CN111039922A - Preparation process of bilastine - Google Patents

Preparation process of bilastine Download PDF

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CN111039922A
CN111039922A CN201911371894.4A CN201911371894A CN111039922A CN 111039922 A CN111039922 A CN 111039922A CN 201911371894 A CN201911371894 A CN 201911371894A CN 111039922 A CN111039922 A CN 111039922A
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compound
reaction
bilastine
stirring
molar ratio
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宋丽丽
王金星
张新涛
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Shandong Yuxin Pharmaceutical Co ltd
Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co ltd
Shandong Luoxin Pharmaceutical Group Co Ltd
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Shandong Yuxin Pharmaceutical Co ltd
Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co ltd
Shandong Luoxin Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation process of bilastine. And carrying out esterification, deprotection, iodination and hydrolysis reactions to generate bilastine. The process has the advantages of stable raw materials, good product quality, integration of bilastine preparation and refining, simplified reaction steps and improved yield.

Description

Preparation process of bilastine
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation process 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:
Figure BDA0002339871190000011
WO2009102155 reports a synthesis method of bilastine, and the synthetic route thereof is shown as follows:
Figure BDA0002339871190000012
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.
The patent CN1105716C and ES2151442 report methods for preparing bilastine and intermediates, and the synthetic routes are shown as follows:
Figure BDA0002339871190000021
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.
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:
Figure BDA0002339871190000022
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 addition, the above routes all use 2- (4-piperidyl) benzimidazole as a raw material, have two easily substituted hydrogens in a molecular structure, have high requirements on selectivity, have severe reaction conditions, and easily generate byproducts.
In synthetic communications,41:1394-1402,2011 and patent CN102675101A, the preparation method of bilastine directly uses 2- (4-piperidyl) benzimidazole instead, so as to solve the problem of substitution selectivity, but the former still uses raw and auxiliary materials with high toxicity and high price, the latter uses Friedel-crafts reaction to generate a large amount of waste acid, uses Kinsell-Walff-Huang Minlon reaction to reduce carbonyl, and uses Zn (Hg) and hydrazine hydrate to achieve high toxicity; due to the existence of the molecular lactone, more side reactions are caused, and the product is difficult to purify.
In patent CN106146459A, cheap and easily available 2-nitroaniline is used as a raw material, and the bilastine is obtained 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.
The synthetic route is as follows:
Figure BDA0002339871190000031
in the reaction route, the compound 2 and the compound 7 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 bilastine synthesis process, so the process time is greatly prolonged, and the industrial production efficiency is reduced.
In conclusion, in the prior art, the preparation of bilastine has the problems of expensive raw materials, high toxicity, easy generation of byproducts, low purity and yield, complex process and the like.
Disclosure of Invention
Compared with the prior art, the preparation process of the bilastine provided by the invention has the advantages of stable raw materials, simple process, and higher product yield and quality.
The preparation process of bilastine provided by the invention comprises the following steps:
(1) the compound III and methyl iodide are subjected to esterification reaction under the action of alkali, triphenylphosphine and imidazole are added after the reaction is finished, iodine is added in batches, and a compound IV is generated through reaction;
(2) reacting a compound II under the action of 1.2mol/L hydrochloric acid, adding sodium hydroxide to adjust the pH value to 10-12 after the reaction is finished, extracting and concentrating, then reacting with a compound IV under the action of a catalyst, decompressing and concentrating after the reaction is finished, adding 6mol/L hydrochloric acid, stirring and dissolving, extracting a mixed solution of normal hexane and ethyl acetate, adjusting the pH value of a water phase to 5.5-6.5 by using sodium hydroxide, adjusting the pH value to 7.0-8.0 by using potassium carbonate, and filtering to obtain a compound V;
(3) hydrolyzing the compound V under the action of sodium hydroxide, concentrating under reduced pressure after the reaction is finished, adding water and ethyl acetate for extraction, adding hydrochloric acid to adjust the pH value to 6.0-7.0, filtering, and recrystallizing isopropanol to obtain bilastine;
the reaction route is as follows:
Figure BDA0002339871190000041
wherein the content of the first and second substances,
the alkali in the step (1) is one or more of potassium carbonate, sodium methoxide and lithium carbonate, and the molar ratio of the alkali to the compound III is 2-5: 1;
the molar ratio of triphenylphosphine, imidazole and the compound III used in the step (1) is 1.5-2.0:0.5-1.5:1, and the molar ratio of iodine and the compound III used is 1.5: 1;
the mol ratio of the 1.2mol/L hydrochloric acid used in the step (2) to the compound I is 2-3: 1;
the catalyst used in the step (2) is one or more of N, N-dimethylformamide, N-dimethylacetamide and N, N-diisopropylethylamine;
the molar ratio of the catalyst, the compound IV and the compound II used in the step (2) is 1-5:1: 1;
the volume ratio of the n-hexane to the ethyl acetate used in the step (2) is 2: 1;
the molar ratio of the sodium hydroxide to the compound V in the step (3) is 2-4: 1.
The invention has the following beneficial technical effects:
(1) the starting raw materials with good stability are adopted, and the product quality is guaranteed.
(2) The preparation and refining of bilastine are combined into one step, the reaction steps are simplified, and the yield is improved.
Detailed Description
Example 1: preparation of Compound VI
A 250mL reaction flask was charged with 10.41g of compound III and 52mL of DMF, and 13.82g of potassium carbonate was added, and 7.10g of methyl iodide was added dropwise with stirring, and stirred at room temperature for 2 hours, and the reaction was terminated by TLC (petroleum ether: ethyl acetate ═ 20:1, Rf ═ 0.35). 120mL of water was added to the reaction solution, extraction was performed three times with 30mL of ethyl acetate, the organic phases were combined, 8.0g of anhydrous sodium sulfate was dried, filtration was performed, the filtrate was concentrated, 80mL of predried dichloromethane, 19.67g of triphenylphosphine, and 1.70g of imidazole were added, after stirring and dissolution, 19.04g of iodine was added in 10 portions, stirring was performed at room temperature for 2 hours, TLC was performed to detect completion of the reaction (petroleum ether: ethyl acetate: 20:1, Rf: 0.45), 100mL of saturated aqueous sodium bisulfite was added, stirring was performed for 30 minutes, liquid separation was performed, the organic phase was washed with 100mL of saturated aqueous sodium bisulfite, 100mL of water, 100mL of saturated saline, dried with 10.0g of anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated to dryness, 80mL of n-hexane was added, stirring was performed for 30 minutes, the filter cake was washed with 10mL of n-hexane, the filtrate was concentrated to obtain 15.28g of compound IV.
Example 2: preparation of Compound VI
A250 mL reaction flask was charged with 10.41g of Compound III and 52mL of DMF, and 8.10g of sodium methoxide was added thereto, and 7.10g of methyl iodide was added dropwise with stirring, and the mixture was stirred at room temperature for 2 hours to complete the reaction by TLC. 120mL of water was added to the reaction solution, extraction was performed three times with 30mL of ethyl acetate, the organic phases were combined, 8.0g of anhydrous sodium sulfate was dried, filtration was performed, the filtrate was concentrated, 80mL of predried dichloromethane, 20.98g of triphenylphosphine, and 3.40g of imidazole were added, after stirring and dissolution, 19.04g of iodine was added in 10 portions, stirring was performed at room temperature for 2 hours, TLC detection was performed for completion of the reaction (petroleum ether: ethyl acetate: 20:1, Rf: 0.45), 100mL of saturated aqueous sodium bisulfite was added, stirring was performed for 30 minutes, liquid separation was performed, the organic phase was washed with 100mL of saturated aqueous sodium bisulfite, 100mL of water, 100mL of saturated saline, dried with 10.0g of anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated to dryness under reduced pressure, 80mL of n-hexane was added, stirring was performed for 30 minutes, filtration was performed, the cake was washed with 10mL of n-hexane, the filtrate was concentrated to obtain 14..
