Preparation method of carteolol hydrochloride

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of carteolol hydrochloride. The preparation method of carteolol hydrochloride comprises the following steps: 1, mixing a compound shown in a formula III, sulfonyl halide, an alkaline reagent and a solvent, and reacting to obtain a compound shown in a formula IV; wherein the sulfonyl halide is RSO2X, R is a para-substituted aryl group, the substituent group contains heteroatoms, and the heteroatoms comprise one or more than two selected from a substance group consisting of O, N, F, Cl, Br and I; wherein X is selected from F, Cl, Br or I; 2, the compound in the formula IV reacts with tert-butylamine, hydrochloric acid is added after the reaction is finished, and carteolol hydrochloride is obtained. The carteolol hydrochloride prepared by adopting the preparation method of the carteolol hydrochloride disclosed by the invention is higher in yield and higher in purity, and the process is simple and is more suitable for industrial application.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing carteolol hydrochloride. Background Technology

[0002] Carteolol hydrochloride is a non-selective β-adrenergic receptor antagonist that blocks both β1 and β2 receptors. It can lower intraocular pressure by inhibiting aqueous humor production and can also be used to treat glaucoma and ocular hypertension.

[0003] The structural formula of carteolol hydrochloride is as follows: The existing synthetic processes for carteolol hydrochloride still have many defects or shortcomings, such as cumbersome processes, low yields, difficulty in separating impurities, high toxicity, or difficulty in industrial application. For example, the literature (Synthesis of optically active 5-(3- tert -Butylamino-2-hydroxypropoxy)-3,4dihydrocarbostyrilHydrochloride and Their β -Adrenergic Blocking Activities, Katsuyoshi Yamamoto et al. Reference 1 (YAKUGAKU ZASSHI, Vol. 96, No. 3, 1976, pp. 289-292) discloses a synthetic process for carteolol hydrochloride with a specific configuration. The specific synthetic route is shown below: In the above-described route for synthesizing carteolol hydrochloride, the synthesis of compound C requires two cumbersome steps. The preparation of compound D from compound C necessitates the separation of disubstituted impurities using column chromatography, and this impurity, at a concentration of 10.9%, is complex, requiring large volumes of chromatographic media that are frequently replaced, leading to high costs and hindering industrial application. Furthermore, the yield of the final carteolol hydrochloride product is low. Additionally, the reaction time for preparing compound D from compound C in this method is excessively long, requiring two days of refrigeration.

[0004] In patent publication number JP1976034168A, Example 1 discloses a method for preparing compound D from compound C with the R configuration. The specification states that the crude product of compound D obtained is syrupy and requires column chromatography to separate impurities, a cumbersome process.

[0005] Therefore, there is an urgent need to develop a method for preparing carteolol hydrochloride that has a high yield, simpler process, lower toxicity, and is suitable for industrial production. Summary of the Invention

[0006] The technical problem solved by this invention is that the existing synthetic process of carteolol hydrochloride has defects or shortcomings such as complicated process, low yield, difficulty in separating impurities, high toxicity, or difficulty in industrial application.

[0007] To address the above problems, the present invention aims to provide a method for preparing carteolol hydrochloride.

[0008] Specifically, the present invention provides the following technical solution: In a first aspect, the present invention provides a method for preparing carteolol hydrochloride, comprising the following steps: Step 1: The compound of formula III, the sulfonyl halide, the basic reagent, and the solvent are mixed and reacted to obtain the compound of formula IV; wherein the sulfonyl halide is RSO2X, wherein R is a para-substituted aryl group, the substituent contains a heteroatom, and the heteroatom includes one or more substances selected from the group consisting of O, N, F, Cl, Br, and I; wherein X is selected from F, Cl, Br, or I; Step 2: React the compound of formula IV with tert-butylamine, and after the reaction is complete, add hydrochloric acid to obtain carteolol hydrochloride.

[0009] Preferably, in step 1, the compound of formula III is dispersed in an alkaline reagent and solvent, cooled to -15 to 25°C, and a sulfonyl halide is added to react and obtain the compound of formula IV; more preferably, the temperature is cooled to 0 to 10°C; even more preferably, the temperature is cooled to 4 to 7°C.

[0010] And / or, preferably, in step 1, the molar ratio of the compound of formula III to the sulfonyl halide is 1:0.8 to 1.5; more preferably, the molar ratio of the compound of formula III to the sulfonyl halide is 1:0.9 to 1.1.

[0011] Preferably, in step 1, the para-substituted aryl group is a para-substituted phenyl group, and the substituent at the para position is selected from alkoxy, nitro, halogen, trihalomethyl, tertiary amine cation, cyano or formyl groups having 1-5 carbon atoms; more preferably, the para-substituted aryl group is selected from p-methoxyphenyl, p-ethoxyphenyl, p-propoxyphenyl, p-butoxyphenyl, p-nitrophenyl, p-chlorophenyl or p-bromophenyl.

[0012] And / or, preferably, in step 1, the alkaline reagent includes one or more substances selected from the group consisting of pyridine, triethylamine, 1,8-diazabicycloundec-7-ene, diisopropylethylamine, 4-dimethylaminopyridine, imidazole, piperidine, pyrrole and morpholine; more preferably, the alkaline reagent includes pyridine.

[0013] And / or, preferably, in step 1, the molar ratio of the compound of formula III to the basic reagent is 1:1.5-5; more preferably, the molar ratio of the compound of formula III to the basic reagent is 1:1.5-2.5.

[0014] And / or, preferably, in step 1, the solvent includes one or more substances selected from the group consisting of dichloromethane, chloroform, ethyl acetate, methyl tert-butyl ether and toluene; more preferably, the solvent includes dichloromethane.

[0015] And / or, preferably, in step 1, the concentration of the compound of formula III in the solvent is 0.1~1.2 mol / L; more preferably, the concentration of the compound of formula III in the solvent is 0.4~0.5 mol / L.

[0016] And / or, preferably, in step 1, the reaction temperature is 10-50°C; more preferably, the reaction temperature is 20-30°C.

[0017] And / or, preferably, in step 1, the reaction time is 2-15 hours; more preferably, the reaction time is 6-7 hours.

[0018] And / or, preferably, in step 1, after the reaction is completed, the reaction solution is adjusted to pH 4-5, separated, concentrated and dried to obtain compound IV; more preferably, after separation, the organic phase is taken, the aqueous phase is extracted with the solvent used in step 1, the organic phases are combined, and then the organic phase is concentrated and dried; even more preferably, the concentrated and dried crude product is recrystallized in ethanol to obtain compound IV.

[0019] And / or, preferably, in step 2, the compound of formula IV and tert-butylamine are reacted in a solvent. More preferably, in step 2, the solvent comprises one or more substances selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; even more preferably, the solvent comprises dimethyl sulfoxide.

[0020] And / or, preferably, in step 2, the concentration of the compound of formula IV in the solvent is 0.1~2.5 mol / L; more preferably, the concentration of the compound of formula IV in the solvent is 0.45~0.55 mol / L.

[0021] And / or, preferably, in step 2, the molar ratio of the compound of formula IV to tert-butylamine is 1:2~16; more preferably, the molar ratio of the compound of formula IV to tert-butylamine is 1:3.5~4.5.

[0022] And / or, preferably, in step 2, the compound of formula IV, tert-butylamine, and solvent are mixed and heated until reflux occurs, and the reaction is continued at this temperature; and / or, preferably, the temperature is raised to above 45°C; more preferably, the temperature is raised to above 55°C; and / or, preferably, the reaction time is 20-60 h; more preferably, the reaction time is 22-26 h.

[0023] And / or, preferably, in step 2, the compound of formula IV, tert-butylamine, and solvent are mixed and reacted. After the reaction is completed, water is added, and solid-liquid separation is performed to obtain a solid. The solid is dispersed in an alcohol solvent, and hydrochloric acid is added to obtain carteolol hydrochloride. More preferably, the alcohol solvent includes ethanol.

[0024] And / or, preferably, the preparation method of the compound of formula III includes the following steps: Step 1.1: reacting 5-hydroxy-3,4-dihydroquinolinone and 3-halo-1,2-propanediol to obtain the compound of formula III; ; Where X is one of the following: F, Cl, Br or I.

[0025] And / or, preferably, in step 1.1, the molar ratio of 5-hydroxy-3,4-dihydroquinoline ketone to 3-halo-1,2-propanediol is 1:1-4; more preferably, the molar ratio of 5-hydroxy-3,4-dihydroquinoline ketone to 3-halo-1,2-propanediol is 1:2-3. And / or, preferably, in step 1.1, the 3-halo-1,2-propanediol comprises one or more substances selected from the group consisting of 3-fluoro-1,2-propanediol, 3-chloro-1,2-propanediol, 3-bromo-1,2-propanediol and 3-iodo-1,2-propanediol; more preferably, the 3-halo-1,2-propanediol comprises 3-chloro-1,2-propanediol.

