A Bilastine intermediate compound and its preparation method

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a bilastine intermediate compound and a preparation method thereof. In the present invention, (E)-2-(1-(2-bromovinyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole is used as a starting material to react with bis(pinacolato)diboron and methyl 2-(4-bromophenyl)-2-methylpropionate to obtain a new intermediate compound, methyl (E)-2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazole-2-yl)piperidin-1-yl)vinyl)phenyl)-2-methylpropionate. At the same time, the present invention provides a method for preparing an important intermediate of bilastine, methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate, by reducing the new intermediate compound. The synthesis method of the new intermediate in the present invention is simple, and the important intermediate of bilastine synthesized has a higher yield and purity compared with the prior art, and the operation is simple and safe, which is suitable for 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 and a preparation method thereof. Background Art

[0002] Bilastine, with the chemical name of 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid and CAS number 202189-78-4, is a second-generation oral 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.

[0003] Its chemical structural formula is:

[0004]

[0005] For the synthesis of bilastine, the most commonly used method at present is to first synthesize the key intermediate 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate through multiple steps, and then hydrolyze this ester to obtain bilastine.

[0006] Chinese Patent CN104326909A and the literature "Synthesis of an Important Intermediate of Bilastine", Chinese Journal of Pharmaceuticals, 2015, 46(7): 677-679 use α,α-dimethylphenylacetate as the starting material, first prepare methyl α,α-dimethyl-4-(2-bromoethyl) phenylacetate through Friedel-Crafts acylation and reduction reactions, and then successively carry out nucleophilic substitution reactions with 2-(4-piperidinyl)-1H-benzimidazole and 2-chloroethyl ether to obtain methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate, and then hydrolyze it to obtain bilastine.

[0007] The reaction route is as follows:

[0008]

[0009] In addition, in the above route, using 2-(4-piperidinyl)benzimidazole as the raw material, the molecular structure contains two hydrogens that are easily substituted, with high requirements for selectivity, harsh reaction conditions, and prone to by-products.

[0010] Chinese patent CN102675101A uses α,α-dimethylphenylacetic acid ester as raw material, and obtains α,α-dimethyl-4-(2-haloethyl)phenylacetic acid ester through Friedel-Crafts acylation and reduction reaction, and then replaces it with 1-(2-ethoxyethyl)-2-(4-piperidinyl)-1H-benzimidazole to obtain the intermediate 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid methyl ester, and hydrolyzes it to obtain the target product.

[0011] 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 high toxicity. In addition, the synthesis of 1-(2-ethoxyethyl)-2-(4-piperidinyl)-1H-benzimidazole requires reactions such as adding protecting groups, substitution, and deprotecting groups, which is cumbersome and not suitable for industrial production.

[0014] References Synth. Commun., 2011, 41(9): 1394-1402, J. Org. Chem., 1988, 53(6): 1170-1176 and Synthesis of Key Intermediates of Bilastine, Hebei Chemical Industry, 2013, 36(3): 14-15 use α,α-dimethyl-4-bromophenylacetic acid methyl ester as raw material, through Stille coupling reaction, and then through hydration, protection group addition, alkylation, deprotection group removal and ester hydrolysis to obtain Bilastine. However, this method uses environmentally unfriendly organic tin and borane dimethyl sulfide complexes, and the post-processing cost is high.

[0015] The reaction route is as follows:

[0016]

[0017] 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 obtained 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.

[0018] The reaction route is as follows:

[0019]

[0020] 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.

[0021] Chinese patent CN110903278A uses piperidine-4-carboxylic acid as the starting material, which is substituted by α,α-dimethyl-4-(2-bromoethyl)phenylacetic acid methyl ester, and then cyclized with o-phenylenediamine to obtain α,α-dimethyl-4-(2-(4-(1H-2-benzo[d]imidazolyl)piperidin-1-yl)ethyl)phenylacetic acid methyl ester, which is then subjected to N-alkylation reaction and hydrolysis reaction with chloroethyl ether to obtain bilastine.

