A bilastine intermediate compound

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a bilastine intermediate compound. The present invention uses 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole as the starting material, and after being substituted by (E)-1,2-dibromoethylene, a new intermediate of bilastine, (E)-2-(1-(2-bromoethenyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole, is obtained. At the same time, the present invention provides a method for preparing bilastine using this new intermediate compound: (E)-2-(1-(2-bromoethenyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole reacts with 2-(4-boronophenyl)-2-methylpropanoic acid under the action of a catalyst, and the obtained product is reduced to obtain bilastine. The synthesis method of the new intermediate provided by the present invention is simple. The synthesis route for preparing bilastine using this new intermediate is short, the yield is high, the reaction conditions are mild, the process is stable, and it is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a bilastine intermediate compound. Background Art

[0002] Bilastine, chemically named 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid, with CAS number 202189-78-4, is an oral second-generation non-sedating histamine H1 receptor antagonist developed by FAES Farmaceutica in Spain. It was approved by the European Union in August 2012 for the treatment of allergic rhinitis and urticaria. This product selectively acts on peripheral histamine receptors, has no effect on other histamine receptors, has no cardiotoxicity, is rapidly absorbed after oral administration, and has good tolerance, safety and high bioavailability. Its chemical structural formula is:

[0003]

[0004] Currently, the main synthetic methods of bilastine are as follows:

[0005] ① Patents EP0818454, EP0580541, US5877187, CN1176964A, CN109694367A, CN1105716C, ES2151442, ES2151442A1, CN104402773A and CN103351380A use methyl 4-bromophenylacetate or its downstream intermediate as the raw material, and obtain 4-[2-methyl-2-(4,5-dihydro-4,4-dimethyl-oxazol-2-yl)ethyl]benzeneethanol through methylation, hydrolysis, carboxyl protection and Grignard reaction. After the hydroxyl group is replaced by a leaving group (such as Cl, Br, I, sulfonate, etc.), it is successively replaced by 2-(4-piperidinyl)-1H-benzoimidazole and 2-chloroethyl ether, and finally hydrolyzed to obtain the target product. The reaction route is as follows:

[0006]

[0007] However, this route has the following problems: ① Butyllithium or Grignard reagent is used in the reaction, which has poor group compatibility and requires anhydrous and anaerobic conditions, and the conditions are demanding; ② At the same time, ethylene oxide is a dangerous product, and the used methylation reagent methyl iodide has a low boiling point and high toxicity, and the operation safety is low; ③ And a relatively special oxazole ring is needed to protect the carboxyl group, and the reaction conditions are harsh; ④ The overall route is long, the yield is low, and it is not suitable for industrial production.

[0008] ②Synthesis of the important intermediate of bilastine in Chinese Patent CN104326909A and the literature, "Chinese Journal of Pharmaceuticals", 2015, 46(7): 677-679. Using α,α-dimethylphenylacetic acid ester as the starting material, α,α-dimethyl-4-(2-bromoethyl)phenylacetic acid methyl ester was prepared by Friedel-Crafts acylation and reduction reactions. After nucleophilic substitution reactions with 2-(4-piperidinyl)-1H-benzimidazole and 2-chloroethyl ethyl ether in sequence, bilastine was obtained by hydrolysis. The reaction route is as follows:

[0009]

[0010] In addition, in the above routes, 2-(4-piperidinyl)benzimidazole was used as the raw material, which contains two hydrogens that are easily substituted in the molecular structure, has high requirements for selectivity, harsh reaction conditions, and is prone to produce by-products.

[0011] ③Chinese Patent CN102675101A uses α,α-dimethylphenylacetic acid ester as the raw material, prepares α,α-dimethyl-4-(2-haloethyl)phenylacetic acid ester through Friedel-Crafts acylation and reduction reactions, and then reacts with 1-(2-ethoxyethyl)-2-(4-piperidinyl)-1H-benzimidazole through substitution, hydrolysis and other reactions to obtain the target product. The reaction route is as follows:

[0012]

[0013] However, this method uses the Wolff-Kishner-Huang Minglong method to reduce the carbonyl group, which requires high temperature and is relatively toxic; and the synthesis of 1-(2-ethoxyethyl)-2-(4-piperidinyl)-1H-benzimidazole requires reactions such as protecting group introduction, substitution, and deprotection, with cumbersome steps and is not suitable for industrial production.

[0014] ④Literatures J. Org. Chem., 1988, 53(6): 1170-1176, Synth. Commun., 2011, 41(9): 1394-1402 and Synthesis of the Key Intermediate of Bilastine, "Hebei Chemical Industry", 2013, 36(3): 14-15 use α,α-dimethyl-4-bromophenylacetic acid methyl ester as the raw material, and bilastine is prepared through Stille coupling reaction, followed by hydration, protecting group introduction, alkylation, deprotection and ester hydrolysis and other reactions. However, this method uses environmentally unfriendly organotin and borane dimethyl sulfide complex, and the post-treatment cost is high. The reaction route is as follows:

[0015]

