CN112110893A - Preparation method of bilastine - Google Patents
Preparation method of bilastine Download PDFInfo
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- CN112110893A CN112110893A CN202011170376.9A CN202011170376A CN112110893A CN 112110893 A CN112110893 A CN 112110893A CN 202011170376 A CN202011170376 A CN 202011170376A CN 112110893 A CN112110893 A CN 112110893A
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- ethyl
- methyl
- phenyl
- piperidin
- bilastine
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- ACCMWZWAEFYUGZ-UHFFFAOYSA-N bilastine Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C(CC1)CCN1CCC1=CC=C(C(C)(C)C(O)=O)C=C1 ACCMWZWAEFYUGZ-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 229960004314 bilastine Drugs 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims description 51
- 238000000034 method Methods 0.000 claims abstract description 23
- MXKMEANVUFWYSG-UHFFFAOYSA-N 2-[2-[4-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]piperidin-1-yl]ethyl]phenyl]propan-2-yl]-4,4-dimethyl-5h-1,3-oxazole Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C(CC1)CCN1CCC(C=C1)=CC=C1C(C)(C)C1=NC(C)(C)CO1 MXKMEANVUFWYSG-UHFFFAOYSA-N 0.000 claims abstract description 22
- CBOACCSFNYMVHU-UHFFFAOYSA-N 2-[4-[2-[4-(1h-benzimidazol-2-yl)piperidin-1-yl]ethyl]phenyl]-2-methylpropanoic acid Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1CCN1CCC(C=2NC3=CC=CC=C3N=2)CC1 CBOACCSFNYMVHU-UHFFFAOYSA-N 0.000 claims abstract description 22
- HBOGHPAOOWUTLB-UHFFFAOYSA-N 2-piperidin-4-yl-1h-benzimidazole Chemical compound C1CNCCC1C1=NC2=CC=CC=C2N1 HBOGHPAOOWUTLB-UHFFFAOYSA-N 0.000 claims abstract description 12
- ZNSMNVMLTJELDZ-UHFFFAOYSA-N Bis(2-chloroethyl)ether Chemical compound ClCCOCCCl ZNSMNVMLTJELDZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- ILCKTEFFKTZBLQ-UHFFFAOYSA-N methyl 2-methyl-2-[4-[2-(4-methylphenyl)sulfonyloxyethyl]phenyl]propanoate Chemical compound C1=CC(C(C)(C)C(=O)OC)=CC=C1CCOS(=O)(=O)C1=CC=C(C)C=C1 ILCKTEFFKTZBLQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 33
- 239000007787 solid Substances 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 17
- 239000000543 intermediate Substances 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- QDVMKQMVBKTSSW-UHFFFAOYSA-N methyl 2-[4-[2-[4-(1h-benzimidazol-2-yl)piperidin-1-yl]ethyl]phenyl]-2-methylpropanoate Chemical compound C1=CC(C(C)(C)C(=O)OC)=CC=C1CCN1CCC(C=2NC3=CC=CC=C3N=2)CC1 QDVMKQMVBKTSSW-UHFFFAOYSA-N 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 230000007935 neutral effect Effects 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- -1 ethyl 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionate Chemical compound 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 7
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 238000007664 blowing Methods 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- GYTVZCSSUMYVDO-UHFFFAOYSA-N 2-methyl-2-[4-[2-(4-methylphenyl)sulfonyloxyethyl]phenyl]propanoic acid Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC1=CC=C(C(C)(C)C(O)=O)C=C1 GYTVZCSSUMYVDO-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- BGUOPDZOVDIWLE-UHFFFAOYSA-N 2-[4-[2-(4,4-dimethyl-5h-1,3-oxazol-2-yl)propan-2-yl]phenyl]ethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC1=CC=C(C(C)(C)C=2OCC(C)(C)N=2)C=C1 BGUOPDZOVDIWLE-UHFFFAOYSA-N 0.000 claims description 2
- HXXNTEDKEYTYPD-UHFFFAOYSA-N 2-ethoxyethyl 4-methylbenzenesulfonate Chemical compound CCOCCOS(=O)(=O)C1=CC=C(C)C=C1 HXXNTEDKEYTYPD-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 125000002971 oxazolyl group Chemical group 0.000 description 4
- 102000000543 Histamine Receptors Human genes 0.000 description 2
- 108010002059 Histamine Receptors Proteins 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 201000010435 allergic urticaria Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001007 flame atomic emission spectroscopy Methods 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention particularly relates to a method for preparing bilastine, which takes 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidine-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid as a key intermediate to react with 2-chloroethyl ether to prepare bilastine, and further provides a method for preparing bilastine, which takes 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazole-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidine-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, or 2-piperidin-4-yl-1H-benzimidazole or 2-methyl-2- {4- [2- (toluene-4-sulfonyloxy) -ethyl ] -phenyl } -propionic acid methyl ester. The synthesis process has the characteristics of easily obtained raw materials, simple operation, high yield and avoidance of impurity generation, and is convenient for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of bilastine.