CN105272977A - Bilastine intermediate preparation method - Google Patents
Bilastine intermediate preparation method Download PDFInfo
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- CN105272977A CN105272977A CN201510597220.1A CN201510597220A CN105272977A CN 105272977 A CN105272977 A CN 105272977A CN 201510597220 A CN201510597220 A CN 201510597220A CN 105272977 A CN105272977 A CN 105272977A
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- ethyl
- phenyl
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- oxazole
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- 0 C[*+]C(NCON(C)C(C)(C)C*)=O Chemical compound C[*+]C(NCON(C)C(C)(C)C*)=O 0.000 description 2
- FGURMUFTHTVTAL-UHFFFAOYSA-N CCC1=NC(C)(C)CO1 Chemical compound CCC1=NC(C)(C)CO1 FGURMUFTHTVTAL-UHFFFAOYSA-N 0.000 description 1
- RPKCLSMBVQLWIN-UHFFFAOYSA-P C[NH2+]c1ccccc1[NH3+] Chemical compound C[NH2+]c1ccccc1[NH3+] RPKCLSMBVQLWIN-UHFFFAOYSA-P 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The present invention relates to a Bilasiting intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1H-benzimidazole preparation method, the compound 2-{1-[4-(2-hydroxyethyl) phenyl]-1-methylethyl}-4,5-2H-4,4-dimethyl-oxazole is dissolved in an organic solvent, trifluoromethanesulfonyl chloride is dissolved, and added dropwise to the system, after the completion of the addition, triethylamine is added for heating and refluxing for 1h to obtain structure II compound 2-[4-(1-(4,4-dimethyl-2H-oxazol-2-yl)-1-methylethyl) phenyl] ethyl triflate, and the resulting compound 2-[4-(1-(4,4-dimethyl-2H-oxazol-2-yl)-1-methylethyl) phenyl] ethyl triflate is dissolved in an organic solvent, under nitrogen protection, sodium methoxide is added for reaction for 2 h, 2-(4-piperidine)-1 H-benzimidazole is added for heating and refluxing for 2h to obtain 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1H-benzimidazole.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to bilastine intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl) preparation of-1H-benzoglyoxaline.
Background technology
Bilastine is the 2nd generation histamine H of FAES drugmaker of Spain 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, the variable sedative effect with antihistamine drug existence and cardiac toxic.
Document is mentioned and is being prepared intermediate 2-[1-(2-{4-[1-(4; 4-dimethyl-4; 5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl-ethyl)-piperidin-4-yl]-1H-benzoglyoxaline time adopt Tosyl chloride as acylating reagent; when preparing owing to utilizing Tosyl chloride; reaction yield is low; be only 65%, and post-reaction treatment is difficult, is difficult to realize industrialization.On benzoglyoxaline ring afterwards in H nucleophilic substitution reaction, the sodium hydride of use belongs to inflammable and explosive reagent, and danger is comparatively large, and requires higher to conversion unit, is the major hidden danger in suitability for industrialized production.
We are at synthesis 2-[1-(2-{4-[1-(4; 4-dimethyl-4; 5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl] find in-1H-benzoglyoxaline process; if utilize trifluoromethanesulfchloride chloride or trifluoromethanesulfanhydride anhydride as acylating reagent; (the former is 86.1% years old can to obtain high yield; the latter 78.5%), the difficulty of aftertreatment can be reduced again, and substantially free of impurities generates.The method yield is high, and toxicity is low, is convenient to industrialization.At 2-[1-(2-{4-[1-(4 afterwards, 4-dimethyl-4,5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl-ethyl)-piperidin-4-yl]-1H-benzoglyoxaline and bromotrifluoromethane ethyl ether reaction in, we use sodium methylate and potassium tert.-butoxide instead, it is gentleer that yield does not reduce reaction conditions, and particular requirement is not had to conversion unit, be easier to realize industrialization.