[0022] The reaction route is as follows:

[0023]

[0024] However, the starting material α,α-dimethyl-4-(2-bromoethyl)phenylacetic acid methyl ester in this process needs to be prepared by referring to the method in the literature Synthesis of Important Intermediates of Bilastin, "Chinese Journal of Pharmaceutical Industry", 2015, 46(7):677-679 (α,α-dimethyl-phenylacetic acid methyl ester and bromoacetyl bromide are first subjected to Friedel-Crafts acylation reaction and then reduced by trifluoroacetic acid / triethylsilane system). This not only prolongs the reaction steps, but also the Friedel-Crafts acylation reaction uses highly active AlCl3 catalysis, which is large in amount and dangerous in post-processing. At the same time, a large amount of aluminum salts produced affect the separation of the product. In addition, the operating cost of the reduction system is 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., which not only have poor atom economy, but also have complicated post-processing, making it difficult to achieve industrial scale-up production.

[0025] Chinese patent CN111039922A uses 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropionic acid as a starting material, reacts with iodomethane to generate 2-(4-(2-iodoethyl)phenyl)-2-methylpropionic acid methyl ester, and uses 4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester as another starting material, first removes the Boc protecting group, then reacts with 2-(4-(2-iodoethyl)phenyl)-2-methylpropionic acid methyl ester, and then hydrolyzes the ester to obtain the target product. However, this process also uses iodomethane with low toxicity and boiling point for iodination reaction, and the operation safety is low.

[0026] The reaction route is as follows:

[0027]

[0028] Chinese patents CN110950837A and CN107365297A use 4-hydroxyethylphenyl tert-butyrate or its downstream intermediate as the starting material. First, 4-acetaldehydephenyl tert-butyrate is generated through an oxidation reaction, and then it reacts with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole. After reductive amination with NaBH4 or LiBH4 and then hydrolysis, bilastine is obtained. However, the oxidation reaction is relatively dangerous in industrialization, and at the same time, it is easy to obtain peroxy acid impurities.

[0029] The reaction route is as follows:

[0030]

[0031] Chinese patents CN104530002A and CN104177331A use p-methylphenethyl alcohol or its downstream intermediate as the starting material. After sulfonylation with p-toluenesulfonyl chloride to obtain a sulfonate ester, it reacts with 1-ethoxyethyl-2-piperidinylbenzimidazole, and then bromination occurs at the benzyl position. After introducing a carboxyl group at the benzyl position through a Grignard reaction, the carboxyl group is converted into a methyl ester. Finally, methyl is introduced with dimethyl sulfate or iodomethane and then hydrolysis is carried out for dimethylation at the benzyl position, and finally a hydrolysis reaction is carried out to obtain bilastine. The use of a Grignard reagent to introduce a carboxyl group in the reaction requires anhydrous and anaerobic operation, with harsh conditions and great difficulty in industrialization;

[0032] The reaction route is as follows:

[0033]

[0034] In addition, Chinese patent CN106146459A and the literature "Synthesis of an Important Intermediate of Bilastine", Chinese Journal of Pharmaceuticals, 2016, 47(11): 1363-1365 use cheap and easily available 2-nitroaniline as the raw material. First, it reacts with tert-butyl 4-formylpiperidine-1-carboxylate through a reduction-cyclization reaction to obtain tert-butyl 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate, and then it undergoes an N-alkylation reaction, a hydrolysis reaction with chloroethyl ethyl ether, and finally a substitution reaction with sodium 2-methyl-2-(4-(2-(tosyloxy)ethyl)phenyl)propionate to obtain bilastine.

[0035] The reaction route is as follows:

[0036]

[0037] However, in this reaction route, tert-butyl 4-formylpiperidine-1-carboxylate and sodium 2-methyl-2-(4-(2-(tosyloxy)ethyl)phenyl)propionate cannot be purchased from the market. Therefore, the reaction route is relatively long. Additionally, during the synthesis of bilastine, purification for 20 hours is required, which greatly prolongs the process time and reduces the industrial production efficiency.

