Preparation method of landiolol hydrochloride intermediate and key impurities thereof

Abstract

The invention relates to a preparation method of a landiolol hydrochloride intermediate and key impurities thereof, which comprises the following steps: carrying out reaction on p-hydroxyphenylpropionic acid and aqueous alkali to generate p-hydroxyphenylpropionic acid salt as shown in a formula II, adding a crystallization solvent after the salt forming reaction is finished, and carrying out cooling crystallization to obtain the p-hydroxyphenylpropionic acid salt; the hydroxyphenylpropionate reacts with a compound shown in a formula III to generate a landiolol hydrochloride intermediate shown in a formula I, and water is added for quenching after the reaction is finished; extracting with an organic solvent for more than three times, and combining organic phases; and concentrating the organic phase, and adding a crystallization solvent for crystallization to obtain the landiolol hydrochloride intermediate. According to the method provided by the invention, the high-purity landiolol hydrochloride intermediate can be obtained, the defects of incomplete reaction, excessive byproducts and the like in the process are overcome, and the method is stable and controllable in process and is more suitable for industrial production. In addition, the invention further provides a preparation method of the key impurity shown in the formula IV, and a basis is provided for quality control of a landiolol hydrochloride intermediate preparation process.

Description

Technical Field

[0001] The invention belongs to the technical field of medicinal chemistry, and particularly relates to a method for preparing a landiolol hydrochloride intermediate and key impurities thereof. Background Art

[0002] The chemical name of Landiolol hydrochloride is [(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-[4-[(S)-2-hydroxy-3-[2-(morpholine-4-carboxamido)ethylamino]propoxy]phenyl]propionate hydrochloride, and its structural formula is as follows:

[0003]

[0004] Landiolol hydrochloride was developed by Ono Pharmaceutical Co., Ltd. of Japan with the trade name Onoact50. It is an ultra-short-acting, highly selective β1 receptor blocker. It was launched in Japan in September 2002. It is mainly used clinically for the emergency treatment of tachycardia-induced arrhythmias (including atrial fibrillation, atrial flutter, and sinus tachycardia) during surgery, and for the emergency treatment of tachycardia-induced arrhythmias under dynamic circulatory monitoring after surgery.

[0005] In the preparation methods of landiolol hydrochloride disclosed in Ono Pharmaceutical Industry Co., Ltd.'s patents Tokukaihei 5-306281, EP0397031, and Chinese patents CN101012217A and CN106608863A, landiolol hydrochloride must be prepared through the intermediate S-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propionate (Formula I). ​​The preparation method is as follows:

[0006]

[0007] The preparation method disclosed in Patent Laid-Open No. 5-306281 involves reacting p-hydroxyphenylpropionic acid with p-toluenesulfonic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester (Formula III) in the presence of potassium hydroxide to obtain a landiolol hydrochloride intermediate (Formula I). ​​This method suffers from incomplete reaction, large by-products, and low yield. The landiolol hydrochloride intermediate (Formula I) requires column chromatography separation and purification, making it unsuitable for industrial production.

[0008] The preparation method disclosed in patent CN101012217A uses S(+)-epichlorohydrin and acetone to react to produce (2,2-dimethyl-1,3-dioxolane-4S)methyl chloride (Formula III), which is then reacted with p-hydroxyphenylpropionic acid under potassium hydroxide conditions to obtain the landiolol hydrochloride intermediate (Formula I). ​​In this method, the reaction of the compound represented by Formula III with p-hydroxyphenylpropionic acid to obtain the landiolol hydrochloride intermediate (Formula I) is incomplete, resulting in large by-products and low yield, making it unsuitable for industrial production.

[0009] Patent CN106608863A discloses a preparation method in which p-hydroxyphenylpropionic acid and (2,2-dimethyl-1,3-dioxolane-4S)methyl chloride (Formula III) react in the presence of potassium hydroxide, potassium carbonate, and a phase transfer catalyst to obtain a landiolol hydrochloride intermediate (Formula I). ​​This method introduces a phase transfer catalyst during the reaction, increasing process costs and making it unsuitable for industrial production.

[0010] The preparation method disclosed in EP0397031B1 involves reacting p-hydroxyphenylpropionic acid with (2,2-dimethyl-1,3-dioxolane-4S)methyl chloride (Formula III) in the presence of potassium carbonate and potassium iodide to produce the landiolol hydrochloride intermediate (Formula I). ​​This method requires column chromatography separation and purification, making it unsuitable for industrial production.

[0011] The preparation methods of the landiolol hydrochloride intermediate (Formula I) used in the above patents all produce a large amount of byproduct impurities, thereby reducing the yield of the landiolol hydrochloride intermediate (Formula I). ​​These impurities may also remain in the final product, landiolol hydrochloride, affecting product quality. They require column chromatography separation and purification or the introduction of a phase transfer catalyst, making them unsuitable for industrial production. Therefore, providing a process for producing a landiolol hydrochloride intermediate (Formula I) that suppresses byproduct formation, is highly pure, and has a stable process has become a key point in the research on the industrial production of landiolol hydrochloride. Summary of the Invention

[0012] The present invention aims to provide a preparation method and detection method for a landiolol hydrochloride intermediate. The method comprises first reacting p-hydroxyphenylpropionic acid with an alkaline solution to form a p-hydroxyphenylpropionic acid salt, and then reacting the p-hydroxyphenylpropionic acid salt with a compound represented by Formula III under heating conditions to obtain a landiolol hydrochloride intermediate represented by Formula I. This method reduces the formation of key impurities represented by Formula IV. The method is simple to operate, has low by-product content, a stable process, is environmentally friendly, and is suitable for industrial production of the landiolol hydrochloride intermediate represented by Formula I.

