Synthesis of 1-ethoxycarbonyl-5-methyl-(3r)-tert-butyldimethylsilyloxyglutarate

A technology of tert-butyldimethylsiloxyglutarate and sodium tert-butyldimethylsiloxyglutarate is applied in the field of compound synthesis technology and can solve the problem that triethylamine is inflammable, unstable, Explosive and other problems, to achieve the effect of simple raw materials, mild reaction conditions, and environmental friendliness

Active Publication Date: 2015-12-23
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(3R)-3-tert-butyldimethylsiloxyglutaric acid monomethyl ester is unstable, and dichloromethane is a low-boiling solvent, which is difficult to recycle
Triethylamine is flammable and explosive

Method used

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  • Synthesis of 1-ethoxycarbonyl-5-methyl-(3r)-tert-butyldimethylsilyloxyglutarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] In a 250ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, add 50ml of water to the reaction flask, then add 28.2 grams of (3R)-3-tert-butyldimethylsiloxysodium glutarate monomethyl ester, cool down to -5°C, Add 40 grams of 10% by mass sodium hydroxide solution, add 0.282 g of tetrabutylammonium chloride, continue cooling to -5 ° C, dropwise add 10.8 grams of ethyl chloroformate, and stir for 5 hours. Add 50 ml of ethyl acetate for extraction, wash once with 30 ml of saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 31.8 g of 1-ethoxycarbonyl-5-methyl-(3R)-tert-butyldimethylsilyloxyglutarate (HPLC 98.7%) Yield: 95.8%.

[0013] 1 HNMR (CDCl 3 )δ:0.08(3H,s);0.09(3H,s);0.85(9H,s);3.69(3H,s);1.3-1.4(3H,t,J=7.3Hz);2.5-2.6(d ,2H,d,J=6.3Hz);2.6-2.8(m,2H);4.26-4.38(2H,q,J=7.3Hz);4.5-4.62(m,1H)

Embodiment 2

[0015] In a 250ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, add 50ml of water into the reaction flask, then add 28.2 grams of (3R)-3-tert-butyldimethylsiloxysodium glutarate monomethyl ester, cool down to 10°C, and place in a constant pressure dropping funnel Add 18.7 g of 30% by mass potassium hydroxide solution, add 0.0282 g of tetrabutylammonium bromide, continue cooling to 10 ° C, dropwise add 21.6 g of ethyl chloroformate, and stir for 10 hours. Add 50 ml of ethyl acetate for extraction, wash once with 30 ml of saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 30.1 g of 1-ethoxycarbonyl-5-methyl-(3R)-tert-butyldimethylsilyloxyglutarate (HPLC 98.5%) Yield: 90.8%.

Embodiment 3

[0017] In a 250ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, add 50ml of water to the reaction flask, then add 28.2 grams of (3R)-3-tert-butyldimethylsiloxysodium glutarate monomethyl ester, cool down to 0°C, and place in a constant pressure dropping funnel Add 12 grams of 20% by mass lithium hydroxide solution, add 0.1 g of tetrabutylammonium chloride, continue cooling to 0°C, dropwise add 15.0 grams of ethyl chloroformate, and stir for 7 hours. Add 50 ml of ethyl acetate for extraction, wash once with 30 ml of saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 29.8 g of 1-ethoxycarbonyl-5-methyl-(3R)-tert-butyldimethylsilyloxyglutarate (HPLC 98.6%) yield: 89.7%.

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Abstract

The invention discloses a synthesis process of 1-ethoxycarbonyl-5-methyl-(3R)-tert-butyldimethylsiloxy glutarate. Using water as a solvent, add (3R)-3-tert-butyldimethylsiloxysodium glutarate monomethyl ester, cool down to -5~10°C, add 10-30% by mass alkali solution dropwise, add For quaternary ammonium salt, add ethyl chloroformate dropwise at -5-10°C, react for 5-10 hours, add ethyl acetate to extract, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1-ethoxycarbonyl -5-Methyl-(3R)-tert-butyldimethylsiloxyglutarate. The method has simple raw materials, mild reaction conditions and environmental friendliness, and can be used in large-scale industrial production.

Description

technical field [0001] The invention relates to a compound synthesis process, in particular to a synthesis process of 1-ethoxycarbonyl-5-methyl-(3R)-tert-butyldimethylsilyloxy glutarate. Background technique [0002] 1-Ethoxycarbonyl-5-methyl-(3R)-tert-butyldimethylsilyloxyglutarate is a key intermediate in the synthesis of rosuvastatin (Current Organic Chemistry, 2010, 14, 816-845). CN101735272 discloses a kind of preparation method of 1-methoxycarbonyl-5-methyl-(3R)-tert-butyldimethylsilyloxy glutarate, using dichloromethane as solvent, N-methylmorpholine as Acid-binding agent, (3R)-3-tert-butyldimethylsiloxyglutaric acid monomethyl ester and methyl chloroformate synthesized 1-methoxycarbonyl-5-methyl-(3R)-tert-butyl Dimethiciloxyglutarate. (3R)-3-tert-butyldimethylsiloxyglutaric acid monomethyl ester is unstable, and dichloromethane is a low-boiling solvent, which is difficult to recycle. Moreover, N-methylmorpholine is flammable, corrosive, slightly toxic, and has a p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/18
Inventor 蒋成君王志华洪蓓蕾张红夺陈普明
Owner ZHEJIANG LEPU PHARMA CO LTD
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