Preparation method of high-purity landiolol hydrochloride

Abstract

The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of high-purity landiolol hydrochloride, which comprises the following steps: mixing a landiolol hydrochloride crude product and a benign solvent, decolorizing, filtering, adding a poor solvent into the filtrate, crystallizing, and filtering to obtain the landiolol hydrochloride, the benign solvent is one or more of dichloromethane, ethyl acetate, absolute ethyl alcohol, methanol, dimethyl sulfoxide and N, N-dimethylformamide, and the poor solvent is one or more of normal hexane, cyclohexane, methylbenzene and petroleum ether; the invention has the advantages of higher purity and fewer impurities.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of high-purity landiolol hydrochloride. Background Art

[0002] Landiolol Hydrochloride, chemical name: [(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-[4-[(S)-2-hydroxy-3-(2-morpholinecarbonylamino)ethylamino]propoxy]phenylpropionate monohydrochloride, CAS number: 144481-98-1, molecular formula: C 25 H 39 N3O8·HCl, molecular weight is 546.05, the structural formula of landiolol hydrochloride is as follows: .

[0003] Landiolol Hydrochloride is an ultra-short-acting, highly selective β1 receptor blocker that mainly antagonizes the β1 receptors present in the heart and improves tachycardia arrhythmias by inhibiting the increase in heart rate caused by catecholamines. Landiolol Hydrochloride was developed by Ono Pharmaceutical Co., Ltd. of Japan and was first launched in Japan in September 2002.

[0004] A lot of research has been done on the synthesis of landiolol hydrochloride at home and abroad, but most of the publicly reported preparation methods use column chromatography purification methods, which are not suitable for large-scale industrial production. In addition, the amide and ketal functional groups in the structure of landiolol hydrochloride are easily hydrolyzed at high temperatures. The refining procedures of the currently reported preparation processes are all refining methods of high-temperature solvent dissolution and cooling crystallization. The product is easily decomposed during the refining process, resulting in low product purity.

[0005] Therefore, the current synthesis of landiolol hydrochloride is complicated, not suitable for industrial production, and has unstable quality. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a method for preparing high-purity landiolol hydrochloride with high purity and less impurities.

[0007] The embodiment of the present invention provides a method for preparing high-purity landiolol hydrochloride, comprising mixing a crude landiolol hydrochloride product and a benign solvent, decolorizing, filtering, adding a poor solvent to the filtrate, crystallizing, filtering, and obtaining landiolol hydrochloride; the benign solvent is one or more of dichloromethane, ethyl acetate, anhydrous ethanol, methanol, dimethyl sulfoxide, and N,N-dimethylformamide, and the poor solvent is one or more of n-hexane, cyclohexane, toluene, and petroleum ether.

[0008] Preferably, the good solvent is dichloromethane, and the poor solvent is n-hexane.

[0009] Preferably, the weight ratio of the crude landiolol hydrochloride to the good solvent is 1:5-10 (preferably 1:6.63), and the weight ratio of the crude landiolol hydrochloride to the poor solvent is 1:2-5 (preferably 1:2.64).

[0010] Preferably, activated carbon is used for decolorization, and the weight ratio of the crude landiolol hydrochloride product to the activated carbon is 1:0.01-0.05 (preferably 1:0.03).

[0011] Preferably, the temperature for mixing the crude landiolol hydrochloride and the benign solvent is 10-40°C (preferably 20-30°C), the temperature for decolorization is 10-40°C (preferably 20-30°C), the temperature for crystallization is 0-30°C (preferably 10-20°C), and the crystallization time is 1-10h (preferably 1-2h).

[0012] Preferably, the method for preparing the crude landiolol hydrochloride is to carry out a condensation reaction between 4-morpholinecarboxamide (SM4-1) and ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)3-(4-((S)-epoxyalkylene-2-ylmethoxy)phenyl)propionic acid methyl ester (intermediate 2) solution, and after the reaction is completed, obtain the crude landiolol hydrochloride by post-treatment.

