CN115745954A - Preparation method of bilastine intermediate - Google Patents
Preparation method of bilastine intermediate Download PDFInfo
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Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a bilastine intermediate; namely, a novel preparation method of 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl ] -1-piperidyl ] -ethyl ] -alpha, alpha-dimethyl phenylacetic acid methyl (ethyl) ester is provided. The method takes 2- (1- (2-bromoethyl) piperidine-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] imidazole as an initial material, and the target product is prepared by cross coupling reaction of the initial material and 2- (4-bromophenyl) -2-methylpropionate after being activated by iodine/zinc. The whole synthesis method is simple and convenient to operate and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a bilastine intermediate.
Background
Bilastine (bilastine) with the chemical name 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl]-1-piperidinyl group]-ethyl radical]-alpha, alpha-Dimethylphenylacetic acid CAS number 202189-78-4, an oral 2 nd generation non-sedating histamine H developed by Spain FAES pharmaceutical 1 Receptor antagonists, approved by the european union at month 8 2012 for the treatment of allergic rhinitis and urticaria. The product selectively acts on peripheral histamine receptor, has no influence on other histamine receptors, has no cardiotoxicity, is absorbed quickly by oral administration, and has good tolerance, safety and high bioavailability.
The chemical structural formula is as follows:
at present, the synthesis methods of bilastine mainly comprise the following steps:
1. the method is characterized in that patents EP0818454, EP0580541, US5877187, CN1176964A, CN109694367A, CN1105716C, ES2151442, ES2151442A1, CN104402773A and CN103351380A take 4-bromobenzene acetic acid methyl ester or downstream intermediates thereof as raw materials, 4- [ 2-methyl-2- (4,5-dihydro-4,4-dimethyl oxazolyl-2-yl) ethyl ] phenethyl alcohol is obtained through methylation, hydrolysis, carboxyl protection and Grignard reaction, hydroxyl is substituted by leaving groups (such as Cl, br, I, sulfonate and the like), and then substituted by 2- (4-piperidyl) -1H-benzimidazole and 2-chloroethyl ether in sequence, and finally hydrolyzed to obtain a target product. The reaction route is as follows:
however, this route has the following problems: (1) butyl lithium or Grignard reagent is used in the reaction, the compatibility to groups is poor, anhydrous and oxygen-free are needed, and the condition requirement is harsh; (2) meanwhile, ethylene oxide is a dangerous product, and the used methylating agent methyl iodide has low boiling point, high toxicity and low operation safety; (2) and a more special oxazole ring is needed to protect carboxyl, and the reaction conditions are harsh; (4) the whole route is long, the yield is low, and the method is not suitable for industrial production.
In order to solve the problem of complex operation in oxazole ring protection, the ester protection strategy is widely applied as follows:
2. chinese patent CN104326909A and the synthesis of important intermediate of Bilastine are disclosed in Chinese journal of medical industry 2015,46 (7). 677-679 uses alpha, alpha-dimethyl phenylacetate as starting material, and makes Friedel-crafts acylation and reduction reaction to obtain alpha, alpha-dimethyl-4- (2-bromoethyl) methyl phenylacetate, then makes nucleophilic substitution reaction with 2- (4-piperidyl) -1H-benzimidazole and 2-chloroethyl ethyl ether, and makes hydrolysis to obtain Bilastine. The reaction route is as follows:
in addition, in the above routes, 2- (4-piperidyl) benzimidazole is used as a raw material, and the molecular structure contains two hydrogens which are easy to be substituted, so that the requirements on selectivity are high, the reaction conditions are severe, and byproducts are easy to generate.
3. Chinese patent CN102675101A uses alpha, alpha-dimethyl phenylacetate as raw material, and makes it undergo the processes of Friedel-crafts acylation and reduction reaction to obtain alpha, alpha-dimethyl-4- (2-haloethyl) phenylacetate, then makes it and 1- (2-ethoxyethyl) -2- (4-piperidyl) -1H-benzimidazole undergo the processes of substitution and hydrolysis reaction so as to obtain the invented target product. The reaction route is as follows:
but the method adopts a Wolff-Kishner-Huang Minlon method to reduce carbonyl, and the reaction condition needs high temperature and has larger toxicity; and the synthesis of 1- (2-ethoxyethyl) -2- (4-piperidyl) -1H-benzimidazole needs to be carried out by reactions of protecting group application, substitution, deprotection and the like, and the steps are complicated and are not suitable for industrial production.
