Synthesis method of mebeverine hydrochloride

Abstract

The invention relates to the technical field of medicine synthesis, and particularly discloses a synthesis method of mebeverine hydrochloride. The preparation method comprises the following steps: adding a compound I, veratric acid and an acid catalyst into a solvent a, and carrying out esterification reaction at 80-110 DEG C to obtain mebeverine; and adding the mebeverine into a solvent b, adding hydrochloric acid, and salifying to obtain the mebeverine hydrochloride. According to the invention, the esterification reaction is mild in condition, the post-treatment process is simple, the operation is simple and easy, and the problem of more impurities in the mebeverine hydrochloride is effectively avoided; the method is simple in process, low in raw material cost, low in overall production cost, high in finished product yield and purity, suitable for large-scale industrial production and good in industrial prospect and social benefit. If the temperature of the esterification reaction exceeds the above range, a lot of side reactions are generated, or the esterification reaction is incomplete, the post-treatment is complicated, and adverse effects on the yield and the purity of the finished product mebeverine hydrochloride are also generated.

Description

Technical Field

[0001] The 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)propan-2-yl]amino]butyl-3,4-dimethoxybenzoate hydrochloride, molecular formula is C 25 H 36 ClNO5, the structural formula is shown in Formula 1. Mebeverine hydrochloride is a myotropic antispasmodic drug, which is used for the symptomatic treatment of abdominal pain and spasm caused by irritable bowel syndrome, intestinal dysfunction and intestinal discomfort, and for the treatment of intestinal spasm secondary to organic diseases. It directly acts on the gastrointestinal smooth muscle to relieve spasm symptoms without affecting normal intestinal motility. At the same time, this effect does not pass through the autonomic nervous system, so it has no anticholinergic effect, and is also suitable for patients with prostatic hypertrophy 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 the 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 and controllable production cost, and is suitable for industrial production.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions: A method for synthesizing mebeverine hydrochloride comprises the following steps: Sa, adding compound I as shown in formula I, veratric acid and an acidic catalyst into solvent a, and performing an esterification reaction at 80° C. to 110° C. to obtain mebeverine; Sb, adding the mebeverine into solvent b, and then adding hydrochloric acid to form a salt, to obtain mebeverine hydrochloride;

[0008] Formula I.

[0009] Relative to the prior art, the synthesis 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 simple and easy, which effectively avoids the problem of more impurities in the mebeverine hydrochloride finished product; at the same time, 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.

[0010] 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-treatment is complicated, and the yield and purity of the finished product mebeverine hydrochloride will be adversely affected; if the temperature of the esterification reaction is 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.

[0011] Preferably, in Sa, the acidic catalyst includes at least one of p-toluenesulfonic acid, formic acid, sulfuric acid or glacial acetic acid, and p-toluenesulfonic acid is more preferably used.

[0012] 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).

[0013] Preferably, in Sa, the solvent a comprises tetrahydrofuran.

[0014] Preferably, in Sa, the mass ratio of the compound I to the solvent a is 1:(4.5~6).

[0015] Preferably, in Sa, the esterification reaction time is 2h~8h, more preferably 5h~6h.

[0016] Preferably, in Sa, after the esterification reaction is completed, the following steps are further included: The obtained reaction solution is concentrated, and solvent c is added to adjust the pH value of the system to be weakly alkaline. The phases are separated, and the organic phase is dried, filtered, and concentrated under reduced pressure in sequence to obtain the mebeverine.

[0017] 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 the solvent c and impurities are removed, mebeverine is obtained.

[0018] 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.

[0019] 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).

[0020] More preferably, in Sa, the weak alkalinity is pH=7~10, more preferably pH=8~9.

[0021] For example, in Sa, a 30% sodium hydroxide aqueous solution is used to adjust the pH of the system to 7-10.

[0022] 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.

[0023] 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).

[0024] Further preferably, in Sa, the drying time is 5 h to 15 h, more preferably 8 h to 10 h.

[0025] Preferably, in Sb, the solvent b is an alcohol solvent.

[0026] Further preferably, in Sb, the solvent b comprises at least one of methanol or ethanol.

[0027] 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, and more preferably 1 g: (7-10) mL: (0.9-1.3) mL.

