Process for the preparation of bilastine and its impurities

Abstract

This application discloses a method for preparing bilastin and its impurities. The method for preparing bilastin includes a reaction step using a compound of formula (I) and / or a salt of a compound of formula (I) as an intermediate, wherein the content of the compound of formula (II) in the intermediate product is not higher than 0.1 wt%. The method of this application yields bilastin with a purity higher than 99.5%, and the content of a single impurity is not more than 0.1%. The purity of the bilastin product meets the quality standards specified in the pharmacopoeia, with a high product qualification rate, which is conducive to large-scale production.

Description

Technical Field

[0001] This application relates to the pharmaceutical field, and more specifically, to a method for preparing bilastin and its impurities. Background Technology

[0002] Bilastine, chemically known as 2-[4-(2-(4-(1(2-ethoxyethyl)benzimidazol-2-yl)piperidin-1-yl)ethyl)phenyl]-2-methylpropionic acid, is a second-generation, non-sedating, long-acting antihistamine developed by the Spanish pharmaceutical company FAES. It selectively antagonizes peripheral H1 receptors, exhibiting a strong affinity for histamine H1 receptors without inhibiting other receptors. Furthermore, bilastine possesses anti-inflammatory properties and is used to treat allergic conditions such as urticaria and allergic rhinitis.

[0003] To ensure the safety and efficacy of bilastine, the purity of the bilastine active pharmaceutical ingredient (API) or finished product must meet the quality standards stipulated in the pharmacopoeia, namely, a purity of not less than 99.5%, and the content of any single unknown impurity should not exceed 0.1%. However, during the manufacturing process of bilastine, the content of related substances often fails to meet these quality standards, resulting in a lower product qualification rate.

[0004] Therefore, there is an urgent need to develop a method for preparing bilastine that can produce a purity higher than 99.5% and a single unknown impurity content of no more than 0.1%. Summary of the Invention

[0005] This application aims to at least partially solve one of the technical problems in the related art. To this end, this application provides a method for preparing bilastin and its impurities. The method of this application yields bilastin with a purity higher than 99.5%, and the content of a single impurity does not exceed 0.1%. The purity of the bilastin product meets the quality standards specified in the pharmacopoeia, and the product qualification rate is high. The method of this application for preparing bilastin impurities BLST-CP-IMP2 and BLST-CP-IMP4 has mild reaction conditions, simple chemical reactions, and high reaction efficiency, which is conducive to large-scale production.

[0006] It should be stated that this application was completed based on the following work of the inventors:

[0007] Bilastin undergoes ether bond cleavage under alkaline conditions, generating the bistantin impurity BLST-CP-IMP4. Once formed, this impurity is difficult to remove and requires strict control to improve the quality of the bistantin product. The inventors attempted to prepare bistantin using the following reaction steps:

[0008]

[0009] However, during the long-term development of the preparation process, it was discovered that the impurity BLST-CP-IMP4 also exists in the synthesis stage of the bilastine compound. And impurity BLST-CP-IMP2 produce.

[0010] In-depth research revealed that when unreacted BLST-SM1 is present in the reaction system, it reacts with BLST-SM2 to form BLST-CP-IMP2. BLST-CP-IMP2 also reacts in the reaction system where BLST-4 is used to generate bilastin, forming BLST-CP-IMP4. Therefore, by controlling the reaction conditions from BLST-SM1 to BLST-3, ensuring that the BLST-SM1 content in the product of BLST-3 is no higher than 0.1%, the formation of BLST-CP-IMP2 and BLST-CP-IMP4 can be effectively reduced. This results in a bilastin product with a purity of no less than 99.5%, and the content of each individual impurity, BLST-CP-IMP2 and BLST-CP-IMP4, is less than or equal to 0.1 wt%.

[0011] Therefore, in a first aspect of this application, this application provides a method for preparing bilastin. According to an embodiment of this application, the method includes a reaction step using a compound of formula (I) and / or a salt of a compound of formula (I) as an intermediate, wherein the content of the compound of formula (II) in the product of the intermediate is not higher than 0.1 wt%;

[0012]

[0013] The bisalisine product prepared according to the method of the embodiments of this application has a purity of over 99.5%, and the content of a single impurity does not exceed 0.1%. The purity of the bisalisine product meets the quality standards specified in the pharmacopoeia, and the product qualification rate is high.

[0014] According to embodiments of this application, the method for preparing bilastin may further include the following additional technical features:

[0015] According to embodiments of this application, the chemical structure of the salt of the compound shown in formula (I) is as shown in formula (III);

[0016]

[0017] According to an embodiment of this application, the method includes the following reaction steps:

[0018]

[0019] According to an embodiment of this application, the first initial reaction system for generating the compound of formula (X) from the compound of formula (II) contains the compound of formula (II), Boc2O, methanol, and potassium carbonate.

[0020] According to embodiments of this application, based on the mass of the compound shown in formula (II), the equivalent of Boc2O is 0.5 eq to 5 eq, and the concentration of methanol is 10 mL / g to 20 mL / g.

[0021] According to an embodiment of this application, the reaction temperature for generating the compound of formula (X) from the compound of formula (II) is 0°C to 7°C, and the reaction time is 0.5h to 1.5h.

[0022] According to an embodiment of this application, the second initial reaction system for generating the compound of formula (Y) from the compound of formula (X) contains the compound of formula (a), potassium tert-butoxide, and dioxane.

[0023] According to an embodiment of this application, the second initial reaction system further includes a catalyst, said catalyst comprising 18-crown ether-6.

[0024] According to embodiments of this application, based on the mass of the compound shown in formula (X), the equivalent of the compound shown in formula (a) is 1 eq to 4 eq, the equivalent of the potassium tert-butoxide is 1 eq to 4 eq, the concentration of the dioxane is 10 mL / g to 30 mL / g; and / or, the concentration of the catalyst is 5% mol to 15% mol.

[0025] According to an embodiment of this application, the reaction temperature for generating the compound of formula (Y) from the compound of formula (X) is 80°C to 120°C, and the reaction time is 1h to 4h.

[0026] According to an embodiment of this application, the reaction solution that generates the compound shown in formula (II) is filtered, the filter cake is washed and dried to obtain a dried product, wherein the content of the compound shown in formula (II) in the dried product is not higher than 0.1 wt%.