4. The synthesis of key intermediates of Bilastine, namely 1394-1402, J.Org.Chem. 1988,53 (6) 1170-1176 and the synthesis of Bilastine key intermediates, wherein alpha, alpha-dimethyl-4-bromobenzoate methyl ester is used as a raw material in the synthesis of Synth.Commun. 2011,41 (9), and the Bilastine is prepared by Stille coupling reaction of 2013,36 (3) 14-15, hydration, protecting group application, alkylation, protecting group removal, ester hydrolysis and the like. However, this method uses an organotin and borane dimethylsulfide complex which are not environmentally friendly, and the post-treatment cost is high. The reaction route is as follows:
5. WO2009102155 (CN 101952273A) uses 4-bromobenzene ethanol as raw material, and the raw material is subjected to palladium catalytic coupling and sulfonylation, and then reacts with 1- (2-ethoxy ethyl) -2- (4-piperidyl) -1H-benzimidazole through substitution, hydrolysis and other reactions to prepare the target product. However, in the method, the key intermediate 2- (4-hydroxyethyl phenyl) -2-ethyl methyl propionate is synthesized by taking p-bromophenol and 1-methoxy-1- (trimethylsilyloxy) -2-methyl-1-propylene as raw materials and reacting in the presence of a catalyst of bis (dibenzylideneacetone) palladium, tri-tert-butylphosphine and zinc fluoride. The reaction route is as follows:
the reaction has three major disadvantages: (1) the raw material 1-methoxy-1- (trimethylsilyloxy) -2-methyl-1-propylene and the catalysts such as bis (dibenzylideneacetone) palladium, tri-tert-butylphosphine and the like are extremely expensive, are not easy to purchase and store; (2) the reaction needs extremely strict anhydrous and anaerobic conditions, the operation is complex, and the obtained product is difficult to purify; (3) the palladium and phosphorus remaining after the reaction are both harmful to the environment.
6. Chinese patent CN110903278A uses piperidine-4-carboxylic acid as a starting material, and after alpha, alpha-dimethyl-4- (2-bromoethyl) methyl phenylacetate is substituted, alpha-dimethyl-4- (2- (4- (1H-2-benzo [ d ] imidazolyl) piperidine-1-yl) ethyl) methyl phenylacetate is prepared by cyclization with o-phenylenediamine, and then the alpha, alpha-dimethyl-4- (2- (4- (1H-2-benzo [ d ] imidazolyl) piperidine-1-yl) ethyl) methyl phenylacetate and chloroethyl ether are subjected to N-alkylation reaction and hydrolysis reaction to prepare bilastine. The reaction route is as follows:
however, the initial material alpha, alpha-dimethyl-4- (2-bromoethyl) methyl phenylacetate in the process needs to be prepared by a method in 677-679 (alpha, alpha-dimethyl-methyl phenylacetate and bromoacetyl bromide are prepared by Friedel-crafts acylation reaction and then reduction by a trifluoroacetic acid/triethylsilane system) according to the synthesis of an important intermediate of Bilastine in reference of documents in China journal of medical industry, 2015,46 (7): 677-679, so that not only are the reaction steps prolonged, but also AlCl with higher activity is used in the Friedel-crafts acylation reaction 3 The catalyst is used in a large amount, the post-treatment is dangerous, a large amount of aluminum salt generated simultaneously influences the separation of products, and in addition, the operation cost of a reduction system is high. A large amount of condensing agent is used in the simultaneous cyclization step, such as: dicyclohexylcarbodiimide, N-hydroxysuccinimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and the like, not only is the atom economy poor, but also the post-treatment is also complex, and the industrial amplification production is difficult to realize.
7. Chinese patent CN111039922A uses 2- (4- (2-hydroxyethyl) phenyl) -2-methylpropanoic acid as a starting material, reacts with iodomethane to generate 2- (4- (2-iodoethyl) phenyl) -2-methylpropanoic acid methyl ester, uses 4- (1- (2-ethoxyethyl) -1H-benzo [ d ] imidazol-2-yl) piperidine-1-tert-butyl formate as another starting material, removes Boc protecting group, reacts with 2- (4- (2-iodoethyl) phenyl) -2-methylpropanoic acid methyl ester, and hydrolyzes the ester to obtain the target product. However, the process also uses iodomethane with low toxicity and boiling point for iodination reaction, and has low operation safety. The reaction route is as follows:
8. chinese patent CN110950837A and CN107365297A use 4-hydroxyethyl phenyl tert-butyrate ester or its downstream intermediate as starting material, firstly generate 4-aldehyde phenyl tert-butyrate ester by oxidation reaction, and then react with 1- (2-ethoxyethyl) -2- (piperidine-4-yl) -1H-benzo [ d]Imidazole via NaBH 4 Or LiBH 4 And hydrolyzing to obtain bilastine after reductive amination. However, the oxidation reaction is dangerous to handle in an industrial scale and also readily produces a peroxidized acid impurity. The reduction reaction results in low purity, the purity of CN110950837A is 96.2%, the yield is 88.2%, and the subsequent preparation of hydrolyzed bilastine is not facilitated. The reaction route is as follows:
9. chinese patents CN104530002A and CN104177331a use p-methylphenylethanol or its downstream intermediate as starting material, prepare sulfonate after sulfonylation by p-toluenesulfonyl chloride, then react with 1-ethoxyethyl-2-piperidyl benzimidazole, brominate at benzyl position, introduce carboxyl at benzyl position by grignard reaction, convert carboxyl into methyl ester, add methyl to dimethyl sulfate or methyl iodide, hydrolyze at benzyl position for dimethylation, and finally perform hydrolysis reaction to prepare bilastine. In the reaction, a Grignard reagent is used for introducing carboxyl, anhydrous and anaerobic operation is required, the condition requirement is strict, and the industrialization difficulty is high. The reaction route is as follows:
10. in addition, the synthesis of the important intermediates of the chinese patent CN106146459a and the document bilastine, journal of the chinese medical industry 2016,47 (11): 1363-1365, which uses cheap and easily available 2-nitroaniline as raw material, firstly performs reduction-ring closure reaction with 4-formylpiperidine-1-carboxylic acid tert-butyl ester to prepare 4- (1H-benzo [ d ] imidazole-2-yl) piperidine-1-carboxylic acid tert-butyl ester, then performs N-alkylation reaction and hydrolysis reaction with chloroethylether, and finally performs substitution reaction with 2-methyl-2- (4- (2- (tosyloxy) ethyl) phenyl) sodium propionate to prepare bilastine. The reaction route is as follows:
however, in the reaction route, the compounds of 4-formylpiperidine-1-carboxylic acid tert-butyl ester and 2-methyl-2- (4- (2- (tosyloxy) ethyl) phenyl) sodium propionate cannot be purchased from the market, so the reaction route is long, and in addition, the purification needs to be carried out for 20 hours in the synthesis process of bilastine, the process time is greatly prolonged, and the industrial production efficiency is reduced.
In summary, the process for preparing bilastine by hydrolyzing the key intermediate 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl ] -1-piperidyl ] -ethyl ] -alpha, alpha-dimethyl phenylacetic acid methyl (ethyl) ester is embodied in a plurality of routes, so that the 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl ] -1-piperidyl ] -ethyl ] -alpha, alpha-dimethyl phenylacetic acid methyl (ethyl) ester is taken as the key intermediate for synthesizing bilastine, which directly influences the production, market supply and quality problems of the drug, and the chemical structural formula is as follows:
in view of the defects in the prior preparation process of the methyl (ethyl) 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl ] -1-piperidyl ] -ethyl ] -alpha, alpha-dimethyl phenylacetate. Therefore, the research and search of a process which has mild reaction conditions, simple and convenient operation process, high product yield and high purity and is suitable for industrial production of the intermediate still needs to be solved at present.
Disclosure of Invention
Aiming at the problems existing in the preparation technology of the existing bilastine key intermediate 4- [2- [4- [1- (2-ethoxy ethyl) -1H-2-benzimidazolyl ] -1-piperidyl ] -ethyl ] -alpha, alpha-dimethyl phenylacetic acid methyl (ethyl) ester, the invention provides a preparation method of the bilastine intermediate; namely, a novel preparation method of 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl ] -1-piperidyl ] -ethyl ] -alpha, alpha-dimethyl phenylacetic acid methyl (ethyl) ester is provided. The method has mild reaction conditions and simple and convenient operation process, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
a preparation method of a bilastine key intermediate 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl ] -1-piperidyl ] -ethyl ] -alpha, alpha-dimethyl phenylacetic acid methyl (ethyl) ester specifically comprises the following operations:
adding iodine and zinc powder into dry reaction solvent at room temperature under the protection of inert gas, stirring at room temperature until iodine red disappears, adding SM-1, and continuously controlling temperature T 1 Reaction, detecting the reaction, controlling the temperature T 2 Adding SM-2 and catalyst, and continuing controlling the temperature T 2 And (4) reacting, detecting that the SM-2 reaction is finished, and carrying out post-treatment to obtain the target product. The reaction route is as follows:
wherein R = methyl or ethyl.
Preferably, the catalyst is Pd (PPh) 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd(dppf)Cl 2 、Ni(PPh 3 ) 2 Cl 2 Of (2), preferably Pd (PPh) 3 ) 2 Cl 2 。
Preferably, the feeding molar ratio of SM-1 to iodine, zinc, SM-2 and catalyst is 1:0.02 to 0.1: 1.2-1.8: 0.8 to 1.0:0.5% to 5.0%, preferably 1:0.05:1.4:0.95:2.0 percent.
Preferably, said reaction temperature T 1 From 60 to 100 ℃ and particularly preferably from 75 to 80 ℃; t is a unit of 2 Is 10 to 30 ℃ and preferably 20 to 25 ℃.
Preferably, the coupling reaction is carried out for a period of time of 1 to 5 hours after completion of the detection of the SM-2 reaction.
Preferably, the reaction solvent is one or a combination of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and N, N-dimethylpropylurea, and N, N-dimethylacetamide is particularly preferred.
Preferably, the post-treatment step is: filtering the reaction solution with diatomite, pouring the filtrate into purified water, extracting with an organic solvent, washing with saturated saline solution, and concentrating under reduced pressure until the filtrate is dry to obtain the target product.
Preferably, the extractant is one or a combination of dichloromethane, chloroform, ethyl acetate and methyl tert-butyl ether, and dichloromethane is preferred.
Preferably, the inert gas is one or a combination of argon and nitrogen, preferably argon.
The invention has the beneficial effects that:
1. the invention provides a preparation method of bilastine key intermediate 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl ] -1-piperidyl ] -ethyl ] -alpha, alpha-dimethyl phenylacetic acid methyl (ethyl) ester, which takes 2- (1- (2-bromoethyl) piperidine-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] imidazole (SM-1) as a starting material, and the target product I is prepared by the cross coupling reaction of the activated 2- (4-bromophenyl) -2-methyl propionic acid methyl (ethyl) ester (SM-2) with iodine/zinc.
2. The preparation process of the 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl ] -1-piperidyl ] -ethyl ] -alpha, alpha-dimethyl phenylacetic acid methyl (ethyl) ester has mild reaction conditions and simple and convenient operation, has higher yield and purity compared with the product obtained by the prior art, is simple and convenient to operate, is safe, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to illustrate the present invention, not to limit the present invention, therefore, the simple modifications of the present invention in the method of the present invention are within the scope of the present invention as claimed.