[0026] And / or, preferably, in step 1.1, the molar ratio of 5-hydroxy-3,4-dihydroquinolineone to the basic reagent is 1:0.9~5.0; more preferably, the molar ratio of 5-hydroxy-3,4-dihydroquinolineone to the basic reagent is 1:1.0~1.5.

[0027] And / or, preferably, in step 1.1, the alkaline reagent includes one or more substances selected from the group consisting of inorganic hydroxides, alkoxides, and quaternary ammonium bases; more preferably, the inorganic hydroxide includes sodium hydroxide and / or potassium hydroxide; and / or, preferably, the alkoxide includes one or more substances selected from the group consisting of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide; and / or, preferably, the quaternary ammonium base includes tetrabutylammonium hydroxide; more preferably, the alkaline reagent includes sodium hydroxide.

[0028] And / or, preferably, in step 1.1, 5-hydroxy-3,4-dihydroquinolineone, 3-halo-1,2-propanediol, a basic reagent, a first solvent, and a second solvent are mixed and reacted; wherein, the first solvent includes water, and the second solvent includes one or more substances selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and acetonitrile; more preferably, the second solvent includes dimethyl sulfoxide.

[0029] And / or, preferably, in step 1.1, the base reagent is dispersed in a first solvent and reacted with 5-hydroxy-3,4-dihydroquinolinone, 3-halo-1,2-propanediol, and a second solvent.

[0030] And / or, preferably, in step 1.1, the concentration of the 5-hydroxy-3,4-dihydroquinolineone in the first solvent is 0.5~5 mol / L; more preferably, the concentration of the 5-hydroxy-3,4-dihydroquinolineone in the first solvent is 1.5~2.5 mol / L.

[0031] And / or, preferably, in step 1.1, the concentration of the 5-hydroxy-3,4-dihydroquinolineone in the second solvent is 0.5~5 mol / L; more preferably, the concentration of the 5-hydroxy-3,4-dihydroquinolineone in the second solvent is 1.5~2.5 mol / L.

[0032] And / or, preferably, in step 1.1, the reaction conditions are: a temperature of 30-55°C and / or a time of 1-48h; more preferably, a temperature of 35-55°C and / or a time of 10-14h; even more preferably, a temperature of 38-42°C and / or a time of 11-13h.

[0033] And / or, preferably, after the reaction is complete, the solid and liquid are separated, and preferably the solid is dried to obtain compound III.

[0034] Beneficial effects of the present invention (1) In this invention, 5-hydroxy-3,4-dihydroquinolinone and 3-halo-1,2-propanediol can be used to synthesize compound III in one step. The reaction route is simpler, the product obtained is single, the yield is higher, and the purity is higher.

[0035] (2) In this invention, sulfonyl halides, especially p-methoxybenzenesulfonyl chloride and p-nitrobenzenesulfonyl chloride, are used to selectively protect the hydroxyl groups on the primary carbon of the compound of formula III to prepare the compound of formula IV. The resulting disubstituted impurities (both hydroxyl groups on the primary and secondary carbons are replaced by sulfonyl halides) are less abundant, and the yield of the target product is higher.

[0036] (3) In this invention, the crude product of the compound of formula IV prepared by sulfonyl halides, especially p-methoxybenzenesulfonyl chloride and p-nitrobenzenesulfonyl chloride, is a solid. It can be recrystallized with ethanol as a solvent to remove disubstituted impurities, simplify the experimental steps, and obtain a compound of formula IV with higher purity.

[0037] (4) The carteolol hydrochloride prepared by the method of the present invention has a higher yield, higher purity, simpler process and is more suitable for industrial application. Attached Figure Description

[0038] Figure 1 The photon spectrum is the proton NMR spectrum of the compound of formula IV obtained in Example 1. Detailed Implementation

[0040] As mentioned above, the preparation method of carteolol hydrochloride disclosed in Reference 1 is cumbersome, yields a low product, and when compound D is prepared from compound C, the resulting product is syrupy, requiring column chromatography to separate disubstituted impurities. This impurity separation process is tedious, involves large volumes of chromatography media requiring frequent replacement, leading to high costs and hindering industrial application. To address these technical problems, the present invention aims to provide a method for preparing carteolol hydrochloride.

[0041] The present invention provides the following technical solution: Technical Solution 1: A method for preparing carteolol hydrochloride, comprising the following steps: Step 1: The compound of formula III, the sulfonyl halide, the basic reagent, and the solvent are mixed and reacted to obtain the compound of formula IV; wherein the sulfonyl halide is RSO2X, wherein R is a para-substituted aryl group, the substituent contains a heteroatom, and the heteroatom includes one or more substances selected from the group consisting of O, N, F, Cl, Br, and I; wherein X is selected from F, Cl, Br, or I; Step 2: React the compound of formula IV with tert-butylamine, and after the reaction is complete, add hydrochloric acid to obtain carteolol hydrochloride.

[0042] Technical Solution 2. The method for preparing carteolol hydrochloride according to Technical Solution 1, wherein in step 1, the compound of formula III is dispersed in an alkaline reagent and solvent, cooled to -15~25°C, and a sulfonyl halide is added to react and obtain the compound of formula IV; preferably, in some specific embodiments, the temperature can be cooled to -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15°C, or a cooling temperature within the numerical range formed by any two of the above specific values ​​as endpoints; And / or, the molar ratio of the compound of formula III to the sulfonyl halide is 1:0.8 to 1.5; preferably, in some specific embodiments, the molar ratio of the compound of formula III to the sulfonyl halide can be 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, or a molar ratio within the range of any two of the above specific values ​​as endpoints.

[0043] Technical Solution 3. The preparation method of carteolol hydrochloride according to Technical Solution 1 or 2, wherein, in step 1, the para-substituted aryl group is a para-substituted phenyl group, and the para-substituent is selected from alkoxy, nitro, halogen, trihalomethyl, tertiary amine cation, cyano or formyl groups having 1-5 carbon atoms. Preferably, the para-substituted aryl group is selected from p-methoxyphenyl, p-ethoxyphenyl, p-propoxyphenyl, p-butoxyphenyl, p-nitrophenyl, p-chlorophenyl, or p-bromophenyl.

[0044] Technical Solution 4. A method for preparing carteolol hydrochloride according to any one of technical solutions 1-3, wherein, in step 1, the alkaline reagent comprises one or more substances selected from the group consisting of pyridine, triethylamine, 1,8-diazabicycloundec-7-ene, diisopropylethylamine, 4-dimethylaminopyridine, imidazole, piperidine, pyrrole, and morpholine; preferably, the alkaline reagent comprises pyridine; And / or, in step 1, the molar ratio of the compound of formula III to the basic reagent is 1:1.5-5; preferably, in some specific embodiments, the molar ratio of the compound of formula III to the basic reagent can be 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1 2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9 or 1:5, or molar ratios within the range of values ​​defined by any two of the above specific values ​​as endpoints.

[0045] Technical Solution 5. The method for preparing carteolol hydrochloride according to any one of technical solutions 1-4, wherein, in step 1, the solvent includes one or more substances selected from the group consisting of dichloromethane, chloroform, ethyl acetate, methyl tert-butyl ether and toluene; preferably, the solvent includes dichloromethane; And / or, in step 1, the concentration of the compound of formula III in the solvent is 0.1~1.2 mol / L; preferably, in some specific embodiments, the concentration of the compound of formula III in the solvent can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1 or 1.2 mol / L, or a concentration within the numerical range formed by any two of the above specific values ​​as endpoints.

[0046] Technical Solution 6. The method for preparing carteolol hydrochloride according to any one of technical solutions 1-5, wherein, in step 1, the reaction temperature is 10-50℃; preferably, the reaction temperature is 20-30℃; And / or, in step 1, the reaction time is 2-15 hours; preferably, the reaction time is 6-7 hours. And / or, in step 1, after the reaction is completed, the reaction solution is adjusted to pH 4-5, separated, concentrated and dried to obtain compound IV; preferably, after separation, the organic phase is taken, the aqueous phase is extracted with the solvent used in step 1, the organic phases are combined, and then the organic phase is concentrated and dried; more preferably, the concentrated and dried crude product is recrystallized in ethanol to obtain compound IV.

[0047] Technical Solution 7. A method for preparing carteolol hydrochloride according to any one of technical solutions 1-6, wherein, in step 2, the compound of formula IV and tert-butylamine are reacted in a solvent; Preferably, in step 2, the solvent includes one or more substances selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; more preferably, the solvent includes dimethyl sulfoxide. And / or, preferably, in step 2, the concentration of the compound of formula IV in the solvent is 0.1~2.5 mol / L; more preferably, in some specific embodiments, the concentration of the compound of formula IV in the solvent can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4 or 2.5 mol / L, or a concentration within the numerical range formed by any two of the above specific values ​​as endpoints.