[0028] Preferably, in Sb, the salt-forming temperature is 0°C to 30°C, and the salt-forming time is 50min to 90min; 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.

[0029] In the Sb of the present invention, after hydrochloric acid is added to the system, the temperature of the system will rise. The present invention controls the temperature of salt formation (the slower the rate of adding hydrochloric acid, the smaller the fluctuation of 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 rate of salt formation and making the salt formation more complete.

[0030] Preferably, in Sb, the salt formation further comprises: The obtained crude solid product is added to solvent d, and a first crystallization is performed to obtain a crude mebeverine hydrochloride product; the crude mebeverine hydrochloride product is dissolved in solvent e, and after decolorization, a second crystallization is performed to obtain the mebeverine hydrochloride product.

[0031] Further preferably, in Sb, the solvent d comprises at least one of ethyl acetate, methanol or dichloromethane, and further preferably ethyl acetate.

[0032] Further preferably, in Sb, the mass volume ratio of the mebeverine to the solvent d is 1 g:(3-3.5) mL.

[0033] 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.

[0034] 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 2h to 3h.

[0035] For example, in Sb, after the first crystallization is completed, the process further comprises: vacuum drying the obtained solid at 40° C. to 60° C. for 4 h to 10 h.

[0036] Further preferably, in Sb, the solvent e comprises isopropanol and ethyl acetate in a volume ratio of (1-2):(8-9).

[0037] 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.

[0038] 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.

[0039] Further preferably, in Sb, the bleaching temperature is 80°C to 85°C, and the bleaching time is 25min to 40min.

[0040] 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.

[0041] 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.

[0042] For example, in Sb, after the second crystallization is completed, the process further comprises: vacuum drying the obtained solid at 50° C. to 60° C. for 6 h to 16 h.

[0043] Preferably, the preparation method of compound I comprises the following steps: 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; S2, adding the compound II and the reducing agent into 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 into a fourth solvent, performing a hydrolysis reaction, and then adjusting the pH of the system to 1-3, and crystallizing to obtain the compound I;

[0044] Formula II

[0045] Formula III

[0046] Formula IV.

[0047] The present invention uses 4-methoxypropiophenone and ethylamine as raw materials, and a Schiff base reaction occurs under the action of a first catalyst to obtain a Schiff base (compound II), which is then reduced to compound III by a reducing agent; under the action of an alkaline substance and a second catalyst, compound III and 4-bromobutyl acetate undergo a condensation reaction to obtain compound IV, and finally under the action of an alkaline catalyst, compound IV is hydrolyzed to compound I. In the entire reaction process, the technical route is reasonably designed, the raw and auxiliary materials are all conventional chemical products, which are cheap and easily available, the process operation is simple and easy, the reaction conditions are mild, compound I can be obtained without the use of special equipment, and the yield and purity are both high, which is suitable for large-scale industrial production.

[0048] 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.

[0049] 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).

[0050] Further preferably, in S1, the first solvent includes at least one of cyclohexane, isooctane, hexane or trimethylpentane, more preferably cyclohexane.

[0051] 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).

[0052] 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.

[0053] 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.

[0054] For example, in S1, after the first reflux reaction is completed, it also includes reduced pressure concentration to remove the first solvent and excess ethylamine; the temperature of reduced pressure concentration is 50° C. to 60° C., and the pressure is ≤-0.08 MPa.

[0055] Further preferably, in S2, the reducing agent includes at least one of potassium borohydride, sodium borohydride or lithium borohydride, more preferably potassium borohydride.

[0056] 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).

[0057] Further preferably, in S2, the second solvent includes at least one of ethanol, methanol or isopropanol, more preferably ethanol.

[0058] 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).

[0059] Further preferably, in S2, the reduction reaction temperature is 25°C to 35°C, and the reduction reaction time is 2h to 3h.

[0060] Further preferably, in S2, the acidity is pH=3~4.

[0061] 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.

[0062] For example, in S2, after adjusting the pH of the system to acidic, the process 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.

[0063] Further preferably, in S3, the molar ratio of the compound III to the 4-bromobutyl acetate is 1:(1.05~1.3).

[0064] 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.

[0065] 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.

[0066] 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).

[0067] 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).

[0068] 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).