[0013] Preferably, the solvent of the methyl ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)3-(4-((S)-epoxyalkylene-2-ylmethoxy)phenyl)propanoate solution is dimethyl sulfoxide; the molar ratio of methyl ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)3-(4-((S)-epoxyalkylene-2-ylmethoxy)phenyl)propanoate:4-morpholinecarboxamide is 1:2.0~5.0 (preferably 1:2.6); the temperature of the condensation reaction is 25~45°C (possibly 30-35°C), and the reaction time is 1~24h (preferably 17h).

[0014] Preferably, the post-treatment step is to add water, sodium chloride and ethyl acetate to the reaction system to quench, extract the aqueous phase with ethyl acetate, combine the organic phases, wash the organic phases with saturated ammonium chloride and sodium chloride aqueous solutions, then dry, filter, concentrate the filtrate under reduced pressure, add acetone to the concentrate, heat it to 50-60° C., stir to dissolve, then cool it, and stir to crystallize.

[0015] Preferably, the preparation method of 4-morpholinecarboxamide (SM4-1) is that 4-morpholinecarboxamide oxalate (SM4) is reacted with potassium hydroxide, and after the reaction is completed, 4-morpholinecarboxamide (SM4-1) is obtained by post-treatment, and the reaction solvent is methanol.

[0016] In the preparation method of 4-morpholinecarboxamide (SM4-1), the molar ratio of SM4: potassium hydroxide is 1:2.0~5.0 (preferably 1:3), and the mass ratio of SM4: methanol is 1:3.0~5.0 (preferably 1:3.16). The reaction temperature is 20~40°C (preferably 20-30°C), and the reaction time is 1~5h (preferably 2-3h). The post-treatment is filtering, concentrating the filtrate under reduced pressure, adding dichloromethane to the concentrate, stirring to dissolve, and concentrating to dryness under reduced pressure.

[0017] Preferably, the preparation method of the ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)3-(4-((S)-epoxyalkylene-2-ylmethoxy)phenyl)propionic acid methyl ester (intermediate 2) is that (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-3-(4-hydroxyphenyl)propionic acid ester (intermediate 1) is reacted with (S)-m-nitrobenzenesulfonic acid glycidyl ester (SM3) to obtain.

[0018] In the reaction of intermediate 1 and SM3, an inorganic base is used as an acid-binding agent and dimethyl sulfoxide is used as a solvent. The molar ratio of intermediate 1: SM3: inorganic base is 1: 1.0-1.3: 2.0-5.0 (preferably 1: 1.1: 3.0), and the mass ratio of intermediate 1: dimethyl sulfoxide is 1: 3.0-5.0 (preferably 1: 4.4). The reaction temperature is 10-40° C. (preferably 20-30° C.), and the reaction time is 2-30 h (preferably 24 h). The inorganic base is one or more of potassium carbonate, potassium hydroxide, sodium carbonate, and sodium hydroxide (preferably potassium carbonate).

[0019] The preparation method of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-3-(4-hydroxyphenyl)propionate, that is, intermediate 1, is that (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol p-toluenesulfonate (SM2) and potassium p-hydroxyphenylpropionate SM1-1 are reacted in dimethyl sulfoxide to prepare (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-3-(4-hydroxyphenyl)propionate (intermediate 1).

[0020] The molar ratio of SM2 to SM1-1 is 1:1.0~1.3 (preferably 1:1.05), and the mass ratio of SM2 to dimethyl sulfoxide is 1:5.0~10.0 (preferably 1:5.5). The reaction temperature is 80~110°C (preferably 100-110°C), and the reaction time is 2~10h (preferably 4-6h). After the reaction is completed, post-treatment is performed, and the post-treatment steps are: quenching with water, extracting the reaction system with ethyl acetate, washing the organic phase with saturated sodium bicarbonate solution and saturated brine in turn, and then drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The concentrate is added with a mixed solvent of ethyl acetate and n-hexane, heated to 50~70°C, stirred to dissolve, and then cooled to 0~10°C, stirred and crystallized.