[0013] To achieve the above object, the technical solution adopted by the present invention is: a method for preparing a landiolol hydrochloride intermediate, the method comprising the following steps:

[0014] S1, p-hydroxyphenylpropionic acid reacts with an alkaline solution to produce a p-hydroxyphenylpropionic acid salt represented by formula II. After the salt-forming reaction is completed, a crystallization solvent is added, and the temperature is lowered for crystallization to prepare a p-hydroxyphenylpropionic acid salt;

[0015] S2, reacting the hydroxyphenylpropionic acid salt with the compound represented by formula III to generate the landiolol hydrochloride intermediate represented by formula I, quenching with water after the reaction; extracting with an organic solvent for more than three times, combining the organic phases; concentrating the organic phases, and adding a crystallizing solvent for crystallization to obtain the landiolol hydrochloride intermediate;

[0016] The reaction scheme of the method is:

[0017]

[0018] Wherein, M is sodium or potassium; X is p-toluenesulfonyloxy, chlorine or 2-nitrobenzenesulfonyloxy.

[0019] Further, in step S1, p-hydroxyphenylpropionic acid reacts with an alkali solution in a first solvent to generate a p-hydroxyphenylpropionic acid salt;

[0020] The first solvent is selected from one of ethanol, methanol, and isopropanol, or a mixture of one of ethanol, methanol, and isopropanol and a small amount of water.

[0021] Further, in step S1, the alkaline solution is obtained by dissolving a solid alkaline reagent in a first solvent;

[0022] The solid alkali reagent is selected from potassium hydroxide, sodium hydroxide, sodium carbonate, and potassium carbonate. Furthermore, in step S1, the reaction molar ratio of p-hydroxyphenylpropionic acid to the solid alkali reagent is 1.0:0.9-1.5.

[0023] Furthermore, in step S1, the reaction temperature for the reaction of p-hydroxyphenylpropionic acid with the alkaline solution to generate p-hydroxyphenylpropionic acid salt is 0-30°C.

[0024] Furthermore, the crystallization solvent is selected from one of n-heptane, n-hexane, and methyl tert-butyl ether.

[0025] Furthermore, in step S1, the specific conditions for the cooling and crystallization are cooling to below 20°C and stirring for crystallization.

[0026] Further, in step S2, the hydroxyphenylpropionic acid salt reacts with the compound represented by formula III in a second solvent to generate the landiolol hydrochloride intermediate represented by formula I;

[0027] The second solvent is selected from one of toluene, N,N-dimethylformamide, dimethyl sulfoxide, and 1,4-dioxane.

[0028] Furthermore, in step S2, the reaction molar ratio of the hydroxyphenylpropionic acid salt to the compound represented by formula III is 1.0:0.7-1.4.

[0029] Furthermore, in step S2, the reaction temperature of the hydroxyphenylpropionic acid salt and the compound represented by formula III to generate the landiolol hydrochloride intermediate represented by formula I is 100-105°C.

[0030] Furthermore, in step S2, after the step of combining the organic phases and before the step of concentrating the organic phases, the combined organic phases are washed sequentially with dilute hydrochloric acid and saturated sodium chloride solution.

[0031] Furthermore, in step S2, the organic phase is concentrated under reduced pressure at 30-40°C.

[0032] The present invention also provides a method for preparing a key impurity of a landiolol hydrochloride intermediate, the method comprising the following steps:

[0033] Under the action of an alkaline reagent, the landiolol hydrochloride intermediate represented by Formula I reacts with the compound represented by Formula III to generate the key impurity represented by Formula IV. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted twice or more with an extraction reagent. The extract phases are combined, concentrated, and then separated and purified by column chromatography to obtain the key impurity represented by Formula IV.

[0034]

[0035] Wherein, X is p-toluenesulfonyloxy, chlorine or 2-nitrobenzenesulfonyloxy.

[0036] Furthermore, the extraction reagent is selected from one of toluene, N,N-dimethylformamide, dimethyl sulfoxide, and 1,4-dioxane.

[0037] Furthermore, the alkaline reagent is selected from one of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.

[0038] Furthermore, the reaction temperature for the reaction of the landiolol hydrochloride intermediate represented by formula I with the compound represented by formula III to generate the key impurity represented by formula IV is 30-80°C.