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Bilastine (bilastine), chemically known as 2- [4- (2- {4- [1- (2-ethoxy-ethyl) -1H-benzimidazol-2-yl ] -piperidin-1-yl } ethyl) -phenyl ] -2-methyl-propionic acid, having the following structure:
bilastine is an oral non-sedating histamine H1 receptor antagonist developed by Spain FAES pharmaceutical company, is approved by European Union at 2012-8 for treating allergic rhinitis and urticaria, and selectively acts on peripheral histamine receptors, has no influence on other histamine receptors, has no cardiotoxicity, is quickly absorbed by oral administration, and has good tolerance, safety and high bioavailability.
The existing preparation method of bilastine, especially in the synthesis process of bilastine by using 2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl p-toluene sulfonic acid ester as raw material, can easily introduce impurities in the hydrolysis process of oxazole ring and is difficult to remove, for example, in patent CN 1105716C, 2-piperidine-4-yl-1H-benzimidazole and 2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl p-toluene sulfonic acid ester are used as raw material to synthesize an intermediate 3, then the intermediate 5 is synthesized with the raw material 4, and the bilastine is obtained by hydrolysis, wherein the synthetic route is as follows:
in the preparation method, strong acid or strong alkali is used in step3 to hydrolyze oxazole ring, so that the ether bond of the intermediate 5 is easily broken, and alcohol impurities (the structural formula is shown as a) are generated, and the product has similar properties and is not easy to remove, so that the quality of the medicine is difficult to be qualified.
Similar defects exist in other prior arts, for example, in patent CN10195273A, 2-piperidin-4-yl-1H-benzimidazole and 2-methyl-2- {4- [2- (toluene-4-sulfonyloxy) -ethyl ] -phenyl } -propionic acid methyl ester are used as raw materials to synthesize an intermediate 3, and then the intermediate 3 is synthesized with the raw material 4 to obtain an intermediate 5, and then the intermediate 5 is hydrolyzed to obtain bilastine. In the preparation method, strong alkali is used for hydrolyzing oxazole ring in step3, so that the ether bond of the intermediate 5 is easily broken, and alcohol impurities are generated, the structure is shown as formula I, the impurities with similar structures in the product are difficult to remove, and the difficulty of post-treatment is increased.
Disclosure of Invention
Aiming at the content recorded in the background technology, the invention provides an optimized bilastine preparation method, the compound shown in the formula I is used as a key intermediate to synthesize bilastine, the intermediate compound only needs to be connected with ether bonds to obtain bilastine, and the defect that in the prior art, the oxazole ring needs to be hydrolyzed to damage the ether bonds to generate impurities with similar structures is avoided. In addition, based on the intermediate, the invention also provides two bilastine synthesis ideas.
Based on the technical effects, the invention provides the following technical scheme:
in a first aspect of the invention, there is provided the use of a compound of formula I as a pharmaceutical intermediate,
in the preparation method provided by the invention, the compound shown in the formula I is used as a key intermediate, and the bilastine can be obtained by one-step reaction with the compound containing ether groups, so that the ether bond is prevented from being damaged by subsequent reaction. In addition, the compounds of formula I can be prepared from esters of 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole or of 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid by hydrolysis reactions which are easier to implement than the preparation of the synthesis of bilastine in the prior art.
Based on the research result, the invention also provides a preparation method of bilastine in the second aspect, the preparation method comprises the steps of preparing 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, or 2-piperidine-4-yl-1H-benzimidazole or 2-methyl-2- {4- [2- (toluene-4-sulfonyloxy) -ethyl ] -phenyl } -propionic acid esterified ester, and hydrolyzing the esterified product to produce the compound shown in the formula I.
The beneficial effects of one or more technical schemes are as follows:
the invention optimizes the existing bilastine preparation process, the raw materials involved in the preparation process are economical and easy to obtain, the reaction conditions are mild, the high-temperature reaction is basically not contained, the reaction yield can reach more than 80 percent on average, the post-treatment mode of the bilastine obtained by production is simpler, and the bilastine preparation process has important economic significance in industrial production.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As introduced in the background art, corresponding alcohol impurities are introduced in the preparation process of the bilastine synthesis process in the prior art and are difficult to remove, and aiming at the technical problem, the invention provides an optimized bilastine preparation method, which can avoid the alcohol impurities brought by the existing preparation process and effectively reduce the post-treatment difficulty.
In a first aspect of the invention, there is provided the use of a compound of formula I as a pharmaceutical intermediate,
preferably, the compound shown in the formula I is used as an intermediate for preparing bilastine.
Further preferred, bilastine is obtained by a method comprising, but not limited to, reacting the compound represented by formula I with 2-chloroethyl ether or ethylene glycol monoethyl ether p-toluenesulfonate.
In a more preferred preparation scheme, the compound shown as the formula I reacts with 2-chloroethyl ether to prepare bilastine.
In some embodiments of the above preferred methods of preparation, the compound of formula I is reacted with 2-chloroethyl ether to produce bilastine, as shown in the following formula:
the preparation method comprises the following steps:
mixing and reacting 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidine-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid (a compound shown in a formula I), DMF (dimethyl formamide) and sodium hydride for a period of time, adding 2-chloroethyl ether, continuing heating for reaction, adjusting the pH value of a reaction system to be neutral through glacial acetic acid after the reaction is finished, and filtering to obtain a white solid, namely bilastine.
In an embodiment of this series, the 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid is mixed with DMF and then sodium hydride is slowly added.
In the series of embodiments, after the 2-chloroethyl ether is added, the temperature is kept at 45-55 ℃ for reaction for 0.5-1.5 h.
In the preparation method provided by the invention, the compound shown in the formula I is used as a key intermediate, and the bilastine can be obtained by one-step reaction with the compound containing ether groups, so that the ether bond is prevented from being damaged by subsequent reaction. In addition, the compounds of formula I can be prepared from esters of 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole or of 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid by hydrolysis reactions which are easier to implement than the preparation of the synthesis of bilastine in the prior art.
Based on the research result, the invention also provides a preparation method of bilastine in the second aspect, the preparation method comprises the steps of preparing 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, or 2-piperidine-4-yl-1H-benzimidazole or 2-methyl-2- {4- [2- (toluene-4-sulfonyloxy) -ethyl ] -phenyl } -propionic acid esterified ester, and hydrolyzing the esterified product to produce the compound shown in the formula I.
Preferably, said 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole is hydrolyzed under acidic conditions with heating to provide a compound of formula I, said reaction being represented by the following formula:
further preferably, the preparation method of the hydrolysis under the acidic condition is as follows: mixing 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole and acid, refluxing for a certain period of time, adding a base to adjust the pH to be neutral after the reaction is finished, and filtering to obtain a solid part, namely the compound shown in the formula I.
In some specific embodiments of the above preferred embodiments, the preparation method of bilastine comprises the following steps:
2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, a hydrochloric acid solution were put into a reaction flask, heating and refluxing, adjusting the pH value to be neutral by using sodium hydroxide after the reaction is finished, filtering, washing a filter cake by using water, and drying by blowing air to obtain a white solid, namely the 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidine-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid.