[0021] The preparation method of potassium p-hydroxyphenylpropionate (SM1-1) is as follows: p-hydroxyphenylpropionic acid (SM1) reacts with potassium hydroxide in anhydrous ethanol, cools down for crystallization, and filters to obtain potassium p-hydroxyphenylpropionate (SM1-1). The molar ratio of SM1 to potassium hydroxide is 1:1.0-1.3, preferably 1:1.05, and the mass ratio of SM1 to anhydrous ethanol is 1:3.0-5.0, preferably 1:3.95; the reaction temperature is 70-80°C, the reaction time is 1-5h (preferably 2-3h), the crystallization temperature is -10-10°C (preferably -2-2°C), and the crystallization time is 1-5h (preferably 1-2h).

[0022] The beneficial effect of the present invention is that the inventors have found that in the prior art, the refining of landiolol hydrochloride uses a single solvent such as acetone for heating and dissolving, and a cooling and crystallization refining method. The product has a risk of degradation during the heating and dissolving process, and the degradation impurities are not easy to remove, resulting in a low purity of the finished product. During the scaled-up production process, the heating and dissolving time is further extended due to the increase in batch size, which increases the risk of product degradation and makes the product quality unstable.

[0023] The inventors found that the reason for the above phenomenon is that the amide and ketal functional groups in the structure of landiolol hydrochloride are easily hydrolyzed under high temperature conditions, and the structure of landiolol hydrochloride itself has a hydrochloride group, which makes the solution system acidic and accelerates the hydrolysis of the above functional groups. Therefore, the conventional recrystallization method of heating dissolution and cooling crystallization causes the product structure to be partially hydrolyzed during the heating dissolution process. As the batch size increases, the heating dissolution time is prolonged, the product hydrolysis is further aggravated, and the purity of the finished product is lower.

[0024] The crude landiolol hydrochloride of the present invention is decolorized and crystallized by a mixed solvent to prepare landiolol hydrochloride. By improving the refining process, a mixed solvent system consisting of a good solvent and a poor solvent is used for room temperature crystallization, thereby avoiding the thermal degradation of the product caused by high temperature dissolution and crystallization of a single solvent, and the finished product has higher purity. In addition, the synthesis process of the present invention is simple, the yield is high, and the cost is low, and it is very suitable for industrial production.

[0025] The present invention uses a mixed solvent system of good solvent / bad solvent to purify the product, thereby avoiding the high-temperature dissolution process of conventional single solvent recrystallization, allowing the entire recrystallization process to be carried out at room temperature, inhibiting the degradation of the product in the recrystallization process, and making the product purity higher and the quality between batches more stable.

[0026] The method for preparing landiolol hydrochloride has simple process, low cost and stable product quality between batches, and is very suitable for large-scale industrial production.

[0027] The present invention selects dichloromethane, ethyl acetate, anhydrous ethanol, methanol, dimethyl sulfoxide and N,N-dimethylformamide as good solvents because they have good solubility for landiolol hydrochloride at room temperature, and selects n-hexane, cyclohexane, toluene and petroleum ether as poor solvents because they have poor solubility for landiolol hydrochloride at room temperature. The good solvent can be added to dissolve at room temperature and the poor solvent can be added to crystallize, and the recrystallization and impurity removal process at room temperature can be completed. Only solvents that meet these two points at the same time can meet the requirements, improve the purity and reduce the impurity content.

[0028] If acetone is used as a good solvent, its solubility for landiolol hydrochloride at room temperature is insufficient. If acetone is used as a poor solvent, its solubility for landiolol hydrochloride at room temperature is too high. Therefore, it does not meet the requirements and cannot achieve the purpose of improving purity and reducing impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 It is the high performance liquid chromatogram of landiolol hydrochloride of Example 1.

[0030] Figure 2 It is the high performance liquid chromatogram of landiolol hydrochloride of Example 2.

[0031] Figure 3 It is the high performance liquid chromatogram of landiolol hydrochloride of embodiment 3.

[0032] Figure 4 It is the high performance liquid chromatogram of landiolol hydrochloride of comparative example 1. DETAILED DESCRIPTION

[0033] The present application is further described in detail below through specific examples and drawings. The following examples are only used to further illustrate the present application and should not be construed as limiting the present application.

