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Method for preparing (5R)-6-cyanogroup-5-hydroxy-3-oxocaproic acid tert-butyl ester

A technology of tert-butyl hexanoate and tert-butyl bromoacetate, which is applied in the preparation of atorvastatin intermediates and the field of preparation of tert-butyl-6-cyano-5-hydroxy-3-oxohexanoate, can Solve the problems that are not suitable for industrial production, difficult to control in terms of safety, and high cost of industrialization, and achieve the effects of mild reaction conditions, reduced production costs, and reduced production processes

Active Publication Date: 2013-12-04
湖北楚维药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the safety aspect of this process is not easy to control, and the industrialization cost is very high, so it is not suitable for industrialized production

Method used

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  • Method for preparing (5R)-6-cyanogroup-5-hydroxy-3-oxocaproic acid tert-butyl ester
  • Method for preparing (5R)-6-cyanogroup-5-hydroxy-3-oxocaproic acid tert-butyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 1. Add 300 mL of anhydrous tetrahydrofuran, 97.5 g of zinc powder and 7.2 g of methanesulfonic acid into the reaction flask, and heat and stir at 65° C. for 1 hour. At 45°C, 214.5 g of tert-butyl bromoacetate was slowly added dropwise, followed by mixing and stirring for 1 hour.

[0029] 2. 119.5 g of (S)-4-chloro-3-hydroxybutyronitrile was slowly added dropwise, and after the dropwise addition was completed, the temperature was raised to 65° C. and maintained for 3 hours. After cooling to 0°C, a hydrochloric acid solution with a mass concentration of 10% was added dropwise, the pH was adjusted to 6-7, the temperature was raised to 20°C, and the mixture was stirred for 1 hour.

[0030] 3. Slowly add 326.7 g of sodium cyanide solution with a mass concentration of 30% dropwise, and stir vigorously for 3 hours at 50°C. The tetrahydrofuran was distilled off under reduced pressure, 200 mL of ethyl acetate was added for extraction, and the layers were separated. The aqueous ...

Embodiment 2

[0032] 1. Add 250 mL of 1,2-dichloroethane, 130 g of zinc powder and 12.2 g of benzoic acid into the reaction flask, and heat and stir at 50° C. for 1 hour. At 55°C, 234 g of tert-butyl bromoacetate was slowly added dropwise, followed by mixing and stirring for 1 hour.

[0033] 2. 119.5 g of (S)-4-chloro-3-hydroxybutyronitrile was slowly added dropwise, and after the dropwise addition was completed, the temperature was raised to 65° C. and maintained for 4 hours. After cooling to 0°C, a nitric acid solution with a mass concentration of 20% was added dropwise, the pH was maintained at 5-6, the temperature was raised to 20°C, and stirred for 1 hour.

[0034] 3. Slowly add 245 g of sodium cyanide solution with a mass concentration of 30% dropwise, and stir vigorously for 4 hours at 55°C. The 1,2-dichloroethane was distilled off under reduced pressure, 150 mL of ethyl acetate was added for extraction, and the layers were separated. The aqueous layer was extracted again with 150 m...

Embodiment 3

[0036] 1. Add 300 mL of anhydrous methyl tert-butyl ether, 98 g of zinc powder, and 14.2 g of p-toluenesulfonic acid into the reaction flask, and heat and stir at 65° C. for 1 hour. At 45°C, 222 g of tert-butyl bromoacetate was slowly added dropwise, followed by mixing and stirring for 1 hour.

[0037] 2. 119.5 g of (S)-4-chloro-3-hydroxybutyronitrile was slowly added dropwise, and after the dropwise addition was completed, the temperature was raised to 65° C. and maintained for 3 hours. After cooling to 0°C, a phosphoric acid solution with a mass concentration of 15% was added dropwise, the pH was maintained at 6-7, the temperature was raised to 20°C, and the mixture was stirred for 1 hour.

[0038] 3. Slowly add 1299.9 g of potassium cyanide solution with a mass concentration of 10% dropwise, and stir vigorously for 5 hours at 50°C. The methyl tert-butyl ether was distilled off under reduced pressure, 200 mL of ethyl acetate was added for extraction, and the layers were sep...

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Abstract

The invention discloses a method for preparing (5R)-6-cyanogroup-5-hydroxy-3-oxocaproic acid tert-butyl ester and belongs to the technical field of medical drug chemical engineering. The method includes the following steps: adding organic acid, zinc powder and tert-butyl acetate in an organic solvent, and reacting at the temperature of 45-55 DEG C to obtain a tert-butyl acetate zinc reagent; adding (S)-4-chlorine-3-hydroxybutyronitrile in the tert-butyl acetate zinc reagent to perform Blaisereaction at the temperature of 65-70 DEG C, adding inorganic acid to adjust the pH value to be 5-7 after the reaction is completely performed, then adding a cyaniding reagent at the temperature of 45-55 DEG C to perform the cyanogroup replacement reaction, and after the reaction is completely performed, separating and purifying to obtain the (5R)-6-cyanogroup-5-hydroxy-3-oxocaproic acid tert-butyl ester, wherein the molar ratio of the (S)-4-chlorine-3-hydroxybutyronitrile, the tert-butyl acetate, the zinc power, the organic acid to the cyaniding reagent is 1:(1-2):(1.5-3): (0.05-0.2): (1.5-3).

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, in particular to a preparation method of an atorvastatin intermediate, in particular to a preparation method of (5R)-6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester. Background technique [0002] Statins are currently the world's best-selling lipid-lowering drugs, and are human 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Inhibits cholesterol synthesis by inhibiting the binding of HMG-CoA reductase to the substrate. At the same time, statins can also reduce low-density lipoprotein (LDL) and triglyceride (TG), and increase high-density lipoprotein (HDL), which is of great significance for the prevention and treatment of atherosclerosis and coronary heart disease. Atorvastatin is a newly synthesized selective inhibitor of HMG-CoA reductase. It is currently the most promising statin lipid-lowering drug. It has the advantages of fast onset, stron...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/21C07C253/30
Inventor 张龑熊进军葛石平
Owner 湖北楚维药业有限公司
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