[0039] The beneficial effects of the present invention are: using a method for preparing a landiolol hydrochloride intermediate and its key impurities provided by the present invention, by first reacting p-hydroxyphenylpropionic acid with an alkaline solution at a relatively low temperature to generate a p-hydroxyphenylpropionic acid salt of formula II, so as to minimize the activation of the phenolic hydroxyl group in the p-hydroxyphenylpropionic acid; then reacting the hydroxyphenylpropionic acid salt with the compound shown in formula III under heating conditions to obtain the landiolol hydrochloride intermediate shown in formula I, thereby reducing the generation of key impurities (disubstituted byproducts) shown in formula IV, and obtaining a high-purity landiolol hydrochloride intermediate, thereby overcoming the defects of incomplete reaction and excessive byproducts in the process. Moreover, in the method provided by the present invention, a crystallization process is used to obtain the p-hydroxyphenylpropionic acid salt shown in formula II, and an extraction, concentration, and crystallization process is used to obtain the landiolol hydrochloride intermediate shown in formula I. These technical means for separating and purifying the hydroxyphenylpropionic acid salt and the landiolol hydrochloride intermediate are all suitable for industrial production, thereby ensuring that the process of the provided method is stable and controllable, and more suitable for industrial production. In addition, the present application also provides a method for preparing the key impurity (disubstituted by-product) represented by Formula IV, which can prepare the key impurity represented by Formula IV with high purity, and can be used as a standard reference substance for the key impurity represented by Formula IV in the production process of the landiolol hydrochloride intermediate represented by Formula I, thereby providing a basis for quality control in the preparation process of the landiolol hydrochloride intermediate. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 This is a schematic diagram of a method for preparing a landiolol hydrochloride intermediate according to an embodiment of the present invention;

[0041] Figure 2 is the HPLC spectrum of the landiolol hydrochloride intermediate represented by Formula I in an embodiment of the present invention;

[0042] Figure 3 HPLC spectrum of the key impurity (disubstituted by-product) represented by Formula IV in the embodiment of the present invention.

[0043] Figure 4 It is the key impurity (disubstituted by-product) shown in formula IV in the embodiment of the present invention. 1 H-NMR spectrum.

[0044] Figure 5 It is the mass spectrum of the key impurity (disubstituted by-product) represented by Formula IV in the embodiment of the present invention. DETAILED DESCRIPTION

[0045] The technical solutions in the embodiments of the present invention will be further clearly and completely described below in conjunction with the drawings and examples. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0046] In Patents No. 5-306281, EP0397031, and Chinese patents CN101012217A and CN106608863A, alkaline reagents were used in the preparation process of the landiolol hydrochloride intermediate S-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propionate (Formula I) to promote the reaction. However, since the phenolic hydroxyl group in the molecular structure of the raw material p-hydroxyphenylpropionic acid also has strong reactivity, under alkaline conditions, the phenolic hydroxyl group will be further combined with the compound shown in Formula III to form a disubstituted byproduct ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propionate (the key impurity shown in Formula IV).

[0047] Therefore, the preparation process of the landiolol hydrochloride intermediate (Formula I) of the above-mentioned patents produces a large amount of disubstituted byproducts (key impurities shown in Formula IV). These disubstituted byproducts seriously affect the yield and product weight of the landiolol hydrochloride intermediate (Formula I). ​​Moreover, they are likely to remain in the landiolol hydrochloride, thereby also affecting the quality of the final product. The generation pathway of the disubstituted byproduct (Formula IV) is:

[0048]

[0049] Wherein, X is p-toluenesulfonyloxy (OTs) or chlorine (Cl).

[0050] Current literature and patents all utilize the reaction of p-hydroxyphenylpropionic acid with the compound represented by Formula III under alkaline conditions to prepare the landiolol hydrochloride intermediate (Formula I). ​​Under alkaline conditions, both the carboxyl and phenolic hydroxyl groups of p-hydroxyphenylpropionic acid readily undergo protonation, forming carboxyl groups and phenoxide anions that react with the compound represented by Formula III, easily generating a disubstituted byproduct (the key impurity represented by Formula IV).

[0051]

[0052] In the technical concept of the present application, in order to avoid the phenolic hydroxyl group of p-hydroxyphenylpropionic acid from reacting with the compound shown in Formula III under alkaline conditions, the inventor first reacts p-hydroxyphenylpropionic acid with an alkaline solution at a lower temperature to generate p-hydroxyphenylpropionic acid salt, so as to minimize the activation of the phenolic hydroxyl group in p-hydroxyphenylpropionic acid; then, the hydroxyphenylpropionic acid salt (Formula II) is reacted with the compound shown in Formula III under heating conditions to obtain the landiolol hydrochloride intermediate (Formula I), thereby reducing the formation of the key impurity (disubstituted by-product) shown in Formula IV. Moreover, the method provided by the present application uses a crystallization process to obtain the generated hydroxyphenylpropionic acid salt (Formula II), and uses an extraction, concentration, and crystallization process to obtain the generated landiolol hydrochloride intermediate (Formula I). ​​These technical means for separating and purifying the hydroxyphenylpropionic acid salt (Formula II) and the landiolol hydrochloride intermediate (Formula I) are all suitable for industrial production. At the same time, the present application also provides a method for preparing the key impurity (disubstituted by-product) represented by Formula IV, which can prepare the key impurity represented by Formula IV with high purity. It can be used as a standard reference substance for the key impurity represented by Formula IV (i.e., disubstituted by-product) in the production process of the landiolol hydrochloride intermediate (Formula I), providing a basis for quality control in the preparation process of the landiolol hydrochloride intermediate (Formula I).

[0053] It should be noted that the raw materials and reagents used in this embodiment are all commercially available products well known to those skilled in the art.

[0054] like Figures 1 to 5 As shown, the present embodiment provides a method for preparing a landiolol hydrochloride intermediate S-(2,2-dimethyl-1,3-dioxolane-4-yl)methyl 3-(4-hydroxyphenyl)propionate compound (Formula I), wherein the method first reacts p-hydroxyphenylpropionic acid with an alkaline solution at a relatively low temperature to form p-hydroxyphenylpropionate, and then reacts the hydroxyphenylpropionate (Formula II) with the compound represented by Formula III under heating conditions to obtain the landiolol hydrochloride intermediate (Formula I). ​​The reaction route of the method is:

[0055]

[0056] Wherein, M is sodium (Na) or potassium (K); X is p-toluenesulfonyloxy (OTs), chlorine (Cl) or 2-nitrobenzenesulfonyloxy (ONs).

[0057] The method comprises the following steps:

[0058] S1. Salt formation: p-hydroxyphenylpropionic acid reacts with an alkaline solution to form p-hydroxyphenylpropionic acid salt. After the salt formation reaction is completed, a crystallization solvent is added, and the temperature is lowered for crystallization to prepare p-hydroxyphenylpropionic acid salt (Formula II);

[0059] Optionally, in step S1, p-hydroxyphenylpropionic acid and an alkaline solution are reacted in a first solvent to generate p-hydroxyphenylpropionic acid salt; the first solvent is selected from one of ethanol, methanol, and isopropanol, or a mixture of one of ethanol, methanol, and isopropanol and a small amount of water.

[0060] In a specific embodiment, the first solvent is preferably ethanol.

[0061] Optionally, in step S1, the alkaline solution is obtained by dissolving a solid alkaline reagent in a first solvent; the solid alkaline reagent is selected from one of potassium hydroxide, sodium hydroxide, sodium carbonate, and potassium carbonate.

[0062] In another specific embodiment, the solid alkaline reagent is preferably potassium hydroxide.

[0063] Specifically, in step S1, a first solvent and p-hydroxyphenylpropionic acid are added to a reaction vessel, stirred and dissolved, and then an alkaline solution is slowly added dropwise under continued stirring. Since the acid-base reaction is very fast and the reaction is exothermic, the temperature of the reaction system in the reaction vessel needs to be controlled during the addition of the alkaline solution. When the alkaline solution is added, the salt formation reaction can be considered to be completed.

[0064] Optionally, in step S1, the reaction molar ratio of p-hydroxyphenylpropionic acid to the solid base reagent is 1.0:0.9-1.5.

[0065] In another specific embodiment, the reaction molar ratio of p-hydroxyphenylpropionic acid to the solid base reagent is preferably 1.0:1.1.

[0066] Optionally, in step S1, the reaction temperature for the reaction of p-hydroxyphenylpropionic acid with the alkaline solution to generate p-hydroxyphenylpropionic acid salt is 0-30° C. In a specific embodiment, the reaction temperature for the reaction of p-hydroxyphenylpropionic acid with the alkaline solution to generate p-hydroxyphenylpropionic acid salt is preferably 20-30° C.

[0067] Optionally, in step S1, the crystallization solvent is selected from one of n-heptane, n-hexane, and methyl tert-butyl ether. In a specific embodiment, the crystallization solvent is preferably n-heptane.

[0068] Specifically, in step S1, the specific conditions for cooling and crystallizing are cooling to below 20°C and stirring for crystallization.

[0069] S2. The hydroxyphenylpropionic acid salt (Formula II) reacts with the compound represented by Formula III to generate the landiolol hydrochloride intermediate represented by Formula I. After the reaction is completed, water is added to quench the mixture; extraction is performed with an organic solvent for more than three times, and the organic phases are combined; the organic phases are concentrated, and a crystallization solvent is added for crystallization to obtain the landiolol hydrochloride intermediate (Formula I).

[0070] Optionally, in step S2, hydroxyphenylpropionic acid salt (Formula II) reacts with the compound represented by Formula III in a second solvent to generate the landiolol hydrochloride intermediate represented by Formula I; the second solvent is selected from one of toluene, N,N-dimethylformamide, dimethyl sulfoxide, and 1,4-dioxane.

[0071] In a specific embodiment, the second solvent is preferably dimethyl sulfoxide.

[0072] Optionally, in step S2, the reaction molar ratio of hydroxyphenylpropionic acid salt (Formula II) to the compound represented by Formula III is 1.0:0.7-1.4.

[0073] In another specific embodiment, the reaction molar ratio of hydroxyphenylpropionic acid salt (Formula II) to the compound represented by Formula III is preferably 1.0:0.9.

[0074] Specifically, in step S2, TLC monitoring (developing solvent: V 正庚烷 :V 乙酸乙酯 =2:1, UV 254nm) compound of formula III to monitor whether the reaction of hydroxyphenylpropionic acid salt (Formula II) and compound of formula III in step S2 is complete. When monitoring the reaction of compound of formula III is complete, the reaction is completed.

[0075] Optionally, in step S2, the reaction temperature for the reaction of hydroxyphenylpropionic acid salt (Formula II) with the compound represented by Formula III to generate the landiolol hydrochloride intermediate represented by Formula I is 0 to 150°C.

[0076] In a specific embodiment, the reaction temperature for the reaction of hydroxyphenylpropionic acid salt (Formula II) with the compound represented by Formula III to produce the landiolol hydrochloride intermediate represented by Formula I is preferably 100-105°C.

[0077] Optionally, after the step of combining the organic phases and before concentrating the organic phases, the combined organic phases are washed sequentially with dilute hydrochloric acid and saturated sodium chloride solution to remove water-soluble impurities in the organic phases.

[0078] Optionally, the specific method for concentrating the organic phase is to concentrate under reduced pressure at 30-40°C.

[0079] Optionally, in step S2, the crystallization solvent is selected from one of n-heptane, n-hexane, and methyl tert-butyl ether. In a specific embodiment, the crystallization solvent is preferably n-heptane.

[0080] In this embodiment, a method for preparing the key impurity represented by Formula IV in the production process of the landiolol hydrochloride intermediate represented by Formula I is also provided, that is, after step S2, further comprising the following steps:

[0081] Under the action of an alkaline reagent, the landiolol hydrochloride intermediate represented by Formula I reacts with the compound represented by Formula III to generate the key impurity represented by Formula IV. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted twice or more with an extraction reagent. The extract phases are combined, concentrated, and then separated and purified by column chromatography to obtain the key impurity represented by Formula IV, which is used as a standard reference substance for the key impurity represented by Formula IV in the production process of the landiolol hydrochloride intermediate represented by Formula I.

[0082] The key impurity represented by Formula IV obtained in this embodiment can be used as a standard reference substance for the key impurity (the disubstituted by-product represented by Formula IV) in the production process of the landiolol hydrochloride intermediate (Formula I), providing a basis for quality control in the preparation process of the landiolol hydrochloride intermediate (Formula I).

[0083] The preparation reaction route of the key impurity shown in Formula IV is:

[0084]

[0085] Wherein, X is p-toluenesulfonyloxy (OTs), chlorine (Cl) or 2-nitrobenzenesulfonyloxy (ONs).

[0086] Optionally, the extraction reagent is selected from one of toluene, N,N-dimethylformamide, dimethyl sulfoxide, and 1,4-dioxane.

[0087] In a specific embodiment, the extraction reagent is preferably N,N-dimethylformamide.

[0088] Optionally, the alkaline reagent is selected from one of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.

[0089] In another specific embodiment, the alkaline reagent is preferably cesium carbonate.

[0090] Optionally, the reaction temperature for the reaction of the landiolol hydrochloride intermediate represented by Formula I with the compound represented by Formula III to generate the key impurity represented by Formula IV is 30-80°C.

[0091] In a specific embodiment, the reaction temperature for the reaction of the landiolol hydrochloride intermediate represented by formula I with the compound represented by formula III to generate the key impurity represented by formula IV is preferably 50-60°C.

[0092] Specifically, TLC monitoring (developing solvent V 二氯甲烷 :V 乙酸乙酯 =9:1, UV254nm, R f When the intermediate of landiolol hydrochloride shown in Formula I is completely reacted, the reaction is completed.

[0093] Optionally, after the step of combining the extraction phases and before concentrating the extraction phases, the combined extraction phases are washed sequentially with purified water and a saturated sodium chloride solution to remove water-soluble impurities in the extraction phases.

[0094] Optionally, the specific method for concentrating the extract phase is concentration under reduced pressure.

[0095] Optionally, during the column chromatography separation and purification process, the eluent is a mixture of ethyl acetate and n-hexane, wherein the volume ratio of ethyl acetate to n-hexane is 1:10 to 2:3.

[0096] The specific embodiments of the present invention are further described below through examples.

[0097] Example 1 Preparation of Potassium p-Hydroxyphenylpropionate

[0098] Add 60 ml of anhydrous ethanol and 20.0 g of p-hydroxyphenylpropionic acid to the reaction flask, stir to dissolve, and then cool to below 20°C; slowly add dropwise an ethanol solution containing 7.4 g of potassium hydroxide at a temperature below 30°C; after the addition, add 120 ml of n-heptane to the system; after the addition, cool to below 20°C, stir to crystallize; filter, and dry to obtain 22.2 g of white potassium p-hydroxyphenylpropionic acid solid, with a yield of 90%.

[0099] Example 2 Preparation of Potassium p-Hydroxyphenylpropionate

[0100] Add 50 ml of anhydrous methanol and 20.0 g of p-hydroxyphenylpropionic acid to the reaction flask, stir to dissolve, and then cool to below 20°C; slowly add dropwise a methanol solution containing 8.0 g of potassium hydroxide at a temperature below 30°C; after the addition, add 5.8 L of n-heptane to the system; after the addition, cool to below 20°C, stir to crystallize; filter, and dry to obtain 21.8 g of white potassium p-hydroxyphenylpropionic acid solid, with a yield of 89%.

[0101] Example 3 Preparation of Potassium p-Hydroxyphenylpropionate

[0102] Add 60 ml of isopropanol and 20.0 g of p-hydroxyphenylpropionic acid to the reaction flask, stir to dissolve, and then cool to below 20°C; slowly add dropwise an ethanol solution containing 7.4 g of potassium hydroxide at a temperature below 30°C; after the addition, add 120 ml of n-heptane to the system; after the addition, cool to below 20°C, stir to crystallize; filter, and dry to obtain 20.5 g of white potassium p-hydroxyphenylpropionic acid solid, with a yield of 84%.

[0103] Example 4 Preparation of Sodium p-Hydroxyphenylpropionate

[0104] Add 60 ml of anhydrous ethanol and 20.0 g of p-hydroxyphenylpropionic acid to the reaction flask, stir to dissolve, and then cool to below 20°C; slowly add dropwise an ethanol solution containing 5.3 g of sodium hydroxide at a temperature below 30°C; after the addition, add 120 ml of n-heptane to the system; after the addition, cool to below 20°C, stir to crystallize; filter, and dry to obtain 20.1 g of white sodium p-hydroxyphenylpropionic acid solid, with a yield of 89%.

[0105] Example 5 Preparation of S-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propionate

[0106] 80 ml of dimethyl sulfoxide, 25.4 g of methyl p-toluenesulfonate (2,2-dimethyl-1,3-dioxolane-4S) and 20.0 g of potassium p-hydroxyphenylpropionate were added to the reaction flask in sequence, stirred, and reacted at a temperature of 100-105 ° C. The reaction was monitored by TLC (developing solvent: V 正庚烷 :V 乙酸乙酯 =2:1, UV 254nm) until the reaction of (2,2-dimethyl-1,3-dioxolane-4S) methyl p-toluenesulfonate is complete; after completion of the reaction, the temperature is lowered to below 30°C and quenched with 100 ml of pure water; extraction is then performed three times with 40 ml of ethyl acetate each time; the organic phases are combined and washed sequentially with 40 ml of dilute hydrochloric acid (with a mass fraction of hydrochloric acid less than 20%) and a saturated sodium chloride solution; the organic phases are concentrated under reduced pressure at 30-40°C, 100 ml of n-heptane is added to the concentrate, and the mixture is stirred at below 30°C for crystallization; filtration and drying are performed to obtain 21.2 g of the intermediate landiolol hydrochloride represented by Formula I, in a yield of 80%.

[0107] The HPLC spectrum of the landiolol hydrochloride intermediate shown in Formula I is as follows Figure 2 As shown, after analysis, Figure 2 The chromatographic peak with a retention time of 19.613 min corresponds to the landiolol hydrochloride intermediate S-(2,2-dimethyl-1,3-dioxolane-4-yl)methyl 3-(4-hydroxyphenyl)propionate shown in Formula I. Figure 2 The chromatographic peak with a retention time of 29.637 min corresponds to the key impurity ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propionate shown in Formula IV.

[0108] Example 6 Preparation of S-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propionate

[0109] 80 ml of dimethyl sulfoxide, 27.4 g of methyl p-toluenesulfonate (2,2-dimethyl-1,3-dioxolane-4S) and 20.0 g of sodium p-hydroxyphenylpropionate were added to the reaction flask in sequence, stirred, and reacted at a temperature of 120-130° C. The reaction was monitored by TLC (developing solvent: V n-heptane: V ethyl acetate = 2:1, UV 254 nm) until the reaction of methyl p-toluenesulfonate (2,2-dimethyl-1,3-dioxolane-4S) was complete. After the reaction was completed, the temperature was lowered to below 30° C., quenched by the addition of 100 ml of pure water, and extracted three times with 40 ml of ethyl acetate each time. The organic phases were combined and washed with 40 ml of dilute hydrochloric acid and saturated sodium chloride solution in sequence. The organic phases were concentrated under reduced pressure at 30-40° C., 100 ml of methyl tert-butyl ether was added to the concentrate, stirred, and crystallized below 30° C. Filtration afforded 20.4 g of the intermediate landiolol hydrochloride of formula I in a yield of 79%.

[0110] Preparation of disubstituted by-product (key impurity shown in formula IV) in the process of Example 7

[0111] Weigh 5.00g of S-(2,2-dimethyl-1,3-dioxolane-4-yl)methyl 3-(4-hydroxyphenyl) propionate (Formula I) (1.0eq), add 25ml of N,N-dimethylformamide into a 100ml reaction bottle, add 5.81g of cesium carbonate (1.0eq), control the temperature at 20-30℃, stir for 1 hour; add 6.13g of (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol p-toluenesulfonate (Formula III) (1.2eq), raise the temperature to 50-60℃, react for 2 hours, and monitor by TLC (developer V 二氯甲烷 :V 乙酸乙酯 =9:1, UV254nm, R f value = 0.2) to complete the reaction of S-(2,2-dimethyl-1,3-dioxolane-4-yl)methyl 3-(4-hydroxyphenyl)propionate; after completion of the reaction, 100 ml of water was added, and the mixture was extracted twice with 60 ml of ethyl acetate each time. The ethyl acetate phases were combined and washed sequentially with 60 ml of purified water and 60 ml of saturated sodium chloride solution. The ethyl acetate phase was concentrated under reduced pressure at 45°C to obtain a brown oil, which was separated and purified by column chromatography (eluent: ethyl acetate: n-hexane (1:10→2:3)) to obtain 3.81 g of the disubstituted compound of formula IV in a yield of 54% and a purity of 96.246%.

[0112] The HPLC spectrum of the key impurity (disubstituted by-product) represented by Formula IV ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propionate is as follows: Figure 3 As shown. After analysis, we know that Figure 3The chromatographic peak with a retention time of 29.638 min corresponds to the key impurity ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propionate shown in Formula IV.

