A kind of synthetic method of mebeverine hydrochloride

Abstract

The present invention relates to the technical field of drug synthesis, and specifically discloses a method for synthesizing mebeverine hydrochloride. The present invention adds compound I, veratric acid and an acidic catalyst to a solvent a, performs an esterification reaction at 80°C to 110°C, and obtains mebeverine; the mebeverine is added to a solvent b, and hydrochloric acid is added to form a salt to obtain mebeverine hydrochloride. The conditions of the esterification reaction in the present invention are mild, the post-processing process is simple, and the operation is simple and easy, which effectively avoids the problem of more impurities in mebeverine hydrochloride; the raw material cost is low, the overall production cost is low, and the finished product yield and purity are high, which is suitable for large-scale industrial production and has good industrial prospects and social benefits. If the temperature of the esterification reaction exceeds the above range, a large number of side reactions will be generated, or the esterification reaction will be incomplete, resulting in complicated post-processing, and will also have an adverse effect on the yield and purity of the finished product mebeverine hydrochloride.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing mebeverine hydrochloride. Background Art

[0002] Mebeverine Hydrochloride, chemical name is 4-[ethyl-[1-(4-methoxyphenyl)prop-2-yl]amino]butyl-3,4-dimethoxybenzoate hydrochloride, molecular formula is C 25 H 36 ClNO5, with a structural formula shown in Formula 1. Mebeverine hydrochloride is a myotropic antispasmodic drug used for the symptomatic treatment of abdominal pain and spasms, intestinal dysfunction, and intestinal discomfort caused by irritable bowel syndrome, as well as intestinal spasms secondary to organic diseases. It acts directly on gastrointestinal smooth muscle to relieve spasm symptoms without affecting normal intestinal motility. This action does not act through the autonomic nervous system, so it has no anticholinergic effects. It is also suitable for patients with benign prostatic hyperplasia and glaucoma.

[0003]

[0004] Formula 1.

[0005] However, there is no report on the synthesis method of mebeverine hydrochloride. Therefore, it is urgent to develop a synthesis method of mebeverine hydrochloride to meet the market demand for this drug. Summary of the Invention

[0006] In view of the above problems, the present invention provides a method for synthesizing mebeverine hydrochloride, which has mild reaction conditions, high product yield, controllable production costs, and is suitable for industrial production.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0008] A method for synthesizing mebeverine hydrochloride comprises the following steps:

[0009] Sa, adding compound I as shown in formula I, veratric acid and an acidic catalyst to solvent a, and conducting an esterification reaction at 80° C. to 110° C. to obtain mebeverine;

[0010] Sb, adding the mebeverine to solvent b, and then adding hydrochloric acid to form a salt to obtain mebeverine hydrochloride;

[0011]

[0012] Formula I.

[0013] Relative to the prior art, the synthetic method of mebeverine hydrochloride provided by the present invention, Compound I and veratric acid are subjected to esterification reaction under an acidic catalyst to obtain mebeverine, and then hydrochloric acid is added to form a salt to obtain a mebeverine hydrochloride finished product. In the present invention, the conditions of the esterification reaction are mild, the post-processing process is simple, and the operation is easy, which effectively avoids the problem of more impurities in the mebeverine hydrochloride finished product; simultaneously, the raw material cost is low, the overall production cost is low, and the finished product yield and purity are higher, so it is suitable for large-scale industrial production, and has good industrial prospects and social benefits.

[0014] The present invention has found through a large number of experiments that if the temperature of the esterification reaction is higher than the above range, a large number of side reactions will occur, the post-processing will be complicated, and the yield and purity of the finished product mebeverine hydrochloride will be adversely affected; if the temperature of the esterification reaction is too low, the esterification reaction will be incomplete, which will also have an adverse effect on the yield and purity of the finished product mebeverine hydrochloride.

[0015] Preferably, in Sa, the acidic catalyst includes at least one of p-toluenesulfonic acid, formic acid, sulfuric acid or glacial acetic acid, and is more preferably p-toluenesulfonic acid.

[0016] Preferably, in Sa, the molar ratio of the compound I, the veratric acid and the acidic catalyst is 1:(1-1.3):(0.3-0.5).

[0017] Preferably, in Sa, the solvent a comprises tetrahydrofuran.

[0018] Preferably, in Sa, the mass ratio of the compound I to the solvent a is 1:(4.5~6).

[0019] Preferably, in Sa, the esterification reaction time is 2 h to 8 h, more preferably 5 h to 6 h.

[0020] Preferably, in Sa, after the esterification reaction is completed, the process further comprises:

[0021] The obtained reaction solution is concentrated, and solvent c is added to adjust the pH value of the system to weak alkalinity. The phases are separated, and the organic phase is dried, filtered, and concentrated under reduced pressure in sequence to obtain the mebeverine.

[0022] In the post-treatment of Sa of the present invention, the reaction solution is first concentrated to remove the solvent a, and then the solvent c is added for phase separation. After removing the solvent c and impurities, mebeverine is obtained.

[0023] Further preferably, in Sa, the solvent c comprises at least one of methanol, ethanol, ethyl acetate or water, more preferably ethyl acetate and water in a mass ratio of (0.9~1.1):1.

[0024] Further preferably, in Sa, the mass ratio of the compound I to the solvent c is 1:(2~7.8), more preferably 1:(2.3~2.8).

[0025] More preferably, in Sa, the weak alkalinity is pH=7~10, more preferably pH=8~9.

[0026] For example, in Sa, a 30% sodium hydroxide aqueous solution is used to adjust the pH of the system to 7-10.

[0027] The present invention effectively removes the acidic catalyst in the system by controlling the pH value of the system and ensures that the system does not dissociate.

[0028] Further preferably, in Sa, the drying adopts anhydrous sodium sulfate, and the mass ratio of the compound I to the anhydrous sodium sulfate is 1:(3~15), more preferably 1:(4~6).

[0029] Further preferably, in Sa, the drying time is 5 h to 15 h, more preferably 8 h to 10 h.

[0030] Preferably, in Sb, the solvent b is an alcohol solvent.