[0038] In summary, the process for preparing bilastine by hydrolyzing methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl]piperidin-1-yl]ethyl]-α,α-dimethylphenylacetate is reflected among multiple routes. Therefore, as the key intermediate for synthesizing bilastine, methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl]piperidin-1-yl]ethyl]-α,α-dimethylphenylacetate directly affects the production, market supply, and quality of this drug. Its chemical structural formula is as follows:

[0039]

[0040] In view of the above-mentioned many deficiencies in the current preparation process of methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl]piperidin-1-yl]ethyl]-α,α-dimethylphenylacetate. Therefore, it is still a problem to be solved at present to research and find a process suitable for industrial production of this intermediate with mild reaction conditions, simple operation process, high product yield, and high purity. Summary of the Invention

[0041] Aiming at the problems existing in the current preparation technology of the key intermediate of bilastine, methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl]piperidin-1-yl]ethyl]-α,α-dimethylphenylacetate, the present invention provides a new intermediate compound and its preparation method, and at the same time provides a preparation method of this new compound for preparing methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl]piperidin-1-yl]ethyl]-α,α-dimethylphenylacetate. This method has mild reaction conditions, simple operation process, and the obtained target product has high purity and high yield.

[0042] The specific technical solution of the present invention is as follows:

[0043] In the first aspect of the present invention, a bilastine intermediate compound is provided, and its structure is shown in Formula I-2:

[0044]

[0045] The second aspect of the present invention provides a method for preparing the bilastine intermediate compound I-2, which specifically comprises the following steps: under the protection of an inert gas, at room temperature, compound I-1, compound SM-1, a base, and a catalyst are added to reaction solvent A, and the temperature is controlled and stirred for reaction. After monitoring the reaction to completion, the reaction solution is cooled to room temperature, a base and purified water are added to the reaction solution, compound SM-2 is added, and after controlling the temperature until the reaction is completed, the reaction is post-treated to obtain intermediate I-2. The synthetic route is as follows:

[0046]

[0047] Preferably, the catalyst is selected from one of Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2, and Pd(PPh3)4 is particularly preferred.

[0048] Preferably, the base is selected from one of KOAc, K2CO3, Na2CO3, K3PO4, Na3PO4, and NaOAc, and KOAc is particularly preferred.

[0049] Preferably, the molar ratio of compound I-1 to compound SM-1, compound SM-2, the base, and the catalyst in the feed is 1:1.0 - 1.5:1.5 - 2.5:1.3 - 2.2:0.03 - 0.08, and 1:1.3:2.0:1.6:0.05 is particularly preferred.

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

[0051] Preferably, the reaction temperature is 80 - 110 °C, and 100 - 105 °C is particularly preferred.

[0052] In a preferred embodiment, the post-treatment step is: filtering the reaction solution, pouring the filtrate into purified water, extracting with dichloromethane, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain the intermediate compound I-2.

[0053] The third aspect of the present invention provides the use of the bilastine intermediate compound I-2 for preparing the important bilastine intermediate methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl]ethyl]-α,α-dimethylphenylacetate.

[0054] The method for preparing the important intermediate of bilastine, methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-1-piperidinyl]ethyl]-α,α-dimethylphenylacetate, from bilastine intermediate compound I-2 includes the following steps: At room temperature, add intermediate I-2, compound SM-3, and palladium carbon into reaction solvent B. After controlling the temperature until the reaction ends, the reaction mixture is post-treated to obtain the target product, bilastine intermediate I. The synthetic route is as follows:

[0055]

[0056] Preferably, the reaction solvent B is selected from one or a combination of xylene, toluene, 1,4-dioxane, and N,N-dimethylformamide, and xylene is particularly preferred.

[0057] Preferably, the molar ratio of compound I-2 to compound SM-3 in the feed is 1:1.5 - 2.8, and 1:2.1 is particularly preferred.

[0058] Preferably, the mass ratio of compound I-2 to palladium carbon in the feed is 1:0.05 - 0.15, and 1:0.10 is particularly preferred.

[0059] Preferably, the reaction temperature is 95 - 130 °C, and 110 - 115 °C is particularly preferred.

[0060] In a preferred embodiment, the post-treatment steps are as follows: Cool the reaction solution to room temperature, filter, wash the filtrate with purified water, extract with ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain bilastine intermediate compound I.

