Preparation method of beta receptor blocker crude product

Abstract

The invention discloses a preparation method of a beta receptor blocker crude product, which comprises the following steps: (1) adding [(S)-2, 2-dimethyl-1, 3-dioxolane-4-yl] methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholine formylamino) ethylamino] propoxy] phenylpropionate into a solvent, and reacting with oxalic acid to generate [(S)-2, 2-dimethyl-1, 3-dioxolane-4-yl] methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholine formylamino) ethylamino] propoxy] phenylpropionate; the preparation method comprises the following steps: preparing 1, 3-dioxolane-4-yl] methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholine formylamino) ethylamino] propoxy] phenylpropionate oxalate; (2) dissolving the [(S)-2, 2-dimethyl-1, 3-dioxolane-4-yl] methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholine formylamino) ethylamino] propoxy] phenylpropionate oxalate obtained in the step (1), and then forming a beta receptor blocker with a hydrogen chloride and ethyl acetate solution by using the dissolved [(S)-2, 2-dimethyl-1, 3-dioxolane-4-yl] methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholine formylamino) ethylamino] propoxy] phenylpropionate oxalate and the hydrogen chloride and ethyl acetate solution; wherein the oxalic acid is oxalic acid dihydrate. The beta receptor blocker crude product obtained in the invention has relatively high purity and yield.

Description

Technical Field

[0001] This application belongs to the field of drug synthesis technology, specifically relating to a method for preparing a crude β-receptor blocker. Background Technology

[0002] Landilol hydrochloride was approved for marketing by Ono Pharmaceutical Co., Ltd. on September 1, 2002. Its Chinese chemical name is [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarboxymethylamino)ethylamino]propoxy]phenylpropionate monohydrochloride, CAS number: 144481-98-1, and its chemical structure is as follows.

[0003]

[0004] Landilol hydrochloride is a selective β1 receptor blocker that primarily antagonizes β receptors present in the heart. It improves tachycardia-related arrhythmias by inhibiting the increase in heart rate induced by catecholamines. The antiarrhythmic mechanism of action is mainly due to landilol hydrochloride acting on cardiac receptors and inhibiting the increase in heart rate caused by norepinephrine and epinephrine released from sympathetic nerve endings and the adrenal medulla.

[0005] Landilol hydrochloride contains two chiral centers and has four stereoisomers. Clinically used landilol hydrochloride specifically refers to the S,S-isomer. However, the presence of the other three stereoisomers may affect the quality and efficacy of the drug and may also have potential side effects.

[0006] There are multiple routes for synthesizing brandylol hydrochloride in the existing technology. These routes all start from different starting materials, and through a series of chemical transformations, brandylol is finally prepared. Then, brandylol is further converted into the form of hydrochloride to obtain the final brandylol hydrochloride product.

[0007] Patent CN108752308B describes a method for preparing landilol hydrochloride, which involves crystallizing landilol into hydrochloride using ammonium chloride and acetonitrile solution. Acetonitrile is a toxic, relatively expensive, and environmentally unfriendly solvent, which increases production costs and imposes an additional burden on solvent treatment and recycling.

[0008] Patent CN117865927A discloses a method for preparing landilol hydrochloride and its intermediates, which involves reacting compound 2 (4-[(2S)-3-cyclopropoxy]phenylpropionic acid [(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl ester) and SM4 ((N-(2-aminoethyl)-4-morpholinocarboxamide) in tetrahydrofuran and dioxane, followed by salt formation via saturated ammonium chloride, and recrystallization with acetone to obtain landilol hydrochloride.

[0009] Patent CN104003973B describes a method for preparing landilol oxalate, which involves reacting compound III (N-(2-aminoethyl)-4-morpholinocarboxamide oxalate) and compound II ((2,2-dimethyl-1,3-dioxocycloalkyl-4S-yl)methyl-3-[4-(2(S),3-epoxypropyl)phenyl]propionate) in the presence of an alkali metal, followed by salt formation with anhydrous oxalic acid to obtain landilol oxalate.

[0010] Patent CN101768148B discloses a novel method for preparing brandilol hydrochloride, which involves reacting brandilol with anhydrous oxalic acid in anhydrous methanol to obtain brandilol oxalate, and further reacting brandilol oxalate with sodium bicarbonate and ammonium chloride to obtain brandilol hydrochloride.