[0016] ⑤ Patent WO2009102155 (CN101952273A) uses 4-bromophenethanol as a raw material, undergoes palladium-catalyzed coupling and sulfonylation, and then reacts with 1-(2-ethoxyethyl)-2-(4-piperidinyl)-1H-benzimidazole to obtain the target product through substitution, hydrolysis, etc. However, in this method, the synthesis of the key intermediate 2-(4-hydroxyethylphenyl)-2-methylpropionic acid ethyl ester is prepared by reacting p-bromophenethanol and 1-methoxy-1-(trimethylsilyloxy)-2-methyl-1-propylene as raw materials in the presence of catalyst bis(dibenzylideneacetone) palladium, tri-tert-butylphosphine and zinc fluoride. The reaction route is as follows:

[0017]

[0018] This reaction has three main disadvantages: ① The raw materials 1-methoxy-1-(trimethylsilyloxy)-2-methyl-1-propylene and the catalysts bis(dibenzylideneacetone)palladium and tri-tert-butylphosphine are extremely expensive, difficult to purchase, and difficult to preserve; ② The reaction requires extremely strict anhydrous and oxygen-free conditions, the operation is complicated, and the resulting product is difficult to purify; ③ The remaining palladium and phosphorus after the reaction is completed will cause serious pollution to the environment.

[0019] ⑥ The synthesis of important intermediates of bilastine in Chinese patent CN106146459A and literature, "Chinese Journal of Pharmaceutical Industry", 2016, 47 (11): 1363-1365, uses cheap and readily available 2-nitroaniline as a raw material, first reacts with 4-formylpiperidine-1-carboxylic acid tert-butyl ester through reduction-ring closure reaction to obtain 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester, then reacts with ethyl chloroether to undergo N-alkylation reaction and hydrolysis reaction, and finally reacts with sodium 2-methyl-2-(4-(2-(tosyloxy)ethyl)phenyl)propionate through substitution reaction to obtain bilastine. The reaction route is as follows:

[0020]

[0021] However, the compounds 4-formylpiperidine-1-carboxylic acid tert-butyl ester and sodium 2-methyl-2-(4-(2-(tosyloxy)ethyl)phenyl)propionate in the reaction route are not available on the market, so the reaction route is relatively long. In addition, during the synthesis of bilastine, purification for 20 hours is required, which greatly prolongs the process time and reduces the industrial production efficiency.

[0022] ⑦ Chinese Patent CN110903278 uses piperidine-4-carboxylic acid as the starting material. After being substituted by methyl α,α-dimethyl-4-(2-bromoethyl)phenylacetate, it is cyclized with o-phenylenediamine to obtain methyl α,α-dimethyl-4-(2-(4-(1H-benzo[d]imidazol-1-yl)piperidin-1-yl)ethyl)phenylacetate, and then undergoes N-alkylation reaction and hydrolysis reaction with chloroethyl ethyl ether to prepare bilastine. The reaction route is as follows:

[0023]

[0024] However, the starting material methyl α,α-dimethyl-4-(2-bromoethyl)phenylacetate in this process needs to be prepared by referring to the method in the literature "Synthesis of an Important Intermediate of Bilastine", "Chinese Journal of Pharmaceuticals", 2015, 46(7): 677-679 (prepared by Friedel-Crafts acylation reaction of methyl α,α-dimethylphenylacetate and bromoacetyl bromide first, and then reduction with trifluoroacetic acid / triethylsilane system). This not only prolongs the reaction steps, but also uses highly active AlCl3 as a catalyst in the Friedel-Crafts acylation reaction, with a large amount of its consumption. The post-treatment is not only dangerous, but also the large amount of aluminum salts generated affects the separation of the product. In addition, the operation cost of the reduction system is relatively high. At the same time, a large amount of condensing agents are used in the cyclization step, such as dicyclohexylcarbodiimide, N-hydroxysuccinimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, etc. This not only has poor atom economy, but also the post-treatment is equally cumbersome, making it difficult to achieve industrial-scale production.

[0025] ⑧ Chinese Patent CN111039922 uses 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropanoic acid as one starting material. After reacting with methyl iodide, it generates methyl 2-(4-(2-iodoethyl)phenyl)-2-methylpropanoate. Using tert-butyl 4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate as another starting material, the Boc protecting group is first removed, and then it reacts with methyl 2-(4-(2-iodoethyl)phenyl)-2-methylpropanoate, and the target product is obtained through ester hydrolysis. However, this process also uses methyl iodide with low toxicity and boiling point for iodination reaction, and the operation safety is relatively low. The reaction route is as follows:

[0026]

[0027] ⑨ Chinese patents CN110950837A and CN107365297A use 4-hydroxyethylphenyl tert-butyrate or its downstream intermediate as the starting material, first generate 4-acetaldehydephenyl tert-butyrate through oxidation reaction, then reduce and aminize with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole through NaBH4 or LiBH4 and then hydrolyze to obtain bilastine. However, the oxidation reaction is more dangerous to operate in industrialization, and it is also easy to obtain peroxidized acid impurities. The reaction route is as follows:

[0028] ⑩ Chinese patents CN104530002A and CN104177331A use p-methylphenylethanol or its downstream intermediate as the starting material, and obtain sulfonate after sulfonylation with p-toluenesulfonyl chloride, and then react with 1-ethoxyethyl-2-piperidinylbenzimidazole, and then bromine at the benzylic position, and then convert the carboxyl group into methyl ester after introducing carboxyl group at the benzylic position by Grignard reaction, and then hydrolyze at the benzylic position to dimethylate after methylation with dimethyl sulfate or iodomethane, and finally hydrolyze to obtain bilastine. Grignard reagent is used to introduce carboxyl group in the reaction, and anhydrous and oxygen-free operation is required, and the conditions are harsh, and industrialization is difficult; the reaction route is as follows:

[0029]

[0030] In view of the above-mentioned shortcomings in the current preparation process of bilastine, it is still a problem to be solved to study and find a process suitable for industrial production of bilastine with mild reaction conditions, simple operation process, high product yield and high purity. Summary of the invention

[0031] In view of the problems existing in the current bilastine preparation technology, the present invention provides a new bilastine intermediate compound and a preparation method thereof, and also provides a method for preparing bilastine using the new intermediate. The method has mild reaction conditions, a simple operation process, and the obtained target product has high purity and yield.

[0032] The specific technical solutions of the present invention are as follows:

[0033] The first aspect of the present invention provides a bilastine intermediate compound, the structure of which is shown in Formula I-1:

[0034]

[0035] The second aspect of the present invention provides a method for preparing a bilastine intermediate compound I-1, which specifically comprises the following steps: adding SM-1 and an acid binding agent to a reaction solvent at room temperature, adding (E)-1,2-dibromoethylene, controlling the temperature until the reaction is completed, and obtaining the intermediate I-1 through post-treatment.

[0036]

[0037] Preferably, the reaction solvent is selected from one or a combination of tetrahydrofuran, acetonitrile, 1,4-dioxane, and N,N-dimethylformamide, and N,N-dimethylformamide is particularly preferred.

[0038] Preferably, the acid-binding agent is selected from one or a combination of triethylamine, N,N-diisopropylethylamine, potassium carbonate, and sodium carbonate, and triethylamine is particularly preferred.

[0039] Preferably, the molar ratio of the compound SM-1, the acid-binding agent, and the compound SM-2 in the feeding is 1:1.6 - 3.0:1.0 - 1.5, and 1:2.2:1.05 is particularly preferred.

[0040] Preferably, the reaction temperature is 60 - 110 °C, and 80 - 85 °C is particularly preferred.

[0041] In a preferred embodiment, the post-treatment step is as follows: The reaction solution is cooled to room temperature, filtered, the filtrate is added to purified water, extracted with dichloromethane, the organic phases are combined, the combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to dryness to obtain the intermediate compound I-1.

[0042] The third aspect of the present invention provides a use of the compound I-1 for preparing bilastine.

[0043] The method for using the compound I-1 to prepare bilastine includes the following scheme:

[0044] The compound I-1 reacts with 2-(4-boronophenyl)-2-methylpropanoic acid under the action of a catalyst to obtain the compound I-2; the compound I-2 is reduced to obtain bilastine, and the synthetic route is as follows:

[0045]

[0046] Preferably, the above steps will be introduced in detail in the following part:

[0047] Preparation of the compound I-2

[0048] The preparation method of the compound I-2 specifically includes the following steps: Under the protection of an inert gas, at room temperature, the catalyst is added to the reaction solvent B, after stirring and mixing evenly, an alkali and purified water are added to the reaction solvent, the compound I-1 and the compound SM-3 are added, the temperature is controlled until the reaction ends, and the reaction is subjected to post-treatment to obtain the intermediate I-2.

[0049] Preferably, the catalyst is selected from one or a combination of Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2, and Pd(PPh3)2Cl2 is particularly preferred.

[0050] Preferably, the reaction solvent B is selected from one or a combination of 1,4-dioxane, toluene, N,N-dimethylformamide, and dimethyl sulfoxide, and dimethyl sulfoxide is particularly preferred.

[0051] Preferably, the base is selected from one of K2CO3, Na2CO3, K3PO4, Na3PO4, NaOAc, and KOAc, and K3PO4 is particularly preferred.

[0052] Preferably, the molar ratio of the compound I-1 to the compound SM-3, the base, and the catalyst in the feeding is 1:1.0 - 2.0:2.0 - 3.5:0.03 - 0.08, and 1:1.2:2.8:0.05 is particularly preferred.

[0053] Preferably, the reaction temperature is 80 - 110 °C.

[0054] Preferably, the inert gas is one or a combination of argon and nitrogen, and argon is particularly preferred.

[0055] In a preferred embodiment, the post-treatment step is to control the temperature until the reaction ends, then filter, add the filtrate to purified water, extract with an extractant, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the intermediate I-2; preferably, the extractant is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, and ethyl acetate is particularly preferred.

[0056] Preparation of Bilastine I

[0057] The preparation method of bilastine specifically includes the following steps: at room temperature, add the intermediate I-2, cyclohexene, and palladium carbon to the reaction solvent C, control the temperature until the reaction ends, and obtain the target product bilastine I after post-treatment of the reaction.

[0058] Preferably, the reaction solvent C is selected from one or a combination of toluene and xylene, and toluene is particularly preferred.

[0059] Preferably, the molar ratio of the compound I-2 to cyclohexene in the feeding is 1:1.4 - 2.6, and 1:1.8 is particularly preferred.

[0060] Preferably, the mass ratio of the compound I-2 to palladium carbon in the feeding is 1:0.05 - 0.15, and 1:0.1 is particularly preferred.