EXAMPLE 3 preparation of Compound IV
A250 mL reaction flask was charged with 10.41g of Compound III and 52mL of DMF, 14.78g of lithium carbonate was added, 7.10g of iodomethane was added dropwise with stirring, and the mixture was stirred at room temperature for 2 hours to complete the reaction by TLC. 120mL of water was added to the reaction solution, extraction was performed three times with 30mL of ethyl acetate, the organic phases were combined, 8.0g of anhydrous sodium sulfate was dried, filtration was performed, the filtrate was concentrated, 80mL of predried dichloromethane, 23.61g of triphenylphosphine, and 4.08g of imidazole were added, after stirring and dissolution, 19.04g of iodine was added in 10 portions, stirring was performed at room temperature for 2 hours, TLC was performed to detect completion of the reaction (petroleum ether: ethyl acetate: 20:1, Rf: 0.45), 100mL of saturated aqueous sodium bisulfite was added, stirring was performed for 30 minutes, liquid separation was performed, the organic phase was washed successively with 100mL of saturated aqueous sodium bisulfite, 100mL of water, 100mL of saturated saline, drying was performed with 10.0g of anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated to dryness, 80mL of n-hexane was added, stirring was performed for 30 minutes, the filter cake was washed under reduced pressure, 10mL of n-hexane was performed, the filtrate was concentrated to obtain.
EXAMPLE 4 preparation of Compound IV
A250 mL reaction flask was charged with 10.41g of Compound III and 52mL of DMF, 34.55g of potassium carbonate was added, 7.10g of iodomethane was added dropwise with stirring, and the mixture was stirred at room temperature for 2 hours to complete the reaction by TLC. 120mL of water was added to the reaction solution, extraction was performed three times with 30mL of ethyl acetate, the organic phases were combined, 8.0g of anhydrous sodium sulfate was dried, filtration was performed, the filtrate was concentrated, 80mL of predried dichloromethane, 26.23g of triphenylphosphine, and 5.11g of imidazole were added, after stirring and dissolution, 19.04g of iodine was added in 10 portions, stirring was performed at room temperature for 2 hours, TLC was performed to detect completion of the reaction (petroleum ether: ethyl acetate: 20:1, Rf: 0.45), 100mL of saturated aqueous sodium bisulfite was added, stirring was performed for 30 minutes, liquid separation was performed, the organic phase was washed with 100mL of saturated aqueous sodium bisulfite, 100mL of water, 100mL of saturated saline, dried with 10.0g of anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated to dryness, 80mL of n-hexane was added, stirring was performed for 30 minutes, the filter cake was washed with 10mL of n-hexane, the filtrate was concentrated to obtain 15.21g of compound IV.
EXAMPLE 5 preparation of Compound V
A 250mL reaction flask was charged with 14.94g of compound II and 67mL of 1.2mol/L hydrochloric acid, stirred, warmed to 60 ℃ for 1h, and then the reaction was checked for completion by TLC (dichloromethane: methanol: aqueous ammonia: 10:1:0.1 Rf: 0.85). Cooling to room temperature, adjusting the pH to 10 with 4.8mol/L sodium hydroxide solution, adding 40mL of dichloromethane for extraction, concentrating the organic phase, adding 80mL of acetonitrile, 2.92g N and N-dimethylformamide, stirring for dissolution, adding 12.89g of the compound IV obtained in example 1, heating to 65 ℃ for reaction for 3h, detecting the completion of the reaction of the compound IV by TLC (petroleum ether: ethyl acetate: 20:1, Rf: 0.65), distilling under reduced pressure at 50 ℃ to remove acetonitrile, adding 80mL of 6mol/L hydrochloric acid, stirring for dissolution, washing with 30mL of N-hexane-ethyl acetate mixed solution (2:1) for three times, adjusting the pH of the aqueous phase to 5.5 with sodium hydroxide, adjusting the pH to 7.0 with potassium carbonate, stirring for 1h, filtering, washing the filter cake with 20mL of water, and vacuum drying at 50 ℃ for 4h to obtain 16.1g of the compound, and obtaining 84.8% yield.