[0011] The aforementioned patented technologies primarily improve the quality of landilolol hydrochloride by employing different synthetic processes. However, in existing patented synthetic processes, once landilolol is synthesized, a salting agent is immediately added to convert it to its hydrochloride form. This method results in the ineffective control of isomer content and potential genotoxic impurities in the final product. Summary of the Invention

[0012] To address the shortcomings of existing technologies, this invention provides a method for preparing a crude β-receptor blocker, comprising the following steps:

[0013] (1) The [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate ester, as shown in compound 6, is added to a solvent and reacts with oxalic acid to generate [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate ester oxalate, as shown in compound 7.

[0014] (2) The oxalate of [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate obtained in step (1) is desalted and then reacted with ethyl hydrogen chloride solution to form a crude β-receptor blocker as shown in compound 8.

[0015] The oxalic acid in question is oxalic acid dihydrate.

[0016]

[0017] Further, the molar ratio of the [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate to the oxalic acid dihydrate is 1:(0.7-1.0).

[0018] Furthermore, the solvent is anhydrous ethanol.

[0019] Furthermore, the salt-dissolving agent for [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate oxalate is sodium hydroxide.

[0020] Furthermore, it includes the following steps:

[0021] (1) Add [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate to anhydrous ethanol, add oxalic acid dihydrate under stirring, and after stirring, filtration and drying, obtain [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate oxalate;

[0022] (2) After controlling the system temperature, the [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarboxamido)ethylamino]propoxy]phenylpropionate oxalate obtained in step (1) was dissolved in purified water, sodium bicarbonate was added, and the mixture was stirred. The mixture was extracted multiple times with ethyl acetate, the organic phases were combined, and the mixture was washed with saturated brine. Anhydrous sodium sulfate and activated carbon were added, the mixture was filtered, and the mixture was concentrated under reduced pressure to obtain a pale yellow oil. The pale yellow oil was dissolved in ethyl acetate, impurities were filtered out, and the mixture was cooled to below -5°C. Ethyl hydrochloride solution was slowly added dropwise, the temperature was controlled to be below -5°C, and the pH was adjusted to 4.0-5.0. The mixture was stirred and then filtered under reduced pressure. The filter cake was washed with ethyl acetate and dried to obtain the crude β-receptor blocker.

[0023] Further, the [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate oxalate was dissolved in purified water and the system temperature was controlled at 0-10℃.

[0024] Furthermore, the pH is 4.3 to 4.8.

[0025] Furthermore, the impurities are filtered using a 0.2 μm filter membrane.

[0026] Further, the [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarboxamide)ethylamino]propoxy]phenylpropionate described in step (1) is obtained by reacting N-(2-aminoethyl)-4-morpholinocarboxamide as shown in compound 2 and 4S-(2,2-dimethyl-1,3-dioxolane-4-yl)-(4-(2S,3-epoxypropane)phenyl)propyl ester as shown in compound 5 in a 1,4-dioxane ring.

[0027]

[0028] On the other hand, the present invention provides a crude β-receptor blocker prepared according to the above method, wherein the β-receptor blocker is preferably landilol hydrochloride.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] After repeated experiments, the inventors of this application discovered that, in the preparation of crude β-blocker (hereinafter referred to as crude brandyl hydrochloride), by precisely controlling the reaction conditions of key preparation processes, the yield and purity of crude brandyl hydrochloride can be effectively guaranteed, especially the content of isomers and genotoxic impurities in the product can be well controlled. This operation process is simple and easy to control, making it very suitable for large-scale industrial production applications. Detailed Implementation

[0031] The technical solutions in the embodiments of this application will be clearly described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0032] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0033] The method for preparing crude landiolol hydrochloride of the present invention includes the following steps:

[0034] (1) [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate (hereinafter referred to as "YLD-3") reacts with oxalic acid in anhydrous ethanol solvent to generate [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate oxalate (hereinafter referred to as "YLD-CS");

[0035] (2) YLD-CS is desalted with sodium hydroxide and then reacted with ethyl hydrogen chloride solution to form crude [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarboxylamino)ethylamino]propoxy]phenylpropionate monohydrochloride (hereinafter referred to as "YLD-CP");

[0036] The oxalic acid in question is oxalic acid dihydrate.

