Synthesis process of eperisone hydrochloride intermediate p-ethyl propiophenone

Abstract

The invention discloses a solvent-participation-free synthesis process of p-ethyl propiophenone, which comprises the following steps: by taking ethylbenzene and propionyl chloride as raw materials and phosphorus trichloride and lewis acid as catalysts, carrying out Friedel-Crafts acylation reaction without adding other reaction solvents to obtain the p-ethyl propiophenone. Compared with the prior art, the method has the advantages that the generation of disubstituted impurity 1-(2, 4-diethyl phenyl) propan-1-ketone is unexpectedly and effectively avoided, the impurity generation amount is less than 5%, the yield and the purity of p-ethyl propiophenone are greatly improved, and the synthesis process is green, environment-friendly, low in cost and convenient for realizing industrial production, and can be used for industrial production of eperisone.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically relates to a synthesis process for p-ethylphenylacetone, an intermediate of ethperisone hydrochloride. Background Technology

[0002] Eperisone hydrochloride is a β-aminoketone centrally acting muscle relaxant, chemically named 4'-ethyl-2-methyl-3-piperidinylphenylacetone hydrochloride. It was first marketed in Japan in 1983 under the trade name Myonal. p-Ethylphenylacetone is a key pharmaceutical intermediate in the preparation of eperisone hydrochloride, with the molecular formula C1... 11 H 14 O, with a molecular weight of 162.23. In existing technologies, p-ethylphenylacetone is mostly prepared using ethylbenzene and propionyl chloride as raw materials. p-Ethylphenylacetone and its synthetic route are shown below:

[0003]

[0004] In the synthesis process of p-ethyl phenylacetone involving solvents, substituent isomerism often occurs, generating ortho-isomer impurities (Ⅰ) and meta-isomer impurities (Ⅱ), which remain in the intermediate p-ethyl phenylacetone and are difficult to remove. With subsequent reactions, ortho-isomer impurities of etorizine hydrochloride and meta-isomer impurities of etorizine hydrochloride are generated.

[0005]

[0006] To address the Friedel-Crafts acylation process for generating p-ethyl acetone in the aforementioned synthesis process, Pang Xueliang et al. reported an improved p-ethyl acetone synthesis process: anhydrous aluminum trichloride and ethylbenzene were dissolved in dichloroethane, and propionyl chloride was added dropwise while stirring at a temperature not exceeding 30°C. The p-ethyl acetone with a content greater than 98% was obtained by vacuum distillation.

[0007] Chinese patent CN118047664A discloses a synthesis process for p-ethyl phenylacetone intermediates based on a continuous flow apparatus: Lewis acid and propionyl chloride are mixed in dichloromethane to form solution A; phenethyl group is mixed in dichloromethane to form solution B; and solutions A and B are reacted in a continuous flow apparatus to obtain p-ethyl phenylacetone, thereby improving purity and yield.

[0008] From a green chemistry perspective, the researchers of this invention conducted an in-depth study on the solvent-free Friedel-Crafts acylation reaction to generate p-ethylphenylacetone. They discovered that without the use of additional solvents, the reaction produces a significant amount of another disubstituted impurity: 1-(2,4-diethylphenyl)prop-1-one (CAS: 1806315-57-0). This impurity has a similar structure and solubility to the intermediate p-ethylphenylacetone, and conventional purification methods are ineffective in removing it. Furthermore, the residual impurity can be introduced into the API, generating ethperisone hydrochloride, which greatly affects product yield and quality.

[0009]

[0010] Bisubstituted impurity: 1-(2,4-diethylphenyl)prop-1-one

[0011] A search revealed no existing technology reports on a purification method that can effectively remove this impurity, nor any synthetic process that can effectively avoid generating this impurity. Therefore, how to provide a low-cost, green, and economical synthetic process for p-ethylphenylacetone, a key intermediate of ethperisone hydrochloride, under solvent-free Friedel-Crafts acylation reaction conditions, which can effectively avoid generating the disubstituted impurity 1-(2,4-diethylphenyl)prop-1-one, is a technical problem that has not yet been solved by those skilled in the art. Summary of the Invention

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

[0013] On the one hand, this invention provides a solvent-free synthesis process for p-ethylphenylacetone, using ethylbenzene and propionyl chloride as raw materials, phosphorus trichloride and Lewis acid as catalysts, without adding other reaction solvents, to obtain p-ethylphenylacetone through a Friedel-Crafts acylation reaction, as shown in the following reaction formula:

[0014]

[0015] In some embodiments, the molar ratio of ethylbenzene to phosphorus trichloride in the Friedel-Crafts acylation reaction is 1:(0.01–0.1);

[0016] In a further embodiment, the molar ratio of ethylbenzene to phosphorus trichloride in the Friedel-Crafts acylation reaction is 1:(0.01-0.07);

[0017] In a further embodiment, the molar ratio of ethylbenzene to phosphorus trichloride in the Friedel-Crafts acylation reaction is 1:

[0018] (0.03~0.06).

[0019] In some embodiments, the molar ratio of ethylbenzene, propionyl chloride, Lewis acid, and phosphorus trichloride in the Friedel-Crafts acylation reaction is 1:(0.8–3):(0.5–2):(0.01–0.1).

[0020] In a further embodiment, the molar ratio of ethylbenzene, propionyl chloride, Lewis acid, and phosphorus trichloride in the Friedel-Crafts acylation reaction is 1:(1-2):(0.5-1.5):(0.01-0.07).

[0021] In a further embodiment, the molar ratio of ethylbenzene, propionyl chloride, Lewis acid, and phosphorus trichloride in the Friedel-Crafts acylation reaction is 1:(1-2):(0.5-1.5):(0.03-0.06).

[0022] In some embodiments, the Lewis acid catalyst in the Friedel-Crafts acylation reaction is selected from one or more combinations of AlCl3, FeCl3, ZnCl2, TiCl4, and SnCl2.

[0023] In a further embodiment, the Lewis acid catalyst in the Friedel-Crafts acylation reaction is AlCl3.

[0024] In some embodiments, the reaction temperature of the Friedel-Crafts acylation reaction is -20°C to 20°C;

[0025] In a further embodiment, the reaction temperature of the Friedel-Crafts acylation reaction is -10°C to 0°C.

[0026] In some embodiments, a solvent-free synthesis process for p-ethylphenylacetone includes the following steps:

[0027] S1. Add phosphorus trichloride to ethylbenzene and stir;

[0028] S2. Add Lewis acid and propionyl chloride in batches, and stir at -20℃ to 20℃ until the reaction is complete.

[0029] S3. After the reaction is complete, the reaction solution is added to ice water for mixing and stirring, extraction, separation, and organic phase distillation. The main fraction with a temperature ≥90℃ is collected to obtain p-ethylacetone.

[0030] In some embodiments, the amount of p-ethylphenylacetone generated in the reaction solution is greater than 85%, preferably greater than 90%;

[0031] In some embodiments, the amount of the disubstituted impurity 1-(2,4-diethylphenyl)prop-1-one generated in the reaction solution is less than 5%;

[0032] In a further embodiment, the amount of the disubstituted impurity 1-(2,4-diethylphenyl)prop-1-one generated in the reaction solution is less than 0.5%, preferably 0.05%.

[0033] In some embodiments, the raw material propionyl chloride can be obtained by commercially available materials or by referring to existing technologies (e.g., Pang Xueliang et al. Comparison of production processes of p-methyl acetone and p-ethyl acetone [J]. Chemical Industry Times, 1999(11):31-33.).

[0034] On the other hand, the present invention provides a solvent-free synthesis process for p-ethylphenylacetone and its application in the preparation of etorizine hydrochloride.

[0035] In some implementations, the synthesis route is as follows:

[0036]

[0037] Compared with the prior art, the present invention has achieved at least the following beneficial effects:

[0038] 1. This invention provides a novel solvent-free synthesis process for p-ethyl phenylacetone, which can efficiently synthesize p-ethyl phenylacetone, is environmentally friendly, low in cost, and easy to realize industrial production.

[0039] 2. This invention, by adding an appropriate amount of phosphorus trichloride to the solvent-free p-ethylphenylacetone reaction system, effectively avoids the formation of the disubstituted impurity 1-(2,4-diethylphenyl)prop-1-one compared to existing technologies (Comparative Examples 1-3). The impurity formation amount is less than 5%, significantly improving the yield and purity of the product p-ethylphenylacetone. Furthermore, by controlling the molar ratio of ethylbenzene to phosphorus trichloride to 1:(0.03~0.06), this invention can control the formation amount of the disubstituted impurity 1-(2,4-diethylphenyl)prop-1-one to less than 0.5%. Attached Figure Description

[0040] Figure 1 Example 1: Gas chromatography (GC) chromatogram of the reaction liquid (retention time of p-ethylphenylacetone: 14.924 min, retention time of impurity 1-(2,4-diethylphenyl)prop-1-one: 15.989 min).