[0061] Preferably, the reaction temperature is 90 to 130 °C, and particularly preferably 105 to 110 °C.

[0062] Preferably, the post-treatment step is as follows: cooling the reaction solution to room temperature, filtering, washing the filtrate with purified water, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain bilastine I.

[0063] Advantages of the present invention:

[0064] 1. The present invention provides a new bilastine intermediate compound and a preparation method thereof. The new intermediate uses 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (SM-1) as a starting material, and the new intermediate compound is obtained by substituting with (E)-1,2-dibromoethylene. The synthesis method is simple, and no large impurities are generated in the subsequent substitution reaction.

[0065] 2. The new intermediate obtained in the present invention is coupled with 2-(4-boronophenyl)-2-methylpropanoic acid by Suzuki coupling and then reduced to obtain bilastine. The preparation process of bilastine of the present invention has a higher yield and purity compared with the products obtained by the prior art, and is simple and safe to operate, suitable for industrial production. Specific embodiments

[0066] The present invention will be further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, any simple improvement of the present invention under the premise of the method of the present invention belongs to the scope claimed by the present invention.

[0067] The structure confirmation data of the intermediate and product obtained in the present invention are as follows:

[0068]

[0069] ESI-HRMS (m / z): 380.1158 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.56~7.50 (m, 1H), 7.48~7.43 (m, 1H), 7.20~7.09 (m, 2H), 6.52 (d, J = 15.8 Hz, 1H), 5.07 (d, J = 15.8 Hz, 1H), 4.46 (t, J = 6.9 Hz, 2H), 3.80 (t, J = 6.9 Hz, 2H), 3.66~3.40 (m, 4H), 3.11~2.92 (m, 1H), 2.76~2.56 (m, 2H), 2.30~2.14 (m, 2H), 2.06~1.90 (m, 2H), 1.22 (t, J = 6.8 Hz, 3H);13 13C NMR (101 MHz, DMSO-d6): δ 162.35, 145.80, 138.62, 136.48, 123.50, 122.51, 119.86, 111.81, 78.95, 70.18, 66.68, 48.50, 46.37, 29.15, 27.91, 14.84.

[0070]

[0071] ESI-HRMS (m / z): 460.5978 [M+H] - ; 1 1H NMR (400 MHz, DMSO-d6) δ 7.62~7.54 (m, 3H), 7.52 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.22~7.14 (m, 2H), 5.12 (d, J = 16.1 Hz, 1H), 4.45 (t, J = 6.6 Hz, 2H), 4.00~3.90 (m, 1H), 3.82 (t, J = 6.6 Hz, 2H), 3.49 (d, J = 6.8 Hz, 2H), 3.45~3.33 (m, 2H), 3.16~3.04 (m, 2H), 2.34~2.20 (m, 2H), 1.85~1.74 (m, 2H), 1.66 (s, 6H), 1.20 (t, J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, DMSO-d6): δ 182.78, 162.30, 145.25, 138.80, 138.17, 136.51, 131.41, 128.68, 126.33, 123.52, 122.53, 119.98, 112.81, 95.68, 71.18, 66.87, 48.48, 47.69, 46.35, 29.14, 27.90, 22.80, 14.87.

[0072]

[0073] ESI-HRMS (m / z): 464.2929 [M+H] + ; 11H NMR (400 MHz, CD3OD) δ 7.63 - 7.49 (m, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.31 - 7.21 (m, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.51 (t, J = 4.8 Hz, 2H), 3.77 (t, J = 4.8 Hz, 2H), 3.58 (d, J = 12.3 Hz, 2H), 3.43 (q, J = 6.9 Hz, 3H), 3.12 - 3.07 (m, 2H), 2.96 - 2.82 (m, 4H), 2.28 - 2.17 (m, 4H), 1.51 (s, 6H), 1.08 (t, J = 6.9 Hz, 3H); 13 13C NMR (101 MHz, CD3OD): δ 183.3, 158.6, 147.9, 147.5, 135.4, 134.7, 132.6, 132.5, 130.6, 130.1, 129.8, 129.8, 118.1, 116.7, 71.1, 70.5, 55.6, 50.1, 49.8, 49.3, 34.7, 33.4, 31.4, 29.6, 29.5, 22.1, 20.9, 17.9.

[0074] The purity of bilastine in the present invention is determined by HPLC, and the chromatographic conditions are as follows:

[0075] Chromatographic column: YMC - Triart C 18 Column (4.6 mm × 150 mm, 5 μm) or a chromatographic column with equivalent efficiency;

[0076] Mobile phase A: 10 mmol / L dipotassium hydrogen phosphate: acetonitrile: tetrahydrofuran (adjusted to pH 7.0 with phosphoric acid) (750:150:100);

[0077] Mobile phase B: 10 mmol / L dipotassium hydrogen phosphate: acetonitrile: tetrahydrofuran (adjusted to pH 8.0 with phosphoric acid) (150:800:50);

[0078] Gradient elution (0 - 30 min: A 100% - 70%, 30 - 50 min: A 75% - 0%, 50 - 60 min, 0% - 0%);

[0079] Column temperature: 50 °C;

[0080] Detection wavelength: 210 nm;

[0081] Flow rate: 0.8 ml / min;

[0082] Injection volume: 10 μl;

[0083] Among them, the retention time of bilastine is about 17.7 min.

