CN106146459B - Preparation method of bilastine - Google Patents
Preparation method of bilastine Download PDFInfo
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- CN106146459B CN106146459B CN201610565699.5A CN201610565699A CN106146459B CN 106146459 B CN106146459 B CN 106146459B CN 201610565699 A CN201610565699 A CN 201610565699A CN 106146459 B CN106146459 B CN 106146459B
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
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Abstract
The invention discloses a preparation method of bilastine, which adopts cheap and easily-obtained 2-nitroaniline as a raw material to obtain bilastine through reduction-ring closure reaction, alkylation reaction, hydrolysis, coupling and hydrolysis. The method solves the problems of harsh operating conditions, high toxicity, expensive raw materials and complex operation in the prior art, has mild reaction conditions in each step, simple operation of the synthetic method, easy treatment, few byproducts, high yield and purity and low production cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of bilastine.
Background
Bilastine is a 2 nd generation histamine H1 receptor antagonist developed by spanish FAES pharmaceutical company, which was approved by the european union in 2010 for the treatment of allergic rhinitis and chronic idiopathic urticaria. The product has good safety, and has no sedative effect and cardiotoxicity of conventional antihistamine drugs. The chemical structural formula is as follows:
researchers have successively designed and developed various synthetic methods for bilastine. Several synthetic methods have been reported for the preparation of bilastine and its key intermediates:
route one: WO2009102155 reports a synthesis method of bilastine, and the synthetic route thereof is shown as follows:
in the method, the key intermediate 2- (4-hydroxyethyl phenyl) -2-ethyl methyl propionate is synthesized by condensing p-bromophenol and 1-methoxy-1- (trimethylsilyloxy) -2-methyl-1-propylene which are used as raw materials in the presence of a catalyst of bis (dibenzylideneacetone) palladium, tri-tert-butylphosphine and zinc fluoride.
The reaction mainly has three disadvantages, firstly, the price of raw materials of 1-methoxy-1- (trimethylsilyloxy) -2-methyl-1-propylene, catalysts of bis (dibenzylideneacetone) palladium, tri-tert-butylphosphine and the like is extremely expensive, is not easy to purchase and store; secondly, the reaction requires extremely strict anhydrous and anaerobic conditions, the operation is complex, and the obtained product is difficult to purify; thirdly, the palladium and phosphorus remaining after the reaction are both harmful to the environment. In conclusion, the route has high cost, difficult operation and large pollution, and is difficult to realize industrial production.
And a second route: the preparation of bilastine and intermediates is reported in patents CN1105716C and ES2151442 by spanish chemicals and pharmaceutical products manufacturing companies, and the synthetic route is as follows:
butyl lithium or Grignard reagent is used in the route, and the method needs no water and no oxygen and has strict condition requirements; ethylene oxide is a hazardous product and has high toxicity; the whole route is longer and the yield is lower.
And a third route: synthesis, 41: 1394. sup. 1402,2011 also reports a preparation method for preparing bilastine, and the synthetic route is shown as follows:
as can be seen from the above-mentioned route, the starting materials for the reaction are expensive, the first step requires anhydrous and oxygen-free operation, and expensive Pd (PPh3)4 is used as a catalyst, the boric anhydride or tin reagent is expensive, the tin reagent is more toxic, and the borane dimethyl sulfide in the second step has an unpleasant odor and is more toxic.
And a fourth route: CN102675101A reports a preparation method for preparing bilastine, the synthetic route is shown as follows:
as can be seen from the synthetic route, the method uses Friedel-crafts reaction to generate a large amount of waste acid, uses the Kinsell-Walff-Huang Minlon reaction to reduce carbonyl, uses Zn (Hg) and hydrazine hydrate, and has higher toxicity; due to the existence of the molecular lactone, more side reactions are caused, and the product is difficult to purify.
And a fifth route: US5877187 reports the synthesis of bilastine: taking a compound twelve as a raw material, and carrying out methylation, hydrolysis, carboxyl protection and Grignard reaction to obtain an intermediate seventeen. Hydroxyl is esterified and activated by tosyl chloride and then undergoes condensation, alkylation and deprotection reactions with another intermediate five to obtain bilastine, and the synthetic route is as follows:
due to the poor compatibility of the grignard reaction with the group, a more specific oxazole is required to protect the carboxyl group and the yield of this step is very low. In addition, the Grignard reaction condition is harsh, the requirement for no water and no oxygen is high, and the method is not suitable for large-scale production. Overall, the repeated protecting group-applying process makes the route too long and the cost too high; the methylation reagent with high toxicity can cause great harm to production personnel, so the route is not suitable for industrial production.