The invention adopts HPLC to measure the purity of 4- [2- [4- [1- (2-ethoxy ethyl) -1H-2-benzimidazolyl ] -1-piperidyl ] -ethyl ] -alpha, alpha-dimethyl phenylacetic acid methyl (ethyl) ester, and the chromatographic conditions are as follows:
a chromatographic column: YMC-Triart C 18 A column (4.6 mm. Times.150mm, 5 μm) or a column of comparable performance;
mobile phase A:10mmol/L dipotassium hydrogenphosphate: acetonitrile: tetrahydrofuran (pH 7.0 adjusted with phosphoric acid) (750;
and (3) mobile phase B:10mmol/L dipotassium hydrogenphosphate: acetonitrile: tetrahydrofuran (pH 8.0 with phosphoric acid) (150;
gradient elution (0-30min;
column temperature: 50 ℃;
detection wavelength: 210nm;
flow rate: 0.8ml/min;
sample introduction amount: 10 mu l of the mixture;
in the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
Iodine (1.27g, 0.005mol) and zinc powder (9.15g, 0.14mol) were added to dry N, N-dimethylacetamide (300 ml) under argon atmosphere at room temperature, and after stirring at room temperature until the iodine red disappeared, 2- (1- (2-bromoethyl) piperidin-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] was added]Imidazole (SM-1, 38.03g, 0.10mol), continuously controlling the temperature to be 75-80 ℃ for reaction, controlling the temperature to be 20-25 ℃ after detecting that the SM-1 reaction is finished through TLC (thin layer chromatography), and adding 2- (4-bromophenyl) -2-methyl propionic acid methyl ester (SM-2-1,R = methyl, 24.42g, 0.095mol) and Pd (PPh) 3 ) 2 Cl 2 (1.40g and 0.002mol), continuing to control the temperature to react at 20-25 ℃, detecting that SM-2-1 is reacted, wherein the reaction time is 4 hours after the SM-2-1 is detected, filtering the reaction solution by using diatomite, pouring the filtrate into purified water (3L), extracting dichloromethane (1000 ml multiplied by 3), washing by using saturated saline (1000 ml multiplied by 2), concentrating the organic phase under reduced pressure to be dry to obtain yellow oily matter, namely the target product 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl group]-1-piperidinyl group]-ethyl radical]-alpha, alpha-dimethylphenylacetic acid methyl ester, yield 96.5% (based on SM-2-1), HPLC purity 99.3%.
Example 2
Under the condition of argon protection at room temperature, iodine (1.27g, 0.005mol) and zinc powder (9.15g, 0.14mol) are added into dry N, N-dimethylacetamide (300 ml), stirred at room temperature until iodine red disappears, and then 2- (1- (2-bromoethyl) piperidin-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] is added]Imidazole (SM-1, 38.03g,0.10 mol), continuously controlling the temperature to be 80-85 ℃ for reaction, controlling the temperature to be 25-30 ℃ after detecting that the SM-1 reaction is finished by TLC, and adding 2- (4-bromophenyl) -2-methyl propionic acid methyl ester (SM-2-1,R = methyl, 20.57g, 0.08mol) and Pd (PPh) 3 ) 4 (2.31g and 0.002mol), continuing controlling the temperature to be 25-30 ℃ for reaction, detecting that the SM-2-1 reaction is finished, and then the reaction time is 3 hours, filtering the reaction solution by using diatomite, pouring the filtrate into purified water (3L), extracting dichloromethane (1000 ml multiplied by 3), washing by using saturated saline (1000 ml multiplied by 2), concentrating the organic phase under reduced pressure to be dry to obtain yellow oily matter, namely the target product 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl group]-1-piperidinyl group]-ethyl radical]Methyl- α, α -dimethylphenylacetate in a yield of 97.5% (based on SM-2-1) and an HPLC purity of 98.9%.
Example 3
Iodine (1.27g, 0.005mol) and zinc powder (9.15g, 0.14mol) were added to dry N, N-dimethylacetamide (300 ml) under argon atmosphere at room temperature, and after stirring at room temperature until the iodine red disappeared, 2- (1- (2-bromoethyl) piperidin-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] was added]Imidazole (SM-1, 38.03g,0.10 mol), continuously controlling the temperature to be 75-80 ℃ for reaction, controlling the temperature to be 25-30 ℃ after detecting that the SM-1 reaction is finished by TLC, and adding 2- (4-bromophenyl) -2-methyl propionic acid methyl ester (SM-2-1,R = methyl, 18.00g, 0.07mol) and Pd (PPh) 3 ) 2 Cl 2 (1.40g and 0.002mol), continuing to control the temperature to be 25-30 ℃ for reaction, detecting that the SM-2-1 reaction is finished, and then the reaction time is 2 hours, filtering the reaction solution by using diatomite, pouring the filtrate into purified water (3L), extracting by using chloroform (1000 ml multiplied by 3), washing by using saturated saline (1000 ml multiplied by 2), concentrating the organic phase under reduced pressure to be dry to obtain yellow oily matter, namely the target product 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl]-1-piperidinyl group]-ethyl radical]Methyl-alpha, alpha-dimethylphenylacetate, yield 98.5% (based on SM-2-1) and HPLC purity 97.8%.
