CN103351380A - Preparation method of Bilastine - Google Patents
Preparation method of Bilastine Download PDFInfo
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- CN103351380A CN103351380A CN2013102673834A CN201310267383A CN103351380A CN 103351380 A CN103351380 A CN 103351380A CN 2013102673834 A CN2013102673834 A CN 2013102673834A CN 201310267383 A CN201310267383 A CN 201310267383A CN 103351380 A CN103351380 A CN 103351380A
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Abstract
The invention belongs to the field of medical chemistry, and relates to a preparation method of Bilastine. The preparation method comprises following steps: adding compound 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 into water containing organic acid, then subjecting the mixture to a thermal-reflux reaction for 1 to 36 hours, and finally obtaining Bilastine after post-processing. The preparation method has the advantages of mild reaction conditions, simple operation and easy industrialization.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to bilastine 2-[4-(2-{4-[1-(2-oxyethyl group-ethyl)-1H-benzimidazolyl-2 radicals-yl]-piperidin-1-yl ethyl)-phenyl]-preparation of 2-methyl-propionic acid.
Background technology
Bilastine is the 2nd generation histamine H of Spain FAES drugmaker exploitation
1Receptor antagonist, European Union in 2010 ratifies it and is used for the treatment of rhinallergosis and chronic idiopathic urticaria.This product security is good, variable sedative effect and the cardiac toxic that exists with antihistamine drug.
II
The common synthetic route of bilastine is as follows:
In patent CN 1176964A, (2-{4-[1-(4 with 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline is raw material, in inorganic acid aqueous solution, example hydrochloric acid, under the sulfuric acid condition, hydrolysis obtains bilastine.
In CN 1176964A, use hydrochloric acid as solvent, yield 80%,
Use sulfuric acid as solvent, yield 72%
Those skilled in the art know, under strong acid condition, ehter bond has the tendency of fracture, and the impurity of generation is difficult for removing, the more difficult purifying of product.
If mineral acid changed does organic acid, can obtain high yield (91%), can reduce again the difficulty of aftertreatment, and substantially free of impurities generates, be a kind of good method of synthetic bilastine, the method reaction conditions is gentle, and is simple to operate, is convenient to industrialization.
Summary of the invention
The invention provides a kind of bilastine 2-[4-(2-{4-[1-(2-oxyethyl group-ethyl)-1H-benzimidazolyl-2 radicals-yl]-piperidin-1-yl ethyl)-phenyl]-preparation method of 2-methyl-propionic acid, may further comprise the steps:
(2-{4-[1-(4 with compound 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline adds in the aqueous acid, heating reflux reaction 1-36 hour, obtain bilastine.
The aqueous acid of wherein said adding comprises: formic acid, trifluoro formic acid, acetic acid, oxyacetic acid, Succinic Acid, tartrate, oxysuccinic acid, lactic acid and oxalic acid, wherein preferable formic acid.
The advantage of the inventive method is: simple to operate, purity is high, and yield is high, and reaction conditions is gentle, does not have the generation of side reaction.
Embodiment
Further specify by the following examples the present invention, but not as limitation of the present invention.
Embodiment 1:
(2-{4-[1-(4 with 5g 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline joins in the clean there-necked flask, add 4N formic acid solution 150ml, reflux 36 hours transfers to pH=7 with 10% aqueous sodium hydroxide solution, dichloromethane extraction, screw out solvent, obtain white solid, yield 90.5%.
Embodiment 2:
(2-{4-[1-(4 with 5g 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline joins in the clean there-necked flask, add 4N fluoroform acid solution 150ml, reflux 36 hours transfers to pH=7 with 10% aqueous sodium hydroxide solution, dichloromethane extraction, screw out solvent, obtain white solid, yield 92.6%.
Embodiment 3:
(2-{4-[1-(4 with 5g 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline joins in the clean there-necked flask, add 4N acetic acid solution 150ml, reflux 36 hours transfers to pH=7 with 10% aqueous sodium hydroxide solution, dichloromethane extraction, screw out solvent, obtain white solid, yield 89.7%.
?
Embodiment 4:
(2-{4-[1-(4 with 5g 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline joins in the clean there-necked flask, add 3N oxyacetic acid solution 150ml, reflux 36 hours transfers to pH=7 with 10% aqueous sodium hydroxide solution, dichloromethane extraction, screw out solvent, obtain white solid, yield 91.6%.
Embodiment 5:
(2-{4-[1-(4 with 5g 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline joins in the clean there-necked flask, add 3N Succinic Acid solution 75ml, reflux 36 hours transfers to pH=7 with 10% aqueous sodium hydroxide solution, dichloromethane extraction, screw out solvent, obtain white solid, yield 93.5%.