[0048] Technical Solution 8. A method for preparing carteolol hydrochloride according to any one of technical solutions 1-7, wherein, in step 2, the molar ratio of the compound of formula IV to tert-butylamine is 1:2~16; preferably, in some specific embodiments, the molar ratio of the compound of formula IV to tert-butylamine can be 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10, 1:10.5, 1:11, 1:11.5, 1:12, 1:12.5, 1:13, 1:13.5, 1:14, 1:14.5, 1:15, 1: 15.5 or 1:16, or a molar ratio within the range of any two of the above specific values ​​as endpoints.

[0049] Technical Solution 9. A method for preparing carteolol hydrochloride according to any one of technical solutions 1-8, wherein in step 2, the compound of formula IV, tert-butylamine and solvent are mixed, heated until reflux liquid appears, and the reaction is continued at the same temperature; And / or, preferably, heated to 45°C or higher; more preferably, heated to 55°C or higher; And / or, preferably, the reaction time is 20-60 h; preferably, the reaction time is 22-26 h.

[0050] Technical Solution 10. A method for preparing carteolol hydrochloride according to any one of technical solutions 1-9, wherein, in step 2, the compound of formula IV, tert-butylamine and solvent are mixed and reacted; after the reaction is completed, water is added, and solid-liquid separation is performed to obtain a solid; the solid is dispersed in an alcohol solvent, and hydrochloric acid is added to obtain carteolol hydrochloride; Preferably, the alcohol solvent includes ethanol.

[0051] Technical Solution 11. The method for preparing carteolol hydrochloride according to any one of technical solutions 1-10, wherein the method for preparing the compound of formula III includes the following steps: Step 1.1: reacting 5-hydroxy-3,4-dihydroquinolinone and 3-halo-1,2-propanediol to obtain the compound of formula III; ; Where X is one of the following: F, Cl, Br or I.

[0052] Technical Solution 12. The method for preparing carteolol hydrochloride according to Technical Solution 11, wherein, in step 1.1, the molar ratio of 5-hydroxy-3,4-dihydroquinolineone to 3-halo-1,2-propanediol is 1:1-4; preferably, in some embodiments, the molar ratio of 5-hydroxy-3,4-dihydroquinolineone to 3-halo-1,2-propanediol can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, or 1:1. 7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9 or 1:4, or molar ratios within the range of values ​​defined by any two of the above specific values ​​as endpoints; And / or, in step 1.1, the 3-halo-1,2-propanediol comprises one or more substances selected from the group consisting of 3-fluoro-1,2-propanediol, 3-chloro-1,2-propanediol, 3-bromo-1,2-propanediol and 3-iodo-1,2-propanediol; preferably, the 3-halo-1,2-propanediol comprises 3-chloro-1,2-propanediol.

[0053] Technical Solution 13. The method for preparing carteolol hydrochloride according to Technical Solution 11 or 12, wherein, in step 1.1, the molar ratio of 5-hydroxy-3,4-dihydroquinolineone to the alkaline reagent is 1:0.9~5.0; preferably, in some specific embodiments, the molar ratio of 5-hydroxy-3,4-dihydroquinolineone to the alkaline reagent can be 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2 , 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9 or 1:5, or molar ratios within the range of values ​​defined by any two of the above specific values ​​as endpoints.

[0054] And / or, in step 1.1, the alkaline reagent includes one or more substances selected from the group consisting of inorganic hydroxides, alkoxides, and quaternary ammonium bases; preferably, the inorganic hydroxide includes sodium hydroxide and / or potassium hydroxide; and / or, the alkoxide includes one or more substances selected from the group consisting of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide; and / or, the quaternary ammonium base includes tetrabutylammonium hydroxide; more preferably, the alkaline reagent includes sodium hydroxide.

[0055] Technical Solution 14. A method for preparing carteolol hydrochloride according to any one of technical solutions 11-13, wherein, in step 1.1, 5-hydroxy-3,4-dihydroquinolinone, 3-halo-1,2-propanediol, a basic reagent, a first solvent, and a second solvent are mixed and reacted; wherein, the first solvent includes water, and the second solvent includes one or more substances selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and acetonitrile; preferably, the second solvent includes dimethyl sulfoxide; And / or, preferably, in step 1.1, the base reagent is dispersed in a first solvent and reacted with 5-hydroxy-3,4-dihydroquinolinone, 3-halo-1,2-propanediol, and a second solvent; And / or, preferably, in step 1.1, the concentration of 5-hydroxy-3,4-dihydroquinolineone in the first solvent is 0.5~5 mol / L; more preferably, in some specific embodiments, the concentration of 5-hydroxy-3,4-dihydroquinolineone in the first solvent can be 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1. 9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5 mol / L, or concentrations within the numerical range defined by any two of the above specific values ​​as endpoints; And / or, preferably, in step 1.1, the concentration of the 5-hydroxy-3,4-dihydroquinolineone in the second solvent is 0.5~5 mol / L; more preferably, in some specific embodiments, the concentration of the 5-hydroxy-3,4-dihydroquinolineone in the second solvent can be 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1. 9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5 mol / L, or concentrations within the numerical range defined by any two of the above specific values ​​as endpoints.

[0056] Technical Solution 15. A method for preparing carteolol hydrochloride according to any one of technical solutions 11-14, wherein, in step 1.1, the reaction conditions are: a temperature of 30-55℃ and / or a time of 1-48h; preferably, a temperature of 35-55℃ and / or a time of 10-14h; more preferably, a temperature of 38-42℃ and / or a time of 11-13h; And / or, preferably, after the reaction is complete, the solid and liquid are separated, and the solid is dried to obtain compound III.

[0057] Unless otherwise specified, the reagents used in the embodiments of this invention are all conventional reagents. The information on the raw materials used in the embodiments is shown in Table 1.

[0058] Table 1. Information on raw materials used in this invention The preparation method of the 5% sodium bicarbonate solution of the present invention includes the following steps: weigh 5g of sodium bicarbonate solid and pour it into 95mL of distilled water, and stir until the solid dissolves.

[0059] In this invention, the disubstituted impurity refers to a compound of formula III in which two hydroxyl groups are respectively replaced by sulfonyl halides. The structural formula of the disubstituted impurity is shown below: The preparation method of 5-hydroxy-3,4-dihydro-2-quinolinone (i.e., compound I) is referred to the preparation method of 5-hydroxy-3,4-dihydro-2(1H)-quinolinone (5, i.e., compound I of this application) in Ji Qinggang, Zhang Yubin, Fu Xiangkai, et al. Synthesis of carteolol hydrochloride [J]. China Pharmaceutical Industry Magazine, 2008, (08): 561-563.

[0060] To better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0061] In this invention, the structural formula of compound IV is shown below: .

[0062] The structural formula of compound IV-1 is shown below: .

[0063] The structural formula of compound IV-2 is shown below: .

[0064] The structural formula of compound IV-3 is shown below: .

[0065] The structural formula of compound IV-4 is shown below: .

[0066] The structural formula of compound IV-5 is shown below: .

[0067] Example 1 A method for preparing carteolol hydrochloride includes the following steps: Step 1: 1.1 Preparation of Compounds of Formula III Dissolve 8.1 g (0.2 mol) NaOH in 90 mL of water and cool to room temperature (10-30 °C). Then add 30.0 g (0.18 mol) of 5-hydroxy-3,4-dihydro-2-quinolinone (compound I) and 40.6 g (0.37 mol) of 3-chloro-1,2-propanediol (compound II), and finally add 90 mL of dimethyl sulfoxide. Heat to 40 °C and stir for 12 h. Detect the reaction by thin-layer chromatography (TLC) to confirm completion. Cool to room temperature (10-30 °C). Filter, wash the filter cake with water, and dry under vacuum at 50 °C to obtain 34.9 g of a white solid, yield 81.8%, purity 99.81%.

[0068] 1.2 Preparation of Compound IV-1 10.0 g (42.2 mmol) of compound III was added to 6.79 mL (84.4 mmol) of pyridine and 100 mL of dichloromethane, and stirred until dissolved. The mixture was cooled to 5 °C in an ice bath, and 8.7 g (42.2 mmol) of p-methoxybenzenesulfonyl chloride was added. The mixture was heated to 20-30 °C and stirred for 6 h. The reaction was confirmed by TLC. 1 N hydrochloric acid (equivalent to 1 mol / L hydrochloric acid) was added to the reaction solution to adjust the pH to 4-5. The mixture was separated, and the lower organic phase was collected. The upper aqueous phase was extracted twice with 100 mL of dichloromethane. The organic phases were combined, washed with 5% sodium bicarbonate solution, and concentrated to dryness under reduced pressure to obtain 15.5 g of a white solid. HPLC analysis showed that the peak area ratio of the target product to the disubstituted impurity was 96.1:3.9. The solid was recrystallized in ethanol to give 14.9 g of white crystals, with a yield of 86.67%, a purity of 99.83%, and 0.09% disubstituted impurities. Figure 1 For the proton NMR data of compound-1 of formula IV, H 1 NMR (400 MHz, DMSO- d 6 ) δ 10.03 (s, 1H), 7.80 (d). J =8.9Hz 2H), 7.13-7.02 (m,3H), 6.49 (d, J = 2.5 Hz, 2H), 5.76(s, 1H), 4.07(s, 1H), 3.99(d, J =8.7 Hz, 2H), 3.85(d, J =3.0Hz, 2H), 2.59(d, J =3.1Hz, 2H), 2.50(d, J =1.9Hz, 3H), 2.35 (d, J =7.6Hz, 2H).