[0113] The key impurity shown in formula IV 1 H-NMR spectrum Figure 4 As shown, 1 H NMR (600MHz, CDCl3) δ (ppm) 7.133 ~ 7.118 (m, 2H), 6.862 ~ 6.848 (m, 2H), 4.484 ( m,1H), 4.33~4.28(m,1H), 4.193~4.157(m,3H), 4.115~4.105(m,1H), 4.070~4 0.043 (m, 3H), 3.941-3.898 (m, 3H), 3.720-3.695 (m, 1H), 2.930-2.904 (m, 2H), 2.672-2.646 (m, 2H), 1.480 (s, 4H), 1.443 (s, 4H), 1.421 (s, 4H), 1.384 (s, 4H). The mass spectrum of the key impurity (disubstituted by-product) shown in IV is as follows Figure 5 As shown, among them, MS (ESI + ):m / z=417.48[M+Na] + .Depend on Figure 4 and Figure 5 It can be determined that the structural formula of the compound obtained in Example 7 is consistent with Formula IV.

[0114] Comparative Example 1 Preparation of Landiolol Hydrochloride Intermediate (Formula I) with Reference to Patent Laid-Open No. 5-306281

[0115] Add 2.2g of potassium hydroxide and 30ml of dimethyl sulfoxide to a reaction flask. Add 5.5g of p-hydroxyphenylpropionic acid with stirring. Add a dimethyl sulfoxide solution containing 9.14g of (2,2-dimethyl-1,3-dioxolane-4S)methyl p-toluenesulfonate while controlling the temperature below 40°C. Heat to 110°C and stir for 2 hours. Pour the reaction mixture into 50ml of water and extract with ethyl acetate (50ml x 2). The extract is washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is dissolved in diisopropyl ether, and 20ml of n-hexane is added to precipitate crystals. Filter and dry to obtain 3.5g of landiolol hydrochloride intermediate (Formula I).

[0116] Comparative Example 2 Preparation of Landiolol Hydrochloride Intermediate (Formula I) with Reference to Patent CN106608863A

[0117] To a reaction flask, add 3.3g of potassium carbonate, 1.93g of tetrabutylammonium bromide, and 40ml of dimethyl sulfoxide. Add 10.0g of p-hydroxyphenylpropionic acid with stirring, and heat to 115°C with stirring for 30 minutes. Add 18.07g of (2,2-dimethyl-1,3-dioxolan-4-yl)chloromethane (Formula III) dropwise, and maintain stirring at 115°C for 7 hours. Pour the reaction mixture into 150ml of water and extract with ethyl acetate (150ml x 2). The extract is washed sequentially with saturated sodium bicarbonate, water, and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Recrystallize the mixture with 56ml of a 6:1 mixture of petroleum ether and ethyl acetate to obtain 6.2g of the landiolol hydrochloride intermediate (Formula I).

[0118] Comparative Example 3 Preparation of Landiolol Hydrochloride Intermediate (Formula I) with Reference to Patent EP0397031B1

[0119] To a reaction flask, add 3.8g of potassium hydroxide and 25ml of dimethyl sulfoxide. Add 7.0g of p-hydroxyphenylpropionic acid with stirring. Heat to 100°C and stir for 30 minutes under a nitrogen atmosphere. Add (2,2-dimethyl-1,3-dioxolan-4-yl)chloromethane (Formula III) and stir at 100°C for 15 hours. Pour the reaction mixture into 150ml of water and extract with ethyl acetate (150ml x 2). The extract is washed sequentially with saturated sodium bicarbonate, water, and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (n-hexane:ethyl acetate = 2:1) to obtain 4.00g of landiolol hydrochloride intermediate (Formula I).

[0120] Comparative Example 4: Detection results of key impurities shown in Formula IV of the landiolol hydrochloride intermediate (Formula I)

[0121] The key impurities shown in Formula IV in the landiolol hydrochloride intermediate (Formula I) obtained by the reaction of the embodiment and the comparative example were detected, and the results are shown in Table 1:

[0122] category Key impurity content in the reaction solution Content of key impurities in landiolol hydrochloride intermediates Example 5 2.57％ 0.21％ Example 6 2.02％ 0.19％ Comparative Example 1 10.34％ 5.21％ Comparative Example 2 20.07％ 15.23％ Comparative Example 3 15.23％ 0.02% (column chromatography purification)

[0123] The above test results indicate that, according to existing methods for preparing the landiolol hydrochloride intermediate (Formula I), a large amount of the key impurity represented by Formula IV is generated during the reaction. Except for column chromatography, it is difficult to reduce the content of the key impurity represented by Formula IV to below 0.5% in post-treatment. The embodiments of the present invention, by forming a carboxylic acid into a salt before reacting it with the compound represented by Formula III, significantly suppress the formation of the key impurity represented by Formula IV. Furthermore, during post-treatment, the content of the key impurity represented by Formula IV in the landiolol hydrochloride intermediate product represented by Formula I is controlled to below 0.5%, meeting the requirements of industrial production.

