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Refining method of atorvastatin parent nucleus M4

A technology of refