, postoperative sequelae, post-traumatic sequelae, amyotrophic lateral sclerosis, infantile cerebral palsy, spinocerebellar degeneration, spinal vascular disorders, and spastic paralysis in subacute spinal cord neuropathy.

[0003]

[0004] In existing technologies, p-ethylphenylacetone is often used as the starting material to prepare etorizine hydrochloride via an acylation reaction. Pang Xueliang et al., in "Comparison of Production Processes of p-methylphenylacetone and p-ethylphenylacetone [J]" (Chemical Industry Times, 1999(11):31-33), reported a process for preparing p-ethylphenylacetone using ethylbenzene and propionyl chloride as raw materials, and then using p-ethylphenylacetone to prepare etorizine hydrochloride (as shown in Formula II). During the preparation of p-ethylphenylacetone, impurities, namely m-ethylphenylacetone, are usually generated, with an impurity content of approximately 1.0–1.5%. According to the reaction principle, m-ethylphenylacetone will generate (1-(3-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-propanone hydrochloride) via the Mannich reaction, thus affecting the yield and purity of the final product, etorizine hydrochloride.

[0005]

[0006] Patent US3995047A reported the preparation of etorizine hydrochloride using p-ethylphenylacetone as a starting material via the Mannich reaction, but the yield was only 43%.

[0007] In his article “Synthesis of Eperisone Hydrochloride [J]” (China Pharmaceutical Industry Magazine, 1994(09):392-393), Li Ke reported the preparation of etperisone hydrochloride by the Mannich reaction using p-ethylphenylacetone. The yield was relatively improved but still relatively low.

[0008] In their paper "Determination of Organic Impurities in Eperisone Hydrochloride by High Performance Liquid Chromatography [J]" (Central South Pharmacy, 2019, 17(09):1529-1533), Long Huiling and Liu Zhao established a method for determining organic impurities in eperisone hydrochloride by high performance liquid chromatography and tested three batches of samples. The results showed that the content of the impurity (1-(3-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-propanone hydrochloride) was between 0.17% and 0.18%.

[0009] As can be seen from the above process, the Friedel-Crafts acylation synthesis cannot remove the impurity (i.e., m-ethylphenylacetone) from the preparation of ethperisone hydrochloride using ethylphenylacetone as a starting material. This impurity is derivatized in the Mannich process to (1-(3-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-propanone hydrochloride), and is difficult to remove by crystallization. This indicates that using p-ethylphenylacetone as a starting material not only easily leads to the formation of m-ethylphenylacetone impurities during its synthesis, but also results in difficult-to-remove meta-derivatives in subsequent reactions.

[0010] Therefore, providing a method for preparing etorizine hydrochloride using substances other than ethyl phenylacetone as raw materials, and achieving high yield and purity, has become an urgent problem to be solved in the industry. Summary of the Invention

[0011] To address the limitations of the aforementioned technologies, this invention provides a method for preparing etorizine hydrochloride, which uses (4-ethylphenyl)(piperidin-1-yl) methyl ketone as the starting material and reacts it with isopropenyl magnesium bromide to prepare etorizine hydrochloride.

[0012] To achieve the above-mentioned technical objectives, the present invention adopts the following technical solution:

[0013] This invention provides a method for preparing etorizine hydrochloride, comprising the following steps:

[0014] (1) Disperse (4-ethylphenyl)(piperidin-1-yl) methyl ketone in the first solvent, stir and heat, and then add isopropenyl magnesium bromide dropwise to obtain a mixture;

[0015] (2) Extract the mixture obtained in step (1) with water, allow it to stand and separate, concentrate the organic layer to obtain an oily substance; and

[0016] (3) Add a second solvent to the oily substance obtained in step (2) to prepare a solution. Pass hydrogen chloride into the solution to precipitate a solid. Filter the solution to obtain solid etorizine hydrochloride.

