Process for the preparation of a bilastine intermediate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a bilastine intermediate; namely, a new preparation method of 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidyl]-ethyl]-alpha,alpha-dimethylphenylacetic acid methyl (or ethyl) ester is provided. In the method, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole is used as a starting material, and after being activated by iodine / zinc, the starting material is subjected to a cross-coupling reaction with 2-(4-bromophenyl)-2-methylpropionic acid methyl (or ethyl) ester to obtain the target product. The whole synthesis method is simple in operation and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing a bilastine intermediate. Background Technology

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

[0003] Its chemical structural formula is:

[0004]

[0005] Currently, there are several main methods for synthesizing bilastine:

[0006] 1. Patents EP0818454, EP0580541, US5877187, CN1176964A, CN109694367A, CN1105716C, ES2151442, ES2151442A1, CN104402773A, and CN103351380A use methyl 4-bromophenylacetate or its downstream intermediates as raw materials. Through methylation, hydrolysis, carboxyl protection, and Grignard reaction, 4-[2-methyl-2-(4,5-dihydro-4,4-dimethyloxazol-2-yl)ethyl]phenylethanol is obtained. The hydroxyl group is substituted with leaving groups (such as Cl, Br, I, sulfonates, etc.), followed by 2-(4-piperidinyl)-1H-benzimidazole and 2-chloroethyl ether substitution, and finally hydrolysis yields the target product. The reaction route is as follows:

[0007]

[0008] However, this route has the following problems: ① Butyllithium or Grignard reagents are used in the reaction, which have poor compatibility with functional groups and require anhydrous and oxygen-free conditions, making the conditions very demanding; ② Ethylene oxide is a hazardous material, and the methylating reagent iodomethane has a low boiling point and high toxicity, making the operation less safe; ③ It also requires the use of a special oxazole ring to protect the carboxyl group, making the reaction conditions very demanding; ④ The overall route is long, the yield is low, and it is not suitable for industrial production.

[0009] To address the cumbersome procedures involved in oxazole ring protection, ester protection strategies have been widely adopted, as follows:

[0010] 2. Synthesis of important intermediates of bilastine according to Chinese patent CN104326909A and literature, *China Pharmaceutical Industry Journal*, 2015, 46(7):677-679. Starting with α,α-dimethylphenylacetate, methyl α,α-dimethyl-4-(2-bromoethyl)phenylacetate was first prepared by Friedel-Crafts acylation and reduction reactions. This methyl α,α-dimethyl-4-(2-bromoethyl)phenylacetate then underwent nucleophilic substitution reactions with 2-(4-piperidinyl)-1H-benzimidazole and 2-chloroethyl ether, followed by hydrolysis to obtain bilastine. The reaction route is as follows:

[0011]

[0012] In addition, all of the above routes use 2-(4-piperidinyl)benzimidazole as a starting material. Its molecular structure contains two easily substituted hydrogens, which requires high selectivity, harsh reaction conditions, and easily produces byproducts.

[0013] 3. Chinese Patent CN102675101A uses α,α-dimethylphenylacetate as a raw material, and prepares α,α-dimethyl-4-(2-haloethyl)phenylacetate through Friedel-Crafts acylation and reduction reactions. Then, it reacts with 1-(2-ethoxyethyl)-2-(4-piperidinyl)-1H-benzimidazole through substitution and hydrolysis reactions to obtain the target product. The reaction route is as follows:

[0014]

[0015] However, this method uses the Wolff-Kishner-Huang Minglong method to reduce carbonyl groups, which requires high temperature and has high toxicity. Furthermore, the synthesis of 1-(2-ethoxyethyl)-2-(4-piperidinyl)-1H-benzimidazole requires reactions such as adding a protecting group, substitution, and deprotection, which are complicated and unsuitable for industrial production.