[0031] Further preferably, in Sb, the solvent b comprises at least one of methanol or ethanol.

[0032] Preferably, the mass volume ratio of the mebeverine, the solvent b and the hydrochloric acid is 1 g: (5-10) mL: (0.6-2) mL, more preferably 1 g: (7-10) mL: (0.9-1.3) mL.

[0033] Preferably, in Sb, the salt-forming temperature is 0°C to 30°C, and the salt-forming time is 50 min to 90 min; the temperature for adding the hydrochloric acid is 0°C to 5°C, and the temperature at the end of the salt-forming is 25°C to 30°C.

[0034] In the Sb of the present invention, after hydrochloric acid is added to the system, the system temperature will rise. The present invention controls the temperature of salt formation (the slower the rate of adding hydrochloric acid, the smaller the fluctuation of the salt formation temperature), so that the system temperature is gradually increased from 0°C to 5°C to 25°C to 30°C, thereby effectively controlling the salt formation rate and making the salt formation more complete.

[0035] Preferably, in Sb, the salt formation further comprises:

[0036] The obtained crude solid product is added to solvent d and subjected to a first crystallization to obtain a crude mebeverine hydrochloride product; the crude mebeverine hydrochloride product is dissolved in solvent e, decolorized, and subjected to a second crystallization to obtain the mebeverine hydrochloride product.

[0037] Further preferably, in Sb, the solvent d comprises at least one of ethyl acetate, methanol or dichloromethane, and is further preferably ethyl acetate.

[0038] Further preferably, in Sb, the mass volume ratio of the mebeverine to the solvent d is 1 g:(3-3.5) mL.

[0039] For example, in Sb, after the salt formation is completed, the process further comprises: concentrating under reduced pressure to remove the alcohol solvent in the system to obtain a solid crude product.

[0040] More preferably, in Sb, the temperature of the first crystallization is 30° C. to 70° C. (more preferably 40° C. to 50° C.); and the time of the first crystallization is 2 h to 3 h.

[0041] For example, in Sb, after the first crystallization is completed, the method further comprises: vacuum drying the obtained solid at 40° C. to 60° C. for 4 h to 10 h.

[0042] Further preferably, in Sb, the solvent e comprises isopropyl alcohol and ethyl acetate in a volume ratio of (1-2):(8-9).

[0043] Further preferably, in Sb, the mass volume ratio of the crude mebeverine hydrochloride to the solvent e is 1 g: (7.5~8.5) mL.

[0044] For example, in Sb, in order to accelerate the dissolution rate of the crude mebeverine hydrochloride, it can be dissolved in solvent e at 80°C~85°C.

[0045] More preferably, in Sb, the decolorization temperature is 80° C. to 85° C., and the decolorization time is 25 min to 40 min.

[0046] Further preferably, activated carbon is added to Sb for decolorization, and the mass ratio of the activated carbon to the crude mebeverine hydrochloride is (5~10):100.

[0047] More preferably, in Sb, the temperature of the second crystallization is 0° C. to 5° C., and the time of the second crystallization is 2 h to 3 h.

[0048] For example, in Sb, after the second crystallization is completed, the method further comprises: vacuum drying the obtained solid at 50° C. to 60° C. for 6 h to 16 h.

[0049] Preferably, the preparation method of compound I comprises the following steps:

[0050] S1, dissolving 4-methoxypropiophenone, ethylamine, and a first catalyst in a first solvent, and performing a first reflux reaction to obtain a compound II as shown in Formula II;

[0051] S2, adding the compound II and a reducing agent to a second solvent to carry out a reduction reaction, and then adjusting the pH of the system to acidic to obtain a compound III as shown in formula III;

[0052] S3, adding the compound III, 4-bromobutyl acetate, a basic substance, and a second catalyst into a third solvent, and performing a second reflux reaction to obtain a compound IV as shown in Formula IV;

[0053] S4, adding the compound IV and the alkaline catalyst to a fourth solvent, performing a hydrolysis reaction, then adjusting the pH of the system to 1-3, and crystallizing to obtain the compound I;

[0054]

[0055] Formula II

[0056]

[0057] Formula III

[0058]

[0059] Formula IV.

[0060] The present invention uses 4-methoxypropiophenone and ethylamine as raw materials. A Schiff base reaction occurs under the action of a first catalyst to produce a Schiff base (Compound II), which is then reduced to Compound III using a reducing agent. Compound III is then condensed with 4-bromobutyl acetate under the action of an alkaline substance and a second catalyst to produce Compound IV. Finally, Compound IV is hydrolyzed to Compound I under the action of an alkaline catalyst. Throughout the reaction process, the technical route is rationally designed, the raw and auxiliary materials are all conventional chemical products, are inexpensive and readily available, the process is simple and easy to operate, the reaction conditions are mild, and Compound I can be obtained without the use of special equipment. The yield and purity are both high, making it suitable for large-scale industrial production.

[0061] Further preferably, in S1, the first catalyst comprises at least one of glacial acetic acid, p-toluenesulfonic acid, benzenesulfonic acid or formic acid, more preferably glacial acetic acid.

[0062] Further preferably, in S1, the molar ratio of the 4-methoxypropiophenone, the ethylamine and the first catalyst is 1:(1-1.5):(0.1-1), more preferably 1:(1.1-1.3):(0.5-0.8).

[0063] Further preferably, in S1, the first solvent includes at least one of cyclohexane, isooctane, hexane or trimethylpentane, more preferably cyclohexane.

[0064] Further preferably, in S1, the mass ratio of the ethylamine to the first solvent is 1:(1-10), more preferably 1:(3.5-4.5).

[0065] Further preferably, in S1, the temperature of the first reflux reaction is 80°C to 120°C (more preferably 85°C to 95°C), and the time of the first reflux reaction is 4h to 5h.

[0066] More preferably, in S1, the temperature is first raised to the temperature of the first reflux reaction, and then the first catalyst is added, so that the Schiff base reaction can proceed more fully.