In summary, the existing method for synthesizing bilastine has the disadvantages of harsh operation conditions, high toxicity, expensive raw materials and complicated operation.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a preparation method of bilastine, which solves the defects of harsh operation conditions, high toxicity, expensive raw materials and complex operation in the prior art, has mild reaction conditions in each step, is simple to operate, has high yield and purity, and is suitable for industrial production.
The technical scheme of the invention is as follows:
a preparation method of bilastine is characterized by comprising the following steps:
1) 2-nitroaniline (compound 1) is taken as a raw material, and is subjected to reduction-ring closure reaction with 1-Boc-piperidine-4-formaldehyde (compound 2) under the action of a reducing agent to obtain 4- (1H-benzo [ d ] imidazole-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound 3);
2)4- (1H-benzo [ d ] imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound 3) and 2-chloroethylether (compound 4); carrying out alkylation reaction under the conditions of phase transfer catalyst and alkalinity to obtain a compound 5;
3) hydrolyzing the compound 5 under the condition of organic acid to obtain 1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (compound 6);
4)1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (compound 6) and 2- [4- (2-p-toluenesulfonyl-ethyl) -phenyl ] -2-methyl-sodium propionate (compound 7) are subjected to coupling and hydrolysis reaction under the action of sodium methoxide and organic acid to obtain bilastine (compound 8); the synthetic route is as follows:
preferably, in step 1), the reducing agent is Na2S2O4The reaction solvent is ethanol-water, and the compound 1, the compound 2 and Na2S2O4The molar ratio of the ethanol to the water is 1:1-1.3:2-3, and the volume ratio of the ethanol to the water is 20: 0.5-1.
Preferably, in step 2), the phase transfer catalyst is tetrabutylammonium bromide or polyethylene glycol-400, and the base is mixed base (NaOH + Na)2CO3) The reaction temperature is 40-50 ℃; the dosage ratio of the tetrabutylammonium bromide to the compound 4 is 1g:1mol, and the dosage ratio of the polyethylene glycol-400 to the compound 4 is 20ml:1 mol; compound 3, compound 4, NaOH, Na2CO3The molar ratio of (A) to (B) is 3:3-4:2.5: 1.
Preferably, in step 3) and step 4), the organic acid is formic acid, trifluoroacetic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, malic acid, lactic acid, or oxalic acid.
Preferably, in the step 4), the compound 6 and the compound 7 react for 2 to 3 hours at the temperature of 20 to 50 ℃ under the action of sodium ethoxide to obtain the compound 8, and the molar ratio of the compound 6 to the compound 7 to the sodium ethoxide is 1:1 to 1.2:2 to 3.
Preferably, the compound 7 is obtained by the following reaction process: 4- (2-hydroxyethyl) phenylboronic acid (compound 9) and 2-chloroisobutyric acid (compound 10) are subjected to coupling reaction to obtain 2- [4- (2-hydroxy-ethyl) -phenyl ] -2-methyl-propionic acid (compound 11), the compound 11 is subjected to salt forming reaction to obtain 2- [4- (2-hydroxy-ethyl) -phenyl ] -2-methyl-propionic acid sodium (compound 12), and the compound 12 and p-toluenesulfonyl chloride are subjected to sulfonylation reaction under the action of diisopropylethylamine to obtain a compound 7; the synthetic route is as follows:
preferably, the compound 9 and the compound 10 are subjected to a coupling reaction under the action of a catalyst, wherein the catalyst is PdCl2(PPh3)2、Pd(PPh3)4Or PdCl2(dppf), the molar amount of the catalyst is 5-10% of that of the compound 10, and the reaction molar ratio of the compound 9 to the compound 10 is 1: 1.
Preferably, the sulfonylation reaction solvent is chloroform or dichloromethane; the reaction molar ratio of the compound 12 to the tosyl chloride to the diisopropylethylamine is 1:1-1.3:1.1-1.4, the reaction temperature is 0-5 ℃, and the reaction time is 1-3 h.
Preferably, the compound 2 is obtained by oxidation reaction of N-Boc-4-piperidinemethanol (compound 13) under the action of an oxidation reaction system; the synthetic route is as follows:
preferably, the oxidation reaction system is a system consisting of 2,2,6, 6-tetramethyl-1-piperidone (TEMPO), sodium periodate and sodium bromide, the oxidation reaction solvent is tetrahydrofuran, DMF, dichloromethane or trichloromethane, the reaction temperature is 20-25 ℃, and the reaction time is 5-12 h; the molar ratio of the 2,2,6, 6-tetramethyl-1-piperidone (TEMPO), the N-Boc-4-piperidinemethanol, the sodium periodate and the sodium bromide is 1:50-100:100-150: 30-50.
Compared with the prior art, the invention has the following beneficial effects:
1) the invention innovatively adopts the 2-nitroaniline which is cheap and easy to obtain as the raw material, reduces the reaction cost, solves the problems that the prior art uses special oxazole to protect carboxyl and repeatedly carry out protecting group processes, and has the advantages of mild reaction conditions, simple operation, no toxicity, no pollution, less by-products and suitability for industrial production.
Step 1) with Na2S2O4The method is characterized in that the method is a reducing agent, ethanol-water is used as a reaction solvent, and the reduction of nitro and the ring closing reaction are completed in one step, so that the problems that in the prior art, a relatively complex transition metal catalyst (such as Pd/C) is adopted, the o-nitroaniline is reduced firstly, and then the o-nitroaniline is condensed with acid and derivatives (or aldehyde) thereof, the reducing agent (such as Raney-Ni, NaH and the like) is not easy to obtain, the cost is relatively high, the steps are multiple, and the operation is complicated are solved.
And 2) the N-alkylation reaction is carried out under the conditions of a phase transfer catalyst and mixed alkali, the yield is high (more than 90 percent), the operation is simple, and the problems of high cost, long reaction time and complex operation of a potassium iodide reagent adopted in the prior art are solved.
2) The compound 7 is obtained by coupling reaction, salt forming reaction and sulfonylation reaction of 4- (2-hydroxyethyl) phenylboronic acid (compound 9) and 2-chloroisobutyric acid (compound 10). Solves the problems that the prior art uses a methylating agent with high toxicity, the Grignard reaction condition is harsh, the requirement on anhydrous and anaerobic conditions is high, and the prior art is not suitable for large-scale production. The raw materials are easy to obtain, the reaction condition is mild, the operation is simple, and the method is suitable for industrial production.
3) The compound 2 is obtained by oxidation reaction of cheap and easily obtained raw material N-Boc-4-piperidine methanol (compound 13) under the action of an oxidation reaction system; compared with the oxalyl chloride oxidation process, the new oxidation reaction system is applied, the reaction conditions are mild, the reaction operation is simple and convenient, the yield and the purity of the product are high, and the product can be directly used for synthesizing bilastine without further refining. The invention can be used for industrial scale-up production.
4) The novel method for synthesizing bilastine provided by the invention adopts cheap and easily-obtained 2-nitroaniline as a raw material, and obtains bilastine through reduction-ring closure reaction, alkylation reaction, hydrolysis, coupling and hydrolysis. The method solves the problems of harsh operating conditions, high toxicity, expensive raw materials and complex operation in the prior art, has mild reaction conditions in each step, simple operation of the synthetic method, easy treatment, few byproducts, high yield and purity and low production cost, and is suitable for industrial production.
Detailed Description
For better understanding of the present invention, the following description is given with reference to specific examples, but the present invention is not limited to the specific embodiments.
Example 1-1: synthesis of 4- (1H-benzo [ d ] imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (Compound 3)
55.2g of 2-nitroaniline (Compound 1, 0.4mol) and 85.3g of 1-Boc-piperidine-4-carbaldehyde (Compound 2, 0.4mol 1) were added to a mixed solvent of ethanol (3.2L) -water (80ml), and after completion of dissolution, 139.3g of Na was added2S204(0.8mo1), refluxing under heating, TLC tracing reaction, reaction completion after 8h, filtering precipitate, washing filter cake with absolute ethanol (1.6L × 2), combining filtrates and spin-drying to obtain precipitate. Dissolving in ethanol, and recrystallizing with ethanol-water to obtain 101.3g of 4- (1H-benzo [ d ]]Imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound 3) in 84% yield.