Example 4
Adding iodine (0.51g, 0.002mol) and zinc powder (9.15g, 0.14mol) into dry N, N-dimethylacetamide (300 ml) under the condition of argon protection at room temperature, stirring at room temperature until iodine red disappears, and adding 2- (1- (2-bromoethyl) piperidin-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d]Imidazole (SM-1, 38.03g,0.10 mol), continuously controlling the temperature to be 85-90 ℃ for reaction, controlling the temperature to be 20-25 ℃ after the SM-1 reaction is detected by TLC, adding 2- (4-bromophenyl) -2-methyl propionic acid methyl ester (SM-2-1,R = methyl, 24.42g,0.095 mol) and Ni (PPh) 3 ) 2 Cl 2 (1.31g and 0.002mol), continuing controlling the temperature to 20-25 ℃ for reaction, detecting that SM-2-1 reaction is finished, wherein the reaction time is 4 hours, filtering the reaction solution by using diatomite, pouring the filtrate into purified water (3L), extracting dichloromethane (1000 ml multiplied by 3), washing by using saturated saline (1000 ml multiplied by 2), concentrating the organic phase under reduced pressure to dryness to obtain a yellow oily substance, namely the target product 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl group]-1-piperidinyl group]-ethyl radical]Methyl-alpha, alpha-dimethylphenylacetate in a yield of 96.4% (based on SM-2-1) HPLC purity of 98.8%.
Example 5
Adding iodine (1.27g, 0.005mol) and zinc powder (7.85g, 0.12mol) into dry dimethyl sulfoxide (300 ml) under argon protection at room temperature, stirring at room temperature until iodine red disappears, and adding 2- (1- (2-bromoethyl) piperidin-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] to the mixture]Imidazole (SM-1, 38.03g,0.10 mol), continuously controlling the temperature to be between 90 and 95 ℃ for reaction, controlling the temperature to be between 20 and 25 ℃ after the detection of the completion of the SM-1 reaction by TLC, adding 2- (4-bromophenyl) -2-methyl propionic acid methyl ester (SM-2-1,R = methyl, 24.42g,0.095 mol) and Pd (PPh) 3 ) 2 Cl 2 (1.40g and 0.002mol), continuing to control the temperature to react at 20-25 ℃, detecting that SM-2-1 is reacted, wherein the reaction time is 4 hours after the SM-2-1 is detected, filtering the reaction solution by using diatomite, pouring the filtrate into purified water (3L), extracting dichloromethane (1000 ml multiplied by 3), washing by using saturated saline (1000 ml multiplied by 2), concentrating the organic phase under reduced pressure to be dry to obtain yellow oily matter, namely the target product 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl group]-1-piperidinyl group]-ethyl radical]Methyl- α, α -dimethylphenylacetate in a yield of 96.5% (based on SM-2-1) and an HPLC purity of 98.9%.
Example 6
Under the condition of argon protection at room temperature, iodine (1.27g, 0.005mol) and zinc powder (11.77g, 0.18mol) were added to dry N, N-dimethylformamide (300 ml), and stirred at room temperature until the iodine red disappeared, and then 2- (1- (2-bromoethyl) piperidin-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] was added]Imidazole (SM-1, 38.03g, 0.10mol), continuously controlling the temperature to be 65-70 ℃ for reaction, controlling the temperature to be 20-25 ℃ after detecting that the SM-1 reaction is finished through TLC (thin layer chromatography), and adding 2- (4-bromophenyl) -2-methyl propionic acid methyl ester (SM-2-1,R = methyl, 24.42g, 0.095mol) and Pd (PPh) 3 ) 2 Cl 2 (1.40g and 0.002mol), continuing to control the temperature to react at 20-25 ℃, detecting that SM-2-1 is reacted, wherein the reaction time is 5 hours after the SM-2-1 is detected, filtering the reaction solution by using diatomite, pouring the filtrate into purified water (3L), extracting dichloromethane (1000 ml multiplied by 3), washing by using saturated saline (1000 ml multiplied by 2), concentrating the organic phase under reduced pressure to be dry to obtain yellow oily matter, namely the target product 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl group]-1-piperidinyl group]-ethyl radical]- α, α -dimethylphenylacetic acid methyl ester, yield 95.4% (based on SM-2-1), HPLC purity 98.6%.