[0016] 4. References *Synth. Commun.*, 2011, 41(9): 1394-1402, *J. Org. Chem.*, 1988, 53(6): 1170-1176, and the synthesis of key intermediates for bilastine, *Hebei Chemical Industry*, 2013, 36(3): 14-15, describe the synthesis of bilastine using methyl α,α-dimethyl-4-bromophenylacetate as a raw material via Stille coupling reaction, followed by hydration, protecting group addition, alkylation, deprotection, and ester hydrolysis. However, this method uses environmentally unfriendly organotin and borane dimethyl sulfide complexes, resulting in high post-processing costs. The reaction route is as follows:

[0017]

[0018] 5. Patent WO2009102155 (CN101952273A) describes a method for preparing the target product from 4-bromophenylethanol via palladium-catalyzed coupling and sulfonation, followed by substitution and hydrolysis with 1-(2-ethoxyethyl)-2-(4-piperidinyl)-1H-benzimidazole. However, the key intermediate, ethyl 2-(4-hydroxyethylphenyl)-2-methylpropionate, is synthesized from p-bromophenylethanol and 1-methoxy-1-(trimethylsiloxy)-2-methyl-1-propene in the presence of bis(diphenylacetone)palladium, tri-tert-butylphosphine, and zinc fluoride. The reaction route is as follows:

[0019]

[0020] The reaction has three main drawbacks: ① The raw materials, such as 1-methoxy-1-(trimethylsiloxy)-2-methyl-1-propene and the catalysts, such as bis(di-benzylacetone)palladium and tri-tert-butylphosphine, are extremely expensive, difficult to obtain, and difficult to preserve; ② The reaction requires extremely strict anhydrous and oxygen-free conditions, is complex to operate, and the resulting product is difficult to purify; ③ The remaining palladium and phosphorus after the reaction will cause serious environmental pollution.

[0021] 6. Chinese patent CN110903278A uses piperidine-4-carboxylic acid as a starting material, which is substituted with methyl 4,4-dimethyl-4-(2-bromoethyl)phenylacetate, followed by cyclization with o-phenylenediamine to obtain methyl 4,4-dimethyl-4-(2-(4-(1H-2-benzo[d]imidazolyl)piperidin-1-yl)ethyl)phenylacetate. Then, it undergoes N-alkylation and hydrolysis with chloroethyl ether to obtain bilastine. The reaction route is as follows:

[0022]

[0023] However, the starting material methyl α,α-dimethyl-4-(2-bromoethyl)phenylacetate in this process needs to be prepared according to the method in the literature "Synthesis of Important Intermediates of Bilastin", "China Pharmaceutical Industry Magazine", 2015, 46(7):677-679 (methyl α,α-dimethyl-phenylacetate 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 requires a large amount of highly active AlCl3 catalyst for the Friedel-Crafts acylation reaction. The post-processing is not only dangerous, but the large amount of aluminum salt generated also affects the separation of the product. In addition, the operating cost of the reduction system is high. At the same time, a large number 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 has poor atom economy, but also has complicated post-processing, making it difficult to achieve industrial-scale production.

[0024] 7. Chinese patent CN111039922A uses 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropionic acid as one starting material, which reacts with iodomethane to produce methyl 2-(4-(2-iodoethyl)phenyl)-2-methylpropionate. 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, followed by reaction with methyl 2-(4-(2-iodoethyl)phenyl)-2-methylpropionate, and then ester hydrolysis to obtain the target product. However, this process also uses iodomethane, which has low toxicity and a low boiling point, for the iodination reaction, resulting in low operational safety. The reaction route is as follows:

[0025]

[0026] 8. Chinese patents CN110950837A and CN107365297A use 4-hydroxyethyl phenyl tert-butyrate or its downstream intermediates as starting materials. First, 4-acetaldehyde phenyl tert-butyrate is generated through oxidation. Then, it is reduced and amination with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole using NaBH4 or LiBH4, followed by hydrolysis to obtain bilastine. However, the oxidation reaction is dangerous to operate industrially and easily yields peroxidized acid impurities. The reduction reaction results in low purity; CN110950837A has a purity of 96.2% and a yield of 88.2%, which is unfavorable for subsequent hydrolysis of bilastine. The reaction route is as follows:

[0027]

[0028] 9. Chinese patents CN104530002A and CN104177331A use p-methylphenylethanol or its downstream intermediates as starting materials. After p-toluenesulfonylchlorosulfonation to obtain a sulfonate ester, it reacts with 1-ethoxyethyl-2-piperidinylbenzimidazole, followed by bromination at the benzylic position. A Grignard reaction introduces a carboxyl group at the benzylic position, converting the carboxyl group to a methyl ester. Finally, a methyl group is added with dimethyl sulfate or iodomethane, followed by hydrolysis to dimethylate at the benzylic position. Finally, hydrolysis yields bilastine. The reaction uses Grignard reagents to introduce the carboxyl group, requiring anhydrous and oxygen-free conditions, making industrialization difficult. The reaction route is as follows:

[0029]

[0030] 10. In addition, Chinese patent CN106146459A and literature Synthesis of Important Intermediates of Bilastin, "China Pharmaceutical Industry Magazine", 2016, 47(11):1363-1365, use inexpensive and readily available 2-nitroaniline as raw material. First, it reacts with 4-formylpiperidin-1-carboxylic acid tert-butyl ester via a reduction-ring-closure reaction to obtain 4-(1H-benzo[d]imidazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester. Then, it undergoes an N-alkylation reaction and hydrolysis reaction with chloroethyl ether. Finally, it reacts with sodium 2-methyl-2-(4-(2-(toluenesulfonyloxy)ethyl)phenyl)propionate via a substitution reaction to obtain bilastin. The reaction route is as follows:

[0031]

[0032] However, the compounds 4-formylpiperidin-1-carboxylic acid tert-butyl ester and sodium 2-methyl-2-(4-(2-(toluenesulfonyloxy)ethyl)phenyl)propionate in this reaction route are not commercially available, so the reaction route is relatively long. In addition, the synthesis of bilastine requires 20 hours of purification, which greatly prolongs the process time and reduces the efficiency of industrial production.

[0033] In summary, the process of preparing bilastine by hydrolyzing the key intermediate 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid methyl(ethyl) ester is reflected in multiple routes. Therefore, 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid methyl(ethyl) ester, as a key intermediate in the synthesis of bilastine, directly affects the production, market supply, and quality of this drug. Its chemical structure is as follows:

[0034]

[0035] Given the numerous shortcomings in the current preparation process of methyl(ethyl) 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate, finding a suitable process for the industrial production of this intermediate with mild reaction conditions, simple operation, and high product yield and purity remains a problem to be solved. Summary of the Invention

[0036] To address the problems existing in the preparation technology of methyl (ethyl) 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid methyl(ethyl) ester, a key intermediate of bilastine, this invention provides a method for preparing bilastine intermediates; specifically, a novel method for preparing methyl (ethyl) 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid methyl(ethyl) ester. This method features mild reaction conditions, simple operation, and yields a target product with high purity and yield.

[0037] The specific technical solution of the present invention is as follows:

[0038] A method for preparing methyl (ethyl) α,α-dimethylphenylacetate, a key intermediate of bilastine, specifically includes the following steps:

[0039] Under inert gas protection at room temperature, iodine and zinc powder were added to a dry reaction solvent. The mixture was stirred at room temperature until the iodine red color disappeared. Then, SM-1 was added, and the reaction was continued at temperature T1. After the reaction was confirmed to be complete, SM-2 and the catalyst were added at temperature T2, and the reaction was continued at temperature T2. After the reaction of SM-2 was confirmed to be complete, the product was obtained through post-processing. The reaction route is as follows:

[0040]

[0041] Where R = methyl or ethyl.

[0042] Preferably, the catalyst is one of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, and Ni(PPh3)2Cl2, with Pd(PPh3)2Cl2 being the most preferred.

[0043] Preferably, the molar ratio of SM-1 to iodine, zinc, SM-2, and catalyst is 1:0.02-0.1:1.2-1.8:0.8-1.0:0.5%-5.0%, more preferably 1:0.05:1.4:0.95:2.0%.

[0044] Preferably, the reaction temperature T1 is 60-100℃, particularly preferably 75-80℃; T2 is 10-30℃, preferably 20-25℃.

[0045] Preferably, after the SM-2 reaction is detected to be complete, the coupling reaction takes 1 to 5 hours.

[0046] Preferably, the reaction solvent is one or a combination of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and N,N-dimethylpropenylurea, with N,N-dimethylacetamide being particularly preferred.

[0047] Preferably, the post-processing step is as follows: filter the reaction liquid into diatomaceous earth, pour the filtrate into purified water, extract with organic solvent, wash with saturated saline, and concentrate under reduced pressure to dryness to obtain the target product.

[0048] Preferably, the extractant is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, with dichloromethane being the most preferred.

[0049] Preferably, the inert gas is one or a combination of argon and nitrogen, with argon being the preferred gas.

[0050] The beneficial effects of this invention are:

[0051] 1. This invention provides a method for preparing methyl(ethyl) 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid methyl(ethyl) ester, a key intermediate of bilastine. Starting with 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzi[d]imidazole (SM-1), after activation with iodine / zinc, it undergoes a cross-coupling reaction with methyl(ethyl) 2-(4-bromophenyl)-2-methylpropionate (SM-2) to obtain the target product I.