Examples 1 to 2: synthesis of 4- (1H-benzo [ d ] imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (Compound 3)
55.2g of 2-nitroaniline (Compound 1, 0.4mol) and 102.4g of 1-Boc-piperidine-4-carbaldehyde (Compound 2, 0.48 mol 1) were added to a mixed solvent of ethanol (3.2L) -water (128ml), and 174.1g of Na was added after complete dissolution2S204(1mo1), heating and refluxing, tracking the reaction by TLC, reacting completely after 8h, filtering the precipitate, washing the filter cake with absolute ethyl alcohol (1.6L multiplied by 2), combining the filtrates and spin-drying to obtain the final productAnd (4) precipitating. Dissolving in ethanol, and recrystallizing with ethanol-water to obtain 108.5g of 4- (1H-benzo [ d ]]Imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound 3) in 90% yield.
Examples 1 to 3: synthesis of 4- (1H-benzo [ d ] imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (Compound 3)
55.2g of 2-nitroaniline (Compound 1, 0.4mol) and 110.9g of 1-Boc-piperidine-4-carbaldehyde (Compound 2, 0.52 mol 1) were added to a mixed solvent of ethanol (3.2L) -water (160ml), and after completion of dissolution, 208.9g of Na was added2S204(1.2mo1), heating and refluxing, TLC tracing reaction, reacting completely after 8h, filtering precipitate, washing filter cake with absolute ethyl alcohol (1.6L multiplied by 2), combining filtrate and drying by spin drying to obtain precipitate. Dissolving in ethanol, and recrystallizing with ethanol-water to obtain 103.7g of 4- (1H-benzo [ d ]]Imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound 3) in 86% yield.
Example 2-1: synthesis of Compound 5
32.57g of 2-chloroethylether (Compound 4, 0.3mo1) and 90.4g of 4- (1H-benzo [ d ] b]Imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound 3, 0.3mol) (40%) in water, 0.3g tetrabutylammonium bromide was added, and mixed base (0.25mol NaOH +0.1mol Na) was slowly added under cooling in an ice-water bath2CO3) Rapidly stirring at 50 deg.C for 2 hr, standing after the reaction is completed, cooling the reaction solution, extracting with diethyl ether, washing with saturated saline, drying, filtering, and removing the solvent to obtain 98.6g of compound 5 with a yield of 88%.
Example 2-2: synthesis of Compound 5
38.00g of 2-chloroethylether (Compound 4, 0.35mol) and 90.4g of 4- (1H-benzo [ d ] b]Imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound 3, 0.3mol) (40%) aqueous solution, then 7ml polyethylene glycol-400 was added, and mixed base (0.25mol NaOH +0.1mol Na) was slowly added under cooling in ice-water bath2CO3) After completion of the reaction, the reaction mixture was allowed to stand, cooled, extracted with ether, washed with saturated brine, dried, filtered, and the solvent was removed to obtain 103.1g of compound 5 in 92% yield.
Examples 2 to 3: synthesis of Compound 5
43.43g of 2-chloroethylether (Compound 4, 0.4mo1) and 90.4g of 4- (1H-benzo [ d ] were charged in a reaction flask]Imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound 3, 0.3mol) (40%) in water, 0.4g tetrabutylammonium bromide was added, and mixed base (0.25mol NaOH +0.1mol Na) was slowly added under cooling in an ice-water bath2CO3) Rapidly stirring at 50 deg.C for 2 hr, standing after reaction, cooling the reaction solution, extracting with diethyl ether, washing with saturated saline, drying, filtering, and removing solvent to obtain 100.8g of compound 5 with yield of 90%.
Example 3-1: synthesis of 1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (Compound 6)
74.70g of compound 5(0.2mol) was charged in a reaction flask, and 2.2L of a 4N formic acid solution was added thereto, and the mixture was refluxed for 22 hours, adjusted to pH 7 with a 10% aqueous solution of sodium hydroxide, extracted with dichloromethane, and the solvent was removed by evaporation to give 50.3g of 1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (compound 6) in 92% yield.
Example 3-2: synthesis of 1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (Compound 6)
74.70g of compound 5(0.2mol) was put into a reaction flask, and 1.1L of 3N succinic acid solution was added thereto, and the mixture was refluxed for 22 hours, adjusted to pH 7 with 10% aqueous sodium hydroxide solution, extracted with dichloromethane, and the solvent was removed by centrifugation to obtain 50.8g of 1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (compound 6) in 93% yield.