[0084] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0085] Synthesis of Intermediate I-1

[0086] Example 1

[0087] At room temperature, 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (SM-1, 54.68 g, 0.20 mol) and triethylamine (44.52 g, 0.44 mol) were added to N,N-dimethylformamide (300 ml). A solution of (E)-1,2-dibromoethylene (SM-2, 39.03 g, 0.21 mol) in N,N-dimethylformamide (100 ml) was added. The temperature was controlled at 80-85 °C for reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to purified water (2000 ml). It was extracted with dichloromethane (600 ml × 3). The organic phases were combined, washed with saturated brine (500 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-1, with a yield of 88.6% and a purity of 99.62%.

[0088] Example 2

[0089] At room temperature, 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (SM-1, 54.68 g, 0.20 mol) and N,N-diisopropylethylamine (56.87 g, 0.44 mol) were added to N,N-dimethylformamide (300 ml). A solution of (E)-1,2-dibromoethylene (SM-2, 37.17 g, 0.20 mol) in N,N-dimethylformamide (100 ml) was added. The temperature was controlled at 105-110 °C for reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to purified water (2000 ml). It was extracted with dichloromethane (600 ml × 3). The organic phases were combined, washed with saturated brine (500 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-1, with a yield of 84.3% and a purity of 99.23%.

[0090] Example 3

[0091] At room temperature, 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (SM-1, 54.68 g, 0.20 mol) and potassium carbonate (60.81 g, 0.44 mol) were added to tetrahydrofuran (300 ml). A solution of (E)-1,2-dibromoethylene (SM-2, 55.76 g, 0.30 mol) in tetrahydrofuran (100 ml) was added, and the reaction was carried out at 60 °C to 66 °C. After detecting that the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to purified water (2000 ml). It was extracted with dichloromethane (600 ml × 3), the organic phases were combined, washed with saturated brine (500 ml × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-1, with a yield of 85.2% and a purity of 99.21%.

[0092] Example 4

[0093] At room temperature, 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (SM-1, 54.68 g, 0.20 mol) and sodium carbonate (46.64 g, 0.44 mol) were added to acetonitrile (300 ml). A solution of (E)-1,2-dibromoethylene (SM-2, 63.19 g, 0.34 mol) in acetonitrile (100 ml) was added, and the reaction was carried out at 55 °C to 60 °C. After detecting that the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to purified water (2000 ml). It was extracted with dichloromethane (600 ml × 3), the organic phases were combined, washed with saturated brine (500 ml × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-1, with a yield of 80.1% and a purity of 98.81%.

[0094] Example 5

[0095] At room temperature, 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (SM-1, 54.68 g, 0.20 mol) and triethylamine (32.38 g, 0.32 mol) were added to acetonitrile (300 ml). A solution of (E)-1,2-dibromoethylene (SM-2, 39.03 g, 0.21 mol) in acetonitrile (100 ml) was added, and the reaction was carried out by refluxing at 80 to 85 °C. After detecting that the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to purified water (2000 ml). It was extracted with dichloromethane (600 ml × 3), the organic phases were combined, washed with saturated brine (500 ml × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-1, with a yield of 84.0% and a purity of 99.32%.

[0096] Example 6

[0097] At room temperature, 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (SM-1, 54.68 g, 0.20 mol) and triethylamine (60.71 g, 0.60 mol) were added to 1,4-dioxane (300 ml). A solution of (E)-1,2-dibromoethylene (SM-2, 39.03 g, 0.21 mol) in 1,4-dioxane (100 ml) was added, and the reaction was carried out at 90-95 °C. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to purified water (2000 ml). It was extracted with dichloromethane (600 ml × 3), the organic phases were combined, washed with saturated brine (500 ml × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-1, with a yield of 84.8% and a purity of 99.18%.

[0098] Example 7

[0099] At room temperature, 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (SM-1, 54.68 g, 0.20 mol) and triethylamine (28.33 g, 0.28 mol) were added to N,N-dimethylformamide (300 ml). A solution of (E)-1,2-dibromoethylene (SM-2, 39.03 g, 0.21 mol) in N,N-dimethylformamide (100 ml) was added, and the reaction was carried out at 110-115 °C. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to purified water (2000 ml). It was extracted with dichloromethane (600 ml × 3), the organic phases were combined, washed with saturated brine (500 ml × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-1, with a yield of 80.8% and a purity of 98.92%.

[0100] Example 8

[0101] At room temperature, 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (SM-1, 54.68 g, 0.20 mol) and triethylamine (64.76 g, 0.64 mol) were added to 1,4-dioxane (300 ml). A solution of (E)-1,2-dibromoethylene (SM-2, 39.03 g, 0.21 mol) in 1,4-dioxane (100 ml) was added, and the reaction was carried out at 55-60 °C. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to purified water (2000 ml). It was extracted with dichloromethane (600 ml × 3), the organic phases were combined, washed with saturated brine (500 ml × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-1, with a yield of 81.6% and a purity of 98.82%.