[0037] The molar ratio of YLD-3 to oxalic acid dihydrate is 1:(0.7 to 1.0), for example, 1:0.7, 1:0.75, 1:0.8, 1:0.9, or 1:1.0. However, it is not limited to the listed values; other unlisted values ​​within this range also apply.

[0038] In the salt formation process of brandylolol hydrochloride, oxalic acid (H₂C₂O₄), as an organic acid, can combine with basic functional groups (such as amino groups) in brandylolol to form a salt. In this process, oxalic acid acts as the acidic component, which helps improve the stability and crystallinity of the product. However, the inventors found that the final product obtained by using oxalic acid alone was slightly suboptimal in quality.

[0039] In contrast, the use of oxalic acid dihydrate (H2C2O4·2H2O) in the preparation process not only provides the necessary acidic environment, but its water of crystallization can also regulate the physicochemical properties of the reaction medium, such as solubility and reactivity, thereby significantly improving the quality of the final brandilol hydrochloride.

[0040] Furthermore, the dosage of oxalic acid dihydrate is crucial for controlling the impurity content in the final product. An appropriate amount of oxalic acid dihydrate ensures the complete reaction, avoids side reactions caused by excess or deficiency, and thus reduces impurity formation. By precisely controlling the dosage of oxalic acid dihydrate, the purity and yield of the product can be effectively improved, ensuring the high quality of the final product.

[0041] In one embodiment of the present invention, the preparation process includes:

[0042] (1) YLD-3 was added to anhydrous ethanol, and oxalic acid dihydrate was added under stirring. After stirring, filtration and drying, YLD-CS was obtained.

[0043] (2) After controlling the system temperature, dissolve the YLD-CS obtained in step (1) in purified water, add sodium bicarbonate, and stir; extract multiple times with ethyl acetate, combine the organic phases, and wash with saturated brine; add anhydrous sodium sulfate and activated carbon, filter, concentrate under reduced pressure to obtain a pale yellow oily substance; dissolve the pale yellow oily substance with ethyl acetate, filter out impurities, and then cool to below -5℃; slowly add ethyl chloride solution, control the temperature below -5℃, and adjust the pH to 4.0-5.0; continue stirring, then filter under reduced pressure, wash the filter cake with ethyl acetate, and dry to obtain YLD-CP.

[0044] In one embodiment of the present invention, the temperature of the system after YLD-CS is dissolved in purified water is controlled at 0-10°C. In specific embodiments of the present invention, for example, it is 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C. However, it is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0045] In the preparation of landiol oxalate, controlling the temperature of the oxalate system dissolved in water within the range of 0–10°C is crucial. Although the specific mechanism is not fully understood, the inventors discovered that if this temperature is too high, the impurity content of the final product increases significantly, affecting the yield. Therefore, strictly controlling this temperature range is essential to ensuring product quality. By maintaining low-temperature conditions, the problem of increased impurities due to excessively high temperatures can be effectively avoided, thereby ensuring the purity and consistency of the final product.

[0046] In one embodiment of the invention, the pH is adjusted to 4.0–5.0. In a specific embodiment of the invention, the pH is 4.3–4.8, for example, 4.3, 4.4, 4.5, 4.6, 4.7, or 4.8. However, it is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0047] pH value has a significant impact on the formation of hydrochloride. If the pH value is too high, brandylol will have difficulty forming hydrochloride; while if the pH value is too low, the impurity content in the obtained brandylol hydrochloride will increase significantly, and the stability of the product will also be affected. Therefore, precise control of pH value is a key step in ensuring the quality of brandylol hydrochloride products. By optimizing pH conditions, these problems can be effectively avoided, thereby ensuring the purity and stability of the final product.

[0048] In one embodiment of the invention, a 0.2 μm filter membrane is used to filter impurities.

[0049] In one embodiment of the present invention, YLD-3 in step (1) is obtained by reacting N-(2-aminoethyl)-4-morpholinocarboxamide (hereinafter referred to as YLD-1) and 4S-(2,2-dimethyl-1,3-dioxocyclopentan-4-yl)-(4-(2S,3-epoxypropane)phenyl)propyl ester (hereinafter referred to as YLD-2) in 1,4-dioxane.

[0050] YLD-3 can also be obtained through other common methods.

[0051] The YLD-CP obtained by this invention can be purified in a conventional manner (such as with acetone) to obtain brandilol hydrochloride with better purity.

[0052] Nitro-substituted aromatic compounds are typical genotoxic carcinogens, and their warning structures require close attention and analysis during drug preparation. The technical solution of this invention can effectively control the content of such nitrobenzene warning structure impurities, thereby better ensuring the drug safety of landilolol hydrochloride.

[0053] Through the above technical solutions, we have not only improved the overall quality and safety of our products, but also ensured the reliability of the drugs in clinical applications. This achievement is of great significance for enhancing the market competitiveness of our drugs and the safety of patient medication.

[0054] The specific embodiments of the present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the embodiments described herein.

[0055] In an example of this invention, the method for detecting related substances and isomers of crude brandyl hydrochloride is: HPLC method.

[0056] ① Related substances testing

[0057] Column: Octadecylsilane-bonded silica gel as packing material

[0058] Detection wavelength: 223nm

[0059] Flow rate: 1.0 ml / min

[0060] Mobile phase A: 0.02 mol / L sodium dihydrogen phosphate solution, adjusted to pH 4.5.

[0061] Mobile phase B: Acetonitrile

[0062] Elution gradients are defined according to Table 1:

[0063] Table 1

[0064] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 93 7 5 93 7 25 68 32 43 45 55 45 93 7 60 93 7

[0065] Test solution: Take about 10 mg of this product, place it in a 25 ml volumetric flask, add 25 ml of diluent (70 ml of mobile phase A and 30 ml of mobile phase B) and dilute to the mark to prepare the test solution.

[0066] ②Isomer impurity detection

[0067] Testing instruments used in the laboratory:

[0068] Chromatographic column: Normal-phase coated chiral column of polysaccharide derivatives

[0069] Detection wavelength: 220nm

[0070] Flow rate: 1.0 ml / min

[0071] Mobile phase: n-hexane-isopropanol-diethylamine (80:20:0.1)

[0072] Running time: 60 minutes

[0073] [Purity] Calculated using the area normalization method, taking the purity of the principal component as measured under the relevant substances test item.

[0074] YLD-CP yield calculation formula:

[0075] m YLD-CP / M YLD-CP ×M YLD-3 / m YLD-3 ×100%

[0076] m YLD-CP For the quality of YLD-CP, M YLD-CP m is the molecular weight of YLD-CP. YLD-3 For the mass of YLD-3, M YLD-3 The molecular weight of YLD-3

[0077] Example 1: Preparation of YLD-3

[0078] Reaction equation:

[0079]

[0080] Operation Description:

[0081] Add 1136.26 g (6.56 mol) of YLD-1 and 1.1 L of 1,4-dioxane to a 100 L reactor, stir and heat to 55 ± 2 °C, the system gradually dissolves. Add 330 mL of 1,4-dioxane to 551.66 g (1.64 mol) of YLD-2 and stir to dissolve, set aside. Then, rapidly add the YLD-2 solution dropwise to the YLD-1 reaction solution, and maintain the temperature for 2 h.

[0082] The reaction solution was cooled to room temperature (25±5℃), and 2.2L of ethyl acetate and 3.3L of purified water were added to the system. After stirring for 10 min, the mixture was allowed to stand and separated, and the organic phase was collected. Another 2.2L of ethyl acetate was added to the aqueous phase, and the mixture was stirred for 10 min. After standing and separating, the organic phases were combined. 3.3L of saturated brine was added to the organic phase, and the mixture was stirred and washed (10 min). After standing and separating, 1100.00g of anhydrous sodium sulfate was added to the organic phase and the mixture was stirred and dried (0.5h). The mixture was filtered under reduced pressure, and the filter cake was washed with 1.1L of ethyl acetate. The filtrate was concentrated under reduced pressure at 40℃ until no liquid flowed out, yielding a pale yellow oily substance YLD-3680.6g with a purity of 88.3% (determined by HPLC).

[0083] Example 2: Preparation of YLD-CP

[0084] Reaction equation:

[0085]

[0086] Operation Description:

[0087] 10.2 L of anhydrous ethanol and 680.6 g (1.34 mol) of YLD-3 obtained in Example 1 were added to a 100 L reactor. 135.15 g (1.07 mol) of oxalic acid dihydrate was added with stirring, and the mixture was stirred for 1 h. The mixture was then filtered under reduced pressure and dried under vacuum at 30 °C to obtain a white solid, YLD-CS.

[0088] After cooling the system to 5°C, 4.6 L of purified water and 291.5 g (3.47 mol) of sodium bicarbonate were added. The mixture was stirred for 1 hour and extracted with ethyl acetate (2.0 L * 4 times). The organic phases were combined and washed once with saturated brine (3 L). 1000 g of anhydrous sodium sulfate and 34 g of activated carbon were added and stirred for 0.5 h. The mixture was filtered and concentrated under reduced pressure at 40°C to obtain a pale yellow oily substance (320.0 g). This substance was dissolved in 640 mL of ethyl acetate and filtered through a 0.2 μm filter membrane to remove inorganic salts and other impurities. The filtrate was retained and cooled to below -5°C. 0.2 M ethyl hydrochloride solution was slowly added dropwise to the filtrate (controlled at below -5°C) to adjust the pH to 4.0. The mixture was stirred for 10 min and filtered under reduced pressure. The filter cake was washed once with 300 mL of ethyl acetate and dried under vacuum at 30°C. 511.0 g of white solid YLD-CP was obtained, with a yield of 70.07% and a purity of 99.64%.

[0089] Example 3

[0090] The amount of oxalic acid dihydrate was adjusted from 135.15 g (1.07 mol) to 168.93 g (1.34 mol), and the remaining steps and conditions were the same as in Example 2, yielding 513 g of YLD-CP with a yield of 70.34% and a purity of 99.74%.

[0091] Example 4

[0092] The pH was adjusted from 4.5 to 4.3, and the remaining steps and conditions were the same as in Example 2, yielding 526g of YLD-CP with a yield of 72.12% and a purity of 99.71%.

[0093] Example 5

[0094] The pH was adjusted from 4.5 to 4.8, and the remaining steps and conditions were the same as in Example 2, yielding YLD-CP519g with a yield of 71.16% and a purity of 99.6%.

[0095] Example 6

[0096] The step of "adding 4.6L of purified water and 291.5g (3.47mol) sodium bicarbonate after cooling the system temperature to 5℃" was changed to "adding 4.6L of purified water and 291.5g (3.47mol) sodium bicarbonate after cooling the system temperature to 0℃". The remaining steps and conditions were the same as in Example 2, and 516g of YLD-CP was obtained with a yield of 70.75% and a purity of 99.75%.

[0097] Example 7

[0098] The step of "adding 4.6L of purified water and 291.5g (3.47mol) sodium bicarbonate after cooling the system temperature to 5°C" was changed to "adding 4.6L of purified water and 291.5g (3.47mol) sodium bicarbonate after cooling the system temperature to 10°C". The remaining steps and conditions were the same as in Example 2, yielding 531g of YLD-CP with a yield of 72.81% and a purity of 99.70%.

[0099] Comparative Example 1

[0100] The amount of oxalic acid dihydrate was adjusted from 135.15 g (1.07 mol) to 84.47 g (0.67 mol), and the remaining steps and conditions were the same as in Example 2, yielding 480 g of YLD-CP with a yield of 65.82% and a purity of 98.60%.

[0101] Comparative Example 2

[0102] The amount of oxalic acid dihydrate was adjusted from 135.15 g (1.07 mol) to 202.72 g (1.61 mol), and the remaining steps and conditions were the same as in Example 2, yielding 476 g of YLD-CP with a yield of 65.27% and a purity of 99.00%.

[0103] Comparative Example 3

[0104] The step of "adding 4.6L of purified water and 291.5g (3.47mol) sodium bicarbonate after cooling the system temperature to 5℃" was changed to "adding 4.6L of purified water and 291.5g (3.47mol) sodium bicarbonate after cooling the system temperature to room temperature (25±5℃)". The remaining steps and conditions were the same as in Example 1, and YLD-CP489g was obtained with a yield of 67.05% and a purity of 97.67%.

[0105] Comparative Example 4

[0106] The pH was adjusted from 4.5 to 4.0, and the remaining steps and conditions were the same as in Example 1, yielding 483g of YLD-CP with a yield of 66.23% and a purity of 99.51%.

[0107] Comparative Example 5

[0108] The pH was adjusted from 4.5 to 5.0, and the remaining steps and conditions were the same as in Example 1, yielding 491g of YLD-CP with a yield of 67.33% and a purity of 99.26%.