[0069] Further preferably, in S3, after the second reflux reaction is completed, the following step is further included: 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.

[0070] For example, in S3, hydrochloric acid may be used to adjust the pH of the organic phase.

[0071] 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).

[0072] More preferably, in S3, the drying time is 8 h to 10 h.

[0073] Further preferably, in S4, the alkaline catalyst comprises sodium hydroxide.

[0074] Further preferably, in S4, the molar ratio of the compound IV to the alkaline catalyst is 1:(0.2-1.2), more preferably 1:(0.8-1.1).

[0075] Further preferably, in S4, the fourth solvent includes methanol.

[0076] Further preferably, in S4, the mass ratio of the compound IV to the fourth solvent is 1:(2~2.5).

[0077] Further 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.

[0078] Further preferably, in S4, concentrated hydrochloric acid is used to adjust the pH of the system to 1.5-2.5.

[0079] Further preferably, in S4, the crystallization temperature is 20°C to 50°C, and the crystallization time is 8min to 12min.

[0080] For example, in S4, after the crystallization is completed, the process further includes: 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: (0.1-3), more preferably 1: (0.5-1.0), collecting the elution and spinning it to obtain compound I. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Figure 1 This is the hydrogen spectrum of mebeverine hydrochloride in Example 1 of the present invention; Figure 2 This is a high-resolution mass spectrum of mebeverine hydrochloride in Example 1 of the present invention. DETAILED DESCRIPTION

[0082] In order to make the purpose, technical solution 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 used to limit the present invention.

[0083] The present invention provides a method for synthesizing mebeverine hydrochloride, comprising the following steps: 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; S2, adding the compound II and the reducing agent into 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 into a fourth solvent, performing a hydrolysis reaction, and then adjusting the pH of the system to 1-3, and crystallizing to obtain a compound I as shown in formula I; S5, adding the compound I, veratric acid and an acidic catalyst to solvent a, performing 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 be weakly alkaline, separating the phases, and sequentially drying, filtering and concentrating the organic phase under reduced pressure to obtain mebeverine; S6, adding the mebeverine to solvent b, and then adding hydrochloric acid to form a salt, and then adding the obtained solid crude product to solvent d to perform a first crystallization to obtain a crude mebeverine hydrochloride product; S7, dissolving the crude mebeverine hydrochloride in solvent e, decolorizing, and performing a second crystallization to obtain mebeverine hydrochloride as shown in Formula 1;

[0084] Formula I

[0085] Formula II

[0086] Formula III

[0087] Formula IV

[0088] Formula 1.

[0089] The reaction formula for synthesizing mebeverine hydrochloride is shown in Formula 2:

[0090] Formula 2.

[0091] The water used in the embodiments of the present invention is pure water.

[0092] In order to better illustrate the present invention, further examples are given below.

[0093] Example 1 This embodiment provides a method for synthesizing mebeverine hydrochloride, comprising the following steps: 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 bottle, 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, perform a first reflux reaction at 90°C, keep warm for 4.5 hours, and concentrate to dryness under reduced pressure to obtain compound II as shown in formula II.

[0094] S2, compound II was added to 328.59 g of anhydrous ethanol (the mass ratio of 4-methoxypropiophenone to anhydrous ethanol was 1:2), 26.27 g (0.49 mol) of potassium borohydride was added at 30°C for reduction reaction, and the temperature was kept for 2 hours. Then, the pH of the system was adjusted to 3 with hydrochloric acid, and the obtained solid was vacuum dried at 50°C for 8 hours to obtain 183.62 g (0.95 mol) of compound III as shown in formula III, with a yield of 94.95%.

[0095] S3, 183.02g (0.95mol) of compound III, 203.13g (1.04mol) of 4-bromobutyl acetate, 732.06g of potassium carbonate and 23.79g of tetrabutylammonium bromide were added to 201.29g of toluene and 183.00g of water, the molar ratio of compound III to 4-bromobutyl acetate was 1:1.1, and the mass ratio of compound III, potassium carbonate, tetrabutylammonium bromide and the third solvent (toluene and water) was 1:4:0.13:2.1. The mixture was mixed evenly, and a second reflux reaction was carried out at 90°C. After keeping the temperature for 24h, 183.00g of water was added to the reaction system, and the phases were separated. The pH of the organic phase was adjusted to 3 with hydrochloric acid, and the mixture was dried with anhydrous sodium sulfate for 10h, filtered, and concentrated to dryness under reduced pressure to obtain 259.93g (0.89mol) of compound IV as shown in formula IV, with a yield of 93.56%.

[0096] S4, add 250.00g (0.85mol) of compound IV and 35.15g (0.88mol) of sodium hydroxide to 500.03g of methanol (the molar ratio of compound IV to sodium hydroxide is 1:1, and the mass ratio of compound IV to methanol is 1:2), mix well, carry out hydrolysis reaction at 35°C, keep warm for 4h, then adjust the pH of the system to 1.8 with concentrated hydrochloric acid, stir and crystallize for 10min, filter with suction, remove the first filtrate containing concentrated hydrochloric acid, take the filter cake and rinse it with 125.00g of methanol (the mass ratio of compound IV to methanol is 1:0.5), collect the elution and spin dry, and obtain 191.35g (0.76mol) of compound I as shown in formula I, with a yield of 89.34%.

[0097] 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 and tetrahydrofuran was 1:5), mixed evenly, and esterification reaction was carried out at 85°C. After stirring for 5 hours, 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% sodium hydroxide aqueous solution, the phases were separated, and the organic phase was dried with anhydrous sodium sulfate for 8 hours, filtered, and concentrated to dryness under reduced pressure to obtain 282.28 g (0.66 mol) of mebeverine with a yield of 86.94%.

[0098] S6, add 280.00g (0.65mol) of mebeverine to 2520mL of methanol, control the temperature at 2°C, slowly add 280mL of hydrochloric acid, complete the addition within 20min, control the salt formation temperature at 25°C, continue stirring for 40min, then concentrate to dryness under reduced pressure, add the obtained crude solid to 842mL of ethyl acetate (the mass volume ratio of mebeverine, methanol, hydrochloric acid and ethyl acetate is 1g:8mL:1mL:3mL), mix well, perform the first crystallization at 50°C, keep warm for 2h, and dry the obtained solid at 60°C in vacuum for 6h to obtain 274.54g (0.59mol) of crude mebeverine hydrochloride, with a yield of 90.38%.

[0099] 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 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 keeping warm and stirring for 30 min, hot filtration was performed, the obtained filtrate was subjected to a second crystallization at 2°C, kept warm and stirred for 2 h, and the obtained solid was vacuum dried at 60°C for 10 h to obtain 195.60 g (0.42 mol) of mebeverine hydrochloride as shown in Formula 1, with a yield of 83.95%, an HPLC purity of 99.58%, and a total yield of S5~S7 of 65.96%.

[0100] The mebeverine hydrochloride synthesized in Example 1 was subjected to nuclear magnetic resonance and mass spectrometry detection, and the test results were as follows: Figure 1~2 shown.

[0101] Example 2 This embodiment provides a method for synthesizing mebeverine hydrochloride, comprising the following steps: 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 bottle, 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, perform a first reflux reaction at 100° C., keep warm for 4.5 hours, and concentrate to dryness under reduced pressure to obtain compound II as shown in formula II.

[0102] S2, compound II was added to 246.42 g of methanol (the mass ratio of 4-methoxypropiophenone to methanol was 1:1.5), 11.35 g (0.30 mol) of sodium borohydride was added at 25°C for reduction reaction, and the temperature was kept for 3 h. Then, the pH of the system was adjusted to 3.5 with hydrochloric acid, and the obtained solid was vacuum dried at 60°C for 6 h to obtain 180.3 g (0.93 mol) of compound III as shown in formula III, with a yield of 93.23%.

[0103] 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, 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 mixed evenly and subjected to a second reflux reaction at 100° C. After being kept warm for 20 h, 267.26 g of water was added to the reaction system, and the phases were separated. The pH of the organic phase was adjusted to 3.5 with hydrochloric acid, and the mixture was dried with anhydrous sodium sulfate for 9 h. The mixture was filtered and concentrated to dryness under reduced pressure to obtain 242.21 g (0.83 mol) of compound IV as shown in formula IV, and the yield was 89.64%.