[0102] Synthesis of Compound I-2

[0103] Example 9

[0104] Under the protection of argon at room temperature, Pd(PPh3)2Cl2 (3.51 g, 5.0 mmol) was added to dimethyl sulfoxide (200 ml). After stirring and mixing evenly, an aqueous solution of K3PO4 (59.43 g, 0.28 mol) in purified water (120 ml) was added to the reaction solvent, followed by Compound I-1 (37.83 g, 0.10 mol) and 2-(4-boronophenyl)-2-methylpropanoic acid (SM-3, 24.97 g, 0.12 mol). The reaction was carried out at 90 - 95 °C. After detecting the completion of the reaction, the mixture was filtered. The filtrate was added to purified water (500 ml), and extracted with ethyl acetate (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-2 with a yield of 96.6% and a purity of 99.85%.

[0105] Example 10

[0106] Under the protection of argon at room temperature, Pd(PPh3)4 (5.78 g, 5.0 mmol) was added to dimethyl sulfoxide (200 ml). After stirring and mixing evenly, an aqueous solution of K2CO3 (38.70 g, 0.28 mol) in purified water (50 ml) was added to the reaction solvent, followed by Compound I-1 (37.83 g, 0.10 mol) and 2-(4-boronophenyl)-2-methylpropanoic acid (SM-3, 20.02 g, 0.10 mol). The reaction was carried out at 100 - 105 °C. After detecting the completion of the reaction, the mixture was filtered. The filtrate was added to purified water (500 ml), and extracted with methyl tert-butyl ether (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-2 with a yield of 93.5% and a purity of 99.62%.

[0107] Example 11

[0108] Under the protection of argon at room temperature, Pd(dppf)Cl2 (3.66 g, 5.0 mmol) was added to 1,4-dioxane (200 ml). After stirring and mixing evenly, an aqueous solution of Na2CO3 (29.68 g, 0.28 mol) in purified water (130 ml) was added to the reaction solvent, followed by Compound I-1 (37.83 g, 0.10 mol) and 2-(4-boronophenyl)-2-methylpropanoic acid (40.04 g, 0.2 mol). The reaction was carried out at 85 - 90 °C. After detecting the completion of the reaction, the mixture was filtered. The filtrate was added to purified water (500 ml), and extracted with ethyl acetate (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-2 with a yield of 92.9% and a purity of 99.56%.

[0109] Example 12

[0110] Under the condition of argon protection at room temperature, Pd(dppf)Cl2 (3.66 g, 5.0 mmol) was added to dimethyl sulfoxide (200 ml). After stirring and mixing evenly, an aqueous solution of NaOAc (22.96 g, 0.28 mol) in purified water (130 ml) was added to the reaction solvent, and compound I-1 (37.83 g, 0.10 mol) and 2-(4-boronophenyl)-2-methylpropanoic acid (44.04 g, 0.22 mol) were added. The reaction was carried out at 110-115 °C. After detecting that the reaction was completed, filtration was carried out. The filtrate was added to purified water (500 ml), and extracted with chloroform (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain intermediate I-2 with a yield of 89.3% and a purity of 98.96%.

[0111] Example 13

[0112] Under the condition of argon protection at room temperature, Pd(PPh3)2Cl2 (3.51 g, 5.0 mmol) was added to dimethyl sulfoxide (200 ml). After stirring and mixing evenly, an aqueous solution of K3PO4 (42.45 g, 0.20 mol) in purified water (100 ml) was added to the reaction solvent, and compound I-1 (37.83 g, 0.10 mol) and 2-(4-boronophenyl)-2-methylpropanoic acid (24.97 g, 0.12 mol) were added. The reaction was carried out at 95-100 °C. After detecting that the reaction was completed, filtration was carried out. The filtrate was added to purified water (500 ml), and extracted with dichloromethane (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain intermediate I-2 with a yield of 94.2% and a purity of 99.61%.

[0113] Example 14

[0114] Under the condition of argon protection at room temperature, Pd(PPh3)2Cl2 (3.51 g, 5.0 mmol) was added to toluene (200 ml). After stirring and mixing evenly, an aqueous solution of Na3PO4 (57.38 g, 0.35 mol) in purified water (120 ml) was added to the reaction solvent, and compound I-1 (37.83 g, 0.10 mol) and 2-(4-boronophenyl)-2-methylpropanoic acid (24.97 g, 0.12 mol) were added. The reaction was carried out at 80-85 °C. After detecting that the reaction was completed, filtration was carried out. The organic phase was separated by liquid separation and washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain intermediate I-2 with a yield of 93.6% and a purity of 99.58%.

[0115] Example 15

[0116] Under argon protection at room temperature, Pd(PPh3)2Cl2 (3.51 g, 5.0 mmol) was added to toluene (200 ml). After stirring and mixing evenly, an aqueous solution of Na3PO4 (29.51 g, 0.18 mol) in purified water (120 ml), Compound I-1 (37.83 g, 0.10 mol) and 2-(4-boronophenyl)-2-methylpropanoic acid (24.97 g, 0.12 mol) were added to the reaction solvent. The reaction was carried out at 75-80 °C. After detecting that the reaction was completed, filtration was performed. The organic phase was separated by liquid separation, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-2 with a yield of 90.6% and a purity of 99.88%.