[0052] 2. The preparation process of methyl(ethyl) 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid methyl(ethyl) ester of the present invention has mild reaction conditions and is simple to operate. Compared with the product obtained by the prior art, it has higher yield and purity, and is simple and safe to operate, making it suitable for industrial production. Detailed Implementation

[0053] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0054] This invention employs HPLC to determine the purity of methyl(ethyl) 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid methyl(ethyl) ester. The chromatographic conditions are as follows:

[0055] Column: YMC-Triart C 18Column (4.6 mm × 150 mm, 5 μm) or equivalent chromatographic column;

[0056] Mobile phase A: 10 mmol / L dipotassium hydrogen phosphate: acetonitrile: tetrahydrofuran (adjusted to pH 7.0 with phosphoric acid) (750:150:100);

[0057] Mobile phase B: 10 mmol / L dipotassium hydrogen phosphate: acetonitrile: tetrahydrofuran (adjusted to pH 8.0 with phosphoric acid) (150:800:50);

[0058] Gradient elution (0–30 min: A 100%–70%, 30–50 min: A 75%–0%, 50–60 min: 0%–0%);

[0059] Column temperature: 50℃;

[0060] Detection wavelength: 210nm;

[0061] Flow rate: 0.8 ml / min;

[0062] Injection volume: 10 μl;

[0063] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0064] Example 1

[0065] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (9.15 g, 0.14 mol) were added to dry N,N-dimethylacetamide (300 ml). After stirring at room temperature until the iodine red color disappeared, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzi[d]imidazole (SM-1, 38.03 g, 0.10 mol) was added. The reaction was continued at 75–80 °C. After the reaction of SM-1 was completed as detected by TLC, methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2-1, R = methyl, 24.42 g, 0.095 mol) was added at 20–25 °C. The reaction was continued at 20–25 °C with Pd(PPh3)2Cl2 (1.40 g, 0.002 mol). After SM-2-1 was detected to be completely reacted, the reaction time was 4 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (3 L). It was extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and the organic phase was concentrated under reduced pressure to dryness to obtain a yellow oily substance, which is the target product methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate, with a yield of 96.5% (based on SM-2-1) and an HPLC purity of 99.3%.

[0066] Example 2

[0067] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (9.15 g, 0.14 mol) were added to dry N,N-dimethylacetamide (300 ml). After stirring at room temperature until the iodine red color disappeared, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzimidazole (SM-1, 38.03 g, 0.10 mol) was added. The reaction was continued at 80–85 °C. After the reaction of SM-1 was completed as detected by TLC, methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2-1, R = methyl, 20.57 g, 0.08 mol) was added at 25–30 °C. The reaction was continued at 25-30℃ with Pd(PPh3)4 (2.31 g, 0.002 mol). After SM-2-1 was detected to be completely reacted, the reaction time was 3 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (3 L). It was extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and the organic phase was concentrated under reduced pressure to dryness to obtain a yellow oily substance, which is the target product 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid methyl ester, with a yield of 97.5% (based on SM-2-1) and an HPLC purity of 98.9%.

[0068] Example 3

[0069] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (9.15 g, 0.14 mol) were added to dry N,N-dimethylacetamide (300 ml). After stirring at room temperature until the iodine red color disappeared, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzi[d]imidazole (SM-1, 38.03 g, 0.10 mol) was added. The reaction was continued at 75–80 °C. After the reaction of SM-1 was completed as detected by TLC, methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2-1, R = methyl, 18.00 g, 0.07 mol) was added at 25–30 °C. The reaction was continued at 25–30 °C with Pd(PPh3)2Cl2 (1.40 g, 0.002 mol). After SM-2-1 was detected to be completely reacted, the reaction time was 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (3 L). It was extracted with chloroform (1000 ml × 3), washed with saturated brine (1000 ml × 2), and the organic phase was concentrated under reduced pressure to dryness to obtain a yellow oily substance, which is the target product methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid, with a yield of 98.5% (based on SM-2-1) and an HPLC purity of 97.8%.