[0017] In the above-mentioned technical solution of this application, (4-ethylphenyl)(piperidin-1-yl) methyl ketone can be synthesized using p-ethylbenzoic acid as a starting material. Since p-ethylbenzoic acid has a melting point of 112-113℃, impurities can be removed by crystallization. Therefore, the applicant uses p-ethylbenzoic acid as a starting material, first obtaining (4-ethylphenyl)(piperidin-1-yl) methyl ketone through condensation, and then synthesizing ethylperidone by reacting (4-ethylphenyl)(piperidin-1-yl) methyl ketone with isopropenyl magnesium bromide in a one-pot reaction. The reaction mechanism is as follows:

[0018]

[0019] The preparation method of (4-ethylphenyl)(piperidin-1-yl)methyl ketone is disclosed in the literature "A New Paradigm for Biohydroxylation by Beauveria bassiana ATCC 7159", Herber L. Holland et al., Department of Chemistry, Brock University, St. Catharines, ON L2S3A1, Canada.

[0020] In some embodiments of the present invention, in step (1), the mass of the first solvent is 8 to 15 times the mass of (4-ethylphenyl)(piperidin-1-yl) methyl ketone; specifically, the mass of the first solvent is 8 to 14 times, 8 to 13 times, 8 to 12 times, 8 to 11 times, 8 to 10 times, or 8 to 9 times the mass of (4-ethylphenyl)(piperidin-1-yl) methyl ketone; specifically, the mass of the first solvent is 9 to 15 times, 9 to 14 times, 9 to 13 times, 9 to 12 times, 9 to 11 times, or 9 to 15 times the mass of (4-ethylphenyl)(piperidin-1-yl) methyl ketone. ~10 times; specifically, the mass of the first solvent is 10 to 15 times, 10 to 14 times, 10 to 13 times, 10 to 12 times, or 10 to 11 times the mass of (4-ethylphenyl)(piperidin-1-yl) methyl ketone; specifically, the mass of the first solvent is 11 to 15 times, 11 to 14 times, 11 to 13 times, or 11 to 12 times the mass of (4-ethylphenyl)(piperidin-1-yl) methyl ketone; specifically, the mass of the first solvent is 12 to 15 times, 12 to 14 times, or 12 to 13 times the mass of (4-ethylphenyl)(piperidin-1-yl) methyl ketone. The applicant discovered through research that if the mass of the first solvent is less than 8 times the mass of (4-ethylphenyl)(piperidin-1-yl) methyl ketone, the reaction yield is too low; if the mass of the first solvent is greater than 15 times the mass of (4-ethylphenyl)(piperidin-1-yl) methyl ketone, it will cause unnecessary waste of solvent, and on the other hand, due to the excessive amount of solvent, more energy will be required to reach the reaction temperature.

[0021] In some embodiments of the present invention, in step (1), the heating temperature is not lower than 50°C; further, the heating temperature is 50°C to 110°C, specifically, the heating temperature is 60°C to 110°C, 70°C to 110°C, 80°C to 110°C, 90°C to 110°C, 100°C to 110°C, 50°C to 100°C, 60°C to 100°C, 70°C to 100°C, 80°C to 100°C, 90°C to 100°C, 50°C to 90°C, 60°C to 90°C, 70°C to 90°C, or 80°C to 90°C.

[0022] In step (1), under the reaction system of the present invention, the applicant has found through experimental research that when the temperature is below 50 degrees Celsius, no product is precipitated; when the temperature is above 110 degrees Celsius, side reactions occur, leading to an increase in impurities and thus reducing product purity. The applicant has found that under the reaction system of the present invention, when the heating temperature in step (1) is in the range of 50°C to 110°C, specifically, within the heating temperature ranges of 60°C to 110°C, 70°C to 110°C, 80°C to 110°C, 90°C to 110°C, 100°C to 110°C, 50°C to 100°C, 60°C to 100°C, 70°C to 100°C, 80°C to 100°C, 90°C to 100°C, 50°C to 90°C, 60°C to 90°C, 70°C to 90°C, or 80°C to 90°C, the reaction of the present invention can achieve good yield and purity.

[0023] In step (1), the first solvent can be any solvent that meets the conditions for coexistence with Grignard reagent. However, in terms of yield and purity, in some embodiments of the present invention, in step (1), the first solvent is any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and methyl tert-butyl ether, and is not limited to the above solvent types. Tetrahydrofuran or 2-methyltetrahydrofuran is preferred.

[0024] In some embodiments of the present invention, in step (1), when heating after stirring, the temperature can be refluxed.

[0025] In some embodiments of the present invention, in step (1), the molar ratio of isopropenyl magnesium bromide to (4-ethylphenyl)(piperidin-1-yl) methyl ketone is 1.2 to 1.5. Specifically, in step (1), the molar ratio of isopropenyl magnesium bromide to (4-ethylphenyl)(piperidin-1-yl) methyl ketone is 1.2 to 1.4, 1.2 to 1.3, or 1.3 to 1.4.