[0104] S4, add 230.00g (0.78mol) of compound IV and 20.14g (0.50mol) of sodium hydroxide to 483.64g of methanol (the molar ratio of compound IV to sodium hydroxide is 1:0.6, and the mass ratio of compound IV to methanol is 1:2.1), mix well, carry out hydrolysis reaction at 40°C, keep warm for 3h, then adjust the pH of the system to 1.5 with concentrated hydrochloric acid, stir and crystallize for 10min, filter with suction, remove the first filtrate containing concentrated hydrochloric acid, take the filter cake and rinse it with 368.00g of methanol (the mass ratio of compound IV to methanol is 1:1.6), collect the elution and spin dry, and obtain 168.18g (0.67mol) of compound I as shown in formula I, with a yield of 85.35%.

[0105] 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 and tetrahydrofuran was 1:5), mixed evenly, and esterification reaction was carried out at 95°C. After stirring for 4 hours, the reaction solution was concentrated to dryness, 150.68 g of methanol and 156.27 g of water were added, and the mass ratio of compound I and solvent c (methanol and water) was 1:2. The pH of the system was adjusted to 7.5 with 30% sodium hydroxide aqueous solution, the phases were separated, and the organic phase was dried with anhydrous sodium sulfate for 12 hours, filtered, and concentrated to dryness under reduced pressure to obtain 214.47 g (0.5 mol) of mebeverine with a yield of 83.67%.

[0106] S6, add 210.00g (0.49mol) of mebeverine to 1470mL of anhydrous ethanol, control the temperature at 3°C, slowly add 315mL of hydrochloric acid, complete the addition within 15min, control the salt formation temperature at 30°C, continue stirring for 40min, then concentrate to dryness under reduced pressure, add the obtained crude solid to 630mL of dichloromethane (the mass volume ratio of mebeverine, anhydrous ethanol, hydrochloric acid and dichloromethane is 1g:7mL:1.5mL:3mL), mix well, perform the first crystallization at 60°C, keep warm for 2.5h, and dry the obtained solid at 50°C in vacuum for 8h to obtain 202.65g (0.43mol) of crude mebeverine hydrochloride, with a yield of 88.95%.

[0107] 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 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 keeping warm and stirring for 35 min, hot filtration was performed, the obtained filtrate was subjected to a second crystallization at 3°C, kept warm and stirred for 2.5 h, and the obtained solid was vacuum dried at 55°C for 10 h to obtain 173.52 g (0.37 mol) of mebeverine hydrochloride as shown in Formula 1, with a yield of 86.76%, an HPLC purity of 99.36%, and a total yield of S5~S7 of 64.57%.

[0108] Example 3 This embodiment provides a method for synthesizing mebeverine hydrochloride, comprising the following steps: 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) into a reaction bottle, 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, perform a first reflux reaction at 80°C, keep warm for 5 hours, and concentrate to dryness under reduced pressure to obtain compound II as shown in formula II.

[0109] S2, compound II was added to 410.53 g of isopropanol (the mass ratio of 4-methoxypropiophenone to isopropanol was 1:2.5), 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, and the obtained solid was vacuum dried at 40°C for 12 h to obtain 166.94 g (0.86 mol) of compound III as shown in formula III, with a yield of 86.36%.

[0110] 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, 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 mixed evenly 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, the pH of the organic phase was adjusted to 4 with hydrochloric acid, and the mixture was dried with 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 as shown in formula IV, with a yield of 84.67%.

[0111] S4, add 200.00g (0.68mol) of compound IV and 33.67g (0.84mol) of sodium hydroxide to 500.68g of methanol (the molar ratio of compound IV to sodium hydroxide is 1:1.2, and the mass ratio of compound IV to methanol is 1:2.5), mix well, carry out hydrolysis reaction at 22°C, keep warm for 4h, then adjust the pH of the system to 2.2 with concentrated hydrochloric acid, stir and crystallize for 10min, filter with suction, remove the first filtrate containing concentrated hydrochloric acid, take the filter cake and rinse it with 200.00g of methanol (the mass ratio of compound IV to methanol is 1:1), collect the elution and spin dry, and obtain 141.68g (0.56mol) of compound I as shown in formula I, with a yield of 82.69%.