[0117] Example 16

[0118] Under argon protection at room temperature, Pd(PPh3)2Cl2 (3.51 g, 5.0 mmol) was added to dimethyl sulfoxide (200 ml). After stirring and mixing evenly, an aqueous solution of Na3PO4 (60.66 g, 0.37 mol) in purified water (120 ml), Compound I-1 (37.83 g, 0.10 mol) and 2-(4-boronophenyl)-2-methylpropanoic acid (24.97 g, 0.12 mol) were added to the reaction solvent. The reaction was carried out at 110-115 °C. After detecting that the reaction was completed, filtration was performed. The organic phase was separated by liquid separation, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain Intermediate Compound I-2 with a yield of 89.9% and a purity of 98.88%.

[0119] Example 17

[0120] Under argon protection at room temperature, Pd(PPh3)2Cl2 (2.11 g, 3.0 mmol) was added to dimethyl sulfoxide (200 ml). After stirring and mixing evenly, an aqueous solution of NaOAc (22.97 g, 0.28 mol) in purified water (80 ml), Compound I-1 (37.83 g, 0.10 mol) and 2-(4-boronophenyl)-2-methylpropanoic acid (24.97 g, 0.12 mol) were added to the reaction solvent. The reaction was carried out at 90-95 °C. After detecting that the reaction was completed, filtration was performed. The filtrate was added to purified water (500 ml), and extracted with ethyl acetate (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain Intermediate I-2 with a yield of 93.8% and a purity of 99.72%.

[0121] Example 18

[0122] Under nitrogen protection at room temperature, Pd(PPh3)2Cl2 (5.62 g, 8.0 mmol) was added to N,N-dimethylformamide (200 ml). After stirring and mixing evenly, a solution of KOAc (27.48 g, 0.28 mol) in purified water (30 ml), compound I-1 (37.83 g, 0.10 mol), and 2-(4-boronophenyl)-2-methylpropanoic acid (24.97 g, 0.12 mol) were added to the reaction solvent. The reaction was carried out at 90-95 °C. After detecting that the reaction was completed, filtration was performed. The filtrate was added to purified water (500 ml), and extracted with ethyl acetate (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain intermediate I-2 with a yield of 94.6% and a purity of 99.52%.

[0123] Example 19

[0124] Under argon protection at room temperature, Pd(PPh3)2Cl2 (0.70 g, 1.0 mmol) was added to dimethyl sulfoxide (200 ml). After stirring and mixing evenly, a solution of NaOAc (22.97 g, 0.28 mol) in purified water (80 ml), compound I-1 (37.83 g, 0.10 mol), and 2-(4-boronophenyl)-2-methylpropanoic acid (SM-3, 24.97 g, 0.12 mol) were added to the reaction solvent. The reaction was carried out at 75-80 °C. After detecting that the reaction was completed, filtration was performed. The filtrate was added to purified water (500 ml), and extracted with ethyl acetate (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain intermediate I-2 with a yield of 89.6% and a purity of 98.92%.

[0125] Example 20

[0126] Under argon protection at room temperature, Pd(PPh3)2Cl2 (7.01 g, 10.0 mmol) was added to dimethyl sulfoxide (200 ml). After stirring and mixing evenly, a solution of KOAc (27.48 g, 0.28 mol) in purified water (80 ml), compound I-1 (37.83 g, 0.10 mol), and 2-(4-boronophenyl)-2-methylpropanoic acid (SM-3, 24.97 g, 0.12 mol) were added to the reaction solvent. The reaction was carried out at 110-115 °C. After detecting that the reaction was completed, filtration was performed. The filtrate was added to purified water (500 ml), and extracted with ethyl acetate (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain intermediate I-2 with a yield of 90.3% and a purity of 98.88%.

[0127] Synthesis of Compound I

[0128] Example 21

[0129] At room temperature, add intermediate I-2 (23.08 g, 0.05 mol), cyclohexene (7.39 g, 0.09 mol), and 10% palladium on carbon (2.31 g) to toluene (250 ml), control the temperature at 105 - 110 °C for reaction. After detecting that the reaction is completed, cool the reaction solution to room temperature, filter, wash the filtrate with purified water (80 ml × 2), wash with saturated brine (80 ml × 2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product bilastine I, with a yield of 96.8% and a purity of 99.90%.

[0130] Example 22

[0131] At room temperature, add intermediate I-2 (23.08 g, 0.05 mol), cyclohexene (5.75 g, 0.07 mol), and 10% palladium on carbon (2.31 g) to xylene (250 ml), control the temperature at 125 - 130 °C for reaction. After detecting that the reaction is completed, cool the reaction solution to room temperature, filter, wash the filtrate with purified water (80 ml × 2), wash with saturated brine (80 ml × 2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product bilastine I, with a yield of 92.3% and a purity of 99.63%.

[0132] Example 23

[0133] At room temperature, add intermediate I-2 (23.08 g, 0.05 mol), cyclohexene (10.68 g, 0.13 mol), and 10% palladium on carbon (2.31 g) to toluene (250 ml), control the temperature at 105 - 110 °C for reaction. After detecting that the reaction is completed, cool the reaction solution to room temperature, filter, wash the filtrate with purified water (80 ml × 2), wash with saturated brine (80 ml × 2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product bilastine I, with a yield of 93.0% and a purity of 99.60%.