[0041] Figure 2 Comparative Example 2: Gas chromatography (GC) chromatogram of the reaction liquid (retention time of p-ethylphenylacetone: 14.924 min, retention time of impurity 1-(2,4-diethylphenyl)prop-1-one: 15.992 min). Detailed Implementation

[0042] 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.

[0043] 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.

[0044] Detection method: Determined by gas chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0521).

[0045] Test solution: Take 100 mg of this product, place it in a 10 ml volumetric flask, add solvent to dissolve and dilute to the mark, and shake well.

[0046] Chromatographic conditions: Waters Arc-2489 gas chromatograph with a capillary column of 6% cyanopropylphenyl-94% dimethylpolysiloxane (SH-624 30m × 0.53mm, 3.0µm or similar polarity) as the stationary phase; nitrogen as the carrier gas at a flow rate of 3.0 mL / min and a split ratio of 10:1; initial temperature of 100°C, maintained for 2 minutes, then increased to 250°C at a rate of 10°C / min and maintained for 10 minutes; injection port temperature of 260°C; flame ionization detector (FID) at a detector temperature of 250°C; injection volume of 1 mL; solvent: acetonitrile.

[0047] Determination method: Accurately measure the test solution and inject it into the gas chromatograph, then record the chromatogram. If impurity peaks are present in the chromatogram of the test solution, calculate their value using the peak area normalization method.

[0048] Example 1: A solvent-free synthesis process for p-ethylacetone

[0049]

[0050] Add 100 kg of ethylbenzene (942 mol) to the reactor, purge the reactor with nitrogen gas, cool it to -20℃ to -10℃, add phosphorus trichloride (4.36 kg of phosphorus trichloride (31.75 mol)) and start stirring;

[0051] Anhydrous aluminum chloride (119.31 kg, 894.8 mol) and propionyl chloride (87.14 kg, 942 mol) were added in batches, with a 30-minute interval between each batch. The reaction was carried out at -20°C for 2.0 h. The reaction solution was analyzed by gas chromatography (GC). The reactants reacted completely. The amount of p-ethylphenylacetone formed in the reaction solution was 93.51%, and the amount of the impurity 1-(2,4-diethylphenyl)prop-1-one formed was 0.05%. See [link to relevant documentation]. Figure 1 .

[0052] Post-processing: Add the reaction solution to the ice-water mixture, keep warm and stir, and let stand; separate the lower aqueous phase, transfer the organic phase to the reaction vessel for distillation, collect the main fraction at ≥90℃, and obtain p-ethylacetone, about 107 kg, with a GC purity of 96.83%.

[0053] Example 2: A solvent-free synthesis process for p-ethylphenylacetone

[0054]

[0055] Add freshly distilled ethylbenzene (100 kg, 942 mol) to the reactor, purge the reactor with nitrogen gas, cool to -20℃ to -10℃, add phosphorus trichloride (8.71 kg, 63.42 mol), and start stirring;

[0056] Anhydrous aluminum chloride (119.31 kg, 894.8 mol) and propionyl chloride (87.14 kg, 942 mol) were added in batches, with a 30-minute interval between each batch. The reaction was carried out at -15°C for 2.0 h. The reaction solution was analyzed by gas chromatography (GC). The reaction of the raw materials was complete. The amount of p-ethylphenylacetone produced in the reaction solution was 88.4%, and the amount of impurity 1-(2,4-diethylphenyl)prop-1-one produced was 2.25%.

[0057] Comparative Example 1

[0058] The reaction was carried out according to the reaction feed amount, reaction conditions and reaction steps of Example 1, except that phosphorus trichloride in Example 1 was replaced with an equal amount of phosphorus oxychloride. The reaction formula is as follows:

[0059]

[0060] After the reaction was complete, the reaction solution was analyzed by gas chromatography (GC). The amount of p-ethylphenylacetone produced in the reaction solution was 47.64%, and the amount of impurity 1-(2,4-diethylphenyl)prop-1-one produced was 21.66%.

[0061] Comparative Example 2

[0062] The reaction was carried out according to the reaction feed amount, reaction conditions and reaction steps of Example 2, the difference being that phosphorus trichloride in Example 1 was replaced with an equal amount of dichloromethane, and the reaction formula is as follows:

[0063]

[0064] After the reaction was complete, the reaction solution was analyzed by gas chromatography (GC). The amount of p-ethylphenylacetone formed in the reaction solution was 66.5%, and the amount of the impurity 1-(2,4-diethylphenyl)prop-1-one formed was 16.2%. (See attached table). Figure 2 .