[0112] S5, 140.18g (0.56mol) of compound I, 121.91g (0.67mol) of veratric acid and 48.02g (0.28mol) of p-toluenesulfonic acid were added to 630.81g 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 and tetrahydrofuran was 1:4.5), mixed evenly, and esterification reaction was carried out at 80°C. After stirring for 8h at this temperature, the reaction solution was concentrated to dryness, 616.76g of anhydrous ethanol (the mass ratio of compound I and anhydrous ethanol was 1:4.4) was added, and 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 with anhydrous sodium sulfate for 7h, filtered, and concentrated to dryness under reduced pressure to obtain 192.74g (0.45mol) of mebeverine with a yield of 80.46%.

[0113] S6, add 190.00g (0.44mol) of mebeverine to 1710mL of methanol, control the temperature at 5°C, slowly introduce 171mL of hydrochloric acid, add it over 15min, control the salt formation temperature to 30°C, continue stirring for 50min, then concentrate to dryness under reduced pressure, add the obtained crude solid to 570mL of methanol, the mass volume ratio of mebeverine, solvent b (methanol), methanol hydrochloric acid solution and solvent d (methanol) is 1g:9mL:0.9mL:3mL, mix well, perform the first crystallization at 35°C, keep warm for 3h, and dry the obtained solid at 40°C in vacuum at 10h to obtain 187.20g (0.40mol) of crude mebeverine hydrochloride, with a yield of 90.82%.

[0114] 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 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 keeping warm and stirring for 40 min, hot filtration was performed, the obtained filtrate was subjected to a second crystallization at 0°C, kept warm and stirred for 2 h, and the obtained solid was vacuum dried at 50°C for 12 h to obtain 162.34 g (0.35 mol) of mebeverine hydrochloride as shown in Formula 1, with a yield of 87.75%, an HPLC purity of 99.47%, and a total yield of S5~S7 of 64.12%.

[0115] Example 4 This embodiment provides a method for synthesizing mebeverine hydrochloride, comprising the following steps: 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) into a reaction bottle, 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, perform a first reflux reaction at 120°C, keep warm for 4 hours, and concentrate to dryness under reduced pressure to obtain compound II as shown in formula II.

[0116] 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), 32.35 g (0.6 mol) of potassium borohydride was added at 30°C for reduction reaction, and the temperature was kept for 2.5 hours. Then, the pH of the system was adjusted to 3.5 with hydrochloric acid, and the obtained solid was vacuum dried at 80°C for 4 hours to obtain 181.34 g (0.94 mol) of compound III as shown in formula III, with a yield of 93.82%.

[0117] S3, 180.00g (0.93mol) of compound III, 190.73g (0.98mol) of 4-bromobutyl acetate, 720.00g of sodium hydroxide and 18.00g of benzyltributylammonium chloride were added to 540.00g of tetrahydrofuran, 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 a second reflux reaction was carried out at 120°C. After keeping the temperature for 15h, 540.00g of water was added to the reaction system, the phases were separated, the pH of the organic phase was adjusted to 3.5 with hydrochloric acid, and the mixture was dried with anhydrous sodium sulfate for 9h, filtered, and concentrated to dryness under reduced pressure to obtain 237.44g (0.81mol) of compound IV as shown in formula IV, with a yield of 86.90%.

[0118] S4, add 230.00g (0.78mol) of compound IV and 9.41g (0.24mol) of sodium hydroxide to 529.00g of methanol (the molar ratio of compound IV to sodium hydroxide is 1:0.3, and the mass ratio of compound IV to methanol is 1:2.3), mix well, carry out hydrolysis reaction at 50°C, keep warm for 2h, then adjust the pH of the system to 2.8 with concentrated hydrochloric acid, stir and crystallize for 12min, filter with suction, remove the first filtrate containing concentrated hydrochloric acid, take the filter cake and rinse it with 575.00g of methanol (the mass ratio of compound IV to methanol is 1:2.5), collect the elution and spin dry, and obtain 173.83g (0.69mol) of compound I as shown in formula I, with a yield of 88.22%.

