3- alkoxy -4-carbalkoxyphenylacetate and 3-alkoxy-4-carbalkoxyphenylacetic acid synthesis method

A technology for alkoxycarbonyl phenylacetate and a synthesis method, which is applied in the preparation of carboxylate, chemical instruments and methods, preparation of carboxylate/lactone, etc., can solve the problems of long production cycle, many steps, and high total cost , to achieve the effect of short synthesis route, high reaction yield and easy operation

Active Publication Date: 2006-07-12
ZHEJIANG HISOAR CHUANNAN PHARMA
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

This route has many steps, the total reaction time is long, and the production cycle is long, so the total cost is high, which is not conducive to industrial production

Method used

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  • 3- alkoxy -4-carbalkoxyphenylacetate and 3-alkoxy-4-carbalkoxyphenylacetic acid synthesis method
  • 3- alkoxy -4-carbalkoxyphenylacetate and 3-alkoxy-4-carbalkoxyphenylacetic acid synthesis method
  • 3- alkoxy -4-carbalkoxyphenylacetate and 3-alkoxy-4-carbalkoxyphenylacetic acid synthesis method

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Experimental program
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Effect test

Embodiment 1

[0023] The synthesis of embodiment 1 3-ethoxy-4-methylbenzoic acid ethyl ester

[0024] Put 30.4g (0.2mol) of 4-methylsalicylic acid, 92.5g (0.6mol) of diethyl sulfate and 2g of tetrabutylammonium bromide in a mixed solution of 500mL of dichloromethane and 500mL of water, at room temperature (25°C ) was stirred for 20h, and the dichloromethane layer was separated after the reaction was completed, and the aqueous layer was extracted with dichloromethane (150mL×2), the organic phases were combined, washed with water, and concentrated to obtain the product 3-ethoxy-4-methylbenzoic acid ethyl 36 g of ester, yield 86.5%. The next reaction was carried out without purification.

Embodiment 2

[0025] Example 2 Synthesis of 3-ethoxyl-4-ethoxycarbonylphenylacetic acid ethyl ester

[0026] Under the protection of nitrogen, add 9.7g (0.095mol) of diisopropylamine into 80mL of tetrahydrofuran, stir, and after the system drops to -80°C, add 60mL (0.096mol) of n-hexane solution of butyllithium, stir for 30min, add dropwise 1 The tetrahydrofuran solution of 10 g (0.048 mol) of the obtained 3-ethoxy-4-methylbenzoic acid crude product was stirred for 30 min, then the tetrahydrofuran solution of 7.8 g (0.071 mol) of ethyl chloroformate was added, and after stirring for 3 h, added 5% ammonium chloride solution, raised to room temperature, adjusted to pH = 7 with 2N HCl, separated the organic layer, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated to obtain the product 3-ethoxy-4-ethane 22 g of ethyl oxycarbonyl phenylacetate, the product was directly carried out to the next step without purification.

Embodiment 3

[0027] Example 3 Synthesis of 3-ethoxyl-4-ethoxycarbonylphenylacetic acid

[0028] Dissolve 16 g of the crude ethyl 3-ethoxy-4-ethoxycarbonylphenylacetate obtained in Example 2 in 80 mL of 95% ethanol, lower the reaction solution to 5-10 °C, and then add 2N sodium hydroxide solution in batches to pH Until the value no longer changes, control the reaction temperature at 5-15°C. After the reaction was completed, the reaction solution was adjusted to neutral with 6N hydrochloric acid, concentrated ethanol, then added 50ml of water, extracted with dichloromethane (25mL×2), separated the water layer, and adjusted the pH to 3.5-4 with 6N HCl under ice bath. CH 2 Cl 2 Extraction (30mL×2), the organic layer was successively washed with water (30mL×2), saturated brine (30mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid, which was decolorized and recrystallized with toluene to obtain 6.0 g of a white solid . The overall yield is 58%. mp: 75-76°C...

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Abstract

The invention provides a method for synthesizing 3-alkoxy-4-alkoxycarbonyl phenylacetate and 3-alkoxy-4-alkoxycarbonyl phenylacetic acid. The method for synthesizing 3-alkoxy-4-alkoxycarbonyl phenylacetate comprises: 3-alkoxy-4-methyl benzoate reacts with the chloro-carbonate on the effect of strong base in the organic solution at 190 deg.-0 deg. to obtain the product; the method of the 3-alkoxy-4-alkoxycarbonyl acetic ether cheesed hydrolysis to obtain the 3-alkoxy-4-alkoxycarbonyl phenylacetic acid.

Description

(1) Technical field [0001] The invention relates to a synthesis method of 3-alkoxy-4-alkoxycarbonyl phenylethyl ester and 3-alkoxy-4-alkoxycarbonyl phenylacetic acid. (2) Background technology [0002] Repaglinide is a carbamic acid methylbenzoic acid derivative, which is a non-sulfonylurea insulin-stimulating blood glucose regulating drug during meals. It is used for patients with type II diabetes who cannot effectively control blood sugar through diet and exercise therapy. It has a good effect. It has the characteristics of rapid onset and short duration of action, and is widely used in clinical practice. [0003] 3-ethoxy-4-ethoxycarbonylphenylacetic acid ((3-Ethoxy-4-ethoxycarbonyl-phenyl)-acetic acid) is an important intermediate for the synthesis of repaglinide, document J.Med.Chem.1998, 41 , 5219-5246 discloses a kind of synthetic route, and this route is to be raw material with 4-methyl salicylic acid, react with bromoethane, carry out esterification and etherificat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/30C07C69/73C07C51/09C07C59/64
Inventor 王迷娟郑志国尹大力
Owner ZHEJIANG HISOAR CHUANNAN PHARMA
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