In some specific embodiments of the above preferred embodiments, the preparation method of bilastine comprises the following steps:
2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, ethanol, hydrochloric acid are mixed and heated under reflux for a period of time, after the reaction, the pH value is adjusted to be neutral by using sodium hydroxide, a solid part is reserved by filtering a reaction system, and the solid part is washed and dried to obtain the 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidine-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid.
In this series of embodiments, the present invention also provides a process for the preparation of 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, said preparation comprising the steps of:
mixing 2-piperidin-4-yl-1H-benzimidazole, 2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl p-toluenesulfonate, sodium carbonate and DMF, heating for a reaction time, filtering and drying after the reaction is finished to obtain a solid part, namely 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole.
In this series of embodiments, the bilastine is prepared as shown in the following formula:
preferably, the esterified 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid includes, but is not limited to, methyl 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionate, ethyl 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionate and/or ethyl 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionate Oxazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid propyl ester.
More preferably, the esterified compound of 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid is 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid methyl ester, which has the following structure:
further, the 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidine-1-yl ] -ethyl } -phenyl) -2-methyl propionate is hydrolyzed under the alkaline condition to obtain the compound shown as the formula I; the reaction is shown as follows:
the alkaline environment comprises the addition of sodium hydroxide and/or ethanol or sodium carbonate and/or ethanol to methyl 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionate.
In some specific embodiments of the above preferred embodiments, the preparation method comprises the following steps: mixing 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidine-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid methyl ester, ethanol and sodium hydroxide, heating and refluxing, removing ethanol in a solvent after the reaction is finished, adjusting the pH to be neutral by glacial acetic acid, filtering and drying to obtain a solid part, namely 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidine-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid.
In this series of embodiments, the method of making further comprises the steps of: mixing 2-piperidin-4-yl-1H-benzimidazole, 2-methyl-2- {4- [2- (toluene-4-sulfonyloxy) -ethyl ] -phenyl } -propionic acid methyl ester, sodium carbonate and ethanol, heating to reflux, removing ethanol in the solvent after the reaction is finished, filtering and drying to obtain a solid part, namely 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid methyl ester.
In this series of embodiments, the route of synthesis of bilastine is as follows:
in order to make the technical scheme of the present invention more clearly understood by those skilled in the art, the technical scheme of the present invention will be described in detail below with reference to specific examples and comparative examples, wherein the raw materials in the following examples are all commercially available products.
Example 1
In this example, a process for the preparation of bilastine intermediate 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid is provided, which is shown below:
step 1: preparation of 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole
20.1g of 2-piperidin-4-yl-1H-benzimidazole, 41.6g of 2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl-p-toluenesulfonate, 11.7g of sodium carbonate and 50ml of DMF were charged in a reaction flask and heated to 80 ℃ for reaction for 2 hours, and after the completion of the reaction, 100ml of deionized water was added to the reaction, followed by filtration, and the filter cake was air-dried at 70 ℃ for 3 hours to obtain 35.5g of a white solid. The yield thereof was found to be 79.8%.
Step 2: preparation of 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid
30.0g of 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole and 30ml of 4mol/L hydrochloric acid were put into a reaction flask and heated to reflux for reaction for 3 hours, after completion of the reaction, the pH was adjusted to 7 with 4mol/L sodium hydroxide, filtered, and the filter cake was washed with water and then dried by air blowing at 70 ℃ for 3 hours to obtain 23.7g of a white solid. The yield thereof was found to be 89.8%.
And step 3: preparation of bilastine
20.1g of 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid, 40ml of DMF were charged in a reaction flask, 4.5g of 60% sodium hydride was slowly added thereto, after completion of the addition, reaction was carried out for half an hour, 5.8g of 2-chloroethyl ether was added thereto, the mixture was heated to 50 ℃ for reaction for 1 hour, after completion of the reaction, 80ml of deionized water was slowly added to the reaction flask, the pH value was adjusted to 7 with glacial acetic acid, filtration was carried out, and after washing the filter cake with water, drying was carried out by air blowing at 70 ℃ for 3 hours to obtain 20.1g of a white solid, yield 84.8%.
