Synthesis method of rosuvastatin tert-butyl ester

A technology for the synthesis of rosuvastatin tert-butyl ester and its synthesis method, which is applied in the field of synthesis of rosuvastatin tert-butyl ester, can solve the problems of difficult acquisition of raw materials, difficulty in realizing industrialized production, complicated routes, etc., and achieve broad prospects and industrial applications Value, reduction of waste pollution, convenient and simple operation

Active Publication Date: 2019-11-22
ANHUI QINGYUN PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] This route solves the problem that the two side chains of the route are difficult to oxidize completely and the raw materials are not easy to obtain. However, the docking reaction in this paper is an ultra-low temperature reaction (-60°C), and the yield is only about 50%, so the energy consumption is high and the cost is high, which is difficult to achieve. industrial production
[0015] From the above review, it can be seen that the current synthesis of rosuvastatin tert-butyl ester is either because the route is complex and the total yield is low, or because the reaction conditions are harsh, it is difficult to realize industrial production, or because the stereoselectivity is poor, the cost of the route is high, so the development of raw materials is cheap and easy. Therefore, the route with mild reaction conditions, good atom economy and high yield has broad prospects

Method used

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  • Synthesis method of rosuvastatin tert-butyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] A synthetic method of rosuvastatin tert-butyl ester, comprising the steps of:

[0062]Add 38g (0.36mol) of sodium carbonate, 150mL of water, and 250mL of acetone into a 1000mL four-necked round-bottom flask in sequence, then add 5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl Base-2-[methyl(methylsulfonyl)amino]pyrimidine 100g (0.24mol), 2-mercapto-5-phenyl-1.3.4-thiadiazole 56g (0.288mol), slowly warming up to 50°C, stirring React for 4 hours, take samples for TLC (eluent: petroleum ether: ethyl acetate = 1:1v / v) to detect complete conversion of raw materials, cool down to 0°C, continue to stir for 1 hour, filter, 500mL water beating to obtain the wet product of substance B;

[0063] In a 1000mL four-neck round bottom flask, add the wet product of substance B (theoretical weight 127.3g, 0.24mol), ethanol 635mL, ammonium molybdate tetrahydrate 14.9g (0.012mol), and slowly add 30% hydrogen peroxide 163.5 g (that is, the hydrogen peroxide is 1.44mol), the dropwise addition ...

Embodiment 2

[0068] Replace 2-mercapto-5-phenyl-1.3.4-thiadiazole with 2-mercapto-5-(2-methylphenyl)-1.3.4-thiadiazole, sodium carbonate with potassium hydroxide, 2- The molar ratio of mercapto-5-(2-methylphenyl)-1.3.4-thiadiazole to potassium hydroxide is 1:0.5;

[0069] Replace molybdic acid tetrahydrate with sodium tungstate, the molar ratio of substance B to sodium tungstate is 1:0.5, and the molar ratio of substance B to hydrogen peroxide is 1:1;

[0070] Sodium tert-butoxide was replaced by sodium methoxide, and the molar ratio of substance C to sodium methoxide was 1:0.5; the others were the same as in Example 1.

Embodiment 3

[0072] Replace 2-mercapto-5-phenyl-1.3.4-thiadiazole with 2-mercapto-5-(2-bromophenyl)-1.3.4-thiadiazole, replace sodium carbonate with lithium carbonate, 2- The molar ratio of mercapto-5-(2-bromophenyl)-1.3.4-thiadiazole to lithium carbonate is 1:5;

[0073] The molar ratio of substance B to molybdic acid tetrahydrate is 1:0.01, and the molar ratio of substance B to hydrogen peroxide is 1:20;

[0074] Sodium tert-butoxide was replaced by lithium bis(trimethylsilyl)amide, and the molar ratio of substance C to lithium bis(trimethylsilyl)amide was 1:10; the others were the same as in Example 1.

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Abstract

The invention discloses a synthesis method of rosuvastatin tert-butyl ester. The synthesis method comprises the following steps: reacting 5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidine with a substance A under the action of a first base catalyst to obtain a substance B; oxidizing the substance B with an oxidizing agent to obtain a substance C; then, reacting the substance C with tert-butyl (4R-Cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetate under the action of a second base catalyst to obtain a substance D; and finally, performing acid deprotection toobtain the rosuvastatin tert-butyl ester. The method disclosed by the invention is green and environment-friendly, mild and controllable in reaction condition, convenient and simple to operate, good in stereoselectivity and high in yield, and the prepared rosuvastatin tert-butyl ester is good in purity.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing rosuvastatin tert-butyl ester. Background technique [0002] Rosuvastatin Calcium (Rosuvastatin CalciumL), a statin drug of Astra Zeneca Company, was launched in the United States in 2003 under the trade name Crestor. It has powerful HMG-CoA reductase inhibitory activity, which reduces LDL-C, increases The effect of HDL-C is better than that of other statins on the market, and it is well tolerated and safe. It is known as a "super statin". [0003] Rosuvastatin tert-butyl ester can be hydrolyzed and salt-formed to obtain rosuvastatin calcium, so it is the key intermediate of rosuvastatin calcium, and it is of great significance to study its synthetic route. The structure of rosuvastatin tert-butyl ester is as follows Shown: [0004] [0005] Summarizing the existing literature reports, the current synthetic routes of rosuvastatin tert-but...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 黄欢黄庆云黄庆国李凯
Owner ANHUI QINGYUN PHARMA & CHEM
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