[0119] 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 and tetrahydrofuran was 1:6), mixed evenly, and esterification reaction was carried out at 110°C. After stirring for 3 hours at this temperature, the reaction solution was concentrated to dryness, 640.00 g of ethyl acetate and 635.00 g of water were added, and the mass ratio of compound I and 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 with anhydrous sodium sulfate for 6 hours, filtered, and concentrated to dryness under reduced pressure to obtain 245.86 g (0.57 mol) of mebeverine with a yield of 84.63%.

[0120] S6, add 240.00g (0.56mol) of mebeverine to 2400mL of methanol, control the temperature to 0℃, slowly add 264mL of hydrochloric acid, complete the addition within 20min, control the salt formation temperature to 28℃, continue stirring for 60min, then concentrate to dryness under reduced pressure, add the obtained crude solid to 840mL of ethyl acetate, the mass volume ratio of mebeverine, methanol, methanol hydrochloric acid solution and ethyl acetate is 1g:10mL:1.1mL:3.5mL, mix well, perform the first crystallization at 70℃, keep warm for 2h, and dry the obtained solid at 50℃ in vacuum for 7h to obtain 235.74g (0.51mol) of crude mebeverine hydrochloride, with a yield of 90.54%.

[0121] 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 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 keeping warm and stirring for 25 min, hot filtration was performed, the obtained filtrate was subjected to a second crystallization at 5°C, kept warm and stirred for 3 h, and the obtained solid was vacuum dried at 60°C for 8 h to obtain 199.34 g (0.43 mol) of mebeverine hydrochloride as shown in Formula 1, with a yield of 86.67%, an HPLC purity of 99.28%, and a total yield of S5~S7 of 66.41%.

[0122] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope 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 into solvent a, and performing an esterification reaction at 80° C. to 110° C. to obtain mebeverine; Sb, adding the mebeverine to solvent b, and then adding hydrochloric acid to form a salt to obtain mebeverine hydrochloride; Formula I.

2. The method for synthesizing mebeverine hydrochloride according to claim 1, characterized in that: 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 the reducing agent into 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 into a fourth solvent, performing a hydrolysis reaction, and 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, characterized in that: 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; Sb, after the salt formation, the step further comprises: adding the obtained solid crude product to solvent d, performing a first crystallization to obtain a crude product of mebeverine hydrochloride; dissolving the crude product of mebeverine hydrochloride in solvent e, decolorizing, and performing a second crystallization to obtain the mebeverine hydrochloride; In S3, after the second reflux reaction is completed, the process further comprises: adding water to the reaction system, separating the phases, adjusting the pH value 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, characterized in that: In Sa, the acidic catalyst includes at least one of p-toluenesulfonic acid, formic acid, sulfuric acid or glacial acetic acid; 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); In Sa, the solvent a comprises tetrahydrofuran; In Sa, the mass ratio of the compound I to the solvent a is 1:(4.5-6); In Sa, the esterification reaction time is 2h~8h.

5. The method for synthesizing mebeverine hydrochloride according to claim 1, characterized in that: In Sb, the solvent b comprises at least one of methanol or ethanol; In Sb, the mass volume ratio of the mebeverine, the solvent b and the hydrochloric acid is 1g:(5-10)mL:(0.6-2)mL; In Sb, the salt-forming temperature is 0°C~30°C, and the salt-forming 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-forming is 25°C~30°C.

6. The method for synthesizing mebeverine hydrochloride according to claim 3, characterized in that: In Sa, the solvent c includes 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 comprises 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 comprises isopropanol 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 1g: (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 2h to 3h.

7. The method for synthesizing mebeverine hydrochloride according to claim 2, characterized in that: In S1, the first catalyst includes 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 includes 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 4h to 5h.

8. The method for synthesizing mebeverine hydrochloride according to claim 2, characterized in that: In S2, the reducing agent includes 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 includes 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, characterized in that: 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 includes at least one of potassium carbonate, sodium carbonate, triethylamine, sodium hydroxide or diisopropylethylamine; In S3, the second catalyst includes at least one of tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride or dodecyltrimethylammonium bromide; In S3, the third solvent includes 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, characterized in that: In S4, the alkaline catalyst includes 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 includes methanol; In S4, the mass ratio of the compound IV to the fourth solvent is 1:(2-2.5); In S4, the temperature of the hydrolysis reaction 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 8min to 12min.

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