[0034] Example 1 (1) Synthesis of potassium p-hydroxyphenylpropionate (SM1-1) Add 3.16 kg of anhydrous ethanol and 0.80 kg of SM1 (p-hydroxyphenylpropionic acid) to a 10L three-necked flask, stir to dissolve, add 0.34 kg of potassium hydroxide, heat to 70-80°C and stir for 2.5 hours. After the reaction is completed, stir and cool to 0-10°C, keep at -2-2°C for crystallization for 1.5 hours, filter, and air dry the filter cake at 50-60°C to constant weight to obtain a white solid (SM1-1).

[0035] (2) Synthesis of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-3-(4-hydroxyphenyl)propanoate (Intermediate 1) Add 4.40 kg of dimethyl sulfoxide, 599.2 g of SM1-1, and 0.80 kg of SM2 ((S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol p-toluenesulfonate) into a 20 L reactor, stir and heat to 100-110 °C for 4 h. After the reaction is completed, the system is cooled to 20-30°C, water is added to quench the reaction, the aqueous phase is extracted twice with ethyl acetate, the organic phases are combined, the organic phases are washed with saturated sodium bicarbonate aqueous solution and saturated brine in turn, anhydrous sodium sulfate is added, stirred and dried, filtered, the filtrate is temperature controlled to ≤60°C, vacuum degree ≤-0.08MPa, and concentrated to dryness under reduced pressure, 0.72kg of ethyl acetate and 2.64kg of n-hexane are added to the concentrate, the temperature is raised to 55-65°C, stirred to dissolve, the temperature is lowered to 5-10°C, the temperature is kept stirred and crystallized for 1.5h, filtered, and the filter cake is air-dried at 50-60°C to constant weight to obtain a white solid (intermediate 1).

[0036] (3) Synthesis of methyl ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(4-((S)-epoxyalkyl-2-ylmethoxy)phenyl)propanoate (Intermediate 2) Add 600g of intermediate 1, 610.4g of SM3 ((S)-m-nitrobenzenesulfonic acid glycidyl ester), and 2.66kg of dimethyl sulfoxide into a 5L three-necked flask, stir to dissolve, add 0.88kg of potassium carbonate, and keep at 20-30℃ for 24h. After the reaction is completed, filter to obtain a colorless clear liquid (intermediate 2 dimethyl sulfoxide solution).

[0037] (4) Synthesis of 4-morpholinecarboxamide (SM4-1) prepared by reaction of 4-morpholinecarboxamide oxalate (SM4) with potassium hydroxide Add 1.6 kg SM4 (4-morpholinecarboxamide oxalate), 5.0 kg methanol, and 1.0 kg potassium hydroxide to a 20 L reactor, and stir and react at 20-30 °C for 2.5 h. After the reaction is completed, filter, and concentrate the filtrate to dryness under reduced pressure with the temperature controlled at ≤50 °C and the vacuum degree ≤-0.08 MPa. Add dichloromethane to the concentrate, and concentrate to dryness under reduced pressure with the temperature controlled at ≤50 °C and the vacuum degree ≤-0.08 MPa to obtain a white solid (SM4-1).

[0038] (5) Synthesis of crude landiolol hydrochloride Add the intermediate 2 dimethyl sulfoxide solution and SM4-1 to the 20L reactor, heat to 30~35℃ and stir to react for 17h. After the reaction, cool the system to 15~25℃, add water, sodium chloride and ethyl acetate to quench the reaction, extract the aqueous phase with ethyl acetate, combine the organic phases, wash the organic phase with saturated ammonium chloride and sodium chloride aqueous solution, then add anhydrous sodium sulfate to dry, filter, control the filtrate temperature to ≤45℃, vacuum degree ≤-0.08MPa and concentrate to dryness under reduced pressure, add 1.90kg acetone to the concentrate, heat to 50~55℃ and stir to disperse, cool to 20~30℃ and keep warm for crystallization for 1.5h, filter, and air dry the filter cake at 40~50℃ to constant weight to obtain a white solid (crude landiol hydrochloride).

[0039] (6) Refining of Landiolol Hydrochloride Add 584g of crude landiolol hydrochloride and 3.87kg of dichloromethane to a 5L three-necked flask, stir until dissolved, add 17.5g of activated carbon, and stir to decolorize for 0.5h. Filter, transfer the filtrate to a 20L reactor, slowly add 1.54kg of n-hexane, and after the drop is complete, control the temperature at 10~20℃ and stir to crystallize for 1.5h, filter, and dry the filter cake at 40~50℃ with air blast to constant weight to obtain a white solid (landiolol hydrochloride). Landiol hydrochloride was detected by high performance liquid chromatography, and the relevant parameters of high performance liquid chromatography detection are shown in Table 1.

[0040] Table 1: Figure 1 Detection of relevant parameters of the spectrum

[0041] The results are as follows Figure 1 As shown, the HPLC purity is 99.949% and the maximum single impurity is 0.027%.

[0042] Example 2 (1) Synthesis of potassium p-hydroxyphenylpropionate (SM1-1) Add 3.95 kg of anhydrous ethanol and 1.00 kg of SM1 to a 10L three-necked flask, stir to dissolve, add 0.42 kg of potassium hydroxide, heat to 70-80°C and stir for 2.5 hours. After the reaction is completed, stir and cool to 0-10°C, keep at -2-2°C for crystallization for 1.5 hours, filter, and air dry the filter cake at 50-60°C to constant weight to obtain a white solid (SM1-1).

[0043] (2) Synthesis of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-3-(4-hydroxyphenyl)propanoate (Intermediate 1) 5.50kg dimethyl sulfoxide, 749g SM1-1, and 1.00kg SM2 were added to a 20L reactor, and the mixture was stirred and heated to 100-110°C for 4h. After the reaction was completed, the system was cooled to 20-30°C, and water was added to quench the reaction. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated sodium bicarbonate aqueous solution and saturated brine in turn, and then anhydrous sodium sulfate was added and stirred to dryness, filtered, and the filtrate was concentrated to dryness under reduced pressure at a temperature of ≤60°C and a vacuum degree of ≤-0.08MPa. 0.90kg ethyl acetate and 3.30kg n-hexane were added to the concentrate, and the mixture was heated to 55-65°C and stirred to dissolve, cooled to 5-10°C, and stirred to crystallize for 1.5h, filtered, and the filter cake was dried at 50-60°C with air blast to constant weight to obtain a white solid (intermediate 1).

[0044] (3) Synthesis of methyl ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(4-((S)-epoxyalkyl-2-ylmethoxy)phenyl)propanoate (Intermediate 2) Add 750g of intermediate 1, 763g of SM3, and 3.33kg of dimethyl sulfoxide into a 5L three-necked flask, stir until dissolved, add 1.1kg of potassium carbonate, and keep at 20-30℃ for 24h. After the reaction is completed, filter to obtain a colorless clear liquid (intermediate 2 dimethyl sulfoxide solution).

[0045] (4) Synthesis of 4-morpholinecarboxamide (SM4-1) prepared by reaction of 4-morpholinecarboxamide oxalate (SM4) with potassium hydroxide Add 2.00kg SM4, 6.32kg methanol, and 1.25kg potassium hydroxide to a 20L reactor, and stir and react at 20-30℃ for 2.5h. After the reaction is completed, filter, and concentrate the filtrate to dryness under reduced pressure with the temperature controlled at ≤50℃ and the vacuum degree ≤-0.08MPa. Add dichloromethane to the concentrate, and concentrate to dryness under reduced pressure with the temperature controlled at ≤50℃ and the vacuum degree ≤-0.08MPa to obtain a white solid (SM4-1).

[0046] (5) Synthesis of crude landiolol hydrochloride Add the intermediate 2 dimethyl sulfoxide solution and SM4-1 to the 20L reactor, heat to 30~35℃ and stir to react for 17h. After the reaction, cool the system to 15~25℃, add water, sodium chloride and ethyl acetate to quench the reaction, extract the aqueous phase with ethyl acetate, combine the organic phases, wash the organic phase with saturated ammonium chloride and sodium chloride aqueous solution, then add anhydrous sodium sulfate to dry, filter, control the filtrate temperature to ≤45℃, vacuum degree ≤-0.08MPa and concentrate to dryness under reduced pressure, add 2.37kg acetone to the concentrate, heat to 50~55℃, stir and disperse, cool to 20~30℃, keep warm for crystallization for 1.5h, filter, and air dry the filter cake at 40~50℃ to constant weight to obtain a white solid (crude landiol hydrochloride).