[0061] Advantages of the present invention:

[0062] 1. The present invention provides a new bilastine intermediate compound and its preparation method. The preparation method of this new intermediate is simple, no impurities are generated during the subsequent synthesis of bilastine from this intermediate, and the synthesis process of this intermediate is simple with a high yield.

[0063] 2. The present invention also provides a preparation process for the bilastine intermediate, methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-1-piperidinyl]ethyl]-α,α-dimethylphenylacetate. Compared with the products obtained by the prior art, it has a higher yield and purity, and is easy to operate, safe, and suitable for industrial production. Specific embodiments

[0064] 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 limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all fall within the scope claimed by the present invention.

[0065] The structural confirmation data of the intermediates and products obtained in the present invention are as follows:

[0066]

[0067] ESI-HRMS(m / z): 476.2910 [M+H] + ; 1 H NMR(400MHz, DMSO-d6) δ 7.62~7.53(m, 3H), 7.50(d, J = 7.5Hz, 2H), 7.34(d, J = 7.5Hz, 2H), 7.23~7.14(m, 2H), 5.13(d, J = 16.2Hz, 1H), 4.48(t, J = 7.0Hz, 2H), 4.03~3.91(m, 1H), 3.81(t, J = 7.0Hz, 2H), 3.74(s, 3H), 3.51(q, J = 7.2Hz, 2H), 3.42~3.30(m, 2H), 3.17~3.06(m, 2H), 2.31~2.22(m, 2H), 1.82~1.74(m, 2H), 1.69(s, 6H), 1.20(t, J = 7.2Hz, 3H); 13 C NMR(100MHz, DMSO-d6): δ 178.29, 162.30, 142.97, 138.80, 138.17, 136.51, 132.65, 128.56, 126.22, 123.52, 122.53, 119.98, 112.81, 95.68, 71.18, 66.87, 52.56, 50.13, 48.48, 46.35, 29.14, 27.90, 24.98, 14.87.

[0068]

[0069] ESI-HRMS(m / z): 478.3068 [M+H] + ; 11H NMR (300 MHz, CDCl3) δ 7.78 - 7.75 (m, 1H), 7.33 - 7.20 (m, 7H), 4.31 (t, J = 5.5 Hz, 2H), 3.72 (t, J = 5.5 Hz, 2H), 3.65 (s, 3H), 3.41 (q, J = 7.0 Hz, 2H), 3.20 - 3.17 (m, 4H), 3.04 - 3.01 (m, 1H), 2.87 - 2.82 (m, 2H), 2.70 - 2.67 (m, 2H), 2.23 - 2.20 (m, 4H), 1.59 (s, 6H), 1.10 (t, J = 7.0 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 178.30, 162.31, 141.90, 138.82, 138.30, 136.51, 127.05, 126.93, 123.52, 122.53, 119.98, 112.77, 71.18, 66.87, 56.18, 52.61, 52.56, 50.13, 46.35, 33.63, 29.14, 27.66, 24.96, 14.90.

[0070] The purity of methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl]ethyl]-α,α-dimethylphenylacetate of the present invention was determined by HPLC under the following chromatographic conditions:

[0071] Chromatographic column: YMC-Triart C 18 column (4.6 mm × 150 mm, 5 μm) or a chromatographic column with equivalent efficiency;

[0072] Mobile phase A: 10 mmol / L dipotassium hydrogen phosphate: acetonitrile: tetrahydrofuran (adjusted to pH 7.0 with phosphoric acid) (750:150:100);

[0073] Mobile phase B: 10 mmol / L dipotassium hydrogen phosphate: acetonitrile: tetrahydrofuran (adjusted to pH 8.0 with phosphoric acid) (150:800:50);

[0074] Gradient elution (0 - 30 min: A 100% - 70%, 30 - 50 min: A 75% - 0%, 50 - 60 min, 0% - 0%);

[0075] Column temperature: 50 °C;

[0076] Detection wavelength: 210 nm;

[0077] Flow rate: 0.8 ml / min;

[0078] Injection volume: 10 μl;

[0079] Among them, the retention time of methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl]-1-piperidinyl]ethyl]-α,α-dimethylphenylacetate is about 42.0 min.