[0027] According to embodiments of this application, the chemical structure of the salt of the compound shown in formula (I) is as shown in formula (III);

[0028]

[0029] The method includes the following reaction steps:

[0030]

[0031] According to an embodiment of this application, the method includes the following reaction step (a):

[0032]

[0033] According to an embodiment of this application, the third initial reaction system of reaction step (a) includes the compound shown in formula (IV), acetonitrile, and potassium phosphate.

[0034] According to an embodiment of this application, based on the mass of the compound shown in formula (III), the equivalent number of the compound shown in formula (IV) is 1.2 to 2 eq, and the equivalent number of potassium phosphate is 1 eq to 10 eq.

[0035] According to embodiments of this application, based on the mass of the compound shown in formula (III), the concentration of the acetonitrile is 10 mL / g to 20 mL / g; and / or, the pH of the third initial reaction system is 7 to 8.

[0036] According to an embodiment of this application, the reaction temperature of reaction step (a) is 70°C to 90°C.

[0037] According to an embodiment of this application, the method further includes the following reaction step (b):

[0038]

[0039] According to an embodiment of this application, the reaction step (b) includes: first reacting the compound shown in formula (V), potassium hydroxide, and an aqueous methanol solution, and then mixing the resulting reaction solution with an acid solution to obtain the bilastin.

[0040] According to an embodiment of this application, the volume ratio of methanol to water is 1:(0.5 to 1.5).

[0041] According to an embodiment of this application, the reaction temperature of reaction step (b) is 70°C to 80°C, and the reaction time is 2h to 3h.

[0042] According to an embodiment of this application, the obtained reaction solution is mixed with an acid solution to a pH value of 6-7, and then filtered to obtain the bilastin.

[0043] In another aspect of this application, a method for preparing the bilastine impurity BLST-CP-IMP2 is provided. According to an embodiment of this application, the method includes the following reaction step (a'):

[0044]

[0045] According to an embodiment of this application, the initial reaction system of the reaction step (a') includes: the compound shown in formula (IV), acetonitrile, and potassium phosphate;

[0046] The reaction step (a') includes:

[0047] The compound shown in formula (II) is mixed with acetonitrile and potassium phosphate to obtain a first mixture;

[0048] The compound shown in formula (Ⅳ) was subjected to a second mixing treatment with acetonitrile to obtain a second mixture;

[0049] The first mixture is reacted with the second mixture to obtain the reaction product of the impurity BLST-CP-IMP2.

[0050] According to an embodiment of this application, in the first mixture, the concentration of acetonitrile is 5 to 15 mL / g, preferably 10 mL / g, relative to the mass of the compound shown in formula (II), and the concentration of potassium phosphate is 2.8 to 3.5 wt%, preferably 3.16 wt%.

[0051] According to an embodiment of this application, in the second mixture, the concentration of acetonitrile is 1.5 to 3.5 mL / g, preferably 2.2 mL / g, relative to the mass of the compound shown in formula (Ⅳ).

[0052] According to embodiments of this application, the mass ratio of the compound shown in formula (II) to the compound shown in formula (IV) is 20:(30-60), preferably 20:45.

[0053] According to an embodiment of this application, the first mixing process includes stirring at 20-30°C for 20-40 minutes.

[0054] According to an embodiment of this application, the second mixing process includes: adding the first mixture to the second mixture, and then reacting at a temperature of 20-30°C for 2-6 hours.

[0055] According to an embodiment of this application, the first mixture is added at a rate of 2 to 6 mL / min, preferably 3.5 to 4.5 mL / min.

[0056] According to embodiments of this application, the reaction step (a') further includes:

[0057] The reaction product of the impurity BLST-CP-IMP2 was purified to obtain the purified BLST-CP-IMP2.

[0058] According to an embodiment of this application, the purification process includes:

[0059] The reaction product of the impurity BLST-CP-IMP2 was washed with acetonitrile, the solid component was collected, methanol was added and subjected to a first pulping treatment to obtain a first pulping mixture.

[0060] The first pulping mixture is subjected to a first vacuum filtration process, and the filtrate is collected.

[0061] Water is added to the filtrate and a second pulping treatment is performed to obtain a second pulping mixture;

[0062] The second pulping mixture is subjected to a second filtration process to collect the filter cake.

[0063] The filter cake was dissolved in dichloromethane and methanol to obtain the initial extract of the impurity BLST-CP-IMP2.

[0064] According to an embodiment of this application, the volume ratio of dichloromethane to methanol is (2-6):1, preferably 4:1.

[0065] According to an embodiment of this application, the purification process further includes: separating and purifying the initial extract of the impurity BLST-CP-IMP2 using chromatography, wherein the chromatography conditions include: using a silica gel column as the packing material and using a mixed solution containing dichloromethane and methanol as the eluent for elution.

[0066] According to an embodiment of this application, in the mixed solution, the volume ratio of dichloromethane to methanol is (14-16):1, preferably 15:1.

[0067] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0068] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0069] Figure 1 This is the 1H-NMR spectrum of impurity BLST-CP-IMP2 in Example 1 of this application;

[0070] Figure 2 This is the 1H-NMR spectrum of impurity BLST-CP-IMP4 in Example 1 of this application;

[0071] Figure 3 This is a schematic diagram showing the source of impurity BLST-SM1 in BLST-3 according to an embodiment of this application. Detailed Implementation

[0072] The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0073] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0074] To facilitate understanding of this application, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this application pertains.

[0075] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this application but do not exclude other contents.

[0076] Terms and Definitions

[0077] In this paper, the term "SM" is an abbreviation for "Starting Material," which refers to the "starting material" or "raw material" for a chemical synthesis reaction, and "SMn" represents different raw materials, where n is an integer.

[0078] In this paper, the term "BLST-SMn" refers to the raw material for the chemical synthesis of bilastine.

[0079] In this article, the term “bilastine” is equivalent to “Bilastine” and is abbreviated as “BLST”.