Summary of the invention
The invention provides a kind of bilastine intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl] preparation method of-1-(2-ethoxy-ethyl)-1H-benzoglyoxaline, comprise the following steps:
By compound 2-{1-[4-(2-hydroxyethyl) phenyl]-1-methylethyl }-4,5-2H-4,4-dimethyl oxazoline is dissolved in organic solvent, trifluoromethanesulfchloride chloride drops to system after dissolving, after adding triethylamine after dropwising, room temperature reaction obtains compound 2-[4-(1-(4,4-dimethyl-2H-oxazole-2-base)-1-methylethyl) phenyl] ethyl triflate.The wherein said organic solvent added comprises: methylene dichloride, trichloromethane, wherein preferred methylene dichloride.
By compound 2-[4-(1-(4,4-dimethyl-2H-oxazole-2-base)-1-methylethyl) phenyl] ethyl triflate is dissolved in organic solvent, add 2-(4-piperidines)-1H-benzoglyoxaline and mineral alkali, 80 DEG C of stirrings obtain compound 2-[1-(2-{4-[1-(4 for 4 hours, 4-dimethyl-4,5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1H-benzoglyoxaline.
By compound 2-[1-(2-{4-[1-(4; 4-dimethyl-4; 5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1H-benzoglyoxaline is dissolved in organic solvent; sodium methylate or potassium tert.-butoxide is added after passing into nitrogen protection; bromotrifluoromethane ethyl ether is added after reflux 2h; compound intermediate 2-[1-(2-{4-[1-(4 is obtained after reacting 2h again; 4-dimethyl-4,5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzoglyoxaline.Wherein used organic solvent comprises: ether, methyl tertiary butyl ether, tetrahydrofuran (THF), wherein preferred tetrahydrofuran (THF).
The advantage of the inventive method is: simple to operate, very high purity, and yield is high, and reaction conditions is gentle, does not have the generation of side reaction, cuts and do not have particular requirement to conversion unit, reduce industrialization cost.
Embodiment
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
embodiment 1:
By compound 2-{1-[4-(2-hydroxyethyl) phenyl]-1-methylethyl }-4,5-2H-4,4-dimethyl oxazoline 9.70g is dissolved in methylene dichloride 50mL, open magnetic agitation, then 14.2g trifluoromethanesulfchloride chloride to be dissolved in 10ml methylene dichloride, and be placed in constant pressure funnel and be added dropwise to reaction flask, add 8mL triethylamine again, normal-temperature reaction 4h, TLC point plate is monitored known raw material and is reacted completely, and uses saturated NaHCO
3solution, water and NaCl solution extract, be yellow oily liquid after organic phase is concentrated, add appropriate ethyl acetate to be dissolved under heating, add sherwood oil making beating again, until separate out a large amount of solid, freezing rear filtration (raising productive rate), drying, obtain white powdery solids 11.4g, (single-point) yield is 86.1%.
Get 2-[4-(1-(4,4-dimethyl-2H-oxazole-2-base)-1-methylethyl) phenyl] ethyl triflate.1.6g is dissolved in 18mLDMF, then adds 0.77g2-(4-piperidines)-1H-benzoglyoxaline and 418mgNa
2cO
3, be heated to 80 degrees Celsius and stir, solution gradually becomes muddy khaki color by milk yellow, and TLC monitoring reaction after reaction 10h, BSD-5 and BSD-6 primitive reaction is complete.Use saturated NaHCO
3solution, water and NaCl solution extract, and obtain viscous liquid, it just dissolved with q. s. methylene chloride after organic phase is concentrated, add sherwood oil making beating and separate out yellow solid, obtain 1.3g faint yellow solid after filtration, drying.Yield is 76%.
Get 2g compound 2-[1-(2-{4-[1-(4, 4-dimethyl-4, 5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1H-benzoglyoxaline is dissolved in the 60mLTHF dewatered, add 620mg sodium methylate in batches, produce a large amount of bubble, solution becomes muddy by clarifying, reaction 2h post-heating to 70 DEG C, add 2032 μ L2-bromotrifluoromethane ether, reaction 2h, TLC monitors reaction, a small amount of water quencher reaction is added after stopped reaction, concentrate away THF, add methylene dichloride and wash three times by saturated NaCl solution, organic layer concentrates rear appropriate methylene dichloride and it is just dissolved, add normal hexane making beating, obtain faint yellow solid, solid 2.0g is obtained after filtration drying, yield is 90%.