[0080] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0081] Synthesis of Compound I-1

[0082] Example 1

[0083] At room temperature, 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (54.68 g, 0.20 mol) and triethylamine (44.52 g, 0.44 mol) were added to N,N-dimethylformamide (300 ml), and a solution of (E)-1,2-dibromoethylene (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 detection 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 85.3% and an HPLC purity of 99.63%.

[0084] Synthesis of Compound I-2

[0085] Example 2

[0086] Under argon protection at room temperature, Compound I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (SM-1, 33.01 g, 0.13 mol), potassium acetate (15.70 g, 0.16 mol), and Pd(PPh3)4 (5.78 g, 5.0 mmol) were added to dimethyl sulfoxide (250 ml). The temperature was controlled at 100-105 °C for reaction. After detection that the reaction was completed, the reaction solution was cooled to room temperature, and a solution of K3PO4 (33.96 g, 0.16 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2, 51.42 g, 0.20 mol) were added. The temperature was controlled at 95-100 °C for reaction. After detection that the reaction was completed, it was filtered, and the filtrate was added to purified water (500 ml). It was 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 86.6% and an HPLC purity of 99.66%.

[0087] Example 3

[0088] Under the condition of argon protection at room temperature, compound I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (25.39 g, 0.1 mol), K2CO3 (22.11 g, 0.16 mol), and Pd(PPh3)4 (5.78 g, 5.0 mmol) were added to dimethyl sulfoxide (250 ml). The temperature was controlled at 105 - 110 °C for reaction. After detection that the reaction was completed, the reaction solution was cooled to room temperature. A solution of KOAc (15.70 g, 0.16 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2, 38.57 g, 0.15 mol) were added. The temperature was controlled at 95 - 100 °C for reaction. After detection that the reaction was completed, filtration was carried out. 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 82.5% and an HPLC purity of 99.32%.

[0089] Example 4

[0090] Under the condition of argon protection at room temperature, compound I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (38.09 g, 0.15 mol), K3PO4 (33.96 g, 0.16 mol), and Pd(PPh3)2Cl2 (3.51 g, 5.0 mmol) were added to N,N-dimethylacetamide (250 ml). The temperature was controlled at 80 - 85 °C for reaction. After detection that the reaction was completed, the reaction solution was cooled to room temperature. A solution of K2CO3 (22.11 g, 0.16 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2, 64.28 g, 0.25 mol) were added. The temperature was controlled at 95 - 100 °C for reaction. After detection that the reaction was completed, filtration was carried out. 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 83.3% and an HPLC purity of 99.22%.

[0091] Example 5

[0092] Under argon protection at room temperature, compound I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (43.17 g, 0.17 mol), Na3PO4 (26.23 g, 0.16 mol), Pd(PPh3)2Cl2 (3.51 g, 5.0 mmol) were added to 1,4-dioxane (250 ml), and the temperature was controlled at 75-80 °C for reflux reaction. After detection that the reaction was completed, the reaction solution was cooled to room temperature, and a solution of K3PO4 (33.96 g, 0.16 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2, 51.42 g, 0.27 mol) were added, and the temperature was controlled at 95-100 °C for reaction. After detection that the reaction was completed, filtration was carried out. 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 78.8% and an HPLC purity of 98.82%.

[0093] Example 6

[0094] Under argon protection at room temperature, compound I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (33.01 g, 0.12 mol), KOAc (12.76 g, 0.13 mol), Pd(dppf)Cl2 (3.66 g, 5.0 mmol) were added to dimethyl sulfoxide (250 ml), and the temperature was controlled at 105-110 °C for reaction. After detection that the reaction was completed, the reaction solution was cooled to room temperature, and a solution of KOAc (12.76 g, 0.13 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2, 51.42 g, 0.20 mol) were added, and the temperature was controlled at 95-100 °C for reaction. After detection that the reaction was completed, filtration was carried out. 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 82.5% and an HPLC purity of 99.32%.