[0080] In this document, the term “compound represented by formula (II)” is equivalent to “BLST-SM1”, “compound represented by formula (X)” is equivalent to “BLST-1”, “compound represented by formula (Y)” is equivalent to “BLST-2”, “compound represented by formula (III)” is equivalent to “BLST-3”, “compound represented by formula (IV)” is equivalent to “BLST-SM2”, and “compound represented by formula (V)” is equivalent to “BLST-4”.

[0081] Methods for preparing bilastine

[0082] In a first aspect, this application provides a method for preparing bilastin. According to an embodiment of this application, the method includes a reaction step using a compound of formula (I) and / or a salt of a compound of formula (I) as an intermediate, wherein the content of the compound of formula (II) in the product of the intermediate is not higher than 0.1 wt%;

[0083]

[0084] Further analysis revealed that the impurity BLST-SM1 in BLST-3 originated from, for example... Figure 3 As shown, during the process of BLST-SM1 generating BLST-1, BLST-1-IMP1 will be generated. Therefore, BLST-1 will contain some BLST-1-IMP1. Then, due to the presence of acid in the reaction, the Boc group can easily break the bond to generate BLST-SM1.

[0085] When unreacted BLST-SM1 is present in the reaction system, it will react with BLST-SM2 to generate BLST-CP-IMP2. BLST-CP-IMP2 will also react in the reaction system in which BLST-4 generates bilastine to generate BLST-CP-IMP4.

[0086]

[0087] Therefore, by controlling the reaction system conditions from BLST-SM1 to BLST-3, so that the content of BLST-SM1 in the product of BLST-3 is not higher than 0.1%, the formation of BLST-CP-IMP2 and BLST-CP-IMP4 can be effectively reduced, thereby ensuring that the purity of the obtained bilastine product is not less than 99.5%, and the content of each individual impurity BLST-CP-IMP2 and BLST-CP-IMP4 is less than or equal to 0.1 wt%.

[0088] It should be noted that the term "intermediate product" in this application refers to the substance generated in the reaction solution that produces the compound shown in formula (I) and / or the salt of the compound shown in formula (I), i.e., the solid substance in the product solution. For example, the reaction solution that produces the compound shown in formula (II) is filtered, the filter cake is washed, and the filter cake is dried. The dried product obtained is the intermediate product, wherein the content of the compound shown in formula (II) is not higher than 0.1 wt%.

[0089] According to embodiments of this application, the salt of the compound shown in formula (I) is a hydrochloride salt.

[0090] According to a specific embodiment of this application, the chemical structure of the salt of the compound shown in formula (I) is as shown in formula (III);

[0091]

[0092] According to an embodiment of this application, the method includes the following reaction steps:

[0093]

[0094] According to an embodiment of this application, the first initial reaction system for generating the compound of formula (X) from the compound of formula (II) contains the compound of formula (II), Boc2O, methanol, and potassium carbonate. Therefore, in this reaction system, it is advantageous for the compound of formula (II) to react fully to generate the compound of formula (X).

[0095] In this paper, the term "initial reaction system" refers to the mixture of all reactants, solvents, catalysts, etc., involved at the beginning of a chemical reaction.

[0096] According to embodiments of this application, based on the mass of the compound shown in formula (II), the equivalent of Boc2O is 0.5 eq to 5 eq, for example, 0.5 eq, 1 eq, 1.5 eq, 2 eq, 2.5 eq, 3 eq, 3.5 eq, 4 eq, 4.5 eq, or 5 eq. This facilitates the efficient conversion of the compound shown in formula (II) into the compound shown in formula (X), reduces unreacted compounds shown in formula (II), thereby preventing unreacted BLST-SM1 from reacting with BLST-SM2 to generate the byproduct BLST-CP-IMP2, and improving the conversion rate, product yield, and purity.

[0097] According to embodiments of this application, based on the mass of the compound shown in formula (II), the concentration of methanol is 10 mL / g to 20 mL / g, for example, 10 mL / g, 12 mL / g, 14 mL / g, 15 mL / g, 16 mL / g, 18 mL / g, or 20 mL / g. This facilitates the efficient conversion of the compound shown in formula (II) into the compound shown in formula (X), reduces unreacted compounds shown in formula (II), and thus avoids the reaction of unreacted BLST-SM1 with BLST-SM2 to generate the byproduct BLST-CP-IMP2, thereby improving the conversion rate of the reaction and the yield and purity of the product.

[0098] According to embodiments of this application, the reaction temperature for the formation of the compound shown in formula (II) into the compound shown in formula (X) is 0°C to 7°C, for example, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, or 7°C, and the reaction time is 0.5h to 1.5h, for example, 0.5h, 1h, or 1.5h. This facilitates the efficient conversion of the compound shown in formula (II) into the compound shown in formula (X), reduces the amount of unreacted compound shown in formula (II), and avoids the reaction of unreacted BLST-SM1 with BLST-SM2 to generate the byproduct BLST-CP-IMP2, thereby improving the conversion rate, product yield, and purity.

[0099] According to embodiments of this application, the second initial reaction system for generating the compound of formula (Y) from the compound of formula (X) contains the compound of formula (a), potassium tert-butoxide, and dioxane. Under the action of potassium tert-butoxide, a substitution reaction occurs with 2-chloroethyl ether to generate BLST-2. Numerous studies have reported the use of a NaF / DMF system in this step, but DMF is prone to decomposition under strong alkali conditions. As the reaction proceeds, the reaction system spontaneously heats up, potentially leading to temperature runaway and explosion. This application uses a potassium tert-butoxide / dioxane system as a substitute, significantly reducing safety risks and preventing the unreacted BLST-SM1 from reacting with BLST-SM2 to generate the byproduct BLST-CP-IMP2, thus improving the conversion rate, product yield, and purity.

[0100] According to embodiments of this application, the second initial reaction system further includes a catalyst comprising 18-crown ether-6. This allows for efficient catalysis of the reaction between BLST-1 and BLST-SM3 to generate BLST-2, and also facilitates the further reaction of the compound shown in formula (II) to generate BLST-2. This avoids the unreacted BLST-SM1 reacting with BLST-SM2 to generate the byproduct BLST-CP-IMP2, thereby improving the conversion rate, product yield, and purity.

