CN105254579A - Method for preparing bilastine intermediate through one-kettle process - Google Patents

Method for preparing bilastine intermediate through one-kettle process Download PDF

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Publication number
CN105254579A
CN105254579A CN201510597212.7A CN201510597212A CN105254579A CN 105254579 A CN105254579 A CN 105254579A CN 201510597212 A CN201510597212 A CN 201510597212A CN 105254579 A CN105254579 A CN 105254579A
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CN
China
Prior art keywords
bromo
phenyl
methylethyl
compound
reaction
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Pending
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CN201510597212.7A
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Chinese (zh)
Inventor
李恩民
王进敏
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WANQUAN WANTE PHARMACEUTICAL JIANGSU Co Ltd
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WANQUAN WANTE PHARMACEUTICAL JIANGSU Co Ltd
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Priority to CN201510597212.7A priority Critical patent/CN105254579A/en
Publication of CN105254579A publication Critical patent/CN105254579A/en
Pending legal-status Critical Current

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

The invention provides a method for preparing a bilastine intermediate 2-{1-[4-bromo-phenyl]-1-methylethyl}-4,5-2H-4,4-dimethyloxazole. The method comprises the following steps: dissolving a compound 2-(4-bromo-phenyl)-2-methyl-propionic acid in thionyl chloride, carrying out a refluxing reaction for 4h, carrying out ice bath cooling to -5-0DEG C, adding a dichloromethane solution of 2-amino-2-methyl-1-propanol to the above obtained system in a dropwise manner, maintaining the temperature not greater than 0DEG C, reacting at room temperature for 4h after the dropwise addition ends, adding an aqueous solution of NaOH to adjust the pH value of the system to 7, carrying out dichloromethane extraction, and carrying out rotary evaporation until dryness to obtain the compound 2-{1-[4-bromo-phenyl]-1-methylethyl}-4,5-2H-4,4-dimethyloxazole.

Description

A kind of one kettle way prepares the method for bilastine intermediate
Technical field
The invention belongs to medicinal chemistry art, relate to bilastine intermediate 2-{1-[the bromo-phenyl of 4-]-1-methylethyl the preparation of-4,5-2H-4,4-dimethyl oxazolines.
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 2-{1-[the bromo-phenyl of 4-]-1-methylethyl }-4,5-2H-4,4-dimethyl oxazoline time first by oxyamide after, then become the mode of oxazole ring, by two-step reaction, yield is lower.We find by being dissolved in thionyl chloride by 2-(the bromo-phenyl of 4-)-2-rnethyl-propanoic acid when synthesizing this compound, after reacting by heating 4h, ice bath is down to 0 DEG C once, drip the dichloromethane solution of amino-2 methyl isophthalic acids-propyl alcohol of 2-, dropwise rear room temperature reaction 4 hours, ph is regulated to obtain compound 2-{1-[the bromo-phenyl of 4-]-1-methylethyl to neutrality }-4,5-2H-4,4-dimethyl oxazolines.
Summary of the invention
The invention provides a kind of bilastine intermediate 2-{1-[the bromo-phenyl of 4-]-1-methylethyl } preparation method of-4,5-2H-4,4-dimethyl oxazolines, comprise the following steps:
Compound 2-(the bromo-phenyl of 4-)-2-rnethyl-propanoic acid is dissolved in thionyl chloride, after back flow reaction 4h, ice bath cools to-5 DEG C-0 DEG C, the dichloromethane solution of amino for 2--2 methyl isophthalic acids-propyl alcohol is dropped to system, keep temperature not higher than 0 DEG C, dropwise rear room temperature reaction 4h, add NaOH aqueous solution regulation system pH=7, be spin-dried for after dichloromethane extraction and obtain compound 2-{1-[the bromo-phenyl of 4-]-1-methylethyl-4,5-2H-4,4-dimethyl oxazoline.
The wherein said organic solvent added is sulfur oxychloride.
The advantage of the inventive method is: simple to operate, very high purity, and yield is high, does not have the generation of side reaction.
Embodiment
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
embodiment 1:
Compound 2-(the bromo-phenyl of 4-)-2-rnethyl-propanoic acid 5.0g 20ml sulfur oxychloride is dissolved, heating reflux reaction 4h, the point that TLC monitors reactant disappears, system is cooled between-5 DEG C to 0 DEG C, then amino-2 methyl isophthalic acids-propyl alcohol of 4.0g2-is dissolved with 20ml methylene dichloride, drop in sulfur oxychloride reaction system, keep temperature of reaction not higher than 0 DEG C, cooling is removed after dropwising, room temperature reaction 4h, pH=7 is regulated with the 10%NaOH aqueous solution, separatory collects organic phase, suction filtration after anhydrous sodium sulfate drying, revolve except dissolving, obtain white solid 4.1g, yield 92.3%.