[0095] Example 7

[0096] Under argon protection at room temperature, I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (33.01 g, 0.12 mol), KOAc (21.59 g, 0.22 mol), and Pd(PPh3)4 (5.78 g, 5.0 mmol) were added to 1,4-dioxane (250 ml). The temperature was controlled at 100 - 105 °C for reflux reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature. A solution of KOAc (21.59 g, 0.22 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropanoate (SM-2, 51.42 g, 0.20 mol) were added, and the temperature was controlled at 95 - 100 °C for reaction. After detecting that the reaction was completed, 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 83.1% and an HPLC purity of 99.25%.

[0097] Example 8

[0098] Under argon protection at room temperature, compound I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (33.01 g, 0.12 mol), KOAc (10.79 g, 0.11 mol), and Pd(dppf)Cl2 (3.66 g, 5.0 mmol) were added to dimethyl sulfoxide (250 ml). The temperature was controlled at 75 - 80 °C for reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature. A solution of KOAc (10.79 g, 0.11 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropanoate (SM-2, 51.42 g, 0.20 mol) were added, and the temperature was controlled at 95 - 100 °C for reaction. After detecting that the reaction was completed, 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 78.5% and an HPLC purity of 98.90%.

[0099] Example 9

[0100] Under argon protection at room temperature, I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (33.01 g, 0.12 mol), KOAc (23.55 g, 0.24 mol), and Pd(PPh3)4 (5.78 g, 5.0 mmol) were added to N,N-dimethylacetamide (250 ml). The temperature was controlled at 100 - 105 °C for reaction. After detection that the reaction was completed, the reaction solution was cooled to room temperature. A solution of KOAc (23.55 g, 0.24 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2, 51.42 g, 0.20 mol) were added. The temperature was controlled at 110 - 105 °C for reaction. After detection that the reaction was completed, filtration was carried out. 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 77.8% and an HPLC purity of 98.85%.

[0101] Example 10

[0102] Under argon protection at room temperature, I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (33.01 g, 0.12 mol), NaOAc (13.13 g, 0.16 mol), and Pd(PPh3)4 (3.47 g, 3.0 mmol) were added to N,N-dimethylformamide (250 ml). The temperature was controlled at 105 - 110 °C for reaction. After detection that the reaction was completed, the reaction solution was cooled to room temperature. A solution of NaOAc (13.13 g, 0.16 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2, 51.42 g, 0.20 mol) were added. The temperature was controlled at 95 - 100 °C for reaction. After detection that the reaction was completed, filtration was carried out. 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 82.2% and an HPLC purity of 99.33%.

[0103] Example 11

[0104] Under argon protection at room temperature, I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (33.01 g, 0.12 mol), Na3PO4 (26.23 g, 0.16 mol), and Pd(PPh3)4 (9.24 g, 8.0 mmol) were added to dimethyl sulfoxide (250 ml). The reaction was carried out at 95 - 100 °C. After detecting that the reaction was completed, the reaction solution was cooled to room temperature. A solution of Na3PO4 (32.79 g, 0.20 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2, 51.42 g, 0.20 mol) were added. The reaction was carried out at 95 - 100 °C. After detecting that the reaction was completed, 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 83.0% and an HPLC purity of 99.25%.

[0105] Example 12

[0106] Under argon protection at room temperature, I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (33.01 g, 0.12 mol), Na2CO3 (16.96 g, 0.16 mol), and Pd(PPh3)4 (1.16 g, 1.0 mmol) were added to N,N-dimethylformamide (250 ml). The reaction was carried out at 105 - 110 °C. After detecting that the reaction was completed, the reaction solution was cooled to room temperature. A solution of Na2CO3 (21.20 g, 0.20 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2, 33.43 g, 0.13 mol) were added. The reaction was carried out at 75 - 80 °C. After detecting that the reaction was completed, 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 78.3% and an HPLC purity of 98.92%.