Example 7
Under the condition of argon protection at room temperature, iodine (1.27g, 0.005mol) and zinc powder (9.15g, 0.14mol) are added into dry N, N-dimethylacetamide (300 ml), stirred at room temperature until iodine red disappears, and then 2- (1- (2-bromoethyl) piperidin-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] is added]Imidazole (SM-1, 38.03g, 0.10mol), continuously controlling the temperature to be 75-80 ℃ for reaction, controlling the temperature to be 20-25 ℃ after detecting that the SM-1 reaction is finished through TLC (thin layer chromatography), adding 2- (4-bromophenyl) -2-methyl propionic acid methyl ester (SM-2-1,R = methyl, 24.42g, 0.095mol) andPd(PPh 3 ) 2 Cl 2 (0.35g, 0.0005 mol), continuously controlling the temperature to be 25-30 ℃ for reaction, detecting that the SM-2-1 reaction is finished, and then the reaction time is 5 hours, filtering the reaction solution by using diatomite, pouring the filtrate into purified water (3L), extracting methyl tert-butyl ether (1000 ml multiplied by 3), washing by using saturated saline (1000 ml multiplied by 2), concentrating the organic phase under reduced pressure to dryness to obtain a yellow oily substance, namely the target product 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl group]-1-piperidinyl group]-ethyl radical]Methyl- α, α -dimethylphenylacetate in a yield of 94.4% (based on SM-2-1) and an HPLC purity of 98.6%.
Example 8
Iodine (1.27g, 0.005mol) and zinc powder (9.15g, 0.14mol) were added to dry N-methylpyrrolidone (300 ml) at room temperature under argon atmosphere, and after stirring at room temperature until the iodine red disappeared, 2- (1- (2-bromoethyl) piperidin-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] was added]Imidazole (SM-1, 38.03g, 0.10mol), continuously controlling the temperature to be 75-80 ℃ for reaction, controlling the temperature to be 20-25 ℃ after detecting that the SM-1 reaction is finished through TLC (thin layer chromatography), and adding 2- (4-bromophenyl) -2-methyl propionic acid methyl ester (SM-2-1,R = methyl, 24.42g, 0.095mol) and Pd (PPh) 3 ) 2 Cl 2 (3.51g and 0.005mol), continuously controlling the temperature to 20-25 ℃ for reaction, detecting that the SM-2-1 reaction is finished, wherein the reaction time is 2 hours, filtering the reaction solution by using diatomite, pouring the filtrate into purified water (3L), extracting dichloromethane (1000 ml multiplied by 3), washing by using saturated saline (1000 ml multiplied by 2), concentrating the organic phase under reduced pressure to dryness to obtain a yellow oily substance, namely the target product 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl]-1-piperidinyl group]-ethyl radical]- α, α -dimethylphenylacetic acid methyl ester, yield 93.4% (based on SM-2-1), HPLC purity 97.8%.
Example 9
Iodine (2.53g, 0.01mol) and zinc powder (9.15g, 0.14mol) were added to dry N, N-dimethylpropylurea (300 ml) under nitrogen atmosphere at room temperature, and after stirring at room temperature until the iodine red disappeared, 2- (1- (2-bromoethyl) piperidin-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] was added]Imidazole (SM-1, 38.03g,0.10 mol), continuously controlling the temperature to be 70-75 ℃ for reaction, controlling the temperature to be 20-25 ℃ after detecting that the SM-1 reaction is finished by TLC, adding 2- (4-bromophenyl) -2-methylpropanoic acid ethyl ester (SM-2-2,R = ethyl, 25 ℃76g, 0.095mol) and Pd (PPh) 3 ) 2 Cl 2 (1.40g and 0.002mol), continuing to control the temperature to react at 20-25 ℃, detecting that SM-2-2 reaction is finished, and then the reaction time is 4 hours, filtering the reaction solution by using diatomite, pouring the filtrate into purified water (3L), extracting dichloromethane (1000 ml multiplied by 3), washing by using saturated saline (1000 ml multiplied by 2), concentrating the organic phase under reduced pressure to dryness to obtain yellow oily matter, namely the target product 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl group]-1-piperidinyl group]-ethyl radical]Ethyl- α, α -dimethylphenylacetate in a yield of 96.4% (based on SM-2-2) and an HPLC purity of 98.9%.