Embodiment 6:
(2-{4-[1-(4 with 5g 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline joins in the clean there-necked flask, add 4N tartaric acid solution 75ml, reflux 36 hours transfers to pH=7 with 10% aqueous sodium hydroxide solution, dichloromethane extraction, screw out solvent, obtain white solid, yield 90.7%.
Embodiment 7:
(2-{4-[1-(4 with 5g 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline joins in the clean there-necked flask, add 4N malic acid solution 75ml, reflux 36 hours transfers to pH=7 with 10% aqueous sodium hydroxide solution, dichloromethane extraction, screw out solvent, obtain white solid, yield 92.4%.
Embodiment 8:
(2-{4-[1-(4 with 5g 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline joins in the clean there-necked flask, add 4N lactic acid solution 150ml, reflux 36 hours transfers to pH=7 with 10% aqueous sodium hydroxide solution, dichloromethane extraction, screw out solvent, obtain white solid, yield 87.6%.
?
Embodiment 9:
(2-{4-[1-(4 with 5g 2-[1-, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline joins in the clean there-necked flask, add 4N lactic acid solution 150ml, reflux 36 hours transfers to pH=7 with 10% aqueous sodium hydroxide solution, dichloromethane extraction, screw out solvent, obtain white solid, yield 89.4%.
Claims (3)
1. the preparation method of a bulk drug bilastine (Bilastine), it is characterized in that, may further comprise the steps: (2-{4-[1-(4 with the compound 2-[1-of structure I, 4-dimethyl-4,5-dihydro-oxazole-2-yl)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-oxyethyl group-ethyl)-1H-benzoglyoxaline adds in the organic acid aqueous solution, heating reflux reaction 1-36 hour, obtain the compound of structure II
2. according to claim 1 method is characterized in that, the aqueous acid of adding comprises: formic acid, trifluoro formic acid, acetic acid, oxyacetic acid, Succinic Acid, tartrate, oxysuccinic acid and lactic acid.
3. according to claim 1 method is characterized in that, the aqueous acid of adding is the aqueous solution of formic acid.
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| CN201310267383.4A CN103351380B (en) | 2013-06-30 | 2013-06-30 | A method of preparing bilastine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017211A (en) * | 2014-04-30 | 2015-11-04 | 重庆华邦制药有限公司 | 2-phenyl propionic ester derivative and preparation method and application thereof |
| EP3170817A1 (en) * | 2015-11-20 | 2017-05-24 | Faes Farma, S.A. | Co-crystals of benzimidazole compounds |
| EP3170816A1 (en) * | 2015-11-20 | 2017-05-24 | Faes Farma, S.A. | Supersaturated compositions of benzimidazole compounds |
| CN109694367A (en) * | 2019-03-06 | 2019-04-30 | 湖北省医药工业研究院有限公司 | A method of preparing bilastine |
Citations (2)
| 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 |
| CN101952273A (en) * | 2008-02-12 | 2011-01-19 | 柳韩洋行 | Process for preparation of 2-methyl-2'-phenylpropionic acid derivatives and novel intermediate compounds |
-
2013
- 2013-06-30 CN CN201310267383.4A patent/CN103351380B/en active Active
Patent Citations (2)
| 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 |
| CN101952273A (en) * | 2008-02-12 | 2011-01-19 | 柳韩洋行 | Process for preparation of 2-methyl-2'-phenylpropionic acid derivatives and novel intermediate compounds |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017211A (en) * | 2014-04-30 | 2015-11-04 | 重庆华邦制药有限公司 | 2-phenyl propionic ester derivative and preparation method and application thereof |
| EP3170817A1 (en) * | 2015-11-20 | 2017-05-24 | Faes Farma, S.A. | Co-crystals of benzimidazole compounds |
| EP3170816A1 (en) * | 2015-11-20 | 2017-05-24 | Faes Farma, S.A. | Supersaturated compositions of benzimidazole compounds |
| WO2017085258A1 (en) * | 2015-11-20 | 2017-05-26 | Faes Farma, S.A. | Co-crystals of benzimidazole compounds |
| WO2017085265A1 (en) * | 2015-11-20 | 2017-05-26 | Faes Farma, S.A. | Supersaturated compositions of benzimidazole compounds |
| CN108290857A (en) * | 2015-11-20 | 2018-07-17 | 法斯法尔玛有限公司 | The eutectic of benzimidazole compound |
| US20180344854A1 (en) * | 2015-11-20 | 2018-12-06 | Faes Farma, S.A. | Supersaturated compositions of benzimidazole compounds |
| CN109694367A (en) * | 2019-03-06 | 2019-04-30 | 湖北省医药工业研究院有限公司 | A method of preparing bilastine |
| 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 |
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