[0047] (6) Refining of Landiolol Hydrochloride 730g of crude landiolol hydrochloride and 4.84kg of dichloromethane were added to a 5L three-necked flask, stirred until dissolved, and 21.9g of activated carbon was added, and stirred for decolorization for 0.5h. Filter, transfer the filtrate to a 20L reactor, slowly add 1.93kg of n-hexane, and after the drop is complete, control the temperature at 10~20℃ and stir to crystallize for 1.5h, filter, and dry the filter cake at 40~50℃ with air blast to constant weight to obtain a white solid (landiolol hydrochloride). Landiol hydrochloride was detected by high performance liquid chromatography, and the relevant parameters of high performance liquid chromatography detection are shown in Table 2.

[0048] Table 2: Figure 2 Detection of relevant parameters of the spectrum

[0049] The results are as follows Figure 2 As shown, HPLC purity 100.000%.

[0050] Example 3 (1) Synthesis of potassium p-hydroxyphenylpropionate (SM1-1) Add 4.74 kg of anhydrous ethanol and 1.20 kg of SM1 to a 10L three-necked flask, stir to dissolve, add 0.50 kg of potassium hydroxide, heat to 70-80°C and stir for 2.5 hours. After the reaction is completed, stir and cool to 0-10°C, keep at -2-2°C for crystallization for 2 hours, filter, and air dry the filter cake at 50-60°C to constant weight to obtain a white solid (SM1-1).

[0051] (2) Synthesis of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-3-(4-hydroxyphenyl)propanoate (Intermediate 1) 6.6 kg of dimethyl sulfoxide, 898.8 g of SM1-1, and 1.20 kg of SM2 were added to a 20L reactor, and the mixture was stirred and heated to 100-110 °C for 4 h. After the reaction was completed, the system was cooled to 20-30 °C, and water was added to quench the reaction. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated sodium bicarbonate aqueous solution and saturated brine in turn, and then anhydrous sodium sulfate was added and stirred to dryness, filtered, and the filtrate was concentrated to dryness under reduced pressure at a temperature of ≤60 °C and a vacuum degree of ≤-0.08 MPa. 1.08 kg of ethyl acetate and 3.96 kg of n-hexane were added to the concentrate, and the mixture was heated to 55-65 °C and stirred to dissolve, cooled to 5-10 °C, and stirred to crystallize for 2 h, filtered, and the filter cake was dried at 50-60 °C with air blast to constant weight to obtain a white solid (intermediate 1).

[0052] (3) Synthesis of methyl ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(4-((S)-epoxyalkyl-2-ylmethoxy)phenyl)propanoate (Intermediate 2) Add 900g of intermediate 1, 915.6g of SM3, and 4.0kg of dimethyl sulfoxide into a 5L three-necked flask, stir to dissolve, add 1.32kg of potassium carbonate, and keep at 20-30℃ for 24h. After the reaction is completed, filter to obtain a colorless clear liquid (intermediate 2 dimethyl sulfoxide solution).

[0053] (4) Synthesis of 4-morpholinecarboxamide (SM4-1) prepared by reaction of 4-morpholinecarboxamide oxalate (SM4) with potassium hydroxide Add 2.4 kg SM4, 7.58 kg methanol, and 1.5 kg potassium hydroxide to a 20 L reactor, and stir and react for 2 h at 20-30 °C. After the reaction is completed, filter, and concentrate the filtrate to dryness under reduced pressure with the temperature controlled at ≤50 °C and the vacuum degree ≤-0.08 MPa. Add dichloromethane to the concentrate, and concentrate to dryness under reduced pressure with the temperature controlled at ≤50 °C and the vacuum degree ≤-0.08 MPa to obtain a white solid (SM4-1).