[0069] The structural formula of the disubstituted impurity is shown below: Step 2: Preparation of Carteolol Hydrochloride 10.0 g (24.54 mmol) of compound IV-1 was added to 50 mL of dimethyl sulfoxide, followed by 7.18 g (98.16 mmol) of tert-butylamine. The mixture was heated to 55 °C and stirred under reflux for 24 h. The reaction was monitored by TLC until completion, and then cooled to room temperature (10–30 °C). 100 mL of water was added, and a solid precipitated. The solid was filtered and dried to obtain a white solid. The white solid was dissolved in 100 mL of ethanol, and hydrochloric acid was added to adjust the pH of the solution to 2–3. A solid precipitated, was filtered, and dried under vacuum at 50 °C to obtain 6.1 g of carteolol hydrochloride crystals, with a yield of 75.50%.

[0070] Example 2 A method for preparing carteolol hydrochloride crystals includes the following steps: Step 1: 1.1 Preparation of Compounds of Formula III 0.27 kg (6.75 mol) of NaOH was dissolved in 3 L of water by stirring and cooled to room temperature (10-30 °C). Then, 1.0 kg (6.13 mol) of 5-hydroxy-3,4-dihydro-2-quinolinone (compound I) and 1.35 kg (12.21 mol) of 3-chloro-1,2-propanediol (compound II) were added, followed by 3 L of dimethyl sulfoxide. The mixture was heated to 40 °C and reacted for 12 h. The reaction was monitored by TLC until completion, and then cooled to room temperature (10-30 °C). The mixture was filtered, and the filter cake was washed with water. The product was dried under vacuum at 50 °C to obtain 1.17 kg of a white solid (compound III), with a yield of 80.44% and a purity of 99.60%.

[0071] 1.2 Preparation of Compound IV-1 Take 1.0 kg (4.22 mol) of compound III and add it to 680 mL (8.45 mol) of pyridine and 10 L of dichloromethane, stirring until dissolved. Cool to 6 °C, add 0.87 kg (4.22 mol) of p-methoxybenzenesulfonyl chloride, heat to 20-30 °C and stir for 6 h, monitoring the reaction completion by TLC. Add 1 N hydrochloric acid to the reaction solution to adjust the pH to 4-5, separate the layers, collect the lower organic phase, and extract twice with dichloromethane. Combine the organic phases and wash with 5% sodium bicarbonate solution. Remove most of the dichloromethane by vacuum distillation of the organic phase, add 8 L of anhydrous ethanol, and continue concentrating until no continuous droplets distill off, ending the concentration. Heat the remaining material to reflux and stir until dissolved, then cool to room temperature (10-30 °C) and stir for 1 h (equivalent to the recrystallization of the solid in ethanol in Example 1). The filter cake was filtered, washed with anhydrous ethanol, and dried under vacuum at 50°C to obtain 1.473 kg of white solid, with a yield of 85.7%.

[0072] Step 2: Preparation of Carteolol Hydrochloride 1.0 kg (2.46 mol) of compound IV-1 was added to 5 L of dimethyl sulfoxide, followed by 0.72 kg (9.84 mol) of tert-butylamine. The mixture was heated to 55 °C and stirred under reflux for 24 h. After cooling to room temperature (10-30 °C), 10 L of water was added, and a solid precipitated. The solid was filtered and dried to obtain a white solid. The solid was dissolved in 10 L of ethanol, and hydrochloric acid was added to adjust the pH to 2-3, resulting in crystal precipitation. The crystals were filtered and dried under vacuum to obtain 0.60 kg of carteolol hydrochloride crystals, with a yield of 74.2%.

[0073] Example 3 A method for preparing carteolol hydrochloride crystals includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0074] 1.2 Preparation of Compound IV-2 10.0 g (42.2 mmol) of compound III was added to 6.79 mL (84.4 mmol) of pyridine and 100 mL of dichloromethane, and stirred until dissolved. The mixture was cooled to 5 °C, and 9.35 g (42.2 mmol) of p-nitrobenzenesulfonyl chloride was added. The mixture was heated to 20-30 °C and stirred for 6 h, with the reaction monitored by TLC. The pH of the reaction mixture was adjusted to 4-5 with 1 N hydrochloric acid. The mixture was separated, and the lower organic phase was collected. The mixture was then extracted twice with 100 mL of dichloromethane. The combined organic phases were washed with 5% sodium bicarbonate solution, and concentrated to dryness under reduced pressure to give 14.5 g of a white solid. The peak area ratio of the target product to the disubstituted impurity was 89.40:10.60. The solid was recrystallized from ethanol to give 13.05 g of white crystals, with a yield of 73.20%, a purity of 99.94%, and 0.05% disubstituted impurities.

[0075] The structural formula of the disubstituted impurity is shown below: Step 2: Preparation of Carteolol Hydrochloride 10.35 g (24.5 mmol) of compound IV-2 was added to 50 mL of dimethyl sulfoxide, followed by 7.2 g (98.4 mmol) of tert-butylamine. The mixture was heated to 55 °C and stirred for 24 h. After cooling to room temperature (10–30 °C), 100 mL of water was added, and a solid precipitated. The solid was filtered and dried to obtain a white solid. The white solid was dissolved in 100 mL of ethanol, and hydrochloric acid was added to adjust the pH of the solution to 2–3. The solid precipitated, was filtered, and dried under vacuum to obtain 4.2 g of carteolol hydrochloride crystals, with a yield of 52.1%.

[0076] The yields of the target products obtained from each step in the preparation of carteolol hydrochloride in Examples 1-3 above are summarized in Table 2 below.

[0077] Table 2 Summary of yields and some preparation parameters for each step in the preparation of carteolol hydrochloride Example 4 Example 4-1 A method for preparing carteolol hydrochloride crystals includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0078] 1.2 Preparation of Compound IV-1 Take 1.0 g (4.2 mmol) of compound III and add it to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, stirring until dissolved. Cool the mixture to 5°C in an ice bath, add 0.78 g (3.78 mmol) of p-methoxybenzenesulfonyl chloride, raise the temperature to 20-30°C and stir for 6 h. The reaction is complete as detected by TLC. Adjust the pH to 4-5 by adding 1 N hydrochloric acid to the reaction solution, separate the layers, collect the lower organic phase, and extract the upper aqueous phase twice with 10 mL of dichloromethane. Combine the organic phases, wash them with 5% sodium bicarbonate solution, and concentrate under reduced pressure to dryness to obtain 1.53 g of white solid. HPLC analysis shows that the peak area ratio of the target product and the disubstituted impurity (the disubstituted impurity has the same structural formula as in Example 1) is 96.5:3.5. The white solid was recrystallized in ethanol to give 1.343 g of white crystals (compound IV-1), with a yield of 78.5%, a purity of 99.82%, and 0.16% disubstituted impurities.

[0079] Step 2: The steps are the same as Step 2 in Example 1.

[0080] Example 4-2 A method for preparing carteolol hydrochloride crystals includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0081] 1.2 Preparation of Compound IV-1 Take 1.0 g (4.2 mmol) of compound III and add it to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, stirring until dissolved. Cool the mixture to 5°C in an ice bath, add 0.868 g (4.2 mmol) of p-methoxybenzenesulfonyl chloride, raise the temperature to 20-30°C and stir for 6 h. The reaction is complete as detected by TLC. Adjust the pH to 4-5 by adding 1 N hydrochloric acid to the reaction solution, separate the layers, collect the lower organic phase, and extract the upper aqueous phase twice with 10 mL of dichloromethane. Combine the organic phases, wash them with 5% sodium bicarbonate solution, and concentrate to dryness under reduced pressure to obtain 1.70 g of white solid. HPLC analysis shows that the peak area ratio of the target product and the disubstituted impurity (the disubstituted impurity has the same structural formula as in Example 1) is 96.1:3.9. The white solid was recrystallized in ethanol to give 1.48 g of white crystals (compound IV-1), with a yield of 86.5%, a purity of 99.81%, and 0.17% disubstituted impurities.