[0067] For example, in S1, after the first reflux reaction is completed, the process further includes concentrating under reduced pressure to remove the first solvent and excess ethylamine; the temperature for concentrating under reduced pressure is 50° C. to 60° C., and the pressure is ≤-0.08 MPa.

[0068] Further preferably, in S2, the reducing agent includes at least one of potassium borohydride, sodium borohydride or lithium borohydride, more preferably potassium borohydride.

[0069] Further preferably, in S1-S2, the molar ratio of the 4-methoxypropiophenone to the reducing agent is 1:(0.2-0.8), more preferably 1:(0.4-0.6).

[0070] Further preferably, in S2, the second solvent includes at least one of ethanol, methanol or isopropanol, more preferably ethanol.

[0071] Further preferably, in S1-S2, the mass ratio of the 4-methoxypropiophenone to the second solvent is 1:(1-3), more preferably 1:(2-2.3).

[0072] Further preferably, in S2, the reduction reaction temperature is 25° C. to 35° C., and the reduction reaction time is 2 h to 3 h.

[0073] Further preferably, in S2, the acidity is pH=3~4.

[0074] In the present invention, hydrochloric acid can be used to adjust the pH of the system to 3-4 to dissociate the reaction system, thereby obtaining compound III.

[0075] For example, in S2, after adjusting the pH of the system to acidic, the method further comprises: vacuum drying the obtained solid at 40°C to 80°C for 3h to 12h, more preferably vacuum drying at 50°C to 60°C for 5h to 8h.

[0076] Further preferably, in S3, the molar ratio of the compound III to the 4-bromobutyl acetate is 1:(1.05~1.3).

[0077] Further preferably, in S3, the alkaline substance includes at least one of potassium carbonate, sodium carbonate, triethylamine, sodium hydroxide or diisopropylethylamine, more preferably potassium carbonate or sodium carbonate.

[0078] Further preferably, in S3, the second catalyst includes at least one of tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride or dodecyltrimethylammonium bromide, more preferably tetrabutylammonium bromide.

[0079] Further preferably, in S3, the third solvent includes at least one of dichloromethane, toluene, ethyl acetate, tetrahydrofuran, benzene or water, more preferably water and toluene in a mass ratio of 1: (0.9~1.1).

[0080] Further preferably, in S3, the mass ratio of the compound III, the alkaline substance, the second catalyst and the third solvent is 1:(4-5):(0.1-0.18):(2-3).

[0081] Further preferably, in S3, the temperature of the second reflux reaction is 80°C to 120°C (more preferably 80°C to 90°C), and the time of the second reflux reaction is 12h to 48h (more preferably 24h to 26h).

[0082] Further preferably, in S3, after the second reflux reaction is completed, the following step is further included:

[0083] Water was added to the reaction system, the phases were separated, the pH of the organic phase was adjusted to 3-4, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound IV.

[0084] For example, in S3, hydrochloric acid may be used to adjust the pH of the organic phase.

[0085] More preferably, in S3, the mass ratio of the compound III, the water and the anhydrous sodium sulfate is 1:(0.1-5.5):(5-20), and further preferably 1:(0.8-1.3):(5-8).

[0086] More preferably, in S3, the drying time is 8 h to 10 h.

[0087] Further preferably, in S4, the alkaline catalyst comprises sodium hydroxide.

[0088] Further preferably, in S4, the molar ratio of the compound IV to the basic catalyst is 1:(0.2-1.2), more preferably 1:(0.8-1.1).

[0089] Further preferably, in S4, the fourth solvent includes methanol.

[0090] Further preferably, in S4, the mass ratio of the compound IV to the fourth solvent is 1:(2~2.5).

[0091] More preferably, in S4, the temperature of the hydrolysis reaction is 20°C to 50°C (more preferably 30°C to 40°C), and the hydrolysis reaction time is 2h to 4h.

[0092] Further preferably, in S4, concentrated hydrochloric acid is used to adjust the pH of the system to 1.5-2.5.

[0093] Further preferably, in S4, the crystallization temperature is 20° C. to 50° C., and the crystallization time is 8 min to 12 min.

[0094] For example, in S4, after the crystallization is completed, the process further comprises: filtering with suction, removing the first filtrate containing concentrated hydrochloric acid, taking the filter cake and rinsing it with a fourth solvent (the filter cake is dissolved by the fourth solvent), the mass ratio of compound IV to the fourth solvent is 1: (0.1 to 3), more preferably 1: (0.5 to 1.0), collecting the eluent and drying it to obtain compound I. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 This is the hydrogen spectrum of mebeverine hydrochloride in Example 1 of the present invention;

[0096] Figure 2 This is a high-resolution mass spectrometry spectrum of mebeverine hydrochloride in Example 1 of the present invention. DETAILED DESCRIPTION

[0097] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0098] The present invention provides a method for synthesizing mebeverine hydrochloride, comprising the following steps:

[0099] S1, dissolving 4-methoxypropiophenone, ethylamine, and a first catalyst in a first solvent, and performing a first reflux reaction to obtain a compound II as shown in Formula II;

[0100] S2, adding the compound II and a reducing agent to a second solvent to carry out a reduction reaction, and then adjusting the pH of the system to acidic to obtain a compound III as shown in formula III;

[0101] S3, adding the compound III, 4-bromobutyl acetate, a basic substance, and a second catalyst into a third solvent, and performing a second reflux reaction to obtain a compound IV as shown in Formula IV;

[0102] S4, adding the compound IV and the alkaline catalyst to a fourth solvent to carry out a hydrolysis reaction, then adjusting the pH of the system to 1-3, and crystallizing to obtain the compound I shown in formula I;

[0103] S5, adding the compound I, veratric acid, and an acidic catalyst to solvent a, carrying out an esterification reaction at 80° C. to 110° C., concentrating the resulting reaction solution, adding solvent c, adjusting the pH value of the system to a weak base, separating the phases, and sequentially drying, filtering, and concentrating under reduced pressure the organic phase to obtain mebeverine;

[0104] S6, adding the mebeverine to solvent b, then adding hydrochloric acid to form a salt, and then adding the resulting solid crude product to solvent d, performing a first crystallization to obtain a crude mebeverine hydrochloride product;

[0105] S7, dissolving the crude mebeverine hydrochloride in solvent e, decolorizing, and performing a second crystallization to obtain mebeverine hydrochloride as shown in Formula 1;

[0106]

[0107] Formula I

[0108]

[0109] Formula II

[0110]

[0111] Formula III

[0112]

[0113] Formula IV

[0114]

[0115] Formula 1.