[0026] The applicant discovered through research that when the molar ratio of isopropenyl magnesium bromide to (4-ethylphenyl)(piperidin-1-yl) methyl ketone is less than 1.2, the reaction will be incomplete. When the molar ratio of isopropenyl magnesium bromide to (4-ethylphenyl)(piperidin-1-yl) methyl ketone is greater than 1.5, side reactions will occur, thereby affecting the yield and purity of the final product.

[0027] The dropping rate of isopropenyl magnesium bromide is controlled by the reaction temperature. When the temperature is high, the dropping rate is slowed down to avoid the reaction exothermicly causing the temperature of the reaction system to be too high, which would affect the reaction process and ultimately affect the yield and purity of the final product. When the temperature is low, the dropping rate can be accelerated.

[0028] In some embodiments of the present invention, the volume ratio of the amount of extraction water used in step (2) to the amount of the first solvent used in step (1) is 1:1 to 1.5. Specifically, the volume ratio of the amount of extraction water used in step (2) to the amount of the first solvent used in step (1) is 1:1 to 1.4, 1:1 to 1.3, 1:1 to 1.2, or 1:1 to 1.1.

[0029] The applicant discovered through research that when the volume ratio of the amount of extraction water used in step (2) to the amount of the first solvent used in step (1) is less than 1:1.5, it will cause the separation to be impossible. When the volume ratio of the amount of extraction water used in step (2) to the amount of the first solvent used in step (1) is greater than 1:1, the separation will be indistinct.

[0030] In step (2), the concentration method is not limited to a specific concentration method. From the perspective of yield and purity, in some embodiments of the present invention, the concentration method is vacuum concentration, wherein the temperature of vacuum concentration is 90℃~100℃ and the pressure of vacuum concentration is -0.095MPa to -0.08MPa.

[0031] In some embodiments of the present invention, in step (2), the extraction is performed at least twice.

[0032] In step (3), the second solvent can be any organic solvent. From the perspective of yield and purity, in some embodiments of the present invention, in step (3), the second solvent is any one or more of acetone, isopropanol, ethyl acetate, and toluene, preferably acetone.

[0033] In some embodiments of the present invention, in step (3), the mass of the second solvent is 4 to 10 times the mass of (4-ethylphenyl)(piperidin-1-yl) methyl ketone, specifically, the mass of the second solvent is 4 to 9 times, 4 to 8 times, 4 to 7 times, 4 to 6 times, or 4 to 5 times the mass of (4-ethylphenyl)(piperidin-1-yl) methyl ketone.

[0034] In some embodiments of the present invention, in step (3), the hydrogen chloride can be any one of hydrogen chloride gas, hydrogen chloride solution, or concentrated hydrochloric acid, preferably hydrogen chloride gas.

[0035] In some embodiments of the present invention, in step (3), hydrogen chloride is introduced into the solution to make the pH value of the solution less than 3.

[0036] Controlling the pH of the solution to less than 3 is to ensure complete salt formation and improve the yield of the final product.

[0037] In step (3), since the target product is etorizine hydrochloride, other acidic substances cannot be used to adjust the pH of the solution.

[0038] Compared with the prior art, the present invention has achieved at least the following beneficial effects:

[0039] The present invention provides a method for preparing etorizine hydrochloride from (4-ethylphenyl)(piperidin-1-yl) methyl ketone and isopropenyl magnesium bromide, which involves fewer reaction steps, requires no column chromatography, contains no isomer impurities, has a yield of over 84.5%, and a purity of up to 99.9%, thereby improving the quality of the drug. Attached Figure Description

[0040] Figure 1 This is a high-performance liquid chromatogram of etorizine hydrochloride prepared in Example 3 of the present invention. Detailed Implementation

[0041] The present invention will be further described in detail below with reference to embodiments. The description herein is merely illustrative and is not intended to limit the scope of the invention.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention. All reagents and instruments used herein are commercially available, and the characterization methods involved are described in relevant prior art and will not be repeated herein.