[0082] Step 2: The steps are the same as Step 2 in Example 1.

[0083] Example 4-3 A method for preparing carteolol hydrochloride crystals includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0084] 1.2 Preparation of Compound IV-1 Take 1.0 g (4.2 mmol) of compound III and add it to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, stirring until dissolved. Cool the mixture to 5°C in an ice bath, add 0.955 g (4.62 mmol) of p-methoxybenzenesulfonyl chloride, raise the temperature to 20-30°C and stir for 6 h. The reaction is complete as detected by TLC. Adjust the pH to 4-5 by adding 1 N hydrochloric acid to the reaction solution, separate the layers, collect the lower organic phase, and extract the upper aqueous phase twice with 10 mL of dichloromethane. Combine the organic phases, wash them with 5% sodium bicarbonate solution, and concentrate to dryness under reduced pressure to obtain 1.46 g of white solid. HPLC analysis shows that the peak area ratio of the target product and the disubstituted impurity (the disubstituted impurity has the same structural formula as in Example 1) is 87.7:12.3. The white solid was recrystallized in ethanol to give 1.282 g of white crystals (compound IV-1), with a yield of 75.0%, a purity of 97.57%, and 0.53% disubstituted impurities.

[0085] Step 2: The steps are the same as Step 2 in Example 1.

[0086] Example 4-4 A method for preparing carteolol hydrochloride crystals includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0087] 1.2 Preparation of Compound IV-1 Take 1.0 g (4.2 mmol) of compound III and add it to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, stirring until dissolved. Cool the mixture to 5°C in an ice bath, add 1.04 g (5.04 mmol) of p-methoxybenzenesulfonyl chloride, raise the temperature to 20-30°C and stir for 6 h. The reaction is complete as detected by TLC. Adjust the pH to 4-5 by adding 1 N hydrochloric acid to the reaction solution, separate the layers, collect the lower organic phase, and extract the upper aqueous phase twice with 10 mL of dichloromethane. Combine the organic phases, wash them with 5% sodium bicarbonate solution, and concentrate to dryness under reduced pressure to obtain 1.68 g of white solid. HPLC analysis shows that the peak area ratio of the target product and the disubstituted impurity (the disubstituted impurity has the same structural formula as in Example 1) is 79.4:20.6. The white solid was recrystallized in ethanol to give 0.96 g of white crystals (compound IV-1), with a yield of 56.1%, a purity of 95.11%, and 2.89% disubstituted impurities.

[0088] Step 2: The steps are the same as Step 2 in Example 1.

[0089] Example 5 Example 5-1 A method for preparing carteolol hydrochloride crystals includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0090] 1.2 Preparation of Compound IV-2 Take 1.0 g (4.2 mmol) of compound III and add it to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane. Stir until dissolved. Cool to 5 °C, add 0.84 g (3.79 mmol) of p-nitrobenzenesulfonyl chloride, raise the temperature to 20-30 °C and stir for 6 h. The reaction is complete as detected by TCL. Add 1 N hydrochloric acid to the reaction solution to adjust the pH to 4-5. Separate the layers, collect the lower organic phase, and extract the upper aqueous phase twice with 10 mL of dichloromethane. Combine the organic phases, wash with 5% sodium bicarbonate solution, and concentrate the organic phase to dryness under reduced pressure to obtain 1.63 g of white solid. The peak area ratio of the target product and the disubstituted impurity (the structural formula of the disubstituted impurity is the same as in Example 3) is 90.1:9.9. The solid was recrystallized in ethanol to give 1.195 g of white crystals (compound IV-2), with a yield of 67.4%, a purity of 97.21%, and 0.79% disubstituted impurities.

[0091] Step 2: The steps are the same as Step 2 in Example 1.

[0092] Example 5-2 A method for preparing carteolol hydrochloride crystals includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0093] 1.2 Preparation of Compound IV-2 1 g (4.2 mmol) of compound III was added to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, and stirred until dissolved. The mixture was cooled to 5 °C, and 0.93 g (4.2 mmol) of p-nitrobenzenesulfonyl chloride was added. The mixture was heated to 20-30 °C and stirred for 6 h. The reaction was confirmed by TCL. The pH of the reaction solution was adjusted to 4-5 with 1 N hydrochloric acid. The mixture was separated, and the lower organic phase was collected. The upper aqueous phase was extracted twice with 10 mL of dichloromethane. The combined organic phases were washed with 5% sodium bicarbonate solution, and concentrated to dryness under reduced pressure to obtain 1.78 g of a white solid. The peak area ratio of the target product and the disubstituted impurity (with the same structural formula as in Example 3) was 89.4:10.6. The solid was recrystallized in ethanol to obtain 1.3 g of white crystals (compound IV-2), with a yield of 73.2%, purity of 97.16%, and 0.81% disubstituted impurity.

[0094] Step 2: The steps are the same as Step 2 in Example 1.

[0095] Example 5-3 A method for preparing carteolol hydrochloride crystals includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0096] 1.2 Preparation of Compound IV-2 1 g (4.2 mmol) of compound III was added to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, and stirred until dissolved. The mixture was cooled to 5 °C, and 1.03 g (4.64 mmol) of p-nitrobenzenesulfonyl chloride was added. The mixture was heated to 20-30 °C and stirred for 6 h. The reaction was confirmed by TCL. The pH was adjusted to 4-5 with 1 N hydrochloric acid. The mixture was separated, and the lower organic phase was collected. The upper aqueous phase was extracted twice with 10 mL of dichloromethane. The combined organic phases were washed with 5% sodium bicarbonate solution and concentrated to dryness under reduced pressure to obtain 1.78 g of a white solid. The peak area ratio of the target product and the disubstituted impurity (with the same structural formula as in Example 3) was 74.3:25.7. The solid was recrystallized in ethanol to obtain 1.02 g of white crystals (compound IV-2), with a yield of 57.5%, purity of 93.72%, and 4.33% disubstituted impurities.

[0097] Step 2: The steps are the same as Step 2 in Example 1.

[0098] Example 5-4 A method for preparing carteolol hydrochloride crystals includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0099] 1.2 Preparation of Compound IV-2 Take 1 g (4.2 mmol) of compound III and add it to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane. Stir until dissolved. Cool to 5 °C, add 1.12 g (5.05 mmol) of p-nitrobenzenesulfonyl chloride, raise the temperature to 20-30 °C and stir for 6 h. The reaction is complete as detected by TCL. Add 1 N hydrochloric acid to the reaction solution to adjust the pH to 4-5. Separate the layers, collect the lower organic phase, and extract the upper aqueous phase twice with 10 mL of dichloromethane. Combine the organic phases, wash with 5% sodium bicarbonate solution, and concentrate the organic phase to dryness under reduced pressure to obtain 1.75 g of white solid. The peak area ratio of the target product and the disubstituted impurity (the structure of the disubstituted impurity is the same as in Example 3) is 60.1:39.9. Recrystallize the solid in ethanol to obtain 0.89 g of white crystals (compound IV-2), with a yield of 50.1%, purity of 78.89%, and disubstituted impurity of 18.85%.

[0100] Step 2: The steps are the same as Step 2 in Example 1.

[0101] Example 6 Example 6-1 A method for preparing carteolol hydrochloride includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0102] 1.2 Preparation of Compound IV-3 1 g (4.2 mmol) of compound III was added to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, and stirred until dissolved. The mixture was cooled to 5 °C in an ice bath, and 0.80 g (3.78 mmol) of p-chlorobenzenesulfonyl chloride was added. The mixture was heated to 20-30 °C and stirred for 6 h. The reaction was confirmed by TLC. The pH of the reaction mixture was adjusted to 4-5 with 1 N hydrochloric acid. The mixture was separated, and the lower organic phase was collected. The upper aqueous phase was extracted twice with 10 mL of dichloromethane. The organic phases were combined, washed with 5% sodium bicarbonate solution, and concentrated to dryness under reduced pressure to obtain 1.55 g of a white solid. HPLC analysis showed that the peak area ratio of the target product to the disubstituted impurity was 79.3:20.7. The solid was recrystallized from ethanol to give 0.893 g of white crystals (compound IV-3), with a yield of 51.6%, a purity of 88.09%, and 8.91% disubstituted impurities.

[0103] The structural formula of the disubstituted impurity is shown below: Step 2: The steps are the same as Step 2 in Example 1.

