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Improved preparation method of 4-(2-carboxybenzyloxy) phenylacetic acid

A technology of carboxybenzyloxy and hydroxyphenylacetic acid, applied in the preparation of carboxylate/lactone, organic chemistry, etc., can solve the problems of many steps, poor safety, low yield, etc., shorten the process steps and improve safety , the effect of reducing energy consumption

Inactive Publication Date: 2012-10-31
北京联本医药化学技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] The purpose of the present invention is to provide an improved method for preparing 4-(2-carboxybenzyloxy)phenylacetic acid with high yield, so as to solve the problems in the prior art that are unfavorable for industrialized production such as high cost, low yield, poor safety, and many steps

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  • Improved preparation method of 4-(2-carboxybenzyloxy) phenylacetic acid

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Embodiment 1 8

[0058] Embodiment one to eight 4-(2-carboxybenzyloxy) phenylacetic acid preparation

[0059] Dissolve phthalide in dimethyl sulfoxide and toluene, it can be completely dissolved at about 40°C, and set aside.

[0060] Add 4-hydroxyphenylacetic acid to dimethyl sulfoxide, stir, and when the internal temperature is 48°C, add 50% sodium hydroxide aqueous solution dropwise, the reaction is exothermic, control the temperature below 95°C to prevent flushing; then add toluene , heating and reflux began to separate water. After the water separation is complete, steam the toluene, add about half of the pre-prepared phthalide solution directly, steam the toluene, heat to 125-140°C for reaction, and add the other half of the phthalide after the phthalide is basically completely reacted Solution, distill out toluene, heat to 125-140°C for reaction, and react until all phthalides have reacted. Cool the reaction system to about 100°C, add water, and when the temperature drops to room tempe...

Embodiment 9 10

[0065] Embodiment nine to sixteen 4-(2-carboxybenzyloxy) phenylacetic acid preparation

[0066] Dissolve phthalide in dimethyl sulfoxide and xylene, it can be completely dissolved at about 40°C, and set aside.

[0067] Add 4-hydroxyphenylacetic acid to dimethyl sulfoxide, stir, and when heated to an internal temperature of 48°C, add 50% sodium hydroxide aqueous solution dropwise, the reaction is exothermic, and the temperature is controlled below 95°C to prevent flushing; then add two Toluene, the temperature was raised to reflux and the water was separated. After the water separation is complete, distill out the xylene, directly add about half of the pre-prepared phthalide solution, steam the xylene, heat to 140-150°C for reaction, and add the other half after the phthalide basically reacts completely For phthalide solution, distill out xylene, heat to 140-150°C for reaction, and react until all phthalide has reacted. Cool the reaction system to about 100°C, add water, and ...

Embodiment 17

[0070] Example 17 Preparation of 6,11-dihydro-11-oxo-dibenzo[b,e]oxepadiene-2-acetic acid

[0071] Under stirring, add 28.6g of 4-(2-carboxybenzyloxy)phenylacetic acid, 100g of polyphosphoric acid, and 100ml of glacial acetic acid into the reaction bottle, heat to 80°C for 5 hours, after the reaction is complete, pour the reaction solution into cold water , extracted with 100ml×3 ethyl acetate, washed with 200ml×3 water to weak acidity, after liquid separation, added 3g of activated carbon to the ethyl acetate layer for decolorization, heated to reflux for 30 minutes, and filtered off the activated carbon while hot. Dry over anhydrous sodium sulfate, filter off the desiccant, evaporate ethyl acetate under reduced pressure, and then recrystallize with 65ml 1:1 (v / v) ethyl acetate-n-hexane to obtain 6,11-dihydro-11-oxo- Dibenzo[b,e]oxepadiene-2-acetic acid. After drying, 15.6 g of a light yellow to off-white solid was obtained, with a yield of 58%, a melting point of 137-139° C...

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Abstract

The invention provides an improved preparation method of 4-(2-carboxybenzyloxy) phenylacetic acid. 6, 11-dihydro-11-oxo-dibenz (b, e) oxepin-2-acetic acid which is a raw material for producing the anti-allergic drug of olopatatadine can be obtained through a cyclization reaction of the 4-(2-carboxybenzyloxy) phenylacetic acid.

Description

technical field [0001] The invention relates to 4-(2-carboxybenzyloxy)phenylacetic acid as a pharmaceutical intermediate and a preparation method thereof. Background technique [0002] As a useful preparation method of the antihistamine H1 receptor antagonist olopatadine (olopatadine), Japanese Patent Publication Hei 6-9606 describes the use of 6,11-dihydro-11-oxo-dibenzo [b, e] oxepadiene-2-acetic acid is the method for preparing olopatadine as a raw material, and the technological process is as shown in formula (5), [0003] [0004] Formula (5) [0005] 6,11-Dihydro-11-oxo-dibenzo[b,e]oxepadiene-2-acetic acid via cyclization starting from 4-(2-carboxybenzyloxy)phenylacetic acid For example, the preparation method of 4-(2-carboxybenzyloxy)phenylacetic acid is disclosed in Chinese Journal of New Drugs, 15(23), 2045-2046; 2006 and US Patent No. 4,082,850. [0006] In Chinese Journal of New Drugs, 15 (23), 2045-2046; the preparation method of 4-(2-carboxybenzyloxy) phen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C65/24C07C51/09C07D313/12
Inventor 郭荣耀吕关锋刘贵斌
Owner 北京联本医药化学技术有限公司
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