Examples 3 to 3: synthesis of 1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (Compound 6)
74.70g of compound 5(0.2mol) was put into a reaction flask, and 1.1L of 4N malic acid solution was added thereto, and the mixture was refluxed for 22 hours, adjusted to pH 7 with 10% aqueous sodium hydroxide solution, extracted with dichloromethane, and the solvent was removed by centrifugation to obtain 49.2g of 1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (compound 6) in 90% yield.
Example 4-1: synthesis of bilastine
To a reaction flask were added 24.5g sodium ethoxide (0.36mol), 49.2g1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (compound 6, 0.18mol), 69.2g2- [4- (2-p-toluenesulfonyl-ethyl) -phenyl ] -2-methyl-propionic acid sodium (compound 7, 0.18mol), and the reaction was warmed to 50 ℃ for 2 hours and followed by TLC until the reaction was complete. 2L of saturated ammonium chloride solution and 2L of ethyl acetate are added into the reaction solution, the mixture is subjected to layer extraction, an organic layer is dried for 4 hours by using anhydrous sodium sulfate, the mixture is filtered, 2.5L of 4N trifluoroacetic acid solution is added into the filtrate, the heating reflux is carried out for 20 hours, the pH value is adjusted to 7 by using 10% sodium hydroxide aqueous solution, dichloromethane is used for extraction, the solvent is extracted, and 76.8g of bilastine is obtained, wherein the yield is 92%.
Example 4-2: synthesis of bilastine
30.6g sodium ethoxide (0.45mol), 49.2g1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (compound 6, 0.18mol), 76.1g2- [4- (2-p-toluenesulfonyl-ethyl) -phenyl ] -2-methyl-propionic acid sodium (compound 7, 0.198mol) were added to the reaction flask, the reaction was warmed to 30 ℃ for 2 hours, and the reaction was followed by TLC until the reaction was complete. 2L of saturated ammonium chloride solution and 2L of ethyl acetate are added into the reaction solution, the mixture is subjected to layer extraction, an organic layer is dried for 4 hours by using anhydrous sodium sulfate, the mixture is filtered, 2.5L of 4N acetic acid solution is added into the filtrate, the heating reflux is carried out for 20 hours, the pH value is adjusted to 7 by using 10% sodium hydroxide aqueous solution, dichloromethane is used for extraction, the solvent is separated out, and 75.1g of bilastine is obtained, wherein the yield is 90%.
Examples 4 to 3: synthesis of bilastine
36.7g sodium ethoxide (0.54mol), 49.2g1- (2-ethoxy-ethyl) -2-piperidin-4-yl-1H-benzimidazole (compound 6, 0.18mol), 83.0g2- [4- (2-p-toluenesulfonyl-ethyl) -phenyl ] -2-methyl-propionic acid sodium (compound 7, 0.216mol) were added to the reaction flask, the reaction was warmed to 20 ℃ for 3 hours, and the reaction was followed by TLC until the reaction was complete. 2L of saturated ammonium chloride solution and 2L of ethyl acetate are added into the reaction solution, layered extraction is carried out, an organic layer is dried for 4 hours by using anhydrous sodium sulfate, filtration is carried out, 1.2L of 4N tartaric acid solution is added into the filtrate, heating reflux is carried out for 20 hours, the pH value is adjusted to 7 by using 10% sodium hydroxide aqueous solution, dichloromethane extraction is carried out, the solvent is separated out, 78.4g of bilastine is obtained, and the yield is 94%.
Example 5-1: synthesis of 2- [4- (2-hydroxy-ethyl) -phenyl ] -2-methyl-propionic acid (Compound 11)
To the reaction flaskTo this was added 36.8g of 2-chloroisobutyric acid (Compound 10, 0.3mol), methanol (700mL), 63.6g of sodium carbonate (0.60mol), water (2.5L), 49.8g of 4- (2-hydroxyethyl) phenylboronic acid (Compound 9, 0.3mol) and PdCl2(dppf) (0.015mol), replacing with nitrogen for 3 times, refluxing for reaction for 4h, carrying out suction filtration while the solution is hot, leaching a filter cake with hot methanol, pulping the filter cake with methanol-ethyl acetate (1:2), filtering, and drying the filter cake to obtain 60.0g of 2- [4- (2-hydroxy-ethyl) -phenyl ] -phenyl]-2-methyl-propionic acid (compound 11) in 96% yield.