Example 10
Under the condition of argon protection at room temperature, iodine (1.27g, 0.005mol) and zinc powder (9.15g, 0.14mol) are added into dry N, N-dimethylacetamide (300 ml), stirred at room temperature until iodine red disappears, and then 2- (1- (2-bromoethyl) piperidin-4-yl) -1- (2-ethoxyethyl) -1H-benzo [ d ] is added]Imidazole (SM-1, 38.03g, 0.10mol), continuously controlling the temperature to be 75-80 ℃ for reaction, controlling the temperature to be 15-20 ℃ after detecting that the SM-1 reaction is finished through TLC, and adding 2- (4-bromophenyl) -2-methyl propionic acid methyl ester (SM-2-1,R = methyl, 28.28g, 0.111mol) and Pd (dppf) Cl 2 (1.46g and 0.002mol), continuing to control the temperature to react at 15-20 ℃, detecting that SM-2-1 is reacted, wherein the reaction time is 4 hours after the SM-2-1 is detected, filtering the reaction solution by using diatomite, pouring the filtrate into purified water (3L), extracting dichloromethane (1000 ml multiplied by 3), washing by using saturated saline (1000 ml multiplied by 2), concentrating the organic phase under reduced pressure to be dry to obtain yellow oily matter, namely the target product 4- [2- [4- [1- (2-ethoxyethyl) -1H-2-benzimidazolyl group]-1-piperidinyl group]-ethyl radical]Methyl- α, α -dimethylphenylacetate in a yield of 90.1% (based on SM-2-1) and an HPLC purity of 97.8%.
Comparative example 1
2-methyl-2- (4- (2-oxoethyl) -phenyl) -propionic acid ethyl ester (1.2 g), 1- (2-ethoxyethyl) -2-piperidin-4-yl-1H benzimidazole (1.4 g), tetrahydrofuran (20 mL) were added to a three-necked reaction flask under an argon atmosphere at room temperature to react at room temperature for 4 hours, sodium borohydride acetate (2.1 g) was added in portions to complete the reaction for 4 hours, the mixture was filtered, the filtrate was concentrated under reduced pressure, 20mL of dichloromethane and 10mL of a saturated sodium bicarbonate solution were added to wash the mixture, an organic phase was separated, the mixture was dried over 1g of anhydrous sodium sulfate for 2 hours, the filtrate was filtered, and the filtrate was concentrated to obtain 2- (4- {2- [4- (1- (2-ethoxyethyl) -1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } phenyl) -2-methyl-propionic acid ethyl ester, the yield was 80.2%, and the HPLC purity was 94.1%.
Claims (8)
1. A preparation method of a bilastine intermediate is characterized by comprising the following operations:
adding iodine and zinc powder into dry reaction solvent at room temperature under the protection of inert gas, stirring at room temperature until iodine red disappears, adding SM-1, and continuously controlling temperature T 1 Reacting, detecting the reaction, and controlling the temperature T 2 Adding SM-2 and catalyst, and continuously controlling the temperature T 2 Reacting, detecting that SM-2 is reacted, and carrying out post-treatment to obtain a target product; the reaction route is as follows:
wherein R = methyl or ethyl.
2. The method of claim 1, wherein the catalyst is Pd (PPh) 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd(dppf)Cl 2 、Ni(PPh 3 ) 2 Cl 2 One kind of (1).
3. The preparation method of claim 1, wherein the feeding molar ratio of SM-1 to iodine, zinc, SM-2 and catalyst is 1:0.02 to 0.1: 1.2-1.8: 0.8 to 1.0:0.5 to 5.0 percent.
4. The process according to claim 1, wherein the reaction temperature T is 1 From 60 to 100 ℃ and particularly preferably from 75 to 80 ℃.
5. The process according to claim 1, wherein the reaction temperature T is 2 Is 10 ℃30 ℃ and preferably from 20 to 25 ℃.
6. The method according to claim 1, wherein the reaction solvent is one or a combination of dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and N, N-dimethylpropylurea.
7. The method of claim 1, wherein the post-treating step comprises: filtering the reaction solution with diatomite, pouring the filtrate into purified water, extracting with an organic solvent, washing with saturated saline solution, and concentrating under reduced pressure until the filtrate is dry to obtain the target product.
8. The method according to claim 7, wherein the extractant is one of dichloromethane, chloroform, ethyl acetate, methyl tert-butyl ether, or a combination thereof.
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