[0054] (5) Synthesis of crude landiolol hydrochloride Add the intermediate 2 dimethyl sulfoxide solution and SM4-1 to the 20L reactor, heat to 30~35℃ and stir to react for 17h. After the reaction, cool the system to 15~25℃, add water, sodium chloride and ethyl acetate to quench the reaction, extract the aqueous phase with ethyl acetate, combine the organic phases, wash the organic phase with saturated ammonium chloride and sodium chloride aqueous solution, then add anhydrous sodium sulfate to dry, filter, control the filtrate temperature to ≤45℃, vacuum degree ≤-0.08MPa and concentrate to dryness under reduced pressure, add 2.84kg acetone to the concentrate, heat to 50~55℃, stir and disperse, cool to 20~30℃, keep warm for crystallization for 1.5h, filter, and air dry the filter cake at 40~50℃ to constant weight to obtain a white solid (crude landiol hydrochloride).

[0055] (6) Refining of Landiolol Hydrochloride Add 876g of crude landiolol hydrochloride and 5.8kg of dichloromethane to a 5L three-necked flask, stir until dissolved, add 26.3g of activated carbon, and stir to decolorize for 0.5h. Filter, transfer the filtrate to a 20L reactor, slowly add 2.3kg of n-hexane, and after the drop is complete, control the temperature at 10~20℃ and stir to crystallize for 1.5h, filter, and dry the filter cake at 40~50℃ with air blast to constant weight to obtain a white solid (landiolol hydrochloride). Landiol hydrochloride was detected by high performance liquid chromatography, and the relevant parameters of high performance liquid chromatography detection are shown in Table 3.

[0056] Table 3: Figure 3 Detection of relevant parameters of the spectrum

[0057] The results are as follows Figure 3 As shown, the HPLC purity is 99.972% and the maximum single impurity is 0.028%.

[0058] According to the experimental results, Figure 1 The peak with retention time 14.483min is landiolol hydrochloride. Figure 2 The peak with retention time of 14.412 min is landiolol hydrochloride. Figure 3 The peak with retention time of 14.398 min is landiolol hydrochloride.

[0059] Comparative Example 1 In the preparation method of Comparative Example 1, steps (1) to (5) are the same as those of Example 1, and step (6) is: (6) Refining of Landiolol Hydrochloride Add 584g of crude landiolol hydrochloride and 8.76kg of acetone to a 20L reactor, heat to 55-60℃ and stir until dissolved, add 17.52g of activated carbon, keep at 55-60℃ and stir to decolorize for 0.5h. Filter, transfer the filtrate to a 20L reactor, cool to 10-20℃, keep at 10-20℃ and stir to crystallize for 1.5h, filter, and air dry the filter cake at 40-50℃ to constant weight to obtain a white solid (landiolol hydrochloride). Landiol hydrochloride was detected by high performance liquid chromatography (the relevant parameters of the detection spectrum are shown in Table 1), and the results are as follows Figure 1 As shown, the HPLC purity is 99.109% and the maximum single impurity is 0.452%.

[0060] Table 4: Figure 4 Detection of relevant parameters of the spectrum

[0061] Figure 4 The peak with retention time of 14.398 min is landiolol hydrochloride.

[0062] By comparing the example 1 Figure 4 It can be seen that acetone is used for recrystallization in the refining step, and the finished landiolol hydrochloride product has more impurities, with the maximum single impurity reaching 0.452%, and the product purity is low and cannot meet the pharmaceutical standards.

[0063] The high performance liquid phase detection method of landiolol hydrochloride in Examples 1-3 and Comparative Example 1 is: High performance liquid chromatography: Waters Acquity Acr System, chromatographic column: octadecylsilane bonded silica gel as the stationary phase, mobile phase: acetonitrile-buffered salt (0.01 mol / L potassium dihydrogen phosphate solution), volume ratio of 20:80, flow rate: 1 mL / min, column temperature: 30 °C, detection wavelength: 220 nm, injection volume: 10 μL.

[0064] Determination method: Accurately measure the reference solution and the test solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0065] Preparation of test solution: Take an appropriate amount of the product, weigh accurately, dissolve in solvent and dilute to make a solution containing about 1 mg per 1 ml.

[0066] Preparation of reference solution: Accurately measure 1 mL of reference solution (landiolol hydrochloride), place in a 200 mL volumetric flask, add mobile phase and dilute to the scale as the reference solution.