[0116] The reaction formula for synthesizing mebeverine hydrochloride is shown in Formula 2:

[0117]

[0118] Formula 2.

[0119] The water used in the embodiments of the present invention is pure water.

[0120] In order to better illustrate the present invention, further examples are given below.

[0121] Example 1

[0122] This embodiment provides a method for synthesizing mebeverine hydrochloride, comprising the following steps:

[0123] S1. Add 59.78 g (1.33 mol) of ethylamine and 268.99 g of cyclohexane (the mass ratio of ethylamine to cyclohexane is 1:4.5) to a reaction flask, then add 164.28 g (1.00 mol) of 4-methoxypropiophenone, raise the temperature to 90°C, add 30.03 g (0.50 mol) of glacial acetic acid, mix well, carry out a first reflux reaction at 90°C, keep warm for 4.5 hours, and concentrate under reduced pressure to dryness to obtain compound II as shown in Formula II.

[0124] S2. Compound II was added to 328.59 g of anhydrous ethanol (the mass ratio of 4-methoxypropiophenone to anhydrous ethanol was 1:2), and 26.27 g (0.49 mol) of potassium borohydride was added at 30°C for reduction reaction. The temperature was kept for 2 h, and then the pH of the system was adjusted to 3 with hydrochloric acid. The resulting solid was vacuum dried at 50°C for 8 h to obtain 183.62 g (0.95 mol) of compound III represented by formula III, with a yield of 94.95%.

[0125] S3. Add 183.02 g (0.95 mol) of compound III, 203.13 g (1.04 mol) of 4-bromobutyl acetate, 732.06 g of potassium carbonate, and 23.79 g of tetrabutylammonium bromide to 201.29 g of toluene and 183.00 g of water, wherein the molar ratio of compound III to 4-bromobutyl acetate is 1:1.1, and the mass ratio of compound III, potassium carbonate, tetrabutylammonium bromide, and the third solvent (toluene and water) is 1:4:0.13:2.1. Mix well, and carry out a second reflux reaction at 90°C. After keeping the temperature for 24 h, 183.00 g of water is added to the reaction system, the phases are separated, and the pH of the organic phase is adjusted to 3 with hydrochloric acid. The organic phase is dried over anhydrous sodium sulfate for 10 h, filtered, and concentrated to dryness under reduced pressure to obtain 259.93 g (0.89 mol) of compound IV represented by formula IV, with a yield of 93.56%.

[0126] S4, 250.00 g (0.85 mol) of compound IV and 35.15 g (0.88 mol) of sodium hydroxide were added to 500.03 g of methanol (the molar ratio of compound IV to sodium hydroxide was 1:1, and the mass ratio of compound IV to methanol was 1:2), mixed evenly, and hydrolyzed at 35°C for 4 hours. Then, the pH of the system was adjusted to 1.8 with concentrated hydrochloric acid, stirred for crystallization for 10 minutes, filtered, and the first filtrate containing concentrated hydrochloric acid was removed. The filter cake was rinsed with 125.00 g of methanol (the mass ratio of compound IV to methanol was 1:0.5), and the elution was collected and spin-dried to obtain 191.35 g (0.76 mol) of compound I as shown in formula I, with a yield of 89.34%.

[0127] S5, 190.00 g (0.76 mol) of Compound I, 144.40 g (0.79 mol) of veratric acid and 47.07 g (0.27 mol) of p-toluenesulfonic acid were added to 950.00 g of tetrahydrofuran (the molar ratio of Compound I, veratric acid and p-toluenesulfonic acid was 1:1:0.4, and the mass ratio of Compound I to tetrahydrofuran was 1:5), mixed evenly, and esterification reaction was carried out at 85°C. After stirring at this temperature for 5 h, the reaction solution was concentrated to dryness, 247.06 g of ethyl acetate and 247.21 g of water were added, and the mass ratio of Compound I to solvent C (ethyl acetate and water) was 1:2.6. The pH of the system was adjusted to 8.5 with 30% aqueous sodium hydroxide solution. The phases were separated, and the organic phase was dried over anhydrous sodium sulfate for 8 h, filtered, and concentrated to dryness under reduced pressure to obtain 282.28 g (0.66 mol) of mebeverine with a yield of 86.94%.

[0128] S6, add 280.00 g (0.65 mol) of mebeverine to 2520 mL of methanol, control the temperature at 2°C, slowly add 280 mL of hydrochloric acid, and complete the addition over 20 minutes. Control the salt formation temperature at 25°C, continue stirring for 40 minutes, and then concentrate to dryness under reduced pressure. Add the obtained crude solid to 842 mL of ethyl acetate (the mass volume ratio of mebeverine, methanol, hydrochloric acid and ethyl acetate is 1 g:8 mL:1 mL:3 mL), mix well, perform the first crystallization at 50°C, keep warm for 2 hours, and dry the obtained solid at 60°C in vacuum for 6 hours to obtain 274.54 g (0.59 mol) of crude mebeverine hydrochloride, with a yield of 90.38%.

[0129] S7, at 82°C, 233.00 g (0.50 mol) of crude mebeverine hydrochloride was dissolved in 187 mL of isopropanol and 1677 mL of ethyl acetate. The mass-to-volume ratio of crude mebeverine hydrochloride to solvent e (isopropanol and ethyl acetate) was 1 g:8 mL. 11.60 g of activated carbon was added for decolorization (the mass ratio of activated carbon to crude mebeverine hydrochloride was 5:100). After stirring at this temperature for 30 min, the mixture was hot filtered. The filtrate was crystallized for the second time at 2°C and stirred at this temperature for 2 h. The solid was dried in vacuo at 60°C for 10 h to obtain 195.60 g (0.42 mol) of mebeverine hydrochloride as shown in Formula 1. The yield was 83.95%, the HPLC purity was 99.58%, and the total yield of S5-S7 was 65.96%.

