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Compound 2-methylol-3-substituted phenyl propionic acid and its prepn process and use

A technology for phenylpropionic acid and compounds, applied in the fields of chemical synthesis and medicinal chemistry, which can solve the problems of unsuitability for industrial production, high cost, cumbersome steps, etc., and achieve the effects of low cost, less waste, and simple operation

Active Publication Date: 2008-12-03
SHANGHAI SHYNDEC PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The general steps in the operation of the reported fasidotril synthesis method are relatively cumbersome, and the cost of the raw materials and catalysts used is relatively high, which makes the cost of the product relatively high, and is not suitable for industrial production.

Method used

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  • Compound 2-methylol-3-substituted phenyl propionic acid and its prepn process and use
  • Compound 2-methylol-3-substituted phenyl propionic acid and its prepn process and use
  • Compound 2-methylol-3-substituted phenyl propionic acid and its prepn process and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 26.5g of α-(3,4-methylenedioxy)benzyl malonate diethyl ester and 150ml of absolute ethanol into a 500ml one-mouth eggplant-shaped bottle. Under stirring at room temperature, slowly add dropwise 250ml of ethanol solution in which 13.2g of potassium hydroxide is dissolved, and react for another 30 hours after the dropwise addition is completed. The solvent was distilled off under reduced pressure, and 200 ml of ethylene glycol dimethyl ether was added and stirred for 10 minutes.

[0030] Add 27.2g of potassium borohydride and 150ml of ethylene glycol dimethyl ether into a 500ml four-necked reaction flask equipped with a thermometer and a nitrogen protection device, stir at room temperature for 10 minutes, then add 32.7g of zinc chloride, and stir after the temperature drops to room temperature 0.5 hours. The potassium salt of monoethyl α-(3,4-methylenedioxy)benzylmalonate was slowly added dropwise, and after 0.5 hours of dropping, the reaction was stopped after stirr...

Embodiment 2

[0035] Add 84.5g of α-(3,4-methylenedioxy)benzyl malonate diethyl ester and 150ml of absolute ethanol into a 500ml one-mouth eggplant-shaped bottle. Under stirring at room temperature, slowly add 200ml of 11.5g sodium hydroxide ethanol solution dropwise, and stop the reaction for 30 hours after the addition is complete. Evaporate the solvent under reduced pressure, adjust the pH to 2 with dilute hydrochloric acid, extract twice with 200ml and 100ml ethyl acetate, wash the combined organic phase with 200ml saturated brine once, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain α -(3,4-methylenedioxy)benzylmalonate monoethyl ester.

[0036] Add 38.0g of potassium borohydride and 150ml of ethylene glycol dimethyl ether into a 500ml four-necked reaction flask equipped with a thermometer and a nitrogen protection device, stir at room temperature for 10 minutes, then add 28.4g of lithium chloride, and stir after the temperature drops t...

Embodiment 3

[0038] Add 84.5g of α-(3,4-methylenedioxy)benzyl malonate diethyl ester and 150ml of absolute ethanol into a 500ml one-mouth eggplant-shaped bottle. Under stirring at room temperature, slowly add 200ml of 11.5g sodium hydroxide ethanol solution dropwise, and stop the reaction for 30 hours after the addition is complete. The solvent was distilled off under reduced pressure, and 200 ml of ethylene glycol dimethyl ether was added and stirred for 10 minutes.

[0039] Add 38.0g of potassium borohydride and 150ml of ethylene glycol dimethyl ether into a 500ml four-necked reaction flask equipped with a thermometer and a nitrogen protection device, stir at room temperature for 10 minutes and then add 29.8g of aluminum trichloride. Stir for 0.5 hours. The potassium salt of monoethyl α-(3,4-methylenedioxy)benzylmalonate was slowly added dropwise, and after 0.5 hours of dropping, the reaction was stopped after stirring at room temperature for 40 hours. After evaporating the solvent und...

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Abstract

The present invention provides compound 2-methylol-3-(3, 4-methylene dioxy) phenyl propionic acid, and its preparation process and application as the intermediate for synthesis of fasidotril. The present invention has cheap material and other reagent, less wastes produced, simple operation, high yield and low cost.

Description

technical field [0001] The invention relates to the fields of chemical synthesis and medicinal chemistry, in particular to the synthesis of a 2-hydroxymethyl-3-substituted phenylpropionic acid compound and its use as an intermediate in chemical synthesis. Background of the invention [0002] Fasidotril (fasidotril) is the oral prodrug of altrioprilat, developed by Bioprojet Company, licensed to Lilly Company in 2001, for the treatment of hypertension and congestive heart failure, its structure is shown in the following formula (3): [0003] [0004] Facidotril is a vasopeptidase inhibitor (Vasopeptidase inhibitor, VPI), which can simultaneously inhibit the activities of angiotensin-converting enzyme (ACE) and neutral endopeptidase (neutral endopeptidase, NEP). NEP dual inhibitors have a stronger effect on cardiac hemodynamics and kidneys than the simultaneous application of NEP inhibitors and ACE inhibitors, and are superior to any current antihypertensive drugs in terms ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/48
Inventor 侯建赵惠清王国平何康永陈旭东
Owner SHANGHAI SHYNDEC PHARMA CO LTD