Claims (5)
1. a bilastine intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl] preparation method of-1-(2-ethoxy-ethyl)-1H-benzoglyoxaline.It is characterized in that, comprise the following steps:
1). compound 2-{1-[4-(2-hydroxyethyl) the phenyl]-1-methylethyl by structure I }-4,5-2H-4,4-dimethyl oxazoline is dissolved in organic solvent, trifluoromethanesulfchloride chloride drops to system after dissolving, stirring at room temperature after triethylamine is added after dropwising, obtain compound 2-[4-(1-(4,4-dimethyl-2H-oxazole-2-base)-1-methylethyl) phenyl] the ethyl triflate of structure I I.
2). the compound of the structure I I obtained is dissolved in organic solvent, adds 4-piperidines benzoglyoxaline and acid binding agent, stirring at normal temperature obtains the compound of structure III
2. method according to claim 1, it is characterized in that: adopt trifluoromethanesulfchloride chloride and trifluoromethanesulfanhydride anhydride to prepare key intermediate 2-[4-(1-(4,4-dimethyl-2H-oxazole-2-base)-1-methylethyl) phenyl] ethyl triflate, wherein preferred trifluoromethanesulfchloride chloride.
3. method according to claim 1, it is characterized in that: by key intermediate 2-[4-(1-(4,4-dimethyl-2H-oxazole-2-base)-1-methylethyl) phenyl] ethyl triflate prepares 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl-ethyl)-piperidin-4-yl]-1H-benzoglyoxaline time the solvent that adopts comprise: toluene, N, dinethylformamide, dimethylbenzene, wherein preferred DMF.
4. method according to claim 1, it is characterized in that: by key intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1H-benzoglyoxaline prepares 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzoglyoxaline time the reagent that uses comprise sodium methylate, potassium tert.-butoxide ' wherein particular methanol sodium.
5. method according to claim 1, it is characterized in that: by key intermediate 2-[1-(2-{4-[1-(4, 4-dimethyl-4, 5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl }-ethyl)-piperidin-4-yl]-1H-benzoglyoxaline prepares 2-[1-(2-{4-[1-(4, 4-dimethyl-4, 5-2H-oxazole-2 base)-1-methyl-ethyl]-phenyl-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzoglyoxaline time the solvent that uses comprise ether, methyl tertiary butyl ether, tetrahydrofuran (THF), wherein preferred tetrahydrofuran (THF).
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| CN201510597220.1A CN105272977A (en) | 2015-09-19 | 2015-09-19 | Bilastine intermediate preparation method |
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| CN201510597220.1A CN105272977A (en) | 2015-09-19 | 2015-09-19 | Bilastine intermediate preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456316A (en) * | 2017-09-06 | 2019-03-12 | 万全万特制药江苏有限公司 | A kind of preparation method of bilastine impurity |
| 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 (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 |
| CN103788003A (en) * | 2013-11-14 | 2014-05-14 | 江苏万特制药有限公司 | Method for preparing bilastine intermediate |
| CN104402773A (en) * | 2008-02-12 | 2015-03-11 | 柳韩洋行 | Process for preparation of 2-methyl-2'-phenylpropionic acid derivatives and novel intermediate compounds |
-
2015
- 2015-09-19 CN CN201510597220.1A patent/CN105272977A/en active Pending
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 |
| CN104402773A (en) * | 2008-02-12 | 2015-03-11 | 柳韩洋行 | Process for preparation of 2-methyl-2'-phenylpropionic acid derivatives and novel intermediate compounds |
| CN103788003A (en) * | 2013-11-14 | 2014-05-14 | 江苏万特制药有限公司 | Method for preparing bilastine intermediate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456316A (en) * | 2017-09-06 | 2019-03-12 | 万全万特制药江苏有限公司 | A kind of preparation method of bilastine impurity |
| 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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