Example 2
In contrast to example 1, this example provides a further method for the preparation of 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid:
40.0g of 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, 60ml of ethanol and 10ml of concentrated hydrochloric acid were put into a reaction flask and heated to reflux reaction for 5 hours, after completion of the reaction, the pH was adjusted to 7 with 4mol/L of sodium hydroxide, filtered, the cake was washed with water and then air-dried at 70 ℃ for 3 hours to obtain 31.8g of a white solid. The yield thereof was found to be 90.3%.
Example 3
In this example, a process for the preparation of bilastine based on 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid methyl ester as intermediate is provided, which is shown below
Step 1: preparation of 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid methyl ester
30.2g of 2-piperidin-4-yl-1H-benzimidazole, 56.4g of 2-methyl-2- {4- [2- (toluene-4-sulfonyloxy) -ethyl ] -phenyl } -propionic acid methyl ester, 17.5g of sodium carbonate and 90ml of ethanol were put into a reaction flask and heated to reflux for reaction for 2 hours, after the reaction was completed, ethanol was distilled off, and 200ml of deionized water was added to the residue, which was filtered, and the filter cake was washed with water, dried at 70 ℃ by forced air for 3 hours to obtain 49.3g of a white solid. The yield thereof was found to be 81.1%.
Step 2 preparation of 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid
35.0g of 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid methyl ester, 100ml of ethanol and 10.5g of sodium hydroxide were put into a reaction flask and heated to reflux for 2 hours, after the completion of the reaction, ethanol was distilled off, 100ml of deionized water was added to the residue, the pH value was adjusted to 7 with glacial acetic acid, filtration was carried out, and the filter cake was washed with water and dried by air blow at 70 ℃ for 3 hours to obtain 29.8g of a white solid. The yield thereof was found to be 88.2%.
And step 3: preparation of bilastine
This procedure was the same as procedure 3 described in example 1.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The application of the compound shown in the formula I as a medical intermediate has the following structure,
2. the use of a compound of formula i as defined in claim 1 as a pharmaceutical intermediate for the preparation of bilastine.
3. The use of a compound of formula i as defined in claim 2 as a pharmaceutical intermediate, wherein said bilastine is obtained by a process which comprises, but is not limited to, reacting a compound of formula i with 2-chloroethyl ether or ethylene glycol monoethyl ether p-toluenesulfonate;
preferably, the compound shown as the formula I reacts with 2-chloroethyl ether to prepare bilastine, and further; the reaction is shown as follows:
the preparation method comprises the following steps:
mixing and reacting 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidine-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid (a compound shown in a formula I), DMF (dimethyl formamide) and sodium hydride for a period of time, adding 2-chloroethyl ether, continuing heating for reaction, adjusting the pH value of a reaction system to be neutral through glacial acetic acid after the reaction is finished, and filtering to obtain a white solid, namely bilastine.
4. The use of a compound of formula i as claimed in claim 3 as a pharmaceutical intermediate, wherein 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid is mixed with DMF and then sodium hydride is slowly added;
or, after the 2-chloroethyl ether is added, the temperature is kept at 45-55 ℃ for reaction for 0.5-1.5 h.
5. A process for the preparation of bilastine, comprising 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, or 2-piperidine-4-yl-1H-benzimidazole or 2-methyl-2- {4- [2- (toluene-4-sulfonyloxy) -ethyl ] -phenyl } -propionic acid esterified ester, and hydrolyzing the esterified product to produce the compound shown in the formula I.
6. A process for the preparation of bilastine as claimed in claim 5, wherein 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole is hydrolyzed under acidic conditions with heating to give the compound of formula I:
preferably, the preparation method of the hydrolysis under the acidic condition comprises the following steps: mixing 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole and acid, refluxing for a certain period of time, adding a base to adjust the pH to be neutral after the reaction is finished, and filtering to obtain a solid part, namely the compound shown in the formula I.
