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Preparation method of simvastatin side chain acyl donor

A technology of simvastatin and acyl donor, applied in the field of medicine, can solve the problems of large amount of solvent, environmental pollution and high cost of raw materials, and achieves a simple and easy synthesis method, cheap and easy-to-obtain synthetic raw materials, and strong product competitiveness. Effect

Active Publication Date: 2014-05-07
SHENYANG SUNSHINE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existing problems are: 1. The cost of raw materials for the synthesis of the side chain of the acyl donor methyl ester is high; 2. The methyl 3-mercaptopropionate produced by the side chain of the acyl donor methyl ester in the reaction system has poor stability and is easily hydrolyzed into 3-mercapto Propionic acid, and 3-mercaptopropionic acid has large water solubility and high boiling point, is difficult to recycle and increases raw material cost and pollutes the environment; 3,3-mercaptopropionic acid easily degrades simvastatin products and affects the quality of products; 4, The amount of solvent used is large, the production cost is high, and the product market competitiveness is limited

Method used

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  • Preparation method of simvastatin side chain acyl donor
  • Preparation method of simvastatin side chain acyl donor
  • Preparation method of simvastatin side chain acyl donor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Preparation method of simvastatin acyl donor (two-step method)

[0047] Step 1: Synthesis of ethyl 3-mercaptopropionate (see attached image 3 ):

[0048] In a 50mL three-neck flask, N 2 Under protection, add 20mL of absolute ethanol, 1mL of concentrated sulfuric acid, add 2 grams of anhydrous sodium sulfate, 2 grams of 3-mercaptopropionic acid, GC to track the reaction progress, react at 80 degrees for 12 hours, the raw material 3-mercaptopropionic acid is completely converted, add into 10 mL of ice water and extracted three times with dichloromethane, 10 mL each time. The dichloromethane layer of the organic phase was washed twice with saturated sodium bicarbonate solution, 10 mL each time. The dichloromethane layer of the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain 2.3 g of a colorless oily product with a yield of 90.9%. ( 1 See attached for H NMR figure 1 )...

Embodiment 2

[0051] Example 2: Preparation method of simvastatin acyl donor (two-step method)

[0052] Step 1: its reaction formula is with embodiment 1

[0053] In a 250mL three-necked flask, under the protection of N2, add 100mL of absolute ethanol, 3mL of concentrated sulfuric acid, 4 grams of anhydrous magnesium sulfate, 20 grams of 3-mercaptopropionic acid. The acid conversion was complete, and the ethanol was distilled off under reduced pressure, leaving 20.5 g of colorless oil as the remaining product, with a yield of 81%. used directly in the next reaction.

[0054] Step 2: its reaction formula is with embodiment 1

[0055] Add 100mL of dichloromethane to dilute the remaining product, cool to zero, add 30 grams of sodium carbonate, N 2 For protection, 22.55 g of 2,2-dimethylbutyryl chloride was added dropwise within 10 minutes, and the reaction was carried out at zero temperature for 3 hours after the drop was completed. Naturally, the temperature was raised to about 25 degrees...

Embodiment 3

[0056] Example 3: The preparation method of simvastatin acyl donor (one-step method) (see attached Figure 5 ):

[0057] In a 250mL three-neck flask, add 100mL absolute ethanol, 3mL concentrated sulfuric acid, N 2 For protection, add 4 grams of anhydrous magnesium sulfate, 20 grams of 3-mercaptopropionic acid, GC to detect the reaction process, react at 80 degrees for 12 hours, the raw material 3-mercaptopropionic acid is completely converted, add it to 500mL ice water, and extract it with dichloromethane three times. 80mL each time. The dichloromethane layer of the organic phase was washed twice with saturated sodium bicarbonate solution, 50 mL each time. The dichloromethane layer was collected and dried over anhydrous magnesium sulfate.

[0058] Filter, the filtrate is cooled to zero degree, add 30 grams of sodium carbonate, N 2 For protection, 25.3 g of 2,2-dimethylbutyryl chloride was added dropwise within 10 minutes, and the reaction was carried out at zero temperatur...

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Abstract

The invention relates to a preparation method of a simvastatin side chain acyl donor, which comprises the following steps: (1) in a nitrogen protective atmosphere, reacting anhydrous ethanol and 3-mercaptopropionic acid in the presence of hydrogen ions at 60-90 DEG C for 10-16 hours to obtain ethyl 3-mercaptopropionate; and (2) in the presence of an organic solvent, reacting the ethyl 3-mercaptopropionate with 2,2-dimethylbutyryl chloride to generate the simvastatin side chain acyl donor ethyl 2,2-dimethylbutyric acid-3-mercaptopropionate. The raw materials for synthesizing the ethyl 2,2-dimethylbutyric acid-3-mercaptopropionate are cheap and accessible; the synthesis method is simple and easy to implement; the acyl donor has high stability and can not be easily hydrolyzed in the simvastatin synthesis process; and the 3-mercaptopropionate in the raw materials can be recycled to further lower the cost and avoid the problem of degradation of the simvastatin raw material due to the hydrolysate 3-mercaptopropionic acid, so that the simvastatin product quality is more stable.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for preparing an acyl donor of a side chain of simvastatin and a method for preparing simvastatin ammonium salt. Background technique [0002] Simvastatin is a blood lipid-lowering drug of statins developed by Merck & Co. of the United States. It is a hydroxymethylglutaryl coenzyme A (HMG-COA) reductase inhibitor, which inhibits the synthesis of endogenous cholesterol and regulates blood lipids. agent. The product was first listed in 1988 and was approved by the US FDA in December 1991. In 2000, Merck's Zocor ranked second in the global sales list, with sales of 5.28 billion US dollars. 6.67 billion US dollars, 5.58 billion US dollars in 2002, with huge market demand. [0003] Simvastatin is an HMG-CoA reductase inhibitor semi-synthesized from lovastatin, a synthetic derivative of the fermentation product of Aspergillus terreus. For the synthesis flow char...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C327/32C07C69/30C07C67/03
Inventor 李斌邓阳生
Owner SHENYANG SUNSHINE PHARMA
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