[0104] Example 6-2 A method for preparing carteolol hydrochloride includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0105] 1.2 Preparation of Compound IV-3 Take 1 g (4.2 mmol) of compound III and add it to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, stirring until dissolved. Cool it to 5°C in an ice bath, add 0.89 g (4.2 mmol) of p-chlorobenzenesulfonyl chloride, raise the temperature to 20-30°C and stir for 6 h. The reaction is complete as detected by TLC. Adjust the pH to 4-5 by adding 1 N hydrochloric acid to the reaction solution, separate the layers, collect the lower organic phase, and extract the upper aqueous phase twice with 10 mL of dichloromethane. Combine the organic phases, wash them with 5% sodium bicarbonate solution, concentrate under reduced pressure to dryness, and obtain 1.56 g of white solid. HPLC analysis shows that the peak area ratio of the target product and the disubstituted impurity (the structural formula of the disubstituted impurity is the same as in Example 6-1) is 76.6:23.4. The solid was recrystallized in ethanol to give 0.92 g of white crystals (compound IV-3), with a yield of 53.2%, a purity of 84.32%, and 13.61% disubstituted impurities.

[0106] Step 2: The steps are the same as Step 2 in Example 1.

[0107] Example 6-3 A method for preparing carteolol hydrochloride includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0108] 1.2 Preparation of Compound IV-3 Take 1 g (4.2 mmol) of compound III and add it to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, stirring until dissolved. Cool it to 5°C in an ice bath, add 0.98 g (4.62 mmol) of p-chlorobenzenesulfonyl chloride, raise the temperature to 20-30°C and stir for 6 h. The reaction is complete as detected by TLC. Adjust the pH to 4-5 by adding 1 N hydrochloric acid to the reaction solution, separate the layers, collect the lower organic phase, and extract the upper aqueous phase twice with 10 mL of dichloromethane. Combine the organic phases, wash them with 5% sodium bicarbonate solution, concentrate under reduced pressure to dryness, and obtain 0.7 g of white solid. HPLC analysis shows that the peak area ratio of the target product and the disubstituted impurity (the structural formula of the disubstituted impurity is the same as in Example 6-1) is 62.1:37.9. Recrystallize using ethanol to obtain a white solid. There is no significant difference before and after crystallization as observed by TLC, indicating that crystallization is ineffective.

[0109] Example 6-4 A method for preparing carteolol hydrochloride includes the following steps: Step 1: 1.1 The steps are the same as those for preparing compound III in Example 1.

[0110] 1.2 Preparation of Compound IV-3 Take 1 g (4.2 mmol) of compound III and add it to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, stirring until dissolved. Cool it to 5°C in an ice bath, add 1.06 g (5.04 mmol) of p-chlorobenzenesulfonyl chloride, raise the temperature to 20-30°C and stir for 6 h. The reaction is complete as detected by TLC. Adjust the pH to 4-5 by adding 1 N hydrochloric acid to the reaction solution, separate the layers, collect the lower organic phase, and extract the upper aqueous phase twice with 10 mL of dichloromethane. Combine the organic phases, wash them with 5% sodium bicarbonate solution, and concentrate to dryness under reduced pressure to obtain 0.61 g of white solid. HPLC analysis showed that the peak area ratio of the target product and the disubstituted impurity (the structural formula of the disubstituted impurity is the same as in Example 6-1) was 59.6:40.4. Recrystallize using ethanol to obtain a white solid. There was no significant difference before and after crystallization as observed by TLC, indicating that crystallization was ineffective.

[0111] The yields and some preparation parameters of the compounds of formula IV obtained in step 1 of the preparation of carteolol hydrochloride in Examples 4-6 are summarized in Table 3 below.

[0112] Table 3 Summary of yield and some preparation parameters for step 1 in the preparation of carteolol hydrochloride (Formula IV). As shown in Table 3 above, in step 1 of Examples 1-5, when the sulfonyl halide is p-methoxybenzenesulfonyl chloride and p-nitrobenzenesulfonyl chloride, and the molar ratio of Formula III compound to sulfonyl halide is in the range of 1:0.9-1.2, Formula IV compound can be obtained by recrystallization from ethanol.

[0113] When the molar ratio of compound III to p-methoxybenzenesulfonyl chloride is in the range of 1:0.9-1.1, the disubstituted reaction occurs at a relatively low rate, namely 3.5%-12.3%, and the yield of compound IV obtained by recrystallization from ethanol is higher, namely 75.0%-86.5%.

[0114] When the molar ratio of compound III to p-nitrobenzenesulfonyl chloride is in the range of 1:0.9-1.1, the proportion of disubstituted reaction is relatively low, that is, 9.9%-25.7%, and the yield of compound IV obtained by recrystallization from ethanol is also higher, that is, 57.5%-73.2%.

[0115] Further analysis revealed that when the molar ratio of compound III to sulfonyl halide was 1:1, and the sulfonyl halide was p-methoxybenzenesulfonyl chloride, the yield of compound IV was the highest (86.5%), and the yield of carteolol hydrochloride prepared from compound IV was also relatively high (75.5%). When the sulfonyl halide was p-nitrobenzenesulfonyl chloride, the yield of compound IV was also at its highest level (73.2%). Therefore, a molar ratio of compound III to sulfonyl halide of 1:1 is the optimal reaction molar ratio, which reduces the proportion of disubstituted reactions, resulting in a higher yield and purity of compound IV, and a higher yield of carteolol hydrochloride prepared from it.

[0116] In Example 6, p-chlorobenzenesulfonyl chloride was used as the sulfonyl halide. When the molar ratio of the sulfonyl halide to compound III was consistent, the disubstituted reaction rate was higher than when p-methoxybenzenesulfonyl chloride and p-nitrobenzenesulfonyl chloride were used as the sulfonyl halide. Specifically, when the molar ratio of the sulfonyl halide (p-chlorobenzenesulfonyl chloride) to compound IV was in the range of 1:1.1-1.2, due to the high content of disubstituted impurities, there was no significant difference in TLC results before and after recrystallization from ethanol, indicating that crystallization was ineffective. High-purity compound IV could not be obtained, and the subsequent reaction in step 2 was not carried out. When the molar ratio of the sulfonyl halide (p-chlorobenzenesulfonyl chloride) to compound IV was in the range of 1:0.9-1.0, the yield of compound IV synthesized using p-chlorobenzenesulfonyl chloride was higher. This indicates that in this reaction system, p-chlorobenzenesulfonyl chloride can control the disubstituted reaction to a certain extent, thereby improving the purity and yield of compound IV and carteolol hydrochloride.

[0117] Comparative Example 1 According to the journal (Synthesis of Optically Active 5-(3- tert -Butylamino-2-hydroxypropoxy)-3,4dihydrocarbostyril Hydrochloride and Their β -Adrenergic Blocking Activities, Katsuyoshi Yamamoto et al. The preparation of carteolol hydrochloride is described in YAKUGAKU ZASSHI's 1976 Vol. 96 No. 3, pp. 289-292. The reaction route is shown below: Step 1: Preparation of compound B Dissolve 1.0 g of 5-hydroxy-3,4-dihydro-2-quinolinone and 0.44 g of sodium ethoxide in 18 mL of 2-methyltetrahydrofuran by stirring. Reflux for 10 min, then add 1.9 g of compound A and continue reflux for 3 h. Distill the solvent under reduced pressure to obtain a solid. Dissolve the solid in CHCl3 and water, extract, and collect the lower organic phase. Wash repeatedly with 1 N sodium hydroxide aqueous solution. Distill off excess solvent under reduced pressure and recrystallize in methanol to obtain 0.7 g of colorless needle-like crystals (yield 41.7%). Step 2: Preparation of compound C Take 1.0 g of compound B, add 10 ml of 80% acetic acid to dissolve it, heat in a water bath (50℃) for 30 min, and after the solution cools, add 150 ml of diethyl ether to precipitate the precipitate. Filter to obtain the residue, and recrystallize in ethanol to obtain 0.48 g of colorless needle-like crystals (yield 56.12%).

[0118] Step 3: Preparation of compound D 10.0 g of compound C was dissolved in 50 mL of pyridine. 9.0 g of p-toluenesulfonyl chloride was added under cold water bath conditions until completely dissolved. The mixture was stirred in an ice-water bath for 5 h, then refrigerated for 48 h. The residue was obtained by vacuum distillation and extracted with 200 mL of CHCl3. The lower organic phase was collected, washed with 1 N HCl and saturated NaHCO3 aqueous solution, and then washed with water. Vacuum distillation yielded a syrupy substance. This substance was dissolved in dichloromethane and separated by reverse-phase chromatography to obtain 9.47 g of compound D (yield 54.74%) and 2.78 g (12.80%) of impurity Y.

[0119] To investigate whether the obtained syrupy target product could be recrystallized from ethanol, the following steps were taken: 10.0 g of compound C was dissolved in 50 mL of pyridine. 9.0 g of p-methylbenzenesulfonyl chloride was added under cold water bath conditions until completely dissolved. The mixture was stirred in an ice-water bath for 5 h, then placed in a refrigerator for 48 h. The residue was obtained by vacuum distillation and extracted with 200 mL of CHCl3. The lower organic phase was collected, washed with 1N HCl and saturated NaHCO3 aqueous solution, and then washed with water. Vacuum distillation yielded a syrupy substance. This syrupy substance was dissolved in ethanol solution, and no solid precipitated.