[0109] Comparative Example 6

[0110] 10.2 L of anhydrous ethanol and 680.6 g (1.34 mol) of YLD-3 obtained in Example 1 were added to a 100 L reactor. 96.33 g (1.07 mol) of oxalic acid was added with stirring, and the mixture was stirred for 1 h. The mixture was then filtered under reduced pressure and dried under vacuum at 30 °C to obtain a white solid, YLD-CS.

[0111] After cooling the system to 5°C, 4.6 L of purified water and 291.5 g (3.47 mol) of sodium bicarbonate were added. The mixture was stirred for 1 hour and extracted with ethyl acetate (2.0 L * 4 times). The organic phases were combined and washed once with saturated brine (3 L). 1000 g of anhydrous sodium sulfate and 34 g of activated carbon were added and stirred for 0.5 h. The mixture was filtered and concentrated under reduced pressure at 40°C to obtain a pale yellow oil (320.0 g). This oil was dissolved in 640 mL of ethyl acetate and filtered through a 0.2 μm filter membrane to remove inorganic salts and other impurities. The filtrate was retained and cooled to below -5°C. 3.1 L of 0.2 M ethyl hydrochloride solution was slowly added dropwise to the filtrate (temperature controlled below -5°C) to adjust the pH to 4.0. The mixture was stirred for 10 min and filtered under reduced pressure. The filter cake was washed once with 300 mL of ethyl acetate and dried under vacuum at 30°C. 487 g of white solid YLD-CP was obtained, with a yield of 66.78% and a purity of 99.45%.

[0112] Comparative Example 7

[0113] 10.2 L of anhydrous ethanol and 680.6 g (1.34 mol) of YLD-3 obtained in Example 1 were added to a 100 L reactor. 4 L of saturated ammonium chloride was added and stirred for 1 h. The mixture was then transferred to a separatory funnel and allowed to stand for about 1 h. The mixture was separated, and the oil layer on the wall was removed. The remaining system was transferred to a clean gaiwan flask. Under an ice-water bath and with the temperature controlled below 10 °C, 0.2 N hydrochloric acid was slowly added dropwise to bring the pH of the system to about 4.5. A small amount of sodium chloride was added to resaturate the system. 30 mL of ethyl acetate was added and the mixture was extracted three times. The ethyl acetate layers were combined and dried with anhydrous sodium sulfate. The residue was concentrated to obtain a grayish-white residue. 300 mL of ethyl acetate was added to the residue, and the mixture was heated to reflux until the white residue was completely dissolved. The residue was filtered while hot and transferred to a new gaiwan flask. The mixture was slowly cooled, and flocculent solids precipitated. The solids were filtered and washed three times with ethyl acetate. The filter cake was dried in a vacuum drying oven at 35°C until constant weight, yielding 485g of white solid YLD-CP, with a yield of 66.50% and a purity of 99.4%.

[0114] Table 2. Data on YLD-CP related substances and isomers.

[0115]

[0116]

[0117] Table 3 Impurity Information

[0118]

[0119]

[0120] (Impurities C, D, and E have nitrobenzene warning structures and are genotoxic impurities)

[0121] Data analysis from Examples 2-7 and Comparative Examples 1-7 shows that when YLD-3 is used as the starting material and converted into crude brandyvolol hydrochloride under specific conditions, the contents of related substances and isomers in the obtained product meet the specified requirements, and the contents remain at a low level. This process not only enables the production of high-purity crude brandyvolol hydrochloride from YLD-3 raw material with relatively low purity, but also ensures a high yield.

[0122] Specifically, the product quality obtained during the preparation process was optimal when the ratio of YLD-3 to oxalic acid dihydrate was set to 1:(0.8–1.0) (see Examples 2 and 3). However, if the amount of oxalic acid dihydrate exceeds this range, whether in excess or deficiency (as shown in Comparative Examples 2 and 1, respectively), the total impurity content in the final product will increase, and trace amounts of genotoxic impurity C and isomer 1 may also be detected.

[0123] In addition, the addition of oxalic acid and the control of the reaction temperature before extraction are also crucial. The ideal temperature range should be maintained within 0–10 °C; if the temperature is too high, for example at room temperature (as in Comparative Example 3), the total impurity content in brandylolol hydrochloride will increase significantly to 2.31%, and the concentration of genotoxic impurity C will also approach or reach the specified limit.