Example 5-2: synthesis of 2- [4- (2-hydroxy-ethyl) -phenyl ] -2-methyl-propionic acid (Compound 11)
To a reaction flask were added 36.8g 2-chloroisobutyric acid (Compound 10, 0.3mol), methanol (700mL), 63.6g sodium carbonate (0.60mol), water (2.5L), 49.8g4- (2-hydroxyethyl) phenylboronic acid (Compound 9, 0.3mol), and PdCl2(PPh3)2(0.021mol), replacing with nitrogen for 3 times, refluxing for 4h, filtering while the solution is hot, leaching the filter cake with hot methanol, pulping the filter cake with methanol-ethyl acetate (1:2), filtering, and drying the filter cake to obtain 58.7g of 2- [4- (2-hydroxy-ethyl) -phenyl ] -phenyl]-2-methyl-propionic acid (compound 11) in 94% yield.
Examples 5 to 3: synthesis of 2- [4- (2-hydroxy-ethyl) -phenyl ] -2-methyl-propionic acid (Compound 11)
To a reaction flask were charged 36.8g 2-chloroisobutyric acid (Compound 10, 0.3mol), methanol (700mL), 63.6g sodium carbonate (0.60mol), water (2.5L), 49.8g4- (2-hydroxyethyl) phenylboronic acid (Compound 9, 0.3mol), and Pd (PPh)3)4(0.03mol), replacing nitrogen for 3 times, carrying out reflux reaction for 4h, carrying out suction filtration while the solution is hot, leaching a filter cake by hot methanol, pulping the filter cake by methanol and ethyl acetate (1:2), filtering, and drying the filter cake to obtain 56.9g of 2- [4- (2-hydroxy-ethyl) -phenyl ] -phenyl]-2-methyl-propionic acid (compound 11) in 91% yield.
Example 6-1: synthesis of sodium 2- [4- (2-hydroxy-ethyl) -phenyl ] -2-methyl-propionate (Compound 12)
52.1g of 2- [4- (2-hydroxy-ethyl) -phenyl ] -2-methyl-propionic acid (compound 11, 0.25mol), 300mL of THF, 300mL of water and 0.75mol of NaOH were charged into a reaction flask, and after stirring at room temperature for 2 to 3 hours, THF was removed by concentration under reduced pressure, filtration was carried out, the filter cake was washed with water and dried to obtain 53.5g of 2- [4- (2-hydroxy-ethyl) -phenyl ] -2-methyl-propionic acid sodium (compound 12) in 93% yield.
Example 7-1: synthesis of sodium 2- [4- (2-p-toluenesulfonyl-ethyl) -phenyl ] -2-methyl-propionate (Compound 7)
To the reaction flask was added 46.1g of 2- [4- (2-hydroxy-ethyl) -phenyl ] -ethyl ester]Sodium-2-methyl-propionate (compound 12, 0.2mol), 28.4g diisopropylethylamine (0.22mol), 1.3L dichloromethane, 38.1g p-toluenesulfonyl chloride (0.2mol) added dropwise at 0 ℃ after completion of addition, reaction at this temperature for 1 to 3 hours, TLC tracing the reaction to completion, suction filtration under reduced pressure, and use of CH for the residue2Cl2(200 ml. times.3) washing. The filtrate was concentrated and purified by silica gel column chromatography (V petroleum ether: V ethyl acetate: 5:1) to obtain 74.6g of 2- [4- (2-p-toluenesulfonyl-ethyl) -phenyl ] -ethyl acetate]Sodium-2-methyl-propionate (compound 7) in 97% yield.
Example 7-2: synthesis of sodium 2- [4- (2-p-toluenesulfonyl-ethyl) -phenyl ] -2-methyl-propionate (Compound 7)
To the reaction flask was added 46.1g of 2- [4- (2-hydroxy-ethyl) -phenyl ] -ethyl ester]Sodium-2-methyl-propionate (compound 12, 0.2mol), 32.3g diisopropylethylamine (0.25mol), 1.3L dichloromethane, 43.8g p-toluenesulfonyl chloride (0.23mol) added dropwise at 5 ℃ after completion of addition, reaction at this temperature for 1 to 3 hours, TLC tracing the reaction to completion, suction filtration under reduced pressure, and use of CH for the residue2Cl2(200 ml. times.3) washing. The filtrate was concentrated and purified by silica gel column chromatography (V petroleum ether: V ethyl acetate: 5:1) to obtain 76.1g of 2- [4- (2-p-toluenesulfonyl-ethyl) -phenyl ] -ethyl acetate]Sodium-2-methyl-propionate (compound 7) in 99% yield.
