Preparation method of new anti-allergic medicine Bilastine intermediate

A bilastine and intermediate technology, which is applied in the field of preparation of bilastine intermediates of new antiallergic drugs, can solve the problems of unstable enol silyl ether construction, decreased yield, high price and the like, and achieves low synthesis cost. , the effect of mild reaction conditions and easy operation

Active Publication Date: 2017-04-19
杭州励德生物科技有限公司
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although the above-mentioned route successfully realizes the preparation of the II structure, it needs to construct an unstable enol silyl ether at a low temperature, and needs an expensive metal catalyst to realize coupling. Although the yield is moderately high, it requires extremely harsh conditions ( Absolutely anhydrous and oxygen-free, high temperature for a long time) and treatment conditions (removal of heavy metals), in addition, once the key metal coupling reaction is implemented on a scale exceeding 100 grams, the yield drops sharply
The combination of many factors makes this route have a high yield in the small test, but its implementation cost and energy consumption are very high, and the implementation conditions are also very harsh. In addition, it cannot be scaled up, so that the modified route cannot become a good process route.

Method used

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  • Preparation method of new anti-allergic medicine Bilastine intermediate
  • Preparation method of new anti-allergic medicine Bilastine intermediate
  • Preparation method of new anti-allergic medicine Bilastine intermediate

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preparation example Construction

[0030] The preparation method steps are as follows:

[0031] (1) compound V is added to obtain compound IV after halogen carbanion exchange;

[0032] (2) compound IV obtains compound III through electrophilic cyanation reaction;

[0033] (3) Compound II is obtained after compound III is hydrolyzed.

[0034] In a particularly preferred scheme, the present invention provides the following synthetic route:

[0035]

[0036] This synthetic method comprises the following steps:

[0037] 1) compound shown in formula Va, after carbanion exchange, addition obtains compound shown in formula IVa;

[0038] 2) Compounds shown in formula IVa, electrophilic cyanation to obtain compounds shown in formula IIIa;

[0039] 3) The compound shown in formula IIIa is hydrolyzed to obtain the compound shown in formula II.

[0040] The terms used in the present invention have the following meanings unless otherwise stated.

[0041] "Alkyl" refers to a saturated aliphatic hydrocarbon group, in...

Embodiment

[0044] 1: Synthesis of Compound Va

[0045] Add 4-bromophenylethanol (1.0kg, 5.0mol) to the reaction kettle, dissolve 10 times the volume of dichloromethane, add triethylamine (1.01kg, 10.0mol) and a catalytic amount of DMAP, add TBSCl (0.9kg ,6.0mol). React at room temperature until the raw materials disappear, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to give compound Va (1.5kg, 95.5%) as a colorless oily liquid, which is directly put into the next reaction.

[0046] 2: Synthesis of Compound IVa

[0047] Add the above compound Va (1.5kg, 4.78mol) into the reaction kettle, dissolve in anhydrous THF (10V), cool to -78°C, slowly add n-butyllithium (2.5M, 2.3L) dropwise, after the dropwise addition is completed, keep This temperature was reacted for 2 hours. Anhydrous acetone (0.55 kg) was slowly added dropwise over 1 hour. After the dropwise addition is completed, slowly rise to room temperature and react until the raw ma...

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Abstract

The invention discloses a preparation method of a new anti-allergic medicine Bilastine intermediate. Quaternary carbon atoms difficult to construct are constructed by using a mild addition reaction, carboxylic groups are introduced at room temperature by using a very cheap and easily available raw material, and the unique two-phase property of carboxylic acid is used to purify, so an expensive metal catalyst is not needed in the synthesis process, and strict enforcement conditions are avoided, thereby the preparation method of the Bilastine intermediate has the advantages of mild reaction conditions, simplicity in operation, low synthesis cost, and suitableness for large-scale production.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate, in particular to a preparation method of an antiallergic new drug bilastine intermediate. Background technique [0002] Bilastine (also known as bilastine) raw materials and tablets" is the second generation of histamine H1 receptor antagonist developed by Spanish FAES pharmaceutical company. Bilastine was approved by the European Union on August 21, 2012 It is used for the treatment of allergic rhinitis and urticaria, and is undergoing phase II clinical research in the United States. [0003] [0004] The synthesis of bilastine is extremely difficult, mainly reflected in the compound shown in structure II, its unique quaternary carbon atom is very difficult to construct, the current literature patent report (WO2009 / 102155A2, 2009; US2011 / 9636A1, 2011) synthesis Starting from isobutyrate, an unstable TMS-protected enol silyl ether was constructed at low temperature, followed by a metal-catalyz...

Claims

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Application Information

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IPC IPC(8): C07C59/48C07C51/08
CPCY02P20/55C07C51/08C07F7/1804C07F7/1892C07C59/48
Inventor 任国宝吴彦李传斌
Owner 杭州励德生物科技有限公司
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