[0067] Example 4 In the preparation method of Example 4, steps (1) to (5) are the same as those of Example 1, except for step (6), which is specifically reflected in the difference between the good solvent and the poor solvent as shown in Table 5. The other contents are the same as those of Example 1. The purity and impurity content of the final product of each solvent are measured, and the experimental results are shown in Table 5.

[0068] Table 5 Solvents and corresponding experimental results

[0069] As shown in Table 5, the mixed solvent systems composed of several representative good solvents such as dichloromethane and ethyl acetate and several representative bad solvents such as n-hexane and toluene have good refining effects on landiolol hydrochloride. The products of the refining process have not been degraded and have high purity. Among them, the product after refining with the dichloromethane / n-hexane solvent system has the highest purity.

[0070] A person skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of protection of the present application is limited to these examples. In line with the concept of the present application, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments of the present application as described above, which are not provided in detail for the sake of simplicity.

[0071] One or more embodiments of the present application are intended to cover all such substitutions, modifications and variations that fall within the broad scope of the present application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of one or more embodiments of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing high-purity landiolol hydrochloride, characterized in that: The crude landiolol hydrochloride product and a benign solvent are mixed, decolorized, filtered, a poor solvent is added to the filtrate, crystallized, filtered, and landiolol hydrochloride is obtained; the benign solvent is one or more of dichloromethane, ethyl acetate, anhydrous ethanol, methanol, dimethyl sulfoxide, and N,N-dimethylformamide; the poor solvent is one or more of n-hexane, cyclohexane, toluene, and petroleum ether.

2. The preparation method according to claim 1, characterized in that: The good solvent is dichloromethane, and the poor solvent is n-hexane.

3. The preparation method according to claim 1, characterized in that: The weight ratio of the crude landiolol hydrochloride product to the good solvent is 1:5-10, and the weight ratio of the crude landiolol hydrochloride product to the poor solvent is 1:2-5.

4. The preparation method according to claim 1, characterized in that: Activated carbon is used for decolorization, and the weight ratio of the crude landiolol hydrochloride product to the activated carbon is 1:0.01-0.

05.

5. The preparation method according to claim 1, characterized in that: The temperature for mixing the crude landiolol hydrochloride product and the benign solvent is 10-40°C, the temperature for decolorization is 10-40°C, the temperature for crystallization is 0-30°C, and the crystallization time is 1-10 hours.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The preparation method of the crude landiolol hydrochloride is as follows: condense 4-morpholinecarboxamide with ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)3-(4-((S)-epoxyalkylene-2-ylmethoxy)phenyl)propionic acid methyl ester solution, and after the reaction is completed, obtain the crude landiolol hydrochloride by post-treatment.

7. The preparation method according to claim 6, characterized in that: The solvent of the methyl ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)3-(4-((S)-epoxyalkyl-2-ylmethoxy)phenyl)propanoate solution is dimethyl sulfoxide; the molar ratio of methyl ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)3-(4-((S)-epoxyalkyl-2-ylmethoxy)phenyl)propanoate:4-morpholinecarboxamide is 1:2.0~5.0; and the temperature of the condensation reaction is 25~45°C.

8. The preparation method according to claim 6, characterized in that: The post-treatment steps are as follows: adding water, sodium chloride and ethyl acetate to the reaction system for quenching, extracting the aqueous phase with ethyl acetate, combining the organic phases, washing the organic phases with saturated ammonium chloride and sodium chloride aqueous solutions, and then drying and filtering, concentrating the filtrate under reduced pressure, adding acetone to the concentrate, heating to 50-60° C., stirring to dissolve, cooling, and stirring to crystallize.

9. The preparation method according to claim 6, characterized in that: The preparation method of 4-morpholinecarboxamide comprises the following steps: 4-morpholinecarboxamide oxalate reacts with potassium hydroxide, and after the reaction is completed, 4-morpholinecarboxamide is obtained by post-treatment, and the reaction solvent is methanol.

10. The preparation method according to claim 6, characterized in that: The preparation method of the ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)3-(4-((S)-epoxyalkylene-2-ylmethoxy)phenyl)propionic acid methyl ester is that (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-3-(4-hydroxyphenyl)propionic acid ester is reacted with (S)-glycidyl meta-nitrobenzenesulfonate to obtain.

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