Examples 7 to 3: synthesis of sodium 2- [4- (2-p-toluenesulfonyl-ethyl) -phenyl ] -2-methyl-propionate (Compound 7)
To the reaction flask was added 46.1g of 2- [4- (2-hydroxy-ethyl) -phenyl ] -ethyl ester]Sodium-2-methyl-propionate (compound 12, 0.2mol), 36.2g diisopropylethylamine (0.28mol), 1.3L dichloromethane, 49.6g p-toluenesulfonyl chloride (0.26mol) added dropwise at 3 ℃ after completion of addition, reaction at this temperature for 1-3 hours, TLC tracing the reaction to completion, suction filtration under reduced pressure, and use of CH for the residue2Cl2(200 ml. times.3) washing. Concentrating the filtrate, and separating by silica gel column chromatography (V petroleum ether: V ethyl acetate)The ester was 5:1) purified to give 73.8g of 2- [4- (2-p-toluenesulfonyl-ethyl) -phenyl ] -ethyl ester]Sodium-2-methyl-propionate (compound 7) in 96% yield.
Example 8-1: synthesis of 1-Boc-piperidine-4-carbaldehyde (Compound 4)
To a reaction flask was added 107.6g of N-Boc-4-piperidinemethanol (Compound 13, 0.5mol), 220ml of a solution of TEMPO in dichloromethane (1.6 g of TEMPO, 0.01mol), 230ml of NaIO4Mixed brine solution of NaBr (containing 213.9g NaIO)430.9g NaBr), the reaction was stirred vigorously at 20 ℃ for 12 h. After the reaction is finished, liquid is separated, an organic layer is collected and added with 1mol/L Na2S2O3The solution was washed twice with 450mL of water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give 100.2g of 1-Boc-piperidine-4-carbaldehyde (compound 4) in 94% yield.
Example 8-2: synthesis of 1-Boc-piperidine-4-carbaldehyde (Compound 4)
To a reaction flask was added 172.2g of N-Boc-4-piperidinemethanol (Compound 13, 0.8mol), 220ml of TEEMPO in tetrahydrofuran (containing 1.6g of TEMPO, 0.01mol), 230ml of NaIO4Mixed brine solution of NaBr (containing 256.7g NaIO)441.2g NaBr) was added, and the reaction was stirred vigorously at 23 ℃ for 8 hours. After the reaction is finished, liquid is separated, an organic layer is collected and added with 1mol/L Na2S2O3The solution was washed twice with 450mL of water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give 155.3g of 1-Boc-piperidine-4-carbaldehyde (compound 4) in 91% yield.
Examples 8 to 3: synthesis of 1-Boc-piperidine-4-carbaldehyde (Compound 2)
To a reaction flask was added 215.3g of N-Boc-4-piperidinemethanol (compound 13, 1mol), 220ml of a solution of EMPO in DMF (containing 1.6g of TEMPO, 0.01mol), 230ml of NaIO4Mixed brine solution of NaBr (320.8 g NaIO)451.4g NaBr), the reaction was stirred vigorously at 25 ℃ for 5 h. After the reaction is finished, liquid is separated, an organic layer is collected and added with 1mol/L Na2S2O3The solution was washed twice with 450mL of water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give 196.2g of 1-Boc-piperidine-4-carbaldehyde (compound 2) in 92% yield.
Claims (10)
1. A preparation method of bilastine is characterized by comprising the following steps:
1) 2-nitroaniline (compound 1) is taken as a raw material, and 1-Boc-piperidine-4-formaldehyde (compound 2) is added in a reducing agent Na2S2O4Under the action of the acid to generate reduction-ring closure reaction to obtain 4- (1H-benzo [ d)]Imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound 3);
2)4- (1H-benzo [ d ] imidazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (compound 3) and 2-chloroethylether (compound 4); carrying out alkylation reaction under the conditions of phase transfer catalyst and alkalinity to obtain a compound 5;
3) hydrolyzing the compound 5 under the condition of organic acid to obtain 1- (2-ethoxy-ethyl) -2- (piperidin-4-yl) -1H-benzimidazole (compound 6);
4)1- (2-ethoxy-ethyl) -2- (piperidin-4-yl) -1H-benzimidazole (compound 6) and 2- [4- (2-p-toluenesulfonyloxy-ethyl) -phenyl ] -2-methyl-sodium propionate (compound 7) are subjected to coupling and hydrolysis reaction under the action of sodium ethoxide and organic acid to obtain bilastine (compound 8); the synthetic route is as follows:
2. the method of claim 1, wherein: in the step 1), the reaction solvent is ethanol-water, and the compound 1, the compound 2 and Na2S2O4The molar ratio of the ethanol to the water is 1:1-1.3:2-3, and the volume ratio of the ethanol to the water is 20: 0.5-1.