[0107] Example 13

[0108] Under argon protection at room temperature, compound I-1 (37.83 g, 0.10 mol), bis(pinacolato)diboron (33.01 g, 0.12 mol), Na3PO4 (26.23 g, 0.16 mol), and Pd(PPh3)4 (11.56 g, 10.0 mmol) were added to dimethyl sulfoxide (250 ml). The temperature was controlled at 95 - 100 °C for reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, and a solution of K3PO4 (46.70 g, 0.22 mol) in purified water (110 ml) and methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2, 51.42 g, 0.20 mol) were added. The temperature was controlled at 105 - 110 °C for reaction. After detecting that the reaction was completed, 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 78.1% and an HPLC purity of 98.85%.

[0109] Synthesis of I

[0110] Example 14

[0111] At room temperature, intermediate I-2 (23.78 g, 0.05 mol), α-pinene (SM-3, 14.52 g, 0.105 mol), and 10% palladium on carbon (2.38 g) were added to xylene (200 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 (60 ml × 2) and extracted with ethyl acetate (100 ml × 2). The organic layer was washed with saturated brine (60 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product I with a yield of 95.6% and an HPLC purity of 99.85%.

[0112] Example 15

[0113] At room temperature, intermediate I-2 (23.78 g, 0.05 mol), α-pinene (SM-3, 10.37 g, 0.075 mol), and 10% palladium on carbon (2.38 g) were added to toluene (200 ml). The temperature was controlled at 95 - 100 °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 (60 ml × 2) and extracted with ethyl acetate (100 ml × 2). The organic layer was washed with saturated brine (60 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product I with a yield of 92.1% and an HPLC purity of 99.52%.

[0114] Example 16

[0115] At room temperature, add intermediate I-2 (23.78 g, 0.05 mol), α-pinene (SM-3, 19.36 g, 0.14 mol), and 10% palladium on carbon (2.38 g) to p-xylene (200 ml). Control the temperature at 110-115 °C for reaction. After detecting that the reaction is complete, cool the reaction solution to room temperature, filter, wash the filtrate with purified water (60 ml × 2), extract with ethyl acetate (100 ml × 2), wash the organic layer with saturated brine (60 ml × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product I, with a yield of 91.8% and an HPLC purity of 99.45%.

[0116] Example 17

[0117] At room temperature, add intermediate I-2 (23.78 g, 0.05 mol), α-pinene (SM-3, 8.85 g, 0.065 mol), and 10% palladium on carbon (2.38 g) to toluene (200 ml). Control the temperature at 90-95 °C for reaction. After detecting that the reaction is complete, cool the reaction solution to room temperature, filter, wash the filtrate with purified water (60 ml × 2), extract with ethyl acetate (100 ml × 2), wash the organic layer with saturated brine (60 ml × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product I, with a yield of 87.3% and an HPLC purity of 99.02%.

[0118] Example 18

[0119] At room temperature, add intermediate I-2 (23.78 g, 0.05 mol), α-pinene (SM-3, 20.43 g, 0.15 mol), and 10% palladium on carbon (2.38 g) to m-xylene (200 ml). Control the temperature at 115-120 °C for reaction. After detecting that the reaction is complete, cool the reaction solution to room temperature, filter, wash the filtrate with purified water (60 ml × 2), extract with ethyl acetate (100 ml × 2), wash the organic layer with saturated brine (60 ml × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product I, with a yield of 86.6% and an HPLC purity of 98.85%.

[0120] Example 19

[0121] At room temperature, add intermediate I-2 (23.78 g, 0.05 mol), α-pinene (SM-3, 14.52 g, 0.105 mol), and 10% palladium on carbon (1.19 g) to 1,4-dioxane (200 ml). Control the temperature at 100-105 °C for reaction. After detecting that the reaction is complete, cool the reaction solution to room temperature, filter, wash the filtrate with purified water (60 ml × 2), extract with ethyl acetate (100 ml × 2), wash the organic layer with saturated brine (60 ml × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product I, with a yield of 92.1% and an HPLC purity of 99.66%.