[0120] Step 4: Preparation of compound E 5.0 g of compound D was dissolved in 50 mL of acetonitrile, and 5.0 g of tert-butylamine was added. The mixture was heated in a water bath to 60°C and stirred for 12.5 h. After cooling, it was extracted with 150 mL of CHCl3, and the lower organic phase was collected. The mixture was washed several times with water, and the solvent was removed by vacuum distillation. 50 L of acetone was added, followed by a dry solution of isopropanol hydrochloride. After cooling, crystals precipitated. Recrystallization from acetic acid and ether yielded 0.92 g of crystals (yield 21.20%).

[0121] Comparative Example 2 Comparative Example 2-1 A method for preparing carteolol hydrochloride includes the following steps: Step 1: 1.1 The steps are the same as those in Example 1 for preparing compound III.

[0122] 1.2 Preparation of Compound IV-4 1 g (4.2 mmol) of compound III was added to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, and stirred until dissolved. The mixture was cooled to 5 °C in an ice bath, and 0.84 g (3.78 mmol) of o-nitrobenzenesulfonyl chloride was added. The mixture was heated to 20-30 °C and stirred for 6 h. The reaction was confirmed by TLC. The pH of the reaction mixture was adjusted to 4-5 with 1 N hydrochloric acid. The mixture was separated, and the lower organic phase was collected. The upper aqueous phase was extracted twice with 10 mL of dichloromethane. The organic phases were combined, washed with 5% sodium bicarbonate solution, and concentrated to dryness under reduced pressure to obtain 1.60 g of a white solid. HPLC analysis showed that the peak area ratio of the target product to the disubstituted impurities was 84:16. The solid was recrystallized in ethanol to give 0.454 g of white crystals (compound IV-4), with a yield of 25.6%, HPLC purity of 90.81%, and disubstituted impurities of 7.12%.

[0123] The structural formula of the disubstituted impurity is shown below: Step 2: The steps are the same as Step 2 in Example 1.

[0124] Comparative Example 2-2 A method for preparing carteolol hydrochloride includes the following steps: Step 1: 1.1 The steps are the same as those in Example 1 for preparing compound III.

[0125] 1.2 Preparation of Compound IV-4 Take 1 g (4.2 mmol) of compound III and add it to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, stirring until dissolved. Cool it to 5°C in an ice bath, add 0.93 g (4.20 mmol) of o-nitrobenzenesulfonyl chloride, raise the temperature to 20-30°C and stir for 6 h. The reaction is complete as detected by TLC. Adjust the pH to 4-5 by adding 1 N hydrochloric acid to the reaction solution, separate the layers, collect the lower organic phase, and extract the upper aqueous phase twice with 10 mL of dichloromethane. Combine the organic phases, wash them with 5% sodium bicarbonate solution, concentrate under reduced pressure to dryness, and give 2.2 g of white solid. HPLC analysis shows that the peak area ratio of the target product and the disubstituted impurity (the disubstituted impurity has the same structural formula as Comparative Example 2-1) is 73.2:26.8. The solid was recrystallized in ethanol to give 0.367 g of white crystals (compound IV-4), with a yield of 20.7%, a purity of 86.02%, and 13.31% disubstituted impurities.

[0126] Step 2: The steps are the same as Step 2 in Example 1.

[0127] Comparative Examples 2-3 A method for preparing carteolol hydrochloride includes the following steps: Step 1: 1.1 The steps are the same as those in Example 1 for preparing compound III.

[0128] 1.2 Preparation of Compound IV-4 1 g (4.2 mmol) of compound III was added to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, and stirred until dissolved. The mixture was cooled to 5 °C in an ice bath, and 1.03 g (4.62 mmol) of o-nitrobenzenesulfonyl chloride was added. The mixture was heated to 20-30 °C and stirred for 6 h. The reaction was confirmed to be complete by TLC. The pH of the reaction mixture was adjusted to 4-5 with 1 N hydrochloric acid. The mixture was separated, and the lower organic phase was collected. The upper aqueous phase was extracted twice with 10 mL of dichloromethane. The organic phases were combined, washed with 5% sodium bicarbonate solution, and concentrated to dryness under reduced pressure to obtain 0.49 g of a white solid. HPLC analysis showed that the peak area ratio of the target product and the disubstituted impurity (with the same structural formula as Comparative Example 2-1) was 69.6:30.4. Recrystallization with ethanol yielded a white solid. No significant difference was observed before and after crystallization under TLC, indicating that crystallization was ineffective.

[0129] Comparative Examples 2-4 A method for preparing carteolol hydrochloride includes the following steps: Step 1: 1.1 The steps are the same as those in Example 1 for preparing compound III.

[0130] 1.2 Preparation of Compound IV-4 1 g (4.2 mmol) of compound III was added to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, and stirred until dissolved. The mixture was cooled to 5 °C in an ice bath, and 1.12 g (5.04 mmol) of o-nitrobenzenesulfonyl chloride was added. The mixture was heated to 20-30 °C and stirred for 6 h. The reaction was confirmed to be complete by TLC. The pH of the reaction solution was adjusted to 4-5 with 1 N hydrochloric acid. The mixture was separated, and the lower organic phase was collected. The upper aqueous phase was extracted twice with 10 mL of dichloromethane. The organic phases were combined, washed with 5% sodium bicarbonate solution, and concentrated to dryness under reduced pressure to obtain 0.45 g of a white solid. HPLC analysis showed that the peak area ratio of the target product and the disubstituted impurity (with the same structural formula as Comparative Example 2-1) was 67.1:32.9. Recrystallization with ethanol yielded a white solid. No significant difference was observed before and after crystallization under TLC, indicating that crystallization was ineffective.

[0131] Comparative Example 3 A method for preparing carteolol hydrochloride includes the following steps: Step 1: 1.1 The steps are the same as those in Example 1 for preparing compound III.

[0132] 1.2 Preparation of Compound IV-5 1 g (4.2 mmol) of compound III was added to 0.676 mL (8.4 mmol) of pyridine and 10 mL of dichloromethane, and stirred until dissolved. The mixture was cooled to 5°C in an ice bath, and 0.8 g (4.2 mmol) of p-toluenesulfonyl chloride was added. The mixture was heated to 20-30°C and stirred for 6 h. The reaction was monitored by TLC until complete. The pH of the reaction mixture was adjusted to 4-5 with 1 N hydrochloric acid. The mixture was separated, and the lower organic phase was collected. The upper aqueous phase was extracted twice with 10 mL of dichloromethane. The organic phases were combined, washed with 5% sodium bicarbonate solution, and concentrated to dryness under reduced pressure to obtain a syrupy substance. RP-HPLC analysis showed that the peak area ratio of the target product to the disubstituted impurities was 84.5:15.5. Separation by reversed-phase chromatography yielded 1.06 g of white crystals (compound IV-5), with a yield of 64.5%.

[0133] The structural formula of the disubstituted impurity is shown below: Step 3: The steps are the same as Step 3 in Example 1.

[0134] The yields and some preparation parameters of the target products obtained from each step of the preparation of carteolol hydrochloride in Comparative Examples 1-3 are summarized in Table 4 below.

[0135] Table 4 Summary of yield and some preparation parameters for step 1 in the preparation of carteolol hydrochloride As shown in Table 4 above, Comparative Example 1 is a reproduction of the reaction route in the literature. When preparing the compound of formula IV with the desired configuration in step 3, the crude product obtained is syrupy. According to experimental research, it is not possible to purify it by recrystallization from ethanol to obtain a compound of formula IV with higher purity. The compound of formula IV and the corresponding impurity Y can only be separated by reverse chromatography, which is more complicated and the yield of the compound of formula IV is low.

[0136] In Comparative Example 2, the yield of Compound IV prepared using o-nitrobenzenesulfonyl chloride as a sulfonyl halide was significantly lower than that in Examples 1-6. Specifically, when the molar ratio of the sulfonyl halide (o-nitrobenzenesulfonyl chloride) to Compound III was in the range of 1:1.1-1.2, due to the high content of disubstituted impurities, there was no significant difference in TLC results before and after recrystallization from ethanol, indicating ineffective crystallization. High-purity Compound IV could not be obtained, and the subsequent reaction in step 2 was not carried out. When the molar ratio of o-nitrobenzenesulfonyl chloride to Compound III was in the range of 1:0.9-1.0, the yield of Compound IV synthesized using o-nitrobenzenesulfonyl chloride was low, thus affecting the yield of carteolol hydrochloride.

[0137] In Comparative Example 3, under the experimental method of this application, p-methylbenzenesulfonyl chloride was used as a sulfonyl halide to prepare compound IV. The crude product obtained was syrupy and could not be purified by recrystallization from ethanol to obtain compound IV with higher purity. Compound IV could only be separated by reverse chromatography, which was more complicated.

