Synthesis technology of 1-ethoxycarbonyl-5-methyl-(3R)-(tert-butyldimethylsilyloxy) glutaric ester

A technology of tert-butyldimethylsiloxyglutarate and ethoxycarbonyl, which is applied in the field of compound synthesis technology, can solve the problems of serious environmental pollution, complicated production process, and large discharge of three wastes, and achieve environmental friendliness, The effect of mild reaction conditions and low cost

Active Publication Date: 2015-01-21
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The production process is complex, the discharge of three wastes is large, and the environmental pollution is serious; and the (3R)-3-tert-butyldimethylsiloxyglutaric acid monomethyl ester obtained by the above method has low purity

Method used

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  • Synthesis technology of 1-ethoxycarbonyl-5-methyl-(3R)-(tert-butyldimethylsilyloxy) glutaric ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] In a 1000ml three-necked flask, equipped with a thermometer and constant pressure dropping funnel and magnetic stirring. At room temperature, add 160.0 grams of methanol to the reaction flask, then add 115.0 grams of (R)-(-)-4-cyano-3-hydroxybutyric acid, cool to -5°C, and pass 73.0 grams of dry hydrogen chloride with stirring. React for 5 hours, extract with 500ml of dichloromethane, dry the extract with anhydrous sodium sulfate, filter, distill the filtrate to remove the solvent, and distill the residue under reduced pressure to obtain (R)-(+)-3-hydroxyglutarate monomethyl ester 129.6g, without separation, add 500ml of dichloromethane, 108.8g of imidazole, 240.0g of tert-butyldichlorosilane, react at 20℃ for 5 hours, add 100ml of 5% sodium bicarbonate aqueous solution after the reaction, organic phase Dry with anhydrous sodium sulfate, filter, and evaporate the filtrate to remove the solvent to obtain methyl tert-butyldimethylsilyl-(R)-3-[(tert-butyldimethylsilyl)oxy]g...

Embodiment 2

[0022] In a 1000ml three-necked flask, equipped with a thermometer and constant pressure dropping funnel and magnetic stirring. At room temperature, add 320 grams of methanol to the reaction flask, and then add 115.0 grams of (R)-(-)-4-cyano-3-hydroxybutyric acid. The temperature is lowered to 10°C, and 109.5 grams of dry hydrogen chloride is introduced under stirring. After 10 hours, extract with 500ml of dichloromethane, the extract phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to remove the solvent, and the residue was distilled under reduced pressure to obtain (R)-(+)-3-hydroxyglutarate monomethyl ester 145.8 G, without separation, add 500ml of dichloromethane, 183.6g of imidazole, 405.0g of tert-butyldichlorosilane, react at 50℃ for 10 hours, add 100ml of 10% sodium bicarbonate aqueous solution after the reaction, and use for organic phase Dry with anhydrous sodium sulfate, filter, and evaporate the solvent from the filtrate to obtain...

Embodiment 3

[0024] In a 1000ml three-necked flask, equipped with a thermometer and constant pressure dropping funnel and magnetic stirring. At room temperature, add 300 grams of methanol to the reaction flask, and then add 115.0 grams of (R)-(-)-4-cyano-3-hydroxybutyric acid. The temperature is reduced to 0°C, and 100 grams of dry hydrogen chloride is introduced under stirring. After 8 hours, extract with 500ml of dichloromethane, the extract phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to remove the solvent, and the residue was distilled under reduced pressure to obtain (R)-(+)-3-hydroxyglutarate monomethyl ester 127.5 Gram, without separation, add 500ml of dichloromethane, 180g of imidazole, 400g of tert-butyldichlorosilane, and react at 30℃ for 8 hours. After the reaction, add 100ml of 10% sodium bicarbonate aqueous solution, and use for organic phase. Dry with anhydrous sodium sulfate, filter, and evaporate the solvent from the filtrate to obtain...

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Abstract

The invention discloses a synthesis technology of 1-ethoxycarbonyl-5-methyl-(3R)-(tert-butyldimethylsilyloxy) glutaric ester. The synthesis technology comprises the following steps: adding (R)-(-)-4-cyano-3-hydroxybutyrate to methanol serving as a solvent, introducing dried hydrogen chloride while stirring, extracting with dichloromethane, drying an extraction phase through anhydrous sodium sulfate, filtering, evaporating the filtrate to remove the solvent, and performing pressure-reduced distillation to residuum to obtain (R)-(+)-3-hydroxyl glutaric monomethyl ester; adding imidazole and tertiary butert-butylmethylchlorosilane, adding a sodium hydrogen carbonate water solution after the reaction is finished, drying an organic phase, filtering and evaporating the filtrate to remove the solvent to obtain a product; and with dichloromethane as a solvent, adding the produce and an organic base, dropwise adding ethyl chloroformate, adding ethyl acetate for extraction, washing with saturated saline solution, drying, concentrating under reduced pressure to obtain 1-ethoxycarbonyl-5-methyl-(3R)-(tert-butyldimethylsilyloxy) glutaric ester. In the method disclosed by the invention, (R)-(-)-4-cyano-3-hydroxybutyrate which is a byproduct in production of (R)-(-)-4-cyano-3-hydroxy-butyric acid ethyl ester and is low in price is used as raw material; the reaction conditions are mild; the method is friendly to the environment and can be put into industrial mass production.

Description

Technical field [0001] The present invention relates to a synthesis process of compounds, in particular to a synthesis process of 1-ethoxycarbonyl-5-methyl-(3R)-tert-butyldimethysiloxyglutarate. Background technique [0002] 1-Ethoxycarbonyl-5-methyl-(3R)-tert-butyl disiloxyglutarate is a key intermediate for the synthesis of rosuvastatin (Current Organic Chemistry, 2010, 14, 816-845). CN101735272 discloses a method for preparing 1-methoxycarbonyl-5-methyl-(3R)-tert-butyl disiloxyglutarate, which uses dichloromethane as solvent and N-methylmorpholine as Acid binding agent, (3R)-3-tert-butyldimethylsiloxyglutarate monomethyl ester and methyl chloroformate have synthesized 1-methoxycarbonyl-5-methyl-(3R)-tert-butyl Dimethylsiloxy glutarate. WO2006091771 uses toluene as solvent, triethylamine as acid binding agent, (3R)-3-tert-butyldimethylsiloxy glutaric acid mono-tert-butyl ester and ethyl chloroformate to synthesize 1-ethoxycarbonyl- 5-tert-Butyl-(3R)-tert-butyl disiloxyglutar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
Inventor 蒋成君王志华黄俊
Owner ZHEJIANG LEPU PHARMA CO LTD
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