A kind of synthesis technique of the intermediate of synthetic rosuvastatin

A synthesis process and compound technology, applied in the direction of organic chemistry, etc., can solve the problems of by-products, three wastes, etc., and achieve the effects of less three wastes, low process cost, and less consumption.

Active Publication Date: 2017-11-07
乐普制药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Low temperature reaction is also required, and a large number of by-products are produced as three wastes

Method used

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  • A kind of synthesis technique of the intermediate of synthetic rosuvastatin
  • A kind of synthesis technique of the intermediate of synthetic rosuvastatin
  • A kind of synthesis technique of the intermediate of synthetic rosuvastatin

Examples

Experimental program
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Effect test

Embodiment 1

[0036]

[0037] In a 500ml four-necked bottle, a thermometer, a constant pressure dropping funnel and a magnetic stirrer were installed under N2 protection. At normal temperature, add 14 grams of compound I to the reaction flask, then add about 150 ml of THF, under nitrogen protection, stir to dissolve, then slowly cool down to -5 ~ -10 ° C, slowly start to drop n-butyllithium (2.5 N) n-hexane solution 30ml, the temperature is maintained at -10°C ~ 0°C, the time for dropping is about 45min, the temperature is raised to 0°C ~ 10°C, kept for 30min, the temperature is lowered to about -15°C, and 2, 2, 6 , 6-Tetramethylpiperidine 11g / THF 20ml mixed solution, the dropping time is about 30min, the temperature is controlled at -15±2℃, keep warm for 2 hours, slowly drop trimethylchlorosilane / THF (8g / 20ml ) for 3 hours (TLC detection of cyclohexane: ethyl acetate = 20:1) After the reaction is complete, pour it into 300ml of ice water, extract twice with 200ml of toluene, wash once w...

example 2

[0040] In a 500ml four-necked bottle, a thermometer, a constant pressure dropping funnel and a magnetic stirrer were installed under N2 protection. At normal temperature, add 14 grams of compound I to the reaction flask, then add about 150 ml of THF, under nitrogen protection, stir to dissolve, then slowly cool down to -5 ~ -10 ° C, slowly start to drop n-butyllithium (2.5 N) n-hexane solution 35ml, the temperature is maintained at -10°C ~ 0°C, the dropwise addition time is about 45min, the temperature is raised to 0°C ~ 10°C, kept for 30min, cooled to about -15°C, dropwise added 2, 2, 6 , 6-Tetramethylpiperidine 12.5g / THF 20ml mixed solution, the time for dropping is about 30min, the temperature is controlled at -15±2°C, keep warm for 2 hours, slowly add trimethylchlorosilane / THF (10g / 20ml) for 3 hours (TLC detection of cyclohexane: ethyl acetate = 20:1) After the reaction is complete, pour it into 300ml of ice water, use 200ml of toluene, extract twice, wash once with 100ml...

Embodiment 3

[0042]In a 500ml four-necked bottle, a thermometer, a constant pressure dropping funnel and a magnetic stirrer were installed under N2 protection. At room temperature, add 14 grams of compound I to the reaction bottle, then add about 150ml of THF, under nitrogen protection, stir to dissolve, then slowly cool down to -5 ~ -10°C, slowly start to drop 80ml of LDA (1M) solution , the temperature is maintained at -10°C to 0°C, the time for dropping is about 45 minutes, the temperature is raised to 0°C to 10°C, the temperature is kept for 30 minutes, and trimethylchlorosilane / THF (8.8g / 20ml) is slowly added dropwise and kept for 3 hours ( TLC detection of cyclohexane: ethyl acetate = 20:1) After the reaction is complete, pour it into 300ml of ice water, extract twice with 200ml of toluene, wash once with 100ml of saturated sodium bicarbonate, concentrate under reduced pressure to dryness, add 20ml of n-heptane and 1ml of ethyl acetate were heated to dissolve, slowly cooled to -5°C, ...

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Abstract

The present invention discloses a synthesis process of (4R,6S,E)-2-{6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl (methylsulfonyl) amino) pyrimidin-5-yl] ethenyl]-2,2-dimethyl-1,3-epoxyhexane-4-yl} acetate alkyl ester. With an aprotic polar solvent as solvent, 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonyl amino)-5-pyrimidine methyl, n-butyl lithium, 2,2,6,6-tetramethyl piperidine or LDA react with trimethyl silicon chloride; and then the reaction products react with (4R-cis)-6-[(acetyloxy) methyl]-2,2-dimethyl-1,3-dioxo hexane-4-alkyl acetate under catalysis of cesium fluoride in an aprotic polar solvent to produce the target product. The process uses trimethyl silicon as a condensation agent, and does not use alkali; the cesium fluoride is directly used as a catalyst; and the usage amount and three wastes are less. Z type condensation ethylenic bond is less than 10%, which is much less than the triphenylphosphine process. The reaction process does not need low temperature, is easy to realize industrialization and has the advantages of easily available raw materials and low cost.

Description

technical field [0001] The present invention relates to a synthesis process of an intermediate for the synthesis of rosuvastatin, in particular to a (4R,6S,E)-2-{6-[2-[4-(4-fluorophenyl)-6- Isopropyl-2-(N-methyl(methylsulfonyl)amino)pyrimidin-5-yl]vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid Synthetic process of alkyl esters. Background technique [0002] (4R,6S,E)-2-{6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl(methylsulfonyl)amino)pyrimidine-5 -yl]vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}alkyl acetate is a key intermediate in the synthesis of rosuvastatin, which can be deprotected by acid and hydrolyzed by base , into a calcium salt to obtain the hypolipidemic drug rosuvastatin calcium. [0003] (4R,6S,E)-2-{6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl(methylsulfonyl)amino)pyrimidine-5 -yl]vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}alkyl acetate is generally obtained by wittig reaction. [0004] The preparation process of the disclosed compound is described below. [...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06
CPCC07D405/06
Inventor 王志华洪华斌颜剑波林义
Owner 乐普制药科技有限公司
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