[0124] The pH value of the system after salt formation also has a significant impact on product quality. Studies have found that when the pH value is controlled within the range of 4.3 to 4.8, the content of related substances and isomers in the crude brandylolol hydrochloride is extremely low, even undetectable. Conversely, when the pH value deviates from this range (such as pH values ​​of 4 and 5 in Comparative Examples 4 and 5, respectively), the content of impurity A increases significantly, exceeding the specified limit. At the same time, the presence of isomers can be detected, and their content exceeds the standard.

[0125] Further research showed that using anhydrous oxalic acid for salt formation (as in Comparative Example 6), even under identical conditions, resulted in a significant exceedance of the impurity B content, and the presence of two isomers could be detected. Furthermore, using saturated ammonium chloride solution as the salt-forming reagent (as in Comparative Example 7), although a common practice in traditional methods, resulted in impurity A content approaching the limit, and the presence of two isomers could also be detected.

[0126] In summary, by optimizing the process of converting YLD-3 to oxalate and then to hydrochloride to obtain the target product—crude brandyl hydrochloride—a high yield can be achieved while effectively controlling the impurity content, especially the control of genotoxic impurities and isomers.

[0127] The embodiments of this application have been described above, but this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A method for preparing a crude β-receptor blocker, characterized in that, Includes the following steps: (1) The [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate ester, as shown in compound 6, is added to a solvent and reacts with oxalic acid to generate [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate ester oxalate, as shown in compound 7. (2) The oxalate of [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate obtained in step (1) is desalted and then reacted with ethyl hydrogen chloride solution to form a β-receptor blocker as shown in compound 8. The oxalic acid in question is oxalic acid dihydrate.

2. The method for preparing the crude β-receptor blocker according to claim 1, characterized in that, The molar ratio of the [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate to the oxalic acid dihydrate is 1:(0.7-1.0).

3. The method for preparing the crude β-receptor blocker according to claim 2, characterized in that, The solvent is anhydrous ethanol.

4. The method for preparing the crude β-receptor blocker according to claim 3, characterized in that, The salt-dissolving agent for [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinoamino)ethylamino]propoxy]phenylpropionate oxalate is sodium hydroxide.

5. The method for preparing the crude β-receptor blocker according to claim 4, characterized in that, Includes the following steps: (1) Add [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate to anhydrous ethanol, add oxalic acid dihydrate under stirring, and after stirring, filtration and drying, obtain [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate oxalate; (2) After controlling the system temperature, the [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarboxamido)ethylamino]propoxy]phenylpropionate oxalate obtained in step (1) was dissolved in purified water, sodium bicarbonate was added, and the mixture was stirred. The mixture was extracted multiple times with ethyl acetate, the organic phases were combined, and the mixture was washed with saturated brine. Anhydrous sodium sulfate and activated carbon were added, the mixture was filtered, and the mixture was concentrated under reduced pressure to obtain a pale yellow oil. The pale yellow oil was dissolved in ethyl acetate, impurities were filtered out, and the mixture was cooled to below -5°C. Ethyl hydrochloride solution was slowly added dropwise, the temperature was controlled to be below -5°C, and the pH was adjusted to 4.0-5.

0. The mixture was stirred and then filtered under reduced pressure. The filter cake was washed with ethyl acetate and dried to obtain the crude β-receptor blocker.

6. The method for preparing the crude β-receptor blocker according to claim 5, characterized in that, The [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbamoylamino)ethylamino]propoxy]phenylpropionate oxalate was dissolved in purified water and the system temperature was controlled at 0-10℃.

7. The method for preparing the β-receptor blocker according to claim 6, characterized in that, The pH is 4.3 to 4.

8.

8. The method for preparing the β-receptor blocker according to claim 7, characterized in that, The impurities are filtered using a 0.2 μm filter membrane.

9. The method for preparing the crude β-receptor blocker according to any one of claims 1 to 8, characterized in that, The [(S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarboxamide)ethylamino]propoxy]phenylpropionate described in step (1) is obtained by reacting N-(2-aminoethyl)-4-morpholinocarboxamide as shown in compound 2 and 4S-(2,2-dimethyl-1,3-dioxolane-4-yl)-(4-(2S,3-epoxypropane)phenyl)propyl ester as shown in compound 5 in a 1,4-dioxane ring.

10. A β-receptor blocker prepared by the method according to any one of claims 1 to 9, wherein the β-receptor blocker is preferably landilol hydrochloride.

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