[0122] Example 20

[0123] At room temperature, add intermediate I-2 (23.78 g, 0.05 mol), α-pinene (SM-3, 14.52 g, 0.105 mol), and 10% palladium on carbon (3.57 g) to N,N-dimethylformamide (200 ml). Control the temperature at 110-115 °C for reaction. After detecting that the reaction is complete, cool the reaction solution to room temperature, filter, wash the filtrate with purified water (60 ml × 2), extract with ethyl acetate (100 ml × 2), wash the organic layer with saturated brine (60 ml × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product I, with a yield of 92.9% and an HPLC purity of 99.52%.

[0124] Example 21

[0125] At room temperature, add intermediate I-2 (23.78 g, 0.05 mol), α-pinene (SM-3, 14.52 g, 0.105 mol), and 10% palladium on carbon (0.71 g) to toluene (200 ml). Control the temperature at 90-95 °C for reaction. After detecting that the reaction is complete, cool the reaction solution to room temperature, filter, wash the filtrate with purified water (60 ml × 2), extract with ethyl acetate (100 ml × 2), wash the organic layer with saturated brine (60 ml × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product I, with a yield of 87.6% and an HPLC purity of 99.96%.

[0126] Example 22

[0127] At room temperature, intermediate I-2 (23.78 g, 0.05 mol), α-pinene (SM-3, 14.52 g, 0.105 mol), and 10% palladium on carbon (4.04 g) were added to o-xylene (200 ml), and the temperature was controlled at 115-120 °C for reaction. After detecting that the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filtrate was washed with purified water (60 ml × 2), extracted with ethyl acetate (100 ml × 2), the organic layer was washed with saturated brine (60 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product I, with a yield of 86.9% and an HPLC purity of 98.82%.

Claims

1. A bilastine intermediate compound, characterized in that, Its structure is shown in Formula I-2: 。 2. A preparation method of the bilastine intermediate compound I-2 according to claim 1, characterized in that, It includes the following steps: under inert gas protection, at room temperature, compound I-1, compound SM-1, a base, and a catalyst are added to reaction solvent A, and the temperature is controlled and stirred for reaction. After monitoring the reaction to completion, the reaction solution is cooled to room temperature. A base and purified water are added to the reaction solution, and compound SM-2 is added. After controlling the temperature until the reaction is complete, the reaction is post-treated to obtain intermediate I-2. Compound I-2 prepared through post-treatment is added to the reaction solution. The synthesis route is as follows: 。 3. According to the preparation method described in claim 2, characterized in that, The catalyst selected is one of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2; the base selected is one of KOAc, K2CO3, Na2CO3, K3PO4, Na3PO4, NaOAc.

4. According to the preparation method described in claim 2, characterized in that, The molar ratio of compound I-1 to compound SM-1, compound SM-2, the base, and the catalyst in the feed is 1:1.0 - 1.5:1.5 - 2.5:1.3 - 2.2:0.03 - 0.

08.

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 dimethyl sulfoxide, N , N -dimethylformamide, 1,4-dioxane, N , N -dimethylacetamide; the reaction temperature is 80°C to 110°C.

6. Use of the bilastine intermediate compound described in claim 1 for the preparation of the important bilastine intermediate methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-1-piperidinyl]ethyl]-α,α-dimethylphenylacetate.

7. Use of the bilastine intermediate compound I-2 according to claim 6 for the preparation of the bilastine intermediate methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzoimidazol-2-yl]-1-piperidinyl]ethyl]-α,α-dimethylphenylacetate, characterized in that, It includes the following steps: at room temperature, intermediate I-2, compound SM-3, and palladium on carbon are added to reaction solvent B, and the temperature is controlled until the reaction is complete. After the reaction is post-treated, the target product bilastine intermediate I is obtained. The synthesis route is as follows: 。 8. According to the use described in claim 7, characterized in that, The molar ratio of compound I-2 to compound SM-3 in the feed is 1:1.5 - 2.

8.

9. According to the use described in claim 7, characterized in that, The mass ratio of compound I-2 to palladium on carbon in the feed is 1:0.05 - 0.

15.

10. According to the use described in claim 7, characterized in that, The reaction solvent B selected is one or a combination of xylene, toluene, 1,4-dioxane, N,N-dimethylformamide; the reaction temperature is 95 - 130 °C.

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