[0101] According to embodiments of this application, based on the mass of the compound shown in formula (X), the equivalent of the compound shown in formula (a) is 1 eq to 4 eq, for example, 1 eq, 1.5 eq, 2 eq, 2.5 eq, 3 eq, 3.5 eq, 4 eq; the equivalent of potassium tert-butoxide is 1 eq to 4 eq, for example, 1 eq, 1.5 eq, 2 eq, 2.5 eq, 3 eq, 3.5 eq, 4 eq; and / or, the concentration of dioxane is 10 mL / g to 20 mL / g, for example, 10 mL / g, 12 mL / g, 14 mL / g, 15 mL / g, 16 mL / g, 18 mL / g, 20 mL / g; and / or, the concentration of the catalyst is 5% mol to 15% mol, for example, 5% mol, 8% mol, 10% mol, 12% mol, 14% mol, 15% mol. Therefore, it is beneficial for BLST-1 to react with BLST-SM3 to generate BLST-2, and also beneficial for the compound shown in formula (II) to further react to generate BLST-2, thereby avoiding the reaction of unreacted BLST-SM1 with BLST-SM2 to generate the byproduct BLST-CP-IMP2, and improving the conversion rate of the reaction and the yield and purity of the product.

[0102] According to embodiments of this application, the reaction temperature for the compound of formula (X) to generate the compound of formula (Y) is 80°C to 120°C, for example, 80°C, 90°C, 100°C, 110°C, or 120°C, and the reaction time is 1h to 4h, for example, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, or 4h. This is beneficial for the reaction of BLST-1 and BLST-SM3 to generate BLST-2, and also for the further reaction of the compound of formula (II) to generate BLST-2, thereby avoiding the reaction of unreacted BLST-SM1 and BLST-SM2 to generate the byproduct BLST-CP-IMP2, thus improving the conversion rate of the reaction and the yield and purity of the product.

[0103] According to embodiments of this application, the chemical structure of the salt of the compound shown in formula (I) is as shown in formula (III);

[0104]

[0105] The method includes the following reaction steps (p):

[0106]

[0107] In some embodiments, the initial reaction system of reaction step (p) includes concentrated hydrochloric acid and n-butanol. Based on the mass of the compound shown in formula (Y), the equivalent of concentrated hydrochloric acid is 1–5 eq, for example, 1 eq, 1.5 eq, 2 eq, 2.5 eq, 3 eq, 3.5 eq, 4 eq, 4.5 eq, or 5 eq, and the concentration of concentrated hydrochloric acid is 10 mol / L–15 mol / L; the concentration of n-butanol is 5 mL / g–15 mL / g, for example, 5 mL / g, 6 mL / g, 8 mL / g, 10 mL / g, 12 mL / g, 14 mL / g, or 15 mL / g. Under the action of concentrated hydrochloric acid, blst-2 is deprotected to generate hydrochloride blst-3. Under the above conditions, it is beneficial for the compound shown in formula (Y) to be efficiently converted into the compound shown in formula (III).

[0108] According to an embodiment of this application, the method includes the following reaction step (a):

[0109]

[0110] According to embodiments of this application, the third initial reaction system of reaction step (a) comprises the compound shown in formula (IV), acetonitrile, and potassium phosphate. A substitution reaction occurs between the potassium phosphate / acetonitrile and BLST-SM2 to generate the bilastine intermediate BLST-4. In this reaction, BLST-SM2 is sourced commercially, avoiding the use of palladium catalysts and toxic reagents such as potassium iodide. The reaction conditions are mild, and the resulting crude product is directly used in the next reaction step. Furthermore, this also reduces the likelihood of unreacted BLST-SM1 reacting with BLST-SM2 to generate the byproduct BLST-CP-IMP2.

[0111] According to specific embodiments of this application, based on the mass of the compound shown in formula (III), the equivalent number of the compound shown in formula (IV) is 1.2 eq to 2 eq, and the equivalent number of potassium phosphate is 1 eq to 10 eq. This not only facilitates the reaction of BLST-3 with BLST-SM2 to generate BLST-4, but also avoids the reaction of unreacted BLST-SM1 with BLST-SM2 to generate the byproduct BLST-CP-IMP2, thereby improving the conversion rate of the reaction and the yield and purity of the product.

[0112] According to the embodiments of this application, the reaction temperature of reaction step (a) is 70℃~90℃, for example 70℃, 72℃, 74℃, 75℃, 76℃, 78℃, 80℃, 82℃, 84℃, 85℃, 86℃, 88℃, and 90℃. This not only facilitates the reaction of BLST-3 with BLST-SM2 to generate BLST-4, but also avoids the reaction of unreacted BLST-SM1 with BLST-SM2 to generate the byproduct BLST-CP-IMP2, thereby improving the conversion rate of the reaction and the yield and purity of the product.

[0113] According to an embodiment of this application, the method includes the following reaction step (b):

[0114]

[0115] According to an embodiment of this application, reaction step (b) includes: first reacting the compound shown in formula (V), potassium hydroxide, and an aqueous methanol solution; then mixing the resulting reaction solution with an acid solution to obtain the bistanine. After hydrolysis of BLST-4 in a KOH / MeOH system, a potassium salt of bistanine is generated; the potassium salt is then acidified to form an acid, precipitating the organic compound bistanine.

[0116] According to embodiments of this application, based on the mass of the compound shown in formula (V), the equivalent of potassium hydroxide is 1 eq to 5 eq, for example, 1 eq, 1.5 eq, 2 eq, 2.5 eq, 3 eq, 3.5 eq, 4 eq, 4.5 eq, or 5 eq. This facilitates the efficient conversion of the compound shown in formula (V) into bilastine, reducing the formation of side reactions.

[0117] According to embodiments of this application, based on the mass of the compound shown in formula (V), the amount of methanol-water solution added is 5 mL / g to 15 mL / g, for example, 5 mL / g, 6 mL / g, 8 mL / g, 10 mL / g, 12 mL / g, 14 mL / g, or 15 mL / g; the volume ratio of methanol to water is 1:(0.5 to 1.5), for example, 1:0.5, 1:0.6, 1:0.8, 1:1, 1:1.2, 1:1.4, or 1:1.5. This facilitates the efficient conversion of the compound shown in formula (V) to bilastine, reducing the formation of side reactions.