EXAMPLE 6 preparation of Compound V
A 250mL reaction flask was charged with 14.94g of compound II and 83mL of 1.2mol/L hydrochloric acid, stirred, warmed to 60 ℃ for 1h, and then the reaction was checked for completion by TLC (dichloromethane: methanol: ammonia water: 10:1:0.1 Rf: 0.85). Cooling to room temperature, adjusting the pH to 11 with 4.8mol/L sodium hydroxide solution, adding 40mL of dichloromethane for extraction, concentrating the organic phase, adding 80mL of acetonitrile, 6.97g N and N-dimethylacetamide, stirring for dissolution, adding 12.89g of the compound IV obtained in example 1, heating to 65 ℃ for reaction for 3h, detecting the completion of the reaction of the compound IV by TLC (petroleum ether: ethyl acetate: 20:1, Rf: 0.65), distilling under reduced pressure at 50 ℃ to remove acetonitrile, adding 80mL of 6mol/L hydrochloric acid, stirring for dissolution, washing with 30mL of N-hexane-ethyl acetate mixed solution (2:1) for three times, adjusting the pH of the aqueous phase to 6.0 with sodium hydroxide, adjusting the pH to 7.5 with potassium carbonate, stirring for 1h, filtering, washing the filter cake with 20mL of water, and vacuum drying at 50 ℃ for 4h to obtain 16.65g of the compound with yield of 87.13%.
EXAMPLE 7 preparation of Compound V
A 250mL reaction flask was charged with 14.94g of compound II and 100mL of 1.2mol/L hydrochloric acid, stirred, warmed to 60 ℃ for 1h, and then the reaction was checked for completion by TLC (dichloromethane: methanol: ammonia water: 10:1:0.1 Rf: 0.85). Cooling to room temperature, adjusting the pH to 12 with 4.8mol/L sodium hydroxide solution, adding 40mL of dichloromethane for extraction, concentrating the organic phase, adding 80mL of acetonitrile, 15.51g N and N-diisopropylethylamine, stirring for dissolution, adding 12.89g of the compound IV obtained in example 1, heating to 65 ℃ for reaction for 3h, detecting the completion of the reaction of the compound IV by TLC (petroleum ether: ethyl acetate: 20:1, Rf: 0.65), distilling under reduced pressure at 50 ℃ to remove acetonitrile, adding 80mL of 6mol/L hydrochloric acid, stirring for dissolution, washing with 30mL of N-hexane-ethyl acetate mixed solution (2:1) for three times, adjusting the pH of the aqueous phase to 6.0 with sodium hydroxide, adjusting the pH to 7.5 with potassium carbonate, stirring for 1h, filtering, washing the filter cake with 20mL of water, and vacuum drying at 50 ℃ for 4h to obtain 17.43g of the compound, with a yield of 91.2%.
