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Total synthesis method of bepotastine besilate

A synthetic method, the technology of bepotastine besilate, which is applied in the field of total synthesis of bepotastine besilate, can solve the problems of low yield, harsh reaction conditions, high energy consumption, etc., and achieve cheap and easy-to-obtain raw materials, mild reaction conditions, The effect of simple synthesis method

Pending Publication Date: 2021-10-08
CHENGDU LIKAI CHIRAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Another example is US20140046068, WO2008153289, KR20120063705, Bull.Korean Chem.Soc.2013, 549~552, first synthesize the racemic intermediate compound 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl] Pyridine, and then continue to undergo condensation reaction with chiral esters containing different protective groups, use the resolving agent L-tartaric acid or N-benzyloxycarbonyl-L-aspartic acid to resolve the chiral compound to obtain bepotastine , although its resolution yield can reach about 35%, but the cost of chiral ester synthesis is high, after the etherification reaction, the resolution is performed, the utilization rate of raw materials is low, and the cost is greatly increased
[0008] In summary, the existing methods generally have the disadvantages of low yield, harsh reaction conditions, high energy consumption, and high cost. At the same time, most of the etherification steps use NaH, NaNH 2 and other highly dangerous substances, there are great potential safety hazards and safety risks in the industrial production process

Method used

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  • Total synthesis method of bepotastine besilate
  • Total synthesis method of bepotastine besilate
  • Total synthesis method of bepotastine besilate

Examples

Experimental program
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Effect test

Embodiment 1

[0051] A kind of bepotastine besilate total synthesis method, comprises the following steps:

[0052] (1) Preparation of compound 2

[0053] Add 88g of (4-chlorophenyl)(2-pyridyl)-methanol and 880g of dichloromethane into the reaction flask, and lower the temperature to 0-5°C. Add 22.4g of KOH, slowly add 115.6g of trichloroacetonitrile dropwise, control the reaction temperature below 5°C, after dropping, keep warm for 10 minutes, add 400g of water dropwise, stir and separate the liquid, and concentrate the organic phase to dryness under reduced pressure to obtain 142.7g of compound 2. The yield is 98.0%; its hydrogen spectrum and carbon spectrum are as follows figure 1 , 2 shown;

[0054] (2) Preparation of Compound 3

[0055] Add 124g of N-ethoxycarbonyl-4-hydroxypiperidine and 2kg of dichloromethane into the reaction flask. When the temperature is lowered to about 10°C, add 200g of compound 2. After compound 2 is completely dissolved, add 84g of trifluoromethanesulfonic...

Embodiment 2

[0067] A kind of bepotastine besilate total synthesis method, comprises the following steps:

[0068] (1) Preparation of Compound 2

[0069] Add 61.5g of (4-chlorophenyl)(2-pyridyl)-methanol and 615g of diethyl ether into the reaction flask, and cool down to 0-5°C. Add 31.42 g of potassium tert-butoxide, slowly add 80.86 g of trichloroacetonitrile dropwise, control the reaction temperature below 5°C, after the drop is completed, keep the temperature for 10 minutes, add 300 g of water dropwise, stir and separate the liquids, and concentrate the organic phase to dryness under reduced pressure to obtain 91.1g compound 2, yield 89.5%;

[0070] (2) Preparation of Compound 3

[0071] Add 62 g of N-ethoxycarbonyl-4-hydroxypiperidine and 1 kg of chloroform into the reaction flask. When the temperature is lowered to -10°C, add 100 g of compound 2. After compound 2 is completely dissolved, add 39.0 g of boron trifluoride diethyl ether dropwise to control the reaction. The temperature...

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Abstract

The invention discloses a total synthesis method of bepotastine besilate, belonging to the technical field of organic synthesis. Thetotal synthesis methodcomprises the following steps: with (4-chlorphenyl)(2-pyridyl)methanol as an initial raw material, successively conducting an addition reaction, an etherification reaction, a deprotecting group reaction, chiral resolution, a condensation reaction, a hydrolysis reaction and the like. According to the synthesis method, raw materials are cheap and easy to obtain, an expensive chiral catalyst is not needed, the synthesis method is simpler, conditions are mild, side reactions are few, cost is low, environmental protection is realized, and the synthesis method is suitable for large-scale production of the optical pure anti-allergic medicine bepotastine besilate.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for the total synthesis of bepotastine besilate. Background technique [0002] Bepotastine Besilate is a histamine H compound jointly developed by Tanabe Seiyaku and Ube Industries of Japan. 1 Receptor antagonist, listed in Japan for the first time in 2000, trade name is Talion (Tan Liang), its structure is as follows, [0003] [0004] Bepotastine Besilate has platelet activating factor (PAF) antagonistic effect, can inhibit the infiltration of eosinophils into inflammatory tissues, and reduce allergic inflammation; it can block the release of allergic mediators; the drug rarely enters the brain Inside, no sedative effect, anticholinergic effect and antihistamine effect are separated, and other adverse reactions are minimal. It is mainly used for the treatment of allergic rhinitis, urticaria, itching caused by skin diseases (eczema, dermatitis, prurigo, s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07C303/32C07C309/29
CPCC07D401/12C07C303/32C07B2200/07C07C309/29Y02P20/55
Inventor 胡鑫欣周鸣强陈宇
Owner CHENGDU LIKAI CHIRAL TECH
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