7. The method of preparing bilastine as claimed in claim 6, wherein the method of preparing bilastine comprises the steps of:
2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, a hydrochloric acid solution were put into a reaction flask, heating and refluxing, adjusting the pH value to be neutral by using sodium hydroxide after the reaction is finished, filtering, washing a filter cake by using water, and drying by blowing air to obtain a white solid, namely 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidine-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid;
or the preparation method of the bilastine preparation method comprises the following steps:
2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole, ethanol, hydrochloric acid are mixed and heated under reflux for a period of time, after the reaction is finished, adjusting the pH value to be neutral by using sodium hydroxide, filtering a reaction system to retain a solid part, washing and drying to obtain the 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidine-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid;
preferably, the process for the preparation of 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole comprises the steps of:
mixing 2-piperidin-4-yl-1H-benzimidazole, 2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl p-toluenesulfonate, sodium carbonate and DMF, heating for a reaction time, filtering and drying after the reaction is finished to obtain a solid part, namely 2- [1- (2- {4- [1- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -1-methyl-ethyl ] -phenyl } -ethyl) -piperidin-4-yl ] -1- (2-ethoxy-ethyl) -1H-benzimidazole;
the preparation method of the bilastine is shown as the following formula:
8. a process for the preparation of bilastine as claimed in claim 5, wherein the said esters of 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid include but are not limited to methyl 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionate, ethyl 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionate and/or ethyl 2- (4- {2- [4- (1H-benzimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionate - {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid propyl ester;
preferably, the esterified compound of 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid is 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid methyl ester, which has the following structure:
9. the process for the preparation of bilastine as claimed in claim 8, wherein the 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid methyl ester is hydrolyzed under basic conditions to give the compound of formula i; the reaction is shown as follows:
the alkaline environment comprises the addition of sodium hydroxide and/or ethanol or sodium carbonate and/or ethanol to methyl 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionate.
10. The method of preparing bilastine as claimed in claim 9, comprising the steps of: mixing 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid methyl ester, ethanol and sodium hydroxide, heating and refluxing, removing ethanol in a solvent after the reaction is finished, adjusting the pH to be neutral by using glacial acetic acid, filtering and drying to obtain a solid part, namely 2- (4- {2- [4- (1H-benzoimidazol-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid;
or, the preparation method also comprises the following steps: mixing 2-piperidin-4-yl-1H-benzimidazole, 2-methyl-2- {4- [2- (toluene-4-sulfonyloxy) -ethyl ] -phenyl } -propionic acid methyl ester, sodium carbonate and ethanol, heating to reflux, removing ethanol in the solvent after the reaction is finished, filtering and drying to obtain a solid part, namely 2- (4- {2- [4- (1H-benzimidazole-2-yl) -piperidin-1-yl ] -ethyl } -phenyl) -2-methyl-propionic acid methyl ester;
preferably, the synthetic route of the bilastine is shown as the following formula:
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1176964A (en) * | 1996-06-04 | 1998-03-25 | 西班牙化工品与医药产品生产股份公司 | New benzimidazole derivatives with antihistaminic activity |
| CN104326909A (en) * | 2014-09-22 | 2015-02-04 | 暨南大学 | Methods for preparation of alpha, alpha-dimethyl-4-(2-haloethyl) phenyl acetate and synthesis of bilastine |
| WO2020020873A1 (en) * | 2018-07-24 | 2020-01-30 | Faes Farma, S.A. | Process and intermediates for the preparation of bilastine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1176964A (en) * | 1996-06-04 | 1998-03-25 | 西班牙化工品与医药产品生产股份公司 | New benzimidazole derivatives with antihistaminic activity |
| CN104326909A (en) * | 2014-09-22 | 2015-02-04 | 暨南大学 | Methods for preparation of alpha, alpha-dimethyl-4-(2-haloethyl) phenyl acetate and synthesis of bilastine |
| WO2020020873A1 (en) * | 2018-07-24 | 2020-01-30 | Faes Farma, S.A. | Process and intermediates for the preparation of bilastine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276327A (en) * | 2021-12-20 | 2022-04-05 | 重庆华邦胜凯制药有限公司 | Bilastine impurity and preparation method and application thereof |
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