EXAMPLE 8 preparation of Compound V
A 250mL reaction flask was charged with 14.94g of compound II and 100mL of 1.2mol/L hydrochloric acid, stirred, warmed to 60 ℃ for 1h, and then the reaction was checked for completion by TLC (dichloromethane: methanol: ammonia water: 10:1:0.1 Rf: 0.85). Cooling to room temperature, adjusting the pH to 10 with 4.8mol/L sodium hydroxide solution, adding 40mL of dichloromethane for extraction, concentrating the organic phase, adding 80mL of acetonitrile and 14.62g of N, N-dimethylformamide, stirring for dissolution, adding 12.89g of the compound IV obtained in example 1, heating to 65 ℃ for reaction for 3h, detecting the completion of the reaction of the compound IV by TLC (petroleum ether: ethyl acetate: 20:1, Rf: 0.65), distilling under reduced pressure at 50 ℃ to remove acetonitrile, adding 80mL of 6mol/L hydrochloric acid, stirring for dissolution, washing with 30mL of N-hexane-ethyl acetate mixed solution (2:1) for three times, adjusting the pH of the aqueous phase to 6.0 with sodium hydroxide, adjusting the pH to 7.5 with potassium carbonate, stirring for 1h, filtering, washing the filter cake with 20mL of water, and vacuum drying at 50 ℃ for 4h to obtain 16.28g of the compound Vyield of 85.2%.
Example 9 preparation of bilastine
A250 mL reaction flask was charged with 140mL of ethanol, 14.33g of Compound V obtained in example 10, 7mL of water, and 2.4g of sodium hydroxide in that order. Heating to reflux reaction for 1h, detecting that the compound V completely reacts by TLC (dichloromethane: methanol: ammonia water is 20: 1:0.1, Rf is 0.55), distilling under reduced pressure at 40 ℃ to remove ethanol, adding 70mL of water, stirring to dissolve, washing with 30mL of ethyl acetate for three times, adjusting the pH of an aqueous phase to 6.0 by using 1.2mol/L hydrochloric acid, stirring for 1h, filtering, adding 150mL of isopropanol, stirring and heating to reflux for 1h, cooling to room temperature, stirring for 1h, filtering, and drying in vacuum at 50 ℃ to obtain 11.43g of bilastine, wherein the yield is 82.2%, the purity is 99.9% by HPLC, and the maximum single impurity content is 0.08%.
Example 10 preparation of bilastine
A250 mL reaction flask was charged with 140mL of ethanol, 14.33g of Compound V obtained in example 10, 7mL of water, and 3.6g of sodium hydroxide in that order. Heating to reflux reaction for 1h, detecting that a compound V completely reacts by TLC, distilling under reduced pressure at 40 ℃ to remove ethanol, adding 70mL of water, stirring for dissolving, washing with 30mL of ethyl acetate for three times, adjusting the pH of a water phase to 6.5 by using 1.2mol/L hydrochloric acid, stirring for 1h, filtering, adding 150mL of isopropanol, stirring, heating for refluxing for 1h, cooling to room temperature, stirring for 1h, filtering, and drying in vacuum at 50 ℃ to obtain 12.42g of bilastine, wherein the yield is 89.3%, the purity is 99.9% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity content is 0.06%.
Example 11 preparation of bilastine
A250 mL reaction flask was charged with 140mL of ethanol, 14.33g of Compound V obtained in example 10, 7mL of water 1.2L, and 4.8g of sodium hydroxide, in that order. Heating to reflux reaction for 1h, detecting that a compound V completely reacts by TLC, distilling under reduced pressure at 40 ℃ to remove ethanol, adding 70mL of water, stirring for dissolving, washing with 30mL of ethyl acetate for three times, adjusting the pH of a water phase to 7.0 by using 1.2mol/L hydrochloric acid, stirring for 1h, filtering, adding 150mL of isopropanol, stirring, heating for refluxing for 1h, cooling to room temperature, stirring for 1h, filtering, and drying in vacuum at 50 ℃ to obtain 11.89g of bilastine, wherein the yield is 85.5%, the purity is 99.9% by HPLC detection, and the maximum single impurity content is 0.08%.
Comparative example 1
10.41g of compound III and 52mL of DMF were added to a 250mL reaction flask, 7.10g of methyl iodide was added dropwise with stirring, the mixture was stirred at room temperature for 2h, the TLC detection reaction was carried out for about 10% (petroleum ether: ethyl acetate: 20:1, Rf: 0.35), and after stirring for 2h, the TLC detection reaction was almost unchanged without any post-treatment.