[0043] Example 1: Preparation of (4-ethylphenyl)(piperidin-1-yl) methyl ketone:

[0044] 15.04 g of p-ethylbenzoic acid, 0.5 ml of DMF, and 60 ml of toluene were placed in a 100 ml three-necked flask and magnetically stirred in a 10°C low-temperature bath. 12.02 g of thionyl chloride was added dropwise. The mixture was stirred at room temperature (25°C) for 2 hours. The apparatus was then transferred to a 0°C low-temperature bath, and 22 g of triethylamine was added dropwise, followed by the addition of 17.10 g of piperidine. After the reaction was complete, the reaction mixture was poured into a 100 ml separatory funnel, and 50 ml of tap water was added for extraction and separation. The lower aqueous layer was discarded, and the upper organic layer was retained. Another 50 ml of tap water was added for washing, and the lower aqueous layer was discarded. 60 ml of dilute hydrochloric acid was added for washing, and the lower dilute hydrochloric acid layer was discarded. The organic layer was concentrated under reduced pressure. After concentration, (4-ethylbenzene)-piperidin-1-yl-methyl ketone was obtained, with a yield of 19.76 g and a yield of 91.1%.

[0045] Example 2

[0046] 2.17 g of (4-ethylbenzene)-piperidin-1-yl-methyl ketone and 20 ml of THF were placed in a 100 ml three-necked flask and placed in a magnetic stirrer. 13 ml of isopropenyl magnesium bromide (1.0 M / L, in THF) was added dropwise at reflux temperature (66 °C). After the addition was complete, the mixture was added to 55 ml of water, allowed to stand, and the layers were separated. The organic layer was concentrated to dryness under reduced pressure (concentration temperature: 90 °C, pressure: -0.095 MPa). 10 ml of acetone was added, and the pH was adjusted to <3 by passing hydrogen chloride gas. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried to yield 2.5 g, with a yield of 84.5%. HPLC analysis showed a purity of 99.8%.

[0047] Comparative Example 1

[0048] 2.17 g of (4-ethylbenzene)-piperidin-1-yl-methyl ketone and 20 ml of THF were placed in a 100 ml three-necked flask and placed in a magnetic stirrer. 13 ml of isopropenyl magnesium bromide (1.0 M / L, in THF) was added dropwise at 40 °C. After the addition was complete, the mixture was added to 55 ml of water, allowed to stand, and the organic layer was concentrated to dryness under reduced pressure. 10 ml of acetone was added, and the pH was adjusted to <3 by passing hydrogen chloride gas. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried to yield 2.2 g, with a yield of 74.4%.

[0049] It can be seen that the final product yield is significantly reduced when (4-ethylbenzene)-piperidin-1-yl-methyl ketone reacts with isopropenyl magnesium bromide under heating conditions below 50°C (other reaction conditions are the same as in Example 2).

[0050] Comparative Example 2

[0051] 2.17 g of (4-ethylbenzene)-piperidin-1-yl-methyl ketone and 20 ml of xylene were placed in a 100 ml three-necked flask and placed in a magnetic stirrer. 13 ml of isopropenyl magnesium bromide (1.0 M / L, in THF) was added dropwise at 120 °C. After the addition was complete, the mixture was added to 55 ml of water, allowed to stand, and the layers were separated. The organic layer was concentrated to dryness under reduced pressure. 10 ml of acetone was added, and the pH was adjusted to <3 by passing hydrogen chloride gas. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried to yield 2.1 g, with a yield of 71%.

[0052] It can be seen that the final product yield is significantly reduced when (4-ethylbenzene)-piperidin-1-yl-methyl ketone reacts with isopropenyl magnesium bromide under heating conditions above 110°C and with xylene as the first solvent (other reaction conditions are the same as in Example 2).

[0053] Example 3

[0054] 2.17 g of (4-ethylbenzene)-piperidin-1-yl-methyl ketone and 20 ml of 2-methyltetrahydrofuran were placed in a 100 ml three-necked flask and placed in a magnetic stirrer. 13 ml of isopropenyl magnesium bromide (1.0 M / L, in THF) was added dropwise at reflux temperature (80 °C). After the addition was complete, the mixture was added to 55 ml of water, allowed to stand, and separated. The organic layer was concentrated to dryness under reduced pressure (concentration temperature: 100 °C, pressure: -0.08 MPa). 10 ml of acetone was added, and the pH was adjusted to <3 by passing hydrogen chloride gas. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried to yield 2.8 g, with a yield of 94.6%. The HPLC chromatogram is shown below. Figure 1 As shown, for Figure 1 The spectrum was normalized and the results are shown in Table 1 below, with a purity of 99.9%.