[0065] Comparative Example 3

[0066] The difference from Example 1 is that phosphorus trichloride is not used; the synthetic route is as follows:

[0067]

[0068] Freshly distilled ethylbenzene (10 g, 94.2 mmol) was added to the reactor. Nitrogen gas was purged through the reactor slightly, and the temperature was lowered to -20°C to -10°C. Anhydrous aluminum chloride (11.9 g, 89.4 mmol) was added in batches at 10-15 min intervals. After the addition was complete, propionyl chloride (8.71 g, 94.2 mmol) was added dropwise. The reaction was carried out at -20°C. Samples were taken and analyzed by GC. The reaction of the raw materials was complete. The amount of p-ethylphenylacetone produced in the reaction solution was 75.66%, and the amount of impurity 1-(2,4-diethylphenyl)prop-1-one produced was 13.38%.

[0069] The inhibitory effects of adding different reagents on the disubstituted impurity 1-(2,4-diethylphenyl)prop-1-one were investigated, and the results are shown in Table 1:

[0070] Table 1

[0071]

[0072] The investigation reveals that:

[0073] In the solvent-free synthesis process of p-ethylphenylacetone, the addition of phosphorus trichloride, a specific reagent, can effectively suppress the formation of the disubstituted impurity 1-(2,4-diethylphenyl)prop-1-one.

[0074] Further controlling the molar ratio of ethylbenzene to phosphorus trichloride in the reaction raw materials to 1:(0.01-0.07) can reduce the amount of the disubstituted impurity 1-(2,4-diethylphenyl)prop-1-one to below 5%; when the molar ratio of ethylbenzene to phosphorus trichloride is 1:(0.03-0.06), the amount of impurity generated is only 0.05% (Example 1).

[0075] Using other reagents such as phosphorus oxychloride (Comparative Example 1), dichloromethane (Comparative Example 2), and not using phosphorus oxychloride (Comparative Example 3) did not have this significant effect in inhibiting the formation of impurities.

Claims

1. A process for synthesizing p-ethylphenylacetone, characterized in that, Without the addition of an additional solvent, ethylbenzene and propionyl chloride undergo a Friedel-Crafts acylation reaction in the presence of phosphorus trichloride and a Lewis acid to yield p-ethylphenylacetone, as shown in the following reaction formula:

2. The synthesis process according to claim 1, characterized in that, In the Friedel-Crafts acylation reaction, the molar ratio of ethylbenzene to phosphorus trichloride is 1:(0.01-0.1).

3. The synthesis process according to claim 2, characterized in that, In the Friedel-Crafts acylation reaction, the molar ratio of ethylbenzene to phosphorus trichloride is 1:(0.01-0.07), preferably 1:(0.03-0.06).

4. The synthesis process according to claim 1, characterized in that, In the Friedel-Crafts acylation reaction, the molar ratio of ethylbenzene, propionyl chloride, Lewis acid, and phosphorus trichloride is 1:(0.8–3):(0.5–2):(0.01–0.1).

5. The synthesis process according to claim 4, characterized in that, In the Friedel-Crafts acylation reaction, the molar ratio of ethylbenzene, propionyl chloride, Lewis acid, and phosphorus trichloride is 1:(1-2):(0.5-1.5):(0.01-0.07), preferably 1:(1-2):(0.5-1.5):(0.03-0.06).

6. The synthesis process according to any one of claims 1-5, characterized in that, The Lewis acid catalyst in the Friedel-Crafts acylation reaction is one or a combination of AlCl3, FeCl3, ZnCl2, TiCl4, and SnCl2.

7. The synthesis process according to any one of claims 1-6, characterized in that, The reaction temperature for the Friedel-Crafts acylation reaction is -20℃ to 20℃.

8. The synthesis process according to claim 1, characterized in that, The synthesis process includes the following steps: S1. Add phosphorus trichloride to ethylbenzene and stir; S2. Add anhydrous aluminum trichloride and propionyl chloride in batches, and stir at -20℃ to 20℃ until the reaction is complete. S3. After the reaction is complete, the reaction solution is added to ice water for mixing and stirring, extraction, separation, and organic phase distillation. The main fraction with a temperature ≥90℃ is collected to obtain p-ethylacetone.

9. The application of the synthesis process of p-ethylphenylacetone as described in any one of claims 1 to 8 in the preparation of etorizine hydrochloride.

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