[0130] The mebeverine hydrochloride synthesized in Example 1 was subjected to nuclear magnetic resonance and mass spectrometry detection, and the test results were as follows: Figures 1 and 2 shown.

[0131] Example 2

[0132] This embodiment provides a method for synthesizing mebeverine hydrochloride, comprising the following steps:

[0133] S1. Add 49.60 g (1.10 mol) of ethylamine and 173.60 g of isooctane (the mass ratio of ethylamine to isooctane is 1:3.5) to a reaction flask, then add 164.28 g (1.0 mol) of 4-methoxypropiophenone, raise the temperature to 100°C, add 137.76 g (0.80 mol) of p-toluenesulfonic acid, mix well, carry out a first reflux reaction at 100°C, keep warm for 4.5 hours, and concentrate under reduced pressure to dryness to obtain compound II as shown in Formula II.

[0134] S2. Compound II was added to 246.42 g of methanol (the mass ratio of 4-methoxypropiophenone to methanol was 1:1.5), and 11.35 g (0.30 mol) of sodium borohydride was added at 25°C for reduction reaction. The temperature was kept for 3 h, and then the pH of the system was adjusted to 3.5 with hydrochloric acid. The resulting solid was vacuum dried at 60°C for 6 h to obtain 180.3 g (0.93 mol) of compound III represented by formula III, with a yield of 93.23%.

[0135] S3. 178.00 g (0.92 mol) of compound III, 188.68 g (0.97 mol) of 4-bromobutyl acetate, 765.45 g of sodium carbonate, and 17.80 g of tetrabutylammonium chloride were added to 178.02 g of dichloromethane and 178.00 g of water, where the molar ratio of compound III to 4-bromobutyl acetate was 1:1.05, and the mass ratio of compound III, sodium carbonate, tetrabutylammonium chloride, and the third solvent (dichloromethane and water) was 1:4.3:0.1:2. The mixture was uniformly mixed and subjected to a second reflux reaction at 100° C. After maintaining the temperature for 20 h, 267.26 g of water was added to the reaction system, the phases were separated, and the pH of the organic phase was adjusted to 3.5 with hydrochloric acid. The mixture was dried over anhydrous sodium sulfate for 9 h, filtered, and concentrated to dryness under reduced pressure to obtain 242.21 g (0.83 mol) of compound IV represented by formula IV, with a yield of 89.64%.

[0136] S4, 230.00 g (0.78 mol) of compound IV and 20.14 g (0.50 mol) of sodium hydroxide were added to 483.64 g of methanol (the molar ratio of compound IV to sodium hydroxide was 1:0.6, and the mass ratio of compound IV to methanol was 1:2.1), mixed evenly, and hydrolyzed at 40°C for 3 h. Then, the pH of the system was adjusted to 1.5 with concentrated hydrochloric acid, stirred for crystallization for 10 min, filtered, and the first filtrate containing concentrated hydrochloric acid was removed. The filter cake was rinsed with 368.00 g of methanol (the mass ratio of compound IV to methanol was 1:1.6), and the elution was collected and spin-dried to obtain 168.18 g (0.67 mol) of compound I as shown in formula I, with a yield of 85.35%.

[0137] S5. 150.00 g (0.60 mol) of Compound I, 108.03 g (0.59 mol) of veratric acid, and 8.40 g (0.18 mol) of formic acid were added to 750.00 g of tetrahydrofuran (the molar ratio of Compound I, veratric acid, and formic acid was 1:1:0.3, and the mass ratio of Compound I to tetrahydrofuran was 1:5), mixed evenly, and subjected to esterification at 95°C. After stirring for 4 h, the reaction solution was concentrated to dryness, and 150.68 g of methanol and 156.27 g of water were added (the mass ratio of Compound I to solvent C (methanol and water) was 1:2). The pH of the system was adjusted to 7.5 with a 30% aqueous sodium hydroxide solution. The phases were separated, and the organic phase was dried over anhydrous sodium sulfate for 12 h, filtered, and concentrated to dryness under reduced pressure to obtain 214.47 g (0.5 mol) of mebeverine with a yield of 83.67%.

[0138] S6, add 210.00 g (0.49 mol) of mebeverine to 1470 mL of anhydrous ethanol, control the temperature at 3°C, slowly add 315 mL of hydrochloric acid, and complete the addition over 15 minutes. Control the salt formation temperature at 30°C, continue stirring for 40 minutes, and then concentrate to dryness under reduced pressure. Add the obtained crude solid to 630 mL of dichloromethane (the mass volume ratio of mebeverine, anhydrous ethanol, hydrochloric acid and dichloromethane is 1 g:7 mL:1.5 mL:3 mL), mix well, perform the first crystallization at 60°C, keep warm for 2.5 hours, and dry the obtained solid at 50°C in vacuum for 8 hours to obtain 202.65 g (0.43 mol) of crude mebeverine hydrochloride with a yield of 88.95%.

[0139] S7, at 83°C, 200.00 g (0.43 mol) of crude mebeverine hydrochloride was dissolved in 240 mL of isopropanol and 1360 mL of ethyl acetate. The mass-to-volume ratio of crude mebeverine hydrochloride to solvent e (isopropanol and ethyl acetate) was 1 g:8 mL. 10.02 g of activated carbon was added for decolorization (the mass ratio of activated carbon to crude mebeverine hydrochloride was 5:100). After stirring at this temperature for 35 min, the mixture was hot filtered. The filtrate was crystallized for the second time at 3°C ​​and stirred at this temperature for 2.5 h. The solid was dried in vacuo at 55°C for 10 h to obtain 173.52 g (0.37 mol) of mebeverine hydrochloride as shown in Formula 1. The yield was 86.76%, the HPLC purity was 99.36%, and the total yield of S5-S7 was 64.57%.