[0055] Table 1: Product analysis results of Example 3

[0056]

[0057] Example 4

[0058] 2.17 g of (4-ethylbenzene)-piperidin-1-yl-methyl ketone and 20 ml of 2-methyltetrahydrofuran were placed in a 100 ml three-necked flask and placed in a magnetic stirrer. 13 ml of isopropenyl magnesium bromide (1.0 M / L, in THF) was added dropwise at reflux temperature (80 °C). After the addition was complete, the mixture was added to 55 ml of water, allowed to stand, and the organic layer was concentrated to dryness under reduced pressure. 10 ml of acetone was added, and the pH was adjusted to <3 with concentrated hydrochloric acid. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried to yield 2.1 g, with a yield of 78.0%.

[0059] Therefore, it can be seen that, compared with adjusting the pH value by hydrogen chloride gas, adjusting the pH value of the solution by concentrated hydrochloric acid can still yield the product of this invention, namely etorizine hydrochloride, but the final product yield will be reduced.

[0060] Comparative Example 3

[0061] 2.17 g of (4-ethylbenzene)-piperidin-1-yl-methyl ketone and 20 ml of 2-methyltetrahydrofuran were placed in a 100 ml three-necked flask and placed in a magnetic stirrer. 13 ml of isopropenyl magnesium bromide (1.0 M / L, in THF) was added dropwise at reflux temperature (80 °C). After the addition was complete, the mixture was added to 55 ml of water, allowed to stand, and the organic layer was concentrated to dryness under reduced pressure. 10 ml of acetone was added, and the pH was adjusted to 5 by passing hydrogen chloride gas. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried to yield 2.2 g, with a yield of 74%.

[0062] Therefore, even when using hydrogen chloride gas to adjust the pH value, the final product yield will decrease if the pH value of the solution is not in the range of less than 3.

[0063] It is understood that the above-described embodiments are merely exemplary embodiments used to illustrate the principles of the present invention; however, the present invention is not limited thereto and is therefore not intended to limit this application. For those skilled in the art, various modifications, alterations, equivalent substitutions, or improvements can be made without departing from the spirit and essence of the present invention, and all such modifications, alterations, equivalent substitutions, or improvements are considered to fall within the protection scope of the present invention.

Claims

1. A method for preparing etorizine hydrochloride, characterized in that, The steps include the following: (1) Disperse (4-ethylphenyl)(piperidin-1-yl) methyl ketone in a first solvent, stir and heat, then add isopropenyl magnesium bromide dropwise to obtain a mixture. The heating temperature is 50℃~110℃. The first solvent is any one or a mixture of several of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and methyl tert-butyl ether. (2) Extract the mixture obtained in step (1) with water, allow it to stand and separate, concentrate the organic layer to obtain an oily substance; and (3) Add a second solvent to the oily substance obtained in step (2) to prepare a solution. Pass hydrogen chloride into the solution to precipitate a solid. Filter the solution to obtain solid etorizine hydrochloride. The preparation method does not require column chromatography, and the solid etorizine hydrochloride does not contain isomer impurities. In step (3), the second solvent is any one or a mixture of several of acetone, isopropanol, ethyl acetate, and toluene; In step (3), hydrogen chloride is introduced into the solution to make the pH value of the solution less than 3.

2. The method for preparing etorizine hydrochloride according to claim 1, characterized in that, In step (1), the molar ratio of isopropenyl magnesium bromide to (4-ethylphenyl)(piperidin-1-yl) methyl ketone is 1.2 to 1.

5.

3. The method for preparing etorizine hydrochloride according to claim 1, characterized in that, The volume ratio of the amount of extraction water used in step (2) to the amount of the first solvent used in step (1) is 1:1~1.

5.

4. The method for preparing etorizine hydrochloride according to claim 1, characterized in that, In step (2), the concentration method is vacuum concentration, wherein the vacuum concentration temperature is 90℃~100℃ and the vacuum concentration pressure is -0.095Mpa to -0.08MPa.

5. The method for preparing etorizine hydrochloride according to claim 1, characterized in that, In step (2), the extraction is performed no less than twice.

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