[0118] According to embodiments of this application, the reaction temperature of reaction step (b) is 70°C to 80°C, for example, 70°C, 72°C, 74°C, 75°C, 76°C, 78°C, or 80°C, and the reaction time is 2h to 3h, for example, 2h, 2.5h, or 3h. This facilitates the efficient conversion of the compound shown in formula (V) into bilastine and reduces the formation of side reactions.

[0119] According to an embodiment of this application, the method further includes: adjusting the pH of the reaction solution generated by the reaction of the compound shown in formula (V) to 6-7, filtering, collecting and washing the filter cake to obtain the bilastin.

[0120] According to some optional embodiments of this application, the reaction product of bilastin is recrystallized to obtain pure bilastin.

[0121] According to some optional embodiments of this application, the recrystallization is carried out in a n-butanol / isopropanol system.

[0122] According to embodiments of this application, the preparation method of bilastin includes the following reaction steps:

[0123]

[0124] In some embodiments, the method includes:

[0125] 1. Preparation of BLST-1

[0126] Add BLST-SM1 to the reaction flask and dissolve it in methanol. Then add potassium carbonate to the reaction flask, cool, and stir. Dissolve acid anhydride (Boc₂O) in methanol and add it dropwise. Add purified water, stir, filter, and wash the filter cake several times with purified water. Add cyclohexane, heat and stir, cool to room temperature, filter, wash the filter cake several times with cyclohexane, and dry the filter cake to obtain BLST-1.

[0127] 2. Preparation of BLST-2

[0128] BLST-1, dioxane, potassium tert-butoxide, and catalyst 18-C-6 were added sequentially to the reaction flask and stirred for 30 minutes. 2-Chloroethyl ether was added to the reaction solution, and the mixture was heated and maintained at that temperature. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed several times with dioxane to obtain BLST-2.

[0129] 3. Preparation of BLST-3

[0130] Add the BLST-1 prepared above to n-butanol and stir at room temperature. Add concentrated hydrochloric acid to a four-necked flask, and after the reaction is complete, evaporate the reaction solution to dryness. Add ethyl acetate, stir, cool naturally to room temperature, filter, wash the filter cake with ethyl acetate several times, and dry the filter cake to obtain BLST-3.

[0131] 4. Preparation of BLST-4

[0132] Add BLST-3 to a four-necked flask, then add acetonitrile and anhydrous potassium phosphate, and heat. Separately, dissolve BLST-SM2 in acetonitrile and add it dropwise to the above system to react. Add more BLST-SM2 and continue the reaction. Cool to room temperature, filter, wash the filter cake several times with acetonitrile, collect the filtrate, evaporate to dryness, dissolve in ethyl acetate, wash the EA phase with sodium carbonate solution, and discard the aqueous phase.

[0133] Prepare dilute hydrochloric acid, back-extract the EA phase, collect the aqueous phase, adjust the pH with anhydrous sodium carbonate, a solid precipitates out, filter, wash the filter cake several times with purified water, dry the filter cake, and obtain BLST-4.

[0134] 5. Preparation of BLST-CP

[0135] Add the BLST-4 prepared above to a reaction flask, then add methanol and purified water, and finally add potassium hydroxide. Heat the mixture and maintain the temperature for the reaction.

[0136] After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted with glacial acetic acid. A solid precipitated out. The mixture was then filtered, and the filter cake was washed several times with purified water. The filter cake was then dried to obtain crude BLST-CP.

[0137] 6. Purification of BLST-CP

[0138] Add crude BLST-CP to a reaction flask, then add purified water, heat, and stir while maintaining the temperature. After cooling the reaction solution to room temperature, filter under vacuum, wash the filter cake several times with purified water, dry the filter cake, transfer it to a four-necked flask, add butyl acetate, heat, and stir while maintaining the temperature. After naturally cooling to room temperature, filter under vacuum, wash the filter cake several times with butyl acetate, and dry the filter cake.

[0139] The above filter cake was added to a four-necked flask, followed by n-butanol and isopropanol. The mixture was heated until the solution was completely dissolved. After the reaction solution was allowed to cool naturally to room temperature, it was filtered. The filter cake was washed several times with n-butanol / isopropanol, and then dried to obtain purified bilastine.

[0140] In another aspect of this application, a method for preparing the bilastine impurity BLST-CP-IMP2 is provided, the method comprising the following reaction step (a'):

[0141]

[0142] The initial reaction system of the reaction step (a') includes: the compound shown in formula (IV), acetonitrile, and potassium phosphate.

[0143] According to an embodiment of this application, the reaction step (a') includes:

[0144] The compound shown in formula (II) is mixed with acetonitrile and potassium phosphate to obtain a first mixture;

[0145] The compound shown in formula (Ⅳ) was subjected to a second mixing treatment with acetonitrile to obtain a second mixture;

[0146] The first mixture is reacted with the second mixture to obtain the reaction product of the impurity BLST-CP-IMP2.

[0147] According to an embodiment of this application, in the first mixture, the concentration of acetonitrile relative to the mass of the compound shown in formula (II) is 5-15 mL / g, preferably 10 mL / g, and the concentration of potassium phosphate is 2.8-3.5 wt%, preferably 3.16 wt%; in the second mixture, the concentration of acetonitrile relative to the mass of the compound shown in formula (IV) is 1.5-3.5 mL / g, preferably 2.2 mL / g; the mass ratio of the compound shown in formula (II) to the compound shown in formula (IV) is 20:(30-60), preferably 20:45; the first mixing treatment includes: stirring at 20-30°C for 20-40 min; the second mixing treatment includes: adding the first mixture to the second mixture, and then reacting at 20-30°C for 2-6 h; the addition rate of the first mixture is 2-6 mL / min, preferably 3.5-4.5 mL / min.

[0148] According to an embodiment of this application, the reaction step (a') further includes: purifying the reaction product of the impurity BLST-CP-IMP2 to obtain a purified product of the impurity BLST-CP-IMP2;

[0149] The purification process includes:

[0150] The reaction product of the impurity BLST-CP-IMP2 was washed with acetonitrile, the solid component was collected, methanol was added and subjected to a first pulping treatment to obtain a first pulping mixture.

[0151] The first pulping mixture is subjected to a first vacuum filtration process, and the filtrate is collected.

[0152] Water is added to the filtrate and a second pulping treatment is performed to obtain a second pulping mixture;

[0153] The second pulping mixture is subjected to a second filtration process to collect the filter cake.

[0154] The filter cake was dissolved in dichloromethane and methanol to obtain the initial extract of the impurity BLST-CP-IMP2.

[0155] The volume ratio of dichloromethane to methanol is (2-6):1, preferably 4:1;

[0156] The purification process further includes: separating and purifying the initial extract of the impurity BLST-CP-IMP2 using chromatography, wherein the chromatography conditions include: using a silica gel column as the packing material and using a mixed solution containing dichloromethane and methanol as the eluent for elution;

[0157] In the mixed solution, the volume ratio of dichloromethane to methanol is (14-16):1, preferably 15:1.

[0158] According to embodiments of this application, the preparation method of the bilastine impurity BLST-CP-IMP2 includes:

[0159] 1) Add 50g of BLST-3 to a four-necked flask, then add 500mL of acetonitrile and 158.2g of anhydrous potassium phosphate, and stir at 20-30℃ for 30min.

[0160] 2) Dissolve 112.5g of BLST-SM2 in 250mL of acetonitrile and slowly add it dropwise to the above system.

[0161] 3) After the reaction is complete, cool to room temperature, filter, rinse the filter cake with acetonitrile several times, collect the filter cake and add 500 mL of methanol to slurry for 1 h.

[0162] 4) Filter under reduced pressure, collect the filtrate, concentrate under reduced pressure, add 500 mL of purified water and stir for 1 hour, then filter. Collect the filter cake.

[0163] 5) Dissolve the above filter cake in 200 mL of dichloromethane and 50 mL of methanol, then add silica gel and mix. Purify by column chromatography to obtain a pure product with a purity of 99.69%.

[0164] The structure of BLST-CP-IMP2 is shown below, and the structural characterization parameters are shown in Table 1 and... Figure 1 As shown.

[0165]

[0166] Table 1: Structure Confirmation Information of Impurity BLST-CP-IMP2

[0167] Location 1H δ(ppm) J(Hz) 1,2 2H 7.23～7.18 m 3,6 2H 7.53～7.40 dd 4 -- -- -- 5 -- -- -- 7 -- -- -- 8 1H 2.86～2.80 m 9 2H 1.88～1.81 m 10 2H 2.55～2.53 d 11 2H 2.13～2.08 t 12 2H 2.01～1.98 d 13 2H 3.04～3.01 d 14 2H 2.75～2.72 t 15 -- -- -- 16,20 2H 7.14～7.08 m 17,19 2H 7.23～7.18 m 18 -- -- -- 21 -- -- -- 22 -- -- -- 23,24 6H 1.48 s 25 3H 3.58 s 26 1H 12.16 s

[0168] In another aspect of this application, a method for preparing the bilastine impurity BLST-CP-IMP4 is provided, characterized in that the method comprises the following reaction step (b'):

[0169]

[0170] The reaction step (b') includes: the impurity BLST-CP-IMP2 reacts in the initial reaction system (b'), and after reacting for 2 to 4 hours, the pH of the reaction solution is adjusted to 6.5 to 7.5 with acetic acid to obtain the reaction product of the impurity BLST-CP-IMP4; the initial reaction system (b') includes: potassium hydroxide, methanol, and water;

[0171] Relative to the mass of the impurity BLST-CP-IMP2, the concentration of potassium hydroxide is 50wt% to 70wt%, preferably 58wt% to 60wt%, and the concentration of the 1:1 volume ratio mixture of methanol and water is 6 to 14 mL / g, preferably 8 to 12 mL / g, more preferably 10 mL / g;

[0172] The reaction temperature of the reaction step (b') is 80℃~90℃, preferably 82℃.

[0173] According to embodiments of this application, the preparation method of the bilastine impurity BLST-CP-IMP4 includes:

[0174] 1) Add 15g of BLST-CP-IMP2 to a four-necked flask, then add 75mL of methanol and 75mL of purified water, then add 8.8g of potassium hydroxide, and heat to 82℃ to react for 2h.

[0175] 2) Cool to 20-30℃, adjust the pH of the reaction solution to approximately 7 with glacial acetic acid, filter under reduced pressure, rinse the filter cake several times with 200mL of purified water, discard the filtrate, and dry the filter cake at 50℃ using a forced-air drying method. Purity: 99.23%.

[0176] The structure of BLST-CP-IMP4 is shown below, and the structural characterization parameters are shown in Table 2 and... Figure 2 As shown.

[0177]

[0178] Table 2: Structure Confirmation Information of Impurity BLST-CP-IMP4

[0179] Location 1H δ(ppm) J(Hz) 1,2 2H 7.16～7.09 m 3,6 2H 7.47～7.45 m 4 -- -- -- 5 -- -- -- 7 -- -- -- 8 1H 2.86～2.79 m 9 2H 1.87～1.78 m 10 2H 2.55～2.53 d 11 2H 2.12～2.07 t 12 2H 2.00～1.96 d 13 2H 3.03～3.00 d 14 2H 2.74～2.70 t 15 -- -- -- 16,20 2H 7.16～7.09 m 17,19 2H 7.27～7.25 d 18 -- -- -- 21 -- -- -- 22 -- -- -- 23,24 6H 1.41 s 25 -- -- -- 26 -- -- --

[0180] The present disclosure will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be construed as limiting the scope of the disclosure. Where specific techniques or conditions are not specified in the embodiments, they are performed in accordance with the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0181] Example 1

[0182] In this embodiment, bilastin was prepared based on the following synthetic route.

[0183]

[0184] 1. Preparation of BLST-1

[0185] 100g of BLST-SM1 was added to a four-necked flask and dissolved in 1000mL of methanol. Then, 33.66g of potassium carbonate was added to the reaction flask, the temperature was lowered to 0℃, and the mixture was stirred for 10 minutes. 116.76g of acid anhydride was dissolved in 500mL of methanol and added dropwise over 2 hours. 1600mL of purified water was added and stirred at room temperature for 1 hour. The mixture was then filtered, and the filter cake was washed several times with 200mL of purified water. 2400mL of cyclohexane was added, the mixture was heated to 60℃ and stirred for 1 hour, cooled to room temperature, filtered, and the filter cake was washed several times with 200mL of cyclohexane. The filter cake was dried to obtain BLST-1, with a yield of 93%.