3. The method of claim 1, wherein: in the step 2), the phase transfer catalyst is tetrabutylammonium bromide or polyethylene glycol-400, and the alkali is mixed alkali NaOH + Na2CO3The reaction temperature is 40-50 ℃; the dosage ratio of the tetrabutylammonium bromide to the compound 4 is 1g:1mol, and the dosage ratio of the polyethylene glycol-400 to the compound 4 is 20ml:1 mol; compound 3, compound 4, NaOH, Na2CO3The molar ratio of (A) to (B) is 3:3-4:2.5: 1.
4. The method of claim 1, wherein: in the step 3) and the step 4), the organic acid is formic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, malic acid, lactic acid or oxalic acid.
5. The method of claim 1, wherein: in the step 4), the compound 6 and the compound 7 react for 2 to 3 hours at the temperature of 20 to 50 ℃ under the action of sodium ethoxide to obtain a compound 8, wherein the molar using amount ratio of the compound 6 to the compound 7 to the sodium ethoxide is 1:1 to 1.2:2 to 3.
6. The method of claim 1, wherein: the compound 7 is obtained by the following reaction process: 4- (2-hydroxyethyl) phenylboronic acid (compound 9) and 2-chloroisobutyric acid (compound 10) are subjected to coupling reaction to obtain 2- [4- (2-hydroxy-ethyl) -phenyl ] -2-methyl-propionic acid (compound 11), the compound 11 is subjected to salt forming reaction to obtain 2- [4- (2-hydroxy-ethyl) -phenyl ] -2-methyl-propionic acid sodium (compound 12), and the compound 12 and p-toluenesulfonyl chloride are subjected to sulfonylation reaction under the action of diisopropylethylamine to obtain a compound 7; the synthetic route is as follows:
7. the method of claim 6, wherein: the compound 9 and the compound 10 are subjected to coupling reaction under the action of a catalyst, wherein the catalyst is PdCl2(PPh3)2、Pd(PPh3)4Or PdCl2(dppf), the molar amount of the catalyst is 5-10% of that of the compound 10, and the reaction molar ratio of the compound 9 to the compound 10 is 1: 1.
8. The method of claim 6, wherein: the sulfonylation reaction solvent is chloroform or dichloromethane; the reaction molar ratio of the compound 12 to the tosyl chloride to the diisopropylethylamine is 1:1-1.3:1.1-1.4, the reaction temperature is 0-5 ℃, and the reaction time is 1-3 h.
9. The method of claim 1, wherein: the compound 2 is obtained by oxidation reaction of N-Boc-4-piperidine methanol (compound 13) under the action of an oxidation reaction system; the synthetic route is as follows:
10. the method of claim 9, wherein: the oxidation reaction system is a system consisting of 2,2,6, 6-tetramethyl-1-piperidone (TEMPO), sodium periodate and sodium bromide, the oxidation reaction solvent is tetrahydrofuran, DMF, dichloromethane or trichloromethane, the reaction temperature is 20-25 ℃, and the reaction time is 5-12 h; the molar ratio of the 2,2,6, 6-tetramethyl-1-piperidone (TEMPO), the N-Boc-4-piperidinemethanol, the sodium periodate and the sodium bromide is 1:50-100:100-150: 30-50.
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| CN109705088A (en) * | 2019-01-31 | 2019-05-03 | 深圳市第二人民医院 | A kind of preparation method of Egelieting intermediate |
| CN109694367B (en) * | 2019-03-06 | 2021-06-11 | 湖北省医药工业研究院有限公司 | Method for preparing bilastine |
| CN109942406B (en) * | 2019-04-30 | 2022-11-01 | 上海天慈国际药业有限公司 | Preparation method of 2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionic acid |
| CN112110811A (en) * | 2019-06-20 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | Preparation method of bilastine intermediate |
| CN112110892A (en) * | 2019-06-20 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | Preparation method of bilastine important intermediate |
| CN110903278B (en) * | 2019-12-26 | 2022-08-16 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of bilastine |
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