[0070] Example 4

[0071] Under argon protection at room temperature, iodine (0.51 g, 0.002 mol) and zinc powder (9.15 g, 0.14 mol) were added to 300 ml of dry N,N-dimethylacetamide. The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzi[d]imidazole (SM-1, 38.03 g, 0.10 mol) was added, and the reaction was continued at 85–90 °C. After the reaction of SM-1 was completed as detected by TLC, methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2-1, R = methyl, 24.42 g, 0.095 mol) was added at 20–25 °C. The reaction was continued at 20–25 °C with Ni(PPh3)2Cl2 (1.31 g, 0.002 mol). After SM-2-1 was detected to be completely reacted, the reaction time was 4 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (3 L). It was extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and the organic phase was concentrated under reduced pressure to dryness to obtain a yellow oily substance, which is the target product methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate, with a yield of 96.4% (based on SM-2-1) and an HPLC purity of 98.8%.

[0072] Example 5

[0073] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (7.85 g, 0.12 mol) were added to 300 ml of dry dimethyl sulfoxide. The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole (SM-1, 38.03 g, 0.10 mol) was added, and the reaction was continued at 90–95 °C. After the reaction of SM-1 was complete as detected by TLC, methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2-1, R = methyl, 24.42 g, 0.095 mol) and Pd were added at 20–25 °C. (PPh3)2Cl2 (1.40 g, 0.002 mol) was added and the reaction was continued at a controlled temperature of 20–25 °C. After the reaction of SM-2-1 was completed, the reaction time was 4 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (3 L). It was extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and the organic phase was concentrated under reduced pressure to dryness to obtain a yellow oily substance, which is the target product methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate, with a yield of 96.5% (based on SM-2-1) and an HPLC purity of 98.9%.

[0074] Example 6

[0075] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (11.77 g, 0.18 mol) were added to dry N,N-dimethylformamide (300 ml). After stirring at room temperature until the iodine red color disappeared, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzimidazole (SM-1, 38.03 g, 0.10 mol) was added. The reaction was continued at 65–70 °C. After the reaction of SM-1 was completed as detected by TLC, methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2-1, R = methyl, 24.42 g, 0.095 mol) was added at 20–25 °C. The reaction was continued at 20–25 °C with Pd(PPh3)2Cl2 (1.40 g, 0.002 mol). After SM-2-1 was detected to be completely reacted, the reaction time was 5 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (3 L). It was extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and the organic phase was concentrated under reduced pressure to dryness to obtain a yellow oily substance, which is the target product methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate, with a yield of 95.4% (based on SM-2-1) and an HPLC purity of 98.6%.

[0076] Example 7

[0077] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (9.15 g, 0.14 mol) were added to dry N,N-dimethylacetamide (300 ml). The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzimidazole (SM-1, 38.03 g, 0.10 mol) was added, and the reaction was continued at 75–80 °C. After the reaction of SM-1 was complete as detected by TLC, methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2-1, R = methyl, 24.42 g, 0.095 mol) and P were added at 20–25 °C. d(PPh3)2Cl2 (0.35g, 0.0005mol) was added and the reaction was continued at a controlled temperature of 25-30℃. After the reaction of SM-2-1 was completed, the reaction time was 5 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (3L). Methyl tert-butyl ether (1000ml×3) was used for extraction, followed by washing with saturated brine (1000ml×2). The organic phase was concentrated under reduced pressure to dryness to obtain a yellow oily substance, which is the target product methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetic acid methyl ester, with a yield of 94.4% (based on SM-2-1) and an HPLC purity of 98.6%.

[0078] Example 8

[0079] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (9.15 g, 0.14 mol) were added to dry N-methylpyrrolidone (300 ml). The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzimidazole (SM-1, 38.03 g, 0.10 mol) was added, and the reaction was continued at 75–80 °C. After the reaction of SM-1 was complete as detected by TLC, methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2-1, R = methyl, 24.42 g, 0.095 mol) was added at 20–25 °C. Pd(PPh3)2Cl2 (3.51 g, 0.005 mol) was added and the reaction was continued at a controlled temperature of 20–25 °C. After the reaction of SM-2-1 was completed, the reaction time was 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (3 L). It was extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and the organic phase was concentrated under reduced pressure to dryness to obtain a yellow oily substance, which is the target product methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate, with a yield of 93.4% (based on SM-2-1) and an HPLC purity of 97.8%.