[0186] 2. Preparation of BLST-2

[0187] 40 g of BLST-1, 600 mL of dioxane, 58.35 g of potassium tert-butoxide, and 3.44 g of 18-C-6 were added sequentially to a four-necked flask and stirred at room temperature for 30 min. Then, 23.30 g of 2-chloroethyl ether was added to the reaction mixture, and the temperature was raised to approximately 95 °C and maintained for 2 h. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed several times with dioxane to obtain BLST-2, with a yield of 100%.

[0188] 3. Preparation of BLST-3

[0189] The BLST-1 prepared above was added to n-butanol and stirred at room temperature. 55.3 mL of concentrated hydrochloric acid (12 mol / L) was added to a four-necked flask, and the reaction was allowed to proceed for 2–3 hours. After the reaction was complete, the reaction mixture was evaporated to dryness. Ethyl acetate was added, the mixture was stirred, and allowed to cool naturally to room temperature. The mixture was then filtered, and the filter cake was washed several times with ethyl acetate. The filter cake was then dried to obtain BLST-3, with a yield of 95%.

[0190] 4. Preparation of BLST-4

[0191] Add 20g of BLST-3 to a four-necked flask, then add 150mL of acetonitrile and 61.68g of anhydrous potassium phosphate, and heat to approximately 80℃. Separately, dissolve 38.40g of BLST-SM2 in 150mL of acetonitrile and add it dropwise to the above system, reacting for 2 hours. Add 10.08g of BLST-SM2 (dissolved in acetonitrile) and continue the reaction for 4 hours. Cool to room temperature, filter, wash the filter cake several times with acetonitrile, collect the filtrate, evaporate to dryness, dissolve in ethyl acetate, wash the EA phase with sodium carbonate solution, and discard the aqueous phase.

[0192] Prepare 1 mol / L dilute hydrochloric acid, back-extract the EA phase, collect the aqueous phase, adjust the pH to 7-8 with anhydrous sodium carbonate, filter, wash the filter cake several times with purified water, dry the filter cake, and obtain BLST-4 with a yield of 80%.

[0193] 5. Preparation of BLST-CP

[0194] Add the BLST-4 prepared above to a four-necked flask, then add 175 mL of methanol and 175 mL of purified water, and finally add 20.5 g of potassium hydroxide. Heat to 70 °C and keep the temperature for 2 h.

[0195] After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to about 6-7 with glacial acetic acid, filtered, the filter cake was washed several times with purified water, and the filter cake was dried to obtain crude BLST-CP with a yield of 80%.

[0196] 6. Purification of BLST-CP

[0197] Add 32.40 g of crude BLST-CP to a four-necked flask, then add 324 mL of purified water. Heat to 45°C and stir for 1 hour. After cooling the reaction solution to room temperature, filter under vacuum. Wash the filter cake several times with purified water, dry the filter cake, add it to a four-necked flask, add butyl acetate, heat to 80°C, and stir for 1 hour. After naturally cooling to room temperature, filter under vacuum. Wash the filter cake several times with butyl acetate and dry the filter cake.

[0198] The above filter cake was added to a four-necked flask, followed by n-butanol and isopropanol. The mixture was heated until the solution was completely dissolved. After the reaction solution was allowed to cool naturally to room temperature, it was filtered. The filter cake was washed several times with n-butanol / isopropanol, and then dried to obtain purified bilastine in a yield of 87%.

[0199] Example 2

[0200] Bilastin was prepared according to the method in Example 1, except that step 2 is as follows:

[0201] 1.5 g of BLST-1, 45 mL of N,N-dimethylformamide, and 0.6 g of sodium hydride were added sequentially to a four-necked flask and stirred at room temperature for 1 h. 2.71 g of 2-chloroethyl ether was added to the reaction mixture, and the temperature was raised to approximately 60 °C and maintained for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature, and extracted with 150 mL of toluene and 150 mL of purified water. The organic phase was collected and evaporated to dryness to obtain BLST-2 in 100% yield.

[0202] Example 3

[0203] Bilastin was prepared according to the method of Example 1, except that in step 2, the amount of potassium tert-butoxide added was 89.36 g (6 eq).

[0204] Example 4

[0205] Bilastin was prepared according to the method of Example 1, except that in step 2, the amount of potassium tert-butoxide added was 7.45 g (0.5 eq).

[0206] Example 5

[0207] Bilastin was prepared according to the method of Example 1, except that in step 2, the concentration of dioxane was 320 mL (8 mL / g).

[0208] Example 6

[0209] Bilastin was prepared according to the method in Example 1, except that in step 2, the concentration of dioxane was 1280 ml (32 mL / g).

[0210] Example 7

[0211] Bilastin was prepared according to the method of Example 1, except that in step 2, the amount of 2-chloroethyl ether added was 86.46 g (6 eq).

[0212] Example 8

[0213] Bilastin was prepared according to the method of Example 1, except that in step 2, the amount of 2-chloroethyl ether added was 7.20 g (0.5 eq).

[0214] Example 9

[0215] Bilastin was prepared according to the method of Example 1, except that in step 2, the temperature was raised to 60°C.

[0216] Example 10

[0217] Bilastin was prepared according to the method of Example 1, except that in step 2, the temperature was raised to 140°C.

[0218] Example 11

[0219] Bilastin was prepared according to the method in Example 1, except that in step 2, the reaction time was kept at a constant temperature for 0.5 h.

[0220] Example 12

[0221] Bilastin was prepared according to the method in Example 1, except that in step 2, the reaction time was kept at a constant temperature for 5 hours.

[0222] Example 13

[0223] Bilastin was prepared according to the method in Example 1, except that step 4 is as follows:

[0224] Add 20g of BLST-3 to a four-necked flask, then add 150mL of acetonitrile and 41.72g of N,N-diisopropylethylamine, raising the system temperature to approximately 80℃. Separately, dissolve 38.40g of BLST-SM2 in 150mL of acetonitrile and add it dropwise to the above system, reacting for 2 hours. Add 10.08g of BLST-SM2 (dissolved in acetonitrile) and continue the reaction for 4 hours. Cool to room temperature, evaporate the reaction solution to dryness, dissolve in ethyl acetate, wash the EA phase with 10% sodium carbonate solution, and discard the aqueous phase.

[0225] Prepare 1 mol / L dilute hydrochloric acid, back-extract the EA phase, collect the aqueous phase, adjust the pH to 7-8 with anhydrous sodium carbonate, and a large amount of solid precipitates. Filter, wash the filter cake several times with purified water, and dry the filter cake to obtain BLST-4, with a yield of 49.46%.

[0226] Test case

[0227] The contents of BLST-SM1, BLST-CP-IMP2, and BLST-CP-IMP4 in the filter cake dried in step 2 (hereinafter referred to as BLST-2 in Table 3) and step 3 (hereinafter referred to as BLST-3 in Table 3) of the preparation of bilastine in Examples 1-13 were determined respectively. The methods used for detection were liquid chromatography, and the results are shown in Table 3.

[0228] It can be seen that, overall, the BLST-CP prepared using the method of Example 1 has high purity, and BLST-CP-IMP1 and BLST-CP-IMP2 were not detected during the reaction.

[0229] As can be seen from Examples 1 and 2, when BLST-1 is used in the reaction system of 2-chloroethyl ether, potassium tert-butoxide and dioxane, the final BLST-CP produced has low impurities and high purity.

[0230] As can be seen from Examples 4, 7, 9, and 11, the addition of potassium tert-butoxide is too low, the addition of 2-chloroethyl ether is too high, the heating temperature in step 2 is too low, and the holding time is too short. This will result in a higher residual amount of impurity BLST-SM1 in BLST-2, which in turn leads to a higher amount of BLST-CP-IMP2 and BLST-CP-IMP4 generated, ultimately resulting in a lower purity of BLST-CP.

[0231] As can be seen from Examples 5 and 10, the amount of dioxane added was too low and the heating temperature in step 2 was too high, which caused step 2 to fail to proceed smoothly.

[0232] As can be seen from Examples 1 and 13, replacing anhydrous potassium phosphate in step 4 with N,N-diisopropylethylamine promotes the formation of BLST-CP-IMP2 and BLST-CP-IMP4, resulting in lower purity of BLST-CP.

[0233] Table 3. BLST-SM1 content, purity of finished lanolin product, and maximum single impurity content.

[0234]

[0235]

[0236] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," "some implementations," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0237] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. A process for the preparation of bilastine, characterized by, The method includes a reaction step using the compound shown in formula (I) and / or a salt of the compound shown in formula (I) as an intermediate, wherein the content of the compound shown in formula (II) in the product of the intermediate is not higher than 0.1 wt%.

2. The method of claim 1, wherein, The method includes the following reaction steps:

3. The method of claim 2, wherein, The first initial reaction system in which the compound of formula (II) generates the compound of formula (X) contains the compound of formula (II), Boc2O, methanol and potassium carbonate; Optionally, based on the mass of the compound shown in formula (II), the equivalent of Boc2O is 0.5 eq to 5 eq, and the concentration of methanol is 10 mL / g to 20 mL / g; Optionally, the reaction temperature for generating the compound of formula (X) from the compound of formula (II) is 0°C to 7°C, and the reaction time is 0.5h to 1.5h.

4. The method of claim 2, wherein, The second initial reaction system for generating the compound shown in formula (X) to the compound shown in formula (Y) contains the compound shown in formula (a), potassium tert-butoxide, and dioxane; Optionally, the second initial reaction system further includes a catalyst, said catalyst comprising 18-crown ether-6; Optionally, based on the mass of the compound shown in formula (X), the equivalent of the compound shown in formula (a) is 1 eq to 4 eq, the equivalent of the potassium tert-butoxide is 1 eq to 4 eq, the concentration of the dioxane is 10 mL / g to 30 mL / g; and / or, the concentration of the catalyst is 5% mol to 15% mol. And / or, the reaction temperature for generating the compound of formula (Y) from the compound of formula (X) is 80°C to 120°C, and the reaction time is 1h to 4h.

5. The method of claim 1, wherein, The reaction solution that produces the compound shown in formula (II) is filtered, the filter cake is washed and dried to obtain a dried product, wherein the content of the compound shown in formula (II) in the dried product is not higher than 0.1 wt%.

6. The method of claim 1, wherein, The chemical structure of the salt of the compound shown in formula (I) is shown in formula (III); The method includes the following reaction steps:

7. The method of claim 1, wherein, The chemical structure of the salt of the compound shown in formula (I) is shown in formula (III); The method includes the following reaction step (a):

8. The method according to claim 7, characterized in that, The third initial reaction system of reaction step (a) includes the compound shown in formula (IV), acetonitrile, and potassium phosphate; Optionally, based on the mass of the compound shown in formula (III), the equivalent number of the compound shown in formula (IV) is 1.2 eq to 2 eq, and the equivalent number of the potassium phosphate is 1 eq to 10 eq; Optionally, the concentration of the acetonitrile is 10 mL / g to 20 mL / g; and / or, the pH value of the third initial reaction system is 7 to 8; Optionally, the reaction temperature of reaction step (a) is 70°C to 90°C.

9. The method according to claim 7, characterized in that, The method includes the following reaction step (b): 。 10. The method according to claim 9, characterized in that, The reaction step (b) includes: first reacting the compound shown in formula (V), potassium hydroxide, methanol and water, and then mixing the resulting reaction solution with an acid solution to obtain the bilastin; Optionally, based on the mass of the compound shown in formula (V), the equivalent of potassium hydroxide is 1 eq to 5 eq, and the volume ratio of methanol to water is 1:(0.5 to 1.5). Optionally, the reaction temperature of reaction step (b) is 70°C to 80°C, and the reaction time is 2h to 3h. Optionally, the resulting reaction solution is mixed with an acid solution to a pH of 6-7, filtered, and the filter cake is collected and washed to obtain the bilastin.

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