Claims (3)

1. a bilastine intermediate 4-[1-(4, 5-dihydro-4, 4-dimethyl-2-oxazolyl)-1-methylethyl] preparation method of-phenylethyl alcohol, it is characterized in that, comprise the following steps: compound 2-(the bromo-phenyl of 4-)-2-rnethyl-propanoic acid is dissolved in thionyl chloride, after back flow reaction 4h, ice bath cools to-5 DEG C-0 DEG C, the dichloromethane solution of amino for 2--2 methyl isophthalic acids-propyl alcohol is dropped to system, keep temperature not higher than 0 DEG C, dropwise rear room temperature reaction 4h, add NaOH aqueous solution regulation system pH=7, be spin-dried for after dichloromethane extraction and obtain compound 2-{1-[the bromo-phenyl of 4-]-1-methylethyl-4, 5-2H-4, 4-dimethyl oxazoline.
2. method according to claim 1, is characterized in that, the solvent that reaction system uses is sulfur oxychloride.
3. temperature when dripping 2-amino-2 methyl isophthalic acids-propyl alcohol is-5 DEG C to 0 DEG C.
CN201510597212.7A 2015-09-19 2015-09-19 Method for preparing bilastine intermediate through one-kettle process Pending CN105254579A (en)

Priority Applications (1)

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CN201510597212.7A CN105254579A (en) 2015-09-19 2015-09-19 Method for preparing bilastine intermediate through one-kettle process

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Application Number Priority Date Filing Date Title
CN201510597212.7A CN105254579A (en) 2015-09-19 2015-09-19 Method for preparing bilastine intermediate through one-kettle process

Publications (1)

Publication Number Publication Date
CN105254579A true CN105254579A (en) 2016-01-20

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022344A1 (en) * 1995-12-21 1997-06-26 Albany Molecular Research, Inc. Process for production of piperidine derivatives
ES2151442B1 (en) * 1999-01-11 2001-07-01 Espanola Prod Quimicos NEW DERIVATIVE OF BENCENOETHANOL.
WO2014026657A2 (en) * 2012-08-15 2014-02-20 Zentiva, K.S A process for the preparation of a derivative of 2-methyl-2'-phenylpropionic acid using new intermediates
CN103788003A (en) * 2013-11-14 2014-05-14 江苏万特制药有限公司 Method for preparing bilastine intermediate
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

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022344A1 (en) * 1995-12-21 1997-06-26 Albany Molecular Research, Inc. Process for production of piperidine derivatives
ES2151442B1 (en) * 1999-01-11 2001-07-01 Espanola Prod Quimicos NEW DERIVATIVE OF BENCENOETHANOL.
WO2014026657A2 (en) * 2012-08-15 2014-02-20 Zentiva, K.S A process for the preparation of a derivative of 2-methyl-2'-phenylpropionic acid using new intermediates
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
CN103788003A (en) * 2013-11-14 2014-05-14 江苏万特制药有限公司 Method for preparing bilastine 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

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
STEVEN J. COLLIER ET AL.: "Alternative Synthesis of Bilastine", 《SYNTHETIC COMMUNICATIONS》 *
夏万东 等: "比拉斯汀关键中间体的合成", 《河北化工》 *
薛永强 等: "《现代有机合成方法与技术》", 31 May 2003, 化学工业出版社 *

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