Comparative example 2
A250 mL reaction flask was charged with 10.41g of Compound III and 52mL of DMF, and 13.82g of potassium carbonate was added, followed by dropwise addition of 7.10g of methyl iodide with stirring, stirring at room temperature for 2 hours, and TLC detection of the completion of the reaction. Adding 120mL of water into a reaction solution, extracting three times by using 25mL of ethyl acetate, combining organic phases, drying 8.0g of anhydrous sodium sulfate, filtering, concentrating a filtrate, adding 80mL of pre-dried dichloromethane, 19.67g of triphenylphosphine and 1.0g of sodium hydroxide, stirring, adding 19.04g of iodine in 10 batches, stirring at room temperature for 2h, detecting about half of raw materials by TLC, continuously stirring for 1h, then detecting that the point of the raw materials is not changed greatly, adding 100mL of saturated sodium bisulfite aqueous solution, stirring for 30min, separating, washing an organic phase by using 100mL of saturated sodium bisulfite aqueous solution, 100mL of water and 100mL of saturated saline solution, drying by using 10.0g of anhydrous sodium sulfate, filtering, concentrating a filtrate under reduced pressure to dryness, adding 80m of n-hexane, stirring for 30min by L, filtering, washing a filter cake by using 10mL of n-hexane, concentrating a filtrate to obtain 9.48g of a compound IV, wherein the yield is 57.1%.
Comparative example 3
A250 mL reaction flask was charged with 10.41g of Compound III and 52mL of DMF, and 13.82g of potassium carbonate was added, followed by dropwise addition of 7.10g of methyl iodide with stirring, stirring at room temperature for 2 hours, and TLC detection of the completion of the reaction. Adding 120mL of water into a reaction solution, extracting for three times by using 25mL of ethyl acetate, combining organic phases, drying 8.0g of anhydrous sodium sulfate, filtering, concentrating the filtrate, adding 80mL of pre-dried dichloromethane, 19.67g of triphenylphosphine and 1.97g of pyridine, stirring to dissolve, adding 19.04g of iodine into 10 batches, stirring for 2 hours at room temperature, detecting the reaction by TLC to be almost complete, continuing to stir for 1 hour, detecting the reaction by TLC to be almost complete, adding 100mL of saturated sodium bisulfite aqueous solution, stirring for 30 minutes, separating liquid, sequentially washing the organic phase by using 100mL of saturated sodium bisulfite aqueous solution, 100mL of water and 100mL of saturated saline, drying by using 10.0g of anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, adding 80m of n-hexane, stirring for 30 minutes by L, filtering, washing a filter cake by using 10mL of n-hexane, concentrating the filtrate to obtain 13.72g of a compound IV with the yield of 82..

Claims (10)

1. A preparation process of bilastine is characterized by comprising the following steps:
(1) the compound III and methyl iodide are subjected to esterification reaction under the action of alkali, triphenylphosphine and imidazole are added after the reaction is finished, iodine is added in batches, and a compound IV is generated through reaction;
(2) reacting a compound II under the action of 1.2mol/L hydrochloric acid, adding sodium hydroxide to adjust the pH value to 10-12 after the reaction is finished, extracting and concentrating, then adding a compound IV to react under the action of a catalyst, decompressing and concentrating after the reaction is finished, adding 6mol/L hydrochloric acid, stirring and dissolving, extracting a mixed solution of normal hexane and ethyl acetate, adjusting the pH value of a water phase to 5.5-6.5 by using sodium hydroxide, adjusting the pH value to 7.0-8.0 by using potassium carbonate, and filtering to obtain a compound V;
(3) hydrolyzing the compound V under the action of sodium hydroxide, concentrating under reduced pressure after the reaction is finished, adding water and ethyl acetate for extraction, adding hydrochloric acid to adjust the pH value to 6.0-7.0, filtering, and recrystallizing isopropanol to obtain bilastine;
the reaction route is as follows:
Figure FDA0002339871180000011
2. the process according to claim 1, wherein the base in step (1) is one or more of potassium carbonate, sodium methoxide and lithium carbonate.