[0080] Example 9

[0081] Under nitrogen protection at room temperature, iodine (2.53 g, 0.01 mol) and zinc powder (9.15 g, 0.14 mol) were added to 300 ml of dry N,N-dimethylpropenylurea. The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzi[d]imidazole (SM-1, 38.03 g, 0.10 mol) was added. The reaction was continued at 70–75 °C. After the reaction of SM-1 was completed as detected by TLC, ethyl 2-(4-bromophenyl)-2-methylpropionate (SM-2-2, R = ethyl, 25.76 g, 0.095 mol) was added at 20–25 °C. The reaction was continued at 20–25 °C with Pd(PPh3)2Cl2 (1.40 g, 0.002 mol). After SM-2-2 was detected to be completely reacted, the reaction time was 4 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (3 L). It was extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and the organic phase was concentrated under reduced pressure to dryness to obtain a yellow oily substance, which is the target product ethyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate, with a yield of 96.4% (based on SM-2-2) and an HPLC purity of 98.9%.

[0082] Example 10

[0083] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (9.15 g, 0.14 mol) were added to 300 ml of dry N,N-dimethylacetamide. The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-(1-(2-bromoethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzi[d]imidazole (SM-1, 38.03 g, 0.10 mol) was added, and the reaction was continued at 75–80 °C. After the reaction of SM-1 was completed as detected by TLC, methyl 2-(4-bromophenyl)-2-methylpropionate (SM-2-1, R = methyl, 28.28 g, 0.11 mol) was added at 15–20 °C. The reaction was continued at 15–20 °C with Pd(dppf)Cl2 (1.46 g, 0.002 mol). After SM-2-1 was detected to be completely reacted, the reaction time was 4 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (3 L). It was extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and the organic phase was concentrated under reduced pressure to dryness to obtain a yellow oily substance, which is the target product methyl 4-[2-[4-[1-(2-ethoxyethyl)-1H-2-benzimidazolyl]-1-piperidinyl]-ethyl]-α,α-dimethylphenylacetate, with a yield of 90.1% (based on SM-2-1) and an HPLC purity of 97.8%.

[0084] Comparative Example 1

[0085] Under argon protection at room temperature, ethyl 2-methyl-2-(4-(2-oxoethyl)-phenyl)-propionate (1.2 g), 1-(2-ethoxyethyl)-2-piperidin-4-yl-1H-benzimidazole (1.4 g), and tetrahydrofuran (20 mL) were added to a three-necked reaction flask. The reaction was carried out at room temperature for 4 hours. Sodium borohydride acetate (2.1 g) was added in portions. After 4 hours of reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was washed with 20 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution to separate the organic phase. The organic phase was dried with 1 g of anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to obtain ethyl 2-(4-{2-[4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-yl)-piperidin-1-yl]-ethyl}phenyl)-2-methyl-propionate, with a yield of 80.2% and an HPLC purity of 94.1%.

Claims

1. A process for the preparation of a bilastine intermediate characterized in that, Specifically, the following operations are included: Under inert gas protection at room temperature, iodine and zinc powder were added to a dry reaction solvent. The mixture was stirred at room temperature until the iodine red color disappeared. Then, SM-1 was added, and the reaction was continued at temperature T1. After the reaction was confirmed to be complete, SM-2 and the catalyst were added at temperature T2, and the reaction was continued at temperature T2. After the reaction of SM-2 was confirmed to be complete, the target product was obtained through post-processing. The reaction route is as follows: ； Where R = methyl or ethyl, The catalyst is one of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, and Ni(PPh3)2Cl2; The molar ratio of SM-1 to iodine, zinc, SM-2, and catalyst is 1:0.02-0.1:1.2-1.8:0.8-1.0:0.5%-5.0%. The reaction temperature T1 is 60–100°C; The reaction temperature T2 is 10–30°C; The reaction solvent is one or a combination of dimethyl sulfoxide, N , N- dimethylformamide, N , N dimethylacetamide, N methylpyrrolidone, N,N dimethylpropylene urea.

2. The production method according to claim 1, characterized by, The reaction temperature T1 is 75-80℃.

3. The preparation method according to claim 1, characterized in that, The reaction temperature T2 is 20-25℃.

4. The method of claim 1, wherein, The post-processing steps are as follows: filter the reaction solution into diatomaceous earth, pour the filtrate into purified water, extract with organic solvent, wash with saturated saline, and concentrate under reduced pressure to dryness to obtain the target product.

5. The preparation method according to claim 4, characterized in that, The extractant is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether.

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