[0140] Example 3

[0141] This embodiment provides a method for synthesizing mebeverine hydrochloride, comprising the following steps:

[0142] S1. Add 63.13 g (1.4 mol) of ethylamine and 126.25 g of hexane (the mass ratio of ethylamine to hexane is 1:2) to a reaction flask, then add 164.21 g (1.00 mol) of 4-methoxypropiophenone, raise the temperature to 80°C, add 142.36 g (0.90 mol) of benzenesulfonic acid, mix well, carry out a first reflux reaction at 80°C, keep warm for 5 hours, and concentrate under reduced pressure to dryness to obtain compound II as shown in Formula II.

[0143] S2, compound II was added to 410.53 g of isopropanol (the mass ratio of 4-methoxypropiophenone to isopropanol was 1:2.5), and 17.42 g (0.80 mol) of lithium borohydride was added at 35°C for reduction reaction. The temperature was kept for 2 h, and then the pH of the system was adjusted to 4 with hydrochloric acid. The resulting solid was vacuum dried at 40°C for 12 h to obtain 166.94 g (0.86 mol) of compound III represented by formula III, with a yield of 86.36%.

[0144] S3. 160.00 g (0.83 mol) of compound III, 208.94 g (1.07 mol) of 4-bromobutyl acetate, 800.00 g of triethylamine, and 28.80 g of benzyltriethylammonium chloride were added to 400.00 g of ethyl acetate, where the molar ratio of compound III to 4-bromobutyl acetate was 1:1.29, and the mass ratio of compound III, triethylamine, benzyltriethylammonium chloride, and ethyl acetate was 1:5:0.18:2.5. The mixture was uniformly mixed and subjected to a second reflux reaction at 80° C. After keeping the temperature for 40 h, 96.00 g of water was added to the reaction system, the phases were separated, and the pH of the organic phase was adjusted to 4 with hydrochloric acid. The mixture was dried over anhydrous sodium sulfate for 8 h, filtered, and concentrated to dryness under reduced pressure to obtain 205.64 g (0.70 mol) of compound IV represented by formula IV, with a yield of 84.67%.

[0145] S4, 200.00 g (0.68 mol) of compound IV and 33.67 g (0.84 mol) of sodium hydroxide were added to 500.68 g of methanol (the molar ratio of compound IV to sodium hydroxide was 1:1.2, and the mass ratio of compound IV to methanol was 1:2.5), mixed evenly, and hydrolyzed at 22°C for 4 hours. Then, the pH of the system was adjusted to 2.2 with concentrated hydrochloric acid, stirred for crystallization for 10 minutes, filtered, and the first filtrate containing concentrated hydrochloric acid was removed. The filter cake was rinsed with 200.00 g of methanol (the mass ratio of compound IV to methanol was 1:1), and the eluent was collected and spin-dried to obtain 141.68 g (0.56 mol) of compound I as shown in formula I, with a yield of 82.69%.

[0146] S5. 140.18 g (0.56 mol) of Compound I, 121.91 g (0.67 mol) of veratric acid, and 48.02 g (0.28 mol) of p-toluenesulfonic acid were added to 630.81 g of tetrahydrofuran (the molar ratio of Compound I, veratric acid, and p-toluenesulfonic acid was 1:1.2:0.5, and the mass ratio of Compound I to tetrahydrofuran was 1:4.5), mixed well, and subjected to esterification at 80°C. After stirring at this temperature for 8 h, the reaction solution was concentrated to dryness, and 616.76 g of anhydrous ethanol (the mass ratio of Compound I to anhydrous ethanol was 1:4.4) was added. The pH of the system was adjusted to 9 with a 30% aqueous sodium hydroxide solution. The phases were separated, and the organic phase was dried over anhydrous sodium sulfate for 7 h, filtered, and concentrated to dryness under reduced pressure to obtain 192.74 g (0.45 mol) of mebeverine with a yield of 80.46%.

[0147] S6, add 190.00 g (0.44 mol) of mebeverine to 1710 mL of methanol, control the temperature at 5°C, slowly introduce 171 mL of hydrochloric acid, and complete the addition over 15 minutes. Control the salt formation temperature at 30°C, continue stirring for 50 minutes, and then concentrate to dryness under reduced pressure. Add the obtained crude solid to 570 mL of methanol in a mass volume ratio of mebeverine, solvent b (methanol), methanol hydrochloric acid solution, and solvent d (methanol) of 1 g:9 mL:0.9 mL:3 mL. Mix well, perform the first crystallization at 35°C, keep warm for 3 hours, and dry the obtained solid at 40°C in vacuum for 10 hours to obtain 187.20 g (0.40 mol) of crude mebeverine hydrochloride with a yield of 90.82%.

[0148] S7, at 80°C, 185.00 g (0.40 mol) of crude mebeverine hydrochloride was dissolved in 27.80 mL of isopropanol and 111.20 mL of ethyl acetate. The mass-to-volume ratio of crude mebeverine hydrochloride to solvent e (isopropanol and ethyl acetate) was 1 g:7.5 mL. 18.50 g of activated carbon was added for decolorization (the mass ratio of activated carbon to crude mebeverine hydrochloride was 10:100). After stirring at this temperature for 40 min, the mixture was hot filtered. The filtrate was crystallized for the second time at 0°C and stirred at this temperature for 2 h. The solid was dried in vacuo at 50°C for 12 h to obtain 162.34 g (0.35 mol) of mebeverine hydrochloride as shown in Formula 1. The yield was 87.75%, the HPLC purity was 99.47%, and the total yield of S5-S7 was 64.12%.

[0149] Example 4

[0150] This embodiment provides a method for synthesizing mebeverine hydrochloride, comprising the following steps:

[0151] S1. Add 45.99 g (1.02 mol) of ethylamine and 367.93 g of trimethylpentane (the mass ratio of ethylamine to trimethylpentane is 1:8) to a reaction flask, then add 164.20 g (1.00 mol) of 4-methoxypropiophenone, raise the temperature to 120°C, add 13.81 g (0.30 mol) of formic acid, mix well, carry out a first reflux reaction at 120°C, keep the temperature for 4 h, and concentrate under reduced pressure to dryness to obtain compound II as shown in Formula II.