[0124] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these changes and variations. The above embodiments or implementation methods are merely illustrative of the present invention, and the present invention may also be implemented in other specific ways or other specific forms without departing from the gist or essential features of the present invention. Therefore, the described implementation methods should be regarded as illustrative and not restrictive in any respect. The scope of the present invention should be described by the appended claims, and any changes that are equivalent to the intent and scope of the claims should also be included within the scope of the present invention.

Claims

1. A method for preparing a landiolol hydrochloride intermediate, characterized in that: The method comprises the following steps: S1, p-hydroxyphenylpropionic acid reacts with an alkaline solution to produce a p-hydroxyphenylpropionic acid salt represented by formula II. After the salt-forming reaction is completed, a crystallization solvent is added, and the temperature is lowered for crystallization to prepare a p-hydroxyphenylpropionic acid salt; S2, reacting the hydroxyphenylpropionic acid salt with the compound represented by formula III to generate the landiolol hydrochloride intermediate represented by formula I, quenching with water after the reaction; extracting with an organic solvent for more than three times, combining the organic phases; concentrating the organic phases, and adding a crystallizing solvent for crystallization to obtain the landiolol hydrochloride intermediate; The reaction scheme of the method is: Wherein, M is sodium or potassium; X is p-toluenesulfonyloxy, chlorine or 2-nitrobenzenesulfonyloxy.

2. The method for preparing a landiolol hydrochloride intermediate according to claim 1, wherein In step S1, p-hydroxyphenylpropionic acid reacts with an alkali solution in a first solvent to generate a p-hydroxyphenylpropionic acid salt; The first solvent is selected from one of ethanol, methanol, and isopropanol, or a mixture of one of ethanol, methanol, and isopropanol and a small amount of water.

3. The method for preparing a landiolol hydrochloride intermediate according to claim 2, wherein: In step S1, the alkaline solution is obtained by dissolving a solid alkaline reagent in a first solvent; The solid alkali reagent is selected from one of potassium hydroxide, sodium hydroxide, sodium carbonate and potassium carbonate.

4. The method for preparing a landiolol hydrochloride intermediate according to claim 3, wherein: In step S1, the reaction molar ratio of p-hydroxyphenylpropionic acid to the solid base reagent is 1.0:0.9-1.

5.

5. The method for preparing a landiolol hydrochloride intermediate according to claim 1, wherein In step S1, the reaction temperature for generating p-hydroxyphenylpropionic acid salt by reacting p-hydroxyphenylpropionic acid with an alkaline solution is 0-30°C.

6. The method for preparing a landiolol hydrochloride intermediate according to claim 1, wherein: The crystallization solvent is selected from one of n-heptane, n-hexane and methyl tert-butyl ether.

7. The method for preparing a landiolol hydrochloride intermediate according to claim 1, wherein: In step S1, the specific conditions for the cooling and crystallization are cooling to below 20°C and stirring for crystallization.

8. The method for preparing a landiolol hydrochloride intermediate according to claim 1, wherein: In step S2, the hydroxyphenylpropionic acid salt reacts with the compound represented by formula III in a second solvent to generate the landiolol hydrochloride intermediate represented by formula I; The second solvent is selected from one of toluene, N,N-dimethylformamide, dimethyl sulfoxide, and 1,4-dioxane.

9. The method for preparing a landiolol hydrochloride intermediate according to claim 1, wherein: In step S2, the reaction molar ratio of the hydroxyphenylpropionic acid salt to the compound represented by formula III is 1.0:0.7-1.

4.

10. The method for preparing a landiolol hydrochloride intermediate according to claim 1, characterized in that: In step S2, the reaction temperature for the reaction of hydroxyphenylpropionate with the compound represented by formula III to generate the landiolol hydrochloride intermediate represented by formula I is 100-105°C.

11. The method for preparing a landiolol hydrochloride intermediate according to claim 1, wherein: In step S2, after the step of combining the organic phases and before the step of concentrating the organic phases, the combined organic phases are washed sequentially with dilute hydrochloric acid and saturated sodium chloride solution.

12. The method for preparing a landiolol hydrochloride intermediate according to claim 1, wherein: In step S2, the organic phase is concentrated under reduced pressure at 30-40°C.

13. A method for preparing key impurities of a landiolol hydrochloride intermediate, characterized in that: The method comprises the following steps: Under the action of an alkaline reagent, the landiolol hydrochloride intermediate represented by Formula I reacts with the compound represented by Formula III to generate the key impurity represented by Formula IV. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted twice or more with an extraction reagent. The extract phases are combined, concentrated, and then separated and purified by column chromatography to obtain the key impurity represented by Formula IV. Wherein, X is p-toluenesulfonyloxy, chlorine or 2-nitrobenzenesulfonyloxy.

14. The method for preparing a key impurity of a landiolol hydrochloride intermediate according to claim 13, characterized in that: The extraction reagent is selected from one of toluene, N,N-dimethylformamide, dimethyl sulfoxide, and 1,4-dioxane.

15. The method for preparing a key impurity of a landiolol hydrochloride intermediate according to claim 13, characterized in that: The alkaline reagent is selected from one of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate.

16. The method for preparing a key impurity of a landiolol hydrochloride intermediate according to claim 13, characterized in that: The reaction temperature for the reaction of the landiolol hydrochloride intermediate represented by formula I with the compound represented by formula III to generate the key impurity represented by formula IV is 30-80°C.

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