[0138] The above is a detailed description of feasible embodiments of the present invention. However, these embodiments are not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the spirit of the present invention should be included in the patent scope of the present invention.

Claims

1. A method for preparing carteolol hydrochloride, characterized in that, Includes the following steps: Step 1: The compound of formula III, the sulfonyl halide, the basic reagent, and the solvent are mixed and reacted to obtain the compound of formula IV; wherein the sulfonyl halide is RSO2X, wherein R is a para-substituted aryl group, the substituent contains a heteroatom, and the heteroatom includes one or more substances selected from the group consisting of O, N, F, Cl, Br, and I; wherein X is selected from F, Cl, Br, or I; Step 2: React the compound of formula IV with tert-butylamine, and after the reaction is complete, add hydrochloric acid to obtain carteolol hydrochloride.

2. The method for preparing carteolol hydrochloride according to claim 1, wherein, In step 1, the compound of formula III is dispersed in an alkaline reagent and solvent, cooled to -15 to 25°C, and a sulfonyl halide is added to react and obtain the compound of formula IV; preferably, the temperature is cooled to 0 to 10°C; more preferably, the temperature is cooled to 4 to 7°C. And / or, the molar ratio of the compound of formula III to the sulfonyl halide is 1:0.8 to 1.5; preferably, the molar ratio of the compound of formula III to the sulfonyl halide is 1:0.9 to 1.

1.

3. The method for preparing carteolol hydrochloride according to claim 1 or 2, wherein, In step 1, the para-substituted aryl group is a para-substituted phenyl group, and the substituent at the para position is selected from alkoxy, nitro, halogen, trihalomethyl, tertiary amine cation, cyano or formyl groups having 1-5 carbon atoms. Preferably, the para-substituted aryl group is selected from p-methoxyphenyl, p-ethoxyphenyl, p-propoxyphenyl, p-butoxyphenyl, p-nitrophenyl, p-chlorophenyl, or p-bromophenyl.

4. The method for preparing carteolol hydrochloride according to any one of claims 1-3, wherein, In step 1, the alkaline reagent includes one or more substances selected from the group consisting of pyridine, triethylamine, 1,8-diazabicycloundec-7-ene, diisopropylethylamine, 4-dimethylaminopyridine, imidazole, piperidine, pyrrole, and morpholine; preferably, the alkaline reagent includes pyridine. And / or, in step 1, the molar ratio of the compound of formula III to the basic reagent is 1:1.5-5; preferably, the molar ratio of the compound of formula III to the basic reagent is 1:1.5-2.

5.

5. The method for preparing carteolol hydrochloride according to any one of claims 1-4, wherein, In step 1, the solvent includes one or more substances selected from the group consisting of dichloromethane, chloroform, ethyl acetate, methyl tert-butyl ether, and toluene; preferably, the solvent includes dichloromethane. And / or, in step 1, the concentration of the compound of formula III in the solvent is 0.1~1.2 mol / L; preferably, the concentration of the compound of formula III in the solvent is 0.4~0.5 mol / L.

6. The method for preparing carteolol hydrochloride according to any one of claims 1-5, wherein, In step 1, the reaction temperature is 10-50℃; preferably, the reaction temperature is 20-30℃. And / or, in step 1, the reaction time is 2-15 hours; preferably, the reaction time is 6-7 hours. And / or, in step 1, after the reaction is completed, the reaction solution is adjusted to pH 4-5, separated, concentrated and dried to obtain compound IV; preferably, after separation, the organic phase is taken, the aqueous phase is extracted with the solvent used in step 1, the organic phases are combined, and then the organic phase is concentrated and dried; more preferably, the concentrated and dried crude product is recrystallized in ethanol to obtain compound IV.

7. The method for preparing carteolol hydrochloride according to any one of claims 1-6, wherein, In step 2, the compound of formula IV and tert-butylamine are reacted in a solvent; Preferably, in step 2, the solvent includes one or more substances selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; more preferably, the solvent includes dimethyl sulfoxide. And / or, preferably, in step 2, the concentration of the compound of formula IV in the solvent is 0.1~2.5 mol / L; more preferably, the concentration of the compound of formula IV in the solvent is 0.45~0.55 mol / L.

8. The method for preparing carteolol hydrochloride according to any one of claims 1-7, wherein, In step 2, the molar ratio of compound IV to tert-butylamine is 1:2~16; preferably, the molar ratio of compound IV to tert-butylamine is 1:3.5~4.

5.

9. The method for preparing carteolol hydrochloride according to any one of claims 1-8, wherein, In step 2, the compound of formula IV, tert-butylamine, and solvent are mixed and heated until a reflux liquid appears, and the reaction is continued at this temperature. And / or, preferably, heated to 45°C or higher; more preferably, heated to 55°C or higher; And / or, preferably, the reaction time is 20-60 h; preferably, the reaction time is 22-26 h.

10. The method for preparing carteolol hydrochloride according to any one of claims 1-9, wherein, In step 2, the compound of formula IV, tert-butylamine, and solvent are mixed and reacted. After the reaction is completed, water is added, and solid-liquid separation is performed to obtain a solid. The solid is dispersed in an alcohol solvent, and hydrochloric acid is added to obtain carteolol hydrochloride. Preferably, the alcohol solvent includes ethanol.

11. The method for preparing carteolol hydrochloride according to any one of claims 1-10, wherein, The preparation method of the compound of formula III includes the following steps: Step 1.1: React 5-hydroxy-3,4-dihydroquinolinone and 3-halo-1,2-propanediol to obtain the compound of formula III; ； Where X is one of the following: F, Cl, Br or I.

12. The method for preparing carteolol hydrochloride according to claim 11, wherein, In step 1.1, the molar ratio of 5-hydroxy-3,4-dihydroquinolinone to 3-halo-1,2-propanediol is 1:1-4; preferably, the molar ratio of 5-hydroxy-3,4-dihydroquinolinone to 3-halo-1,2-propanediol is 1:2-3. And / or, in step 1.1, the 3-halo-1,2-propanediol comprises one or more substances selected from the group consisting of 3-fluoro-1,2-propanediol, 3-chloro-1,2-propanediol, 3-bromo-1,2-propanediol and 3-iodo-1,2-propanediol; preferably, the 3-halo-1,2-propanediol comprises 3-chloro-1,2-propanediol.

13. The method for preparing carteolol hydrochloride according to claim 11 or 12, wherein, In step 1.1, the molar ratio of 5-hydroxy-3,4-dihydroquinolineone to the basic reagent is 1:0.9~5.0; preferably, the molar ratio of 5-hydroxy-3,4-dihydroquinolineone to the basic reagent is 1:1.0~1.

5. And / or, in step 1.1, the alkaline reagent includes one or more substances selected from the group consisting of inorganic hydroxides, alkoxides, and quaternary ammonium bases; preferably, the inorganic hydroxide includes sodium hydroxide and / or potassium hydroxide; and / or, the alkoxide includes one or more substances selected from the group consisting of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide; and / or, the quaternary ammonium base includes tetrabutylammonium hydroxide; More preferably, in step 1.1, the alkaline reagent includes sodium hydroxide.

14. The method for preparing carteolol hydrochloride according to any one of claims 11-13, wherein, In step 1.1, 5-hydroxy-3,4-dihydroquinolinone, 3-halo-1,2-propanediol, a basic reagent, a first solvent, and a second solvent are mixed and reacted; wherein, the first solvent includes water, and the second solvent includes one or more substances selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and acetonitrile; preferably, the second solvent includes dimethyl sulfoxide; And / or, preferably, the base reagent is dispersed in a first solvent and reacted with 5-hydroxy-3,4-dihydroquinolinone, 3-halo-1,2-propanediol and a second solvent; And / or, preferably, the concentration of the 5-hydroxy-3,4-dihydroquinolineone in the first solvent is 0.5~5 mol / L; more preferably, the concentration of the 5-hydroxy-3,4-dihydroquinolineone in the first solvent is 1.5~2.5 mol / L; And / or, preferably, the concentration of the 5-hydroxy-3,4-dihydroquinolineone in the second solvent is 0.5~5 mol / L; more preferably, the concentration of the 5-hydroxy-3,4-dihydroquinolineone in the second solvent is 1.5~2.5 mol / L.

15. The method for preparing carteolol hydrochloride according to any one of claims 11-14, wherein, In step 1.1, the reaction conditions are: temperature of 30-55℃ and / or time of 1-48h; preferably, temperature of 35-55℃ and / or time of 10-14h; more preferably, temperature of 38-42℃ and / or time of 11-13h. And / or, preferably, after the reaction is complete, the solid and liquid are separated, and the solid is dried to obtain compound III.

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