[0152] S2. Compound II was added to 459.76 g of anhydrous ethanol (the mass ratio of 4-methoxypropiophenone to anhydrous ethanol was 1:2.8), and 32.35 g (0.6 mol) of potassium borohydride was added at 30°C for reduction reaction. The temperature was kept for 2.5 h, and then the pH of the system was adjusted to 3.5 with hydrochloric acid. The resulting solid was vacuum dried at 80°C for 4 h to obtain 181.34 g (0.94 mol) of compound III represented by formula III, with a yield of 93.82%.

[0153] S3. 180.00 g (0.93 mol) of compound III, 190.73 g (0.98 mol) of 4-bromobutyl acetate, 720.00 g of sodium hydroxide, and 18.00 g of benzyltributylammonium chloride were added to 540.00 g of tetrahydrofuran, where the molar ratio of compound III to 4-bromobutyl acetate was 1:1.05, and the mass ratio of compound III, sodium hydroxide, benzyltributylammonium chloride, and tetrahydrofuran was 1:4:0.1:3. The mixture was uniformly mixed and subjected to a second reflux reaction at 120° C. After keeping the temperature for 15 h, 540.00 g of water was added to the reaction system, the phases were separated, and the pH of the organic phase was adjusted to 3.5 with hydrochloric acid. The mixture was dried over anhydrous sodium sulfate for 9 h, filtered, and concentrated to dryness under reduced pressure to obtain 237.44 g (0.81 mol) of compound IV represented by formula IV, with a yield of 86.90%.

[0154] S4, 230.00 g (0.78 mol) of compound IV and 9.41 g (0.24 mol) of sodium hydroxide were added to 529.00 g of methanol (the molar ratio of compound IV to sodium hydroxide was 1:0.3, and the mass ratio of compound IV to methanol was 1:2.3), mixed evenly, and hydrolyzed at 50°C for 2 h. Then, the pH of the system was adjusted to 2.8 with concentrated hydrochloric acid, stirred for crystallization for 12 min, filtered, and the first filtrate containing concentrated hydrochloric acid was removed. The filter cake was rinsed with 575.00 g of methanol (the mass ratio of compound IV to methanol was 1:2.5), and the elution was collected and spin-dried to obtain 173.83 g (0.69 mol) of compound I as shown in formula I, with a yield of 88.22%.

[0155] S5. 170.00 g (0.68 mol) of Compound I, 160.17 g (0.88 mol) of veratric acid, and 20.31 g (0.34 mol) of glacial acetic acid were added to 1020.00 g of tetrahydrofuran (the molar ratio of Compound I, veratric acid, and glacial acetic acid was 1:1.3:0.5, and the mass ratio of Compound I to tetrahydrofuran was 1:6), mixed well, and subjected to esterification at 110°C. After stirring for 3 h, the reaction solution was concentrated to dryness, and 640.00 g of ethyl acetate and 635.00 g of water were added (the mass ratio of Compound I to solvent C (ethyl acetate and water) was 1:7.5). The pH of the system was adjusted to 10 with 30% aqueous sodium hydroxide solution. The phases were separated, and the organic phase was dried over anhydrous sodium sulfate for 6 h, filtered, and concentrated to dryness under reduced pressure to obtain 245.86 g (0.57 mol) of mebeverine with a yield of 84.63%.

[0156] S6, add 240.00 g (0.56 mol) of mebeverine to 2400 mL of methanol, control the temperature to 0°C, slowly add 264 mL of hydrochloric acid, complete the addition over 20 minutes, control the salt formation temperature to 28°C, continue stirring for 60 minutes, then concentrate to dryness under reduced pressure, add the obtained crude solid to 840 mL of ethyl acetate, the mass volume ratio of mebeverine, methanol, methanol hydrochloric acid solution and ethyl acetate is 1 g:10 mL:1.1 mL:3.5 mL, mix well, perform the first crystallization at 70°C, keep warm for 2 hours, and dry the obtained solid at 50°C in vacuum at 7 hours to obtain 235.74 g (0.51 mol) of crude mebeverine hydrochloride, with a yield of 90.54%.

[0157] S7, at 85°C, 230.00 g (0.49 mol) of crude mebeverine hydrochloride was dissolved in 293 mL of isopropanol and 1662 mL of ethyl acetate. The mass-to-volume ratio of crude mebeverine hydrochloride to solvent e (isopropanol and ethyl acetate) was 1 g:8.5 mL. 18.40 g of activated carbon was added for decolorization (the mass ratio of activated carbon to crude mebeverine hydrochloride was 8:100). After stirring at this temperature for 25 min, the mixture was hot filtered. The filtrate was crystallized for the second time at 5°C and stirred at this temperature for 3 h. The solid was dried in vacuo at 60°C for 8 h to obtain 199.34 g (0.43 mol) of mebeverine hydrochloride as shown in Formula 1. The yield was 86.67%, the HPLC purity was 99.28%, and the total yield of S5-S7 was 66.41%.

[0158] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing mebeverine hydrochloride, characterized in that: The following steps are involved: Sa, adding compound I as shown in formula I, veratric acid and an acidic catalyst to solvent a, and carrying out an esterification reaction at 80° C. to 110° C. to obtain mebeverine; the molar ratio of the compound I to the acidic catalyst is 1:(0.3-0.5), and the esterification reaction time is 2 h to 8 h; Sb, adding the mebeverine to the solvent b, and then adding hydrochloric acid to form a salt to obtain mebeverine hydrochloride; the mass volume ratio of the mebeverine, the solvent b and the hydrochloric acid is 1g: (5-10) mL: (0.6-2) mL; Formula I.