3. The process for preparing bilastine according to claim 2, wherein the molar ratio of the base used in step (1) to the compound III and methyl iodide is 2-5:1: 1.
4. The process according to claim 1, wherein the molar ratio of triphenylphosphine, imidazole and compound III used in step (1) is 1.5-2.0:0.5-1.5: 1.
5. The process of claim 1, wherein the molar ratio of iodine to compound III in step (1) is 1.5: 1.
6. The process for preparing bilastine according to claim 1, wherein the molar ratio of 1.2mol/L hydrochloric acid used in step (2) to compound I is 2-3: 1.
7. The process of claim 1, wherein the catalyst used in step (2) is one or more selected from N, N-dimethylformamide, N-dimethylacetamide and N, N-diisopropylethylamine.
8. The process of claim 7, wherein the molar ratio of the catalyst, the compound IV and the compound II used in the step (2) is 1-5:1: 1.
9. The bilastine preparation process according to claim 1, wherein the volume ratio of n-hexane to ethyl acetate used in step (2) is 2: 1.
10. The process for preparing bilastine according to claim 1, wherein the molar ratio of sodium hydroxide to compound V in step (3) is 2-4: 1.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014188453A2 (en) * 2013-05-24 2014-11-27 Msn Laboratories Private Limited Novel process for the preparation of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1h-benzimidazol-2-yl]-1-piperidinyl}ethyl) phenyl]-2-methylpropanoic acid
CN104177331A (en) * 2014-09-10 2014-12-03 北京科莱博医药开发有限责任公司 Preparation method of bilastine
CN104276952A (en) * 2013-07-11 2015-01-14 南京华威医药科技开发有限公司 Preparation method of bilastine key intermediate
CN107365298A (en) * 2017-03-14 2017-11-21 罗欣生物科技（上海）有限公司 A kind of preparation method of the benzyl propionate derivant of 2 methyl 2 '
CN107365297A (en) * 2016-10-21 2017-11-21 罗欣生物科技（上海）有限公司 A kind of Preparation Method And Their Intermediate of the benzyl propionate derivant of 2 methyl 2 '
CN107857702A (en) * 2017-12-14 2018-03-30 重庆华邦制药有限公司 A kind of preparation method of bilastine intermediate
CN109081827A (en) * 2018-11-06 2018-12-25 北京天弘天达医药科技股份有限公司 A kind of preparation method and application of bilastine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014188453A2 (en) * 2013-05-24 2014-11-27 Msn Laboratories Private Limited Novel process for the preparation of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1h-benzimidazol-2-yl]-1-piperidinyl}ethyl) phenyl]-2-methylpropanoic acid
CN104276952A (en) * 2013-07-11 2015-01-14 南京华威医药科技开发有限公司 Preparation method of bilastine key intermediate
CN104177331A (en) * 2014-09-10 2014-12-03 北京科莱博医药开发有限责任公司 Preparation method of bilastine
CN107365297A (en) * 2016-10-21 2017-11-21 罗欣生物科技（上海）有限公司 A kind of Preparation Method And Their Intermediate of the benzyl propionate derivant of 2 methyl 2 '
CN107365298A (en) * 2017-03-14 2017-11-21 罗欣生物科技（上海）有限公司 A kind of preparation method of the benzyl propionate derivant of 2 methyl 2 '
CN107857702A (en) * 2017-12-14 2018-03-30 重庆华邦制药有限公司 A kind of preparation method of bilastine intermediate
CN109081827A (en) * 2018-11-06 2018-12-25 北京天弘天达医药科技股份有限公司 A kind of preparation method and application of bilastine

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