[0134] Example 24

[0135] At room temperature, add intermediate I-2 (23.08 g, 0.05 mol), cyclohexene (4.93 g, 0.06 mol), and 10% palladium on carbon (2.31 g) to xylene (250 ml), control the temperature at 100 - 105 °C for reaction. After detecting that the reaction is completed, cool the reaction solution to room temperature, filter, wash the filtrate with purified water (80 ml × 2), wash with saturated brine (80 ml × 2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product bilastine I, with a yield of 88.6% and a purity of 99.03%.

[0136] Example 25

[0137] At room temperature, intermediate I-2 (23.08 g, 0.05 mol), cyclohexene (11.50 g, 0.14 mol), and 10% palladium on carbon (2.31 g) were added to toluene (250 ml). The temperature was controlled at 110 - 115 °C for the reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was washed with purified water (80 ml × 2), washed with saturated brine (80 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product bilastine I, with a yield of 89.1% and a purity of 98.96%.

[0138] Example 26

[0139] At room temperature, intermediate I-2 (23.08 g, 0.05 mol), cyclohexene (7.39 g, 0.09 mol), and 10% palladium on carbon (1.15 g) were added to toluene (250 ml). The temperature was controlled at 105 - 110 °C for the reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was washed with purified water (80 ml × 2), washed with saturated brine (80 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product bilastine I, with a yield of 92.9% and a purity of 99.63%.

[0140] Example 27

[0141] At room temperature, intermediate I-2 (23.08 g, 0.05 mol), cyclohexene (7.39 g, 0.09 mol), and 10% palladium on carbon (3.46 g) were added to toluene (250 ml). The temperature was controlled at 105 - 110 °C for the reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was washed with purified water (80 ml × 2), washed with saturated brine (80 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product bilastine I, with a yield of 93.3% and a purity of 99.58%.

[0142] Example 28

[0143] At room temperature, intermediate I-2 (23.08 g, 0.05 mol), cyclohexene (7.39 g, 0.09 mol), and 10% palladium on carbon (0.70 g) were added to toluene (250 ml). The temperature was controlled at 85 - 90 °C for the reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was washed with purified water (80 ml × 2), washed with saturated brine (80 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product bilastine I, with a yield of 88.9% and a purity of 99.03%.

[0144] Example 29

[0145] At room temperature, intermediate I-2 (23.08 g, 0.05 mol), cyclohexene (7.39 g, 0.09 mol), and 10% palladium on carbon (3.92 g) were added to toluene (250 ml). The temperature was controlled at 110-115 °C for reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was washed with purified water (80 ml × 2), saturated brine (80 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product bilastine I, with a yield of 87.4% and a purity of 98.92%.

Claims

1. A bilastine intermediate compound, characterized in that, Its structure is shown in Formula I-1: 。 2. A method for preparing the bilastine intermediate compound according to claim 1, characterized in that, It includes the following steps: At room temperature, add SM-1 and an acid-binding agent into reaction solvent A, add compound SM-2, control the temperature until the reaction ends, and obtain intermediate compound I-1 through post-treatment. The synthetic route is as follows: 。 3. According to the preparation method described in claim 2, characterized in that, The acid-binding agent is selected from one of triethylamine, N , N -diisopropylethylamine, potassium carbonate, and sodium carbonate.

4. According to the preparation method described in claim 2, characterized in that, The molar ratio of the compound SM-1, the acid-binding agent, and the compound SM-2 in the feed is 1: 1.6~3.0: 1.0~1.

5.

5. According to the preparation method described in claim 2, characterized in that, The reaction solvent A is selected from one or a combination of tetrahydrofuran, acetonitrile, 1,4-dioxane, N , N -dimethylformamide; the reaction temperature is 60 °C to 110 °C.

6. The use of the bilastine intermediate compound according to claim 1 for the preparation of bilastine.

7. According to the use of the bilastine intermediate compound according to claim 6 for the preparation of bilastine, characterized in that, It includes the following steps: (1) Under the protection of an inert gas and at room temperature, add a catalyst into reaction solvent B, stir and mix evenly, then add a base and purified water, add compound I-1 and compound SM-3, control the temperature until the reaction ends, and obtain intermediate I-2 after the reaction is post-treated; (2) At room temperature, add intermediate I-2, cyclohexene, and palladium carbon into reaction solvent C, control the temperature until the reaction ends, and obtain the target product bilastine after the reaction is post-treated. The synthetic route is as follows: 。 8. According to the use described in claim 7, characterized in that, The catalyst described in step (1) is selected from one of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2; the base is selected from one of K2CO3, Na2CO3, K3PO4, Na3PO4, NaOAc, KOAc.

9. According to the use described in claim 7, characterized in that, In step (1), the molar ratio of the compound I-1, the compound SM-3, the base, and the catalyst in the feed is 1: 1.0~2.0: 2.0~3.5: 0.03~0.08; the reaction solvent B is selected from one or a combination of 1,4-dioxane, toluene, N,N-dimethylformamide, dimethyl sulfoxide; the reaction temperature is 80~110 °C.

10. According to the use described in claim 7, characterized in that, In step (2), the molar ratio of the compound I-2 and cyclohexene in the feed is 1: 1.4~2.6; the mass ratio of the compound I-2 and palladium carbon in the feed is 1: 0.05~0.15; the reaction temperature is 90~130 °C.

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