2. The method for synthesizing mebeverine hydrochloride according to claim 1, wherein The preparation method of compound I comprises the following steps: S1, dissolving 4-methoxypropiophenone and ethylamine in a first solvent, adding a first catalyst, and performing a first reflux reaction to obtain a compound II as shown in Formula II; S2, adding the compound II and a reducing agent to a second solvent to carry out a reduction reaction, and then adjusting the pH of the system to acidic to obtain a compound III as shown in formula III; S3, adding the compound III, 4-bromobutyl acetate, a basic substance, and a second catalyst into a third solvent, and performing a second reflux reaction to obtain a compound IV as shown in Formula IV; S4, adding the compound IV and the alkaline catalyst to a fourth solvent, performing a hydrolysis reaction, then adjusting the pH of the system to 1-3, and crystallizing to obtain the compound I; Formula II Formula III Formula IV.

3. The method for synthesizing mebeverine hydrochloride according to claim 2, wherein: In Sa, after the esterification reaction is completed, the following steps are further included: concentrating the obtained reaction solution, adding solvent c, adjusting the pH value of the system to be weakly alkaline, separating the phases, and sequentially drying, filtering, and concentrating the organic phase under reduced pressure to obtain the mebeverine; In Sb, after the salt formation, the method further comprises: adding the obtained solid crude product to solvent d, performing a first crystallization to obtain a crude mebeverine hydrochloride product; dissolving the crude mebeverine hydrochloride product in solvent e, decolorizing, and performing a second crystallization to obtain the mebeverine hydrochloride product; In S3, after the second reflux reaction is completed, the following steps are further included: adding water to the reaction system, separating the phases, adjusting the pH of the organic phase to 3-4, drying, filtering, and concentrating under reduced pressure to obtain the compound IV.

4. The method for synthesizing mebeverine hydrochloride according to claim 1, wherein In Sa, the acidic catalyst is selected from at least one of p-toluenesulfonic acid, formic acid, sulfuric acid or glacial acetic acid; In Sa, the molar ratio of the compound I to the veratric acid is 1:(1-1.3); In Sa, the solvent a is tetrahydrofuran; In Sa, the mass ratio of the compound I to the solvent a is 1:(4.5~6).

5. The method for synthesizing mebeverine hydrochloride according to claim 1, wherein In Sb, the solvent b is selected from at least one of methanol and ethanol; In Sb, the salt formation temperature is 0°C~30°C, and the salt formation time is 50min~90min; the temperature for adding the hydrochloric acid is 0°C~5°C, and the temperature at the end of the salt formation is 25°C~30°C.

6. The method for synthesizing mebeverine hydrochloride according to claim 3, wherein: In Sa, the solvent c is selected from at least one of methanol, ethanol, ethyl acetate or water; In Sa, the mass ratio of the compound I to the solvent c is 1:(2-7.8); In Sa, the weak alkalinity is pH=7~10; In Sb, the solvent d is selected from at least one of ethyl acetate, methanol or dichloromethane; In Sb, the mass volume ratio of mebeverine to the solvent d is 1 g: (3-3.5) mL; In Sb, the temperature of the first crystallization is 30°C to 70°C, and the time of the first crystallization is 2h to 3h; In Sb, the solvent e is isopropyl alcohol and ethyl acetate in a volume ratio of (1-2):(8-9); In Sb, the mass volume ratio of the crude mebeverine hydrochloride to the solvent e is 1 g: (7.5-8.5) mL; In Sb, the decolorization temperature is 80°C to 85°C, and the decolorization time is 25min to 40min; In Sb, the temperature of the second crystallization is 0° C. to 5° C., and the time of the second crystallization is 2 h to 3 h.

7. The method for synthesizing mebeverine hydrochloride according to claim 2, wherein: In S1, the first catalyst is selected from at least one of glacial acetic acid, p-toluenesulfonic acid, benzenesulfonic acid or formic acid; In S1, the molar ratio of the 4-methoxypropiophenone, the ethylamine and the first catalyst is 1:(1-1.5):(0.1-1); In S1, the first solvent is selected from at least one of cyclohexane, isooctane, hexane or trimethylpentane; In S1, the mass ratio of the ethylamine to the first solvent is 1:(1-10); In S1, the temperature of the first reflux reaction is 80° C. to 120° C., and the time of the first reflux reaction is 4 h to 5 h.

8. The method for synthesizing mebeverine hydrochloride according to claim 2, wherein: In S2, the reducing agent is selected from at least one of potassium borohydride, sodium borohydride or lithium borohydride; In S1-S2, the molar ratio of the 4-methoxypropiophenone to the reducing agent is 1:(0.2-0.8); In S2, the second solvent is selected from at least one of ethanol, methanol or isopropanol; In S1-S2, the mass ratio of the 4-methoxypropiophenone to the second solvent is 1:(1-3); In S2, the reduction reaction temperature is 25°C to 35°C, and the reduction reaction time is 2h to 3h; In S2, the acidity is pH=3~4.

9. The method for synthesizing mebeverine hydrochloride according to claim 2, wherein: In S3, the molar ratio of the compound III to the 4-bromobutyl acetate is 1:(1.05-1.3); In S3, the alkaline substance is selected from at least one of potassium carbonate, sodium carbonate, triethylamine, sodium hydroxide or diisopropylethylamine; In S3, the second catalyst is selected from at least one of tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride or dodecyltrimethylammonium bromide; In S3, the third solvent is selected from at least one of dichloromethane, toluene, ethyl acetate, tetrahydrofuran, benzene or water; In S3, the mass ratio of the compound III, the alkaline substance, the second catalyst and the third solvent is 1:(4-5):(0.1-0.18):(2-3); In S3, the temperature of the second reflux reaction is 80° C. to 120° C., and the time of the second reflux reaction is 12 h to 48 h.

10. The method for synthesizing mebeverine hydrochloride according to claim 2, wherein: In S4, the alkaline catalyst is sodium hydroxide; In S4, the molar ratio of the compound IV to the basic catalyst is 1:(0.2-1.2); In S4, the fourth solvent is methanol; In S4, the mass ratio of the compound IV to the fourth solvent is 1:(2-2.5); In S4, the hydrolysis reaction temperature is 20°C to 50°C, and the hydrolysis reaction time is 2h to 4h; In S4, concentrated hydrochloric acid is used to adjust the pH of the system to 1.5-2.5; In S4, the crystallization temperature is 20° C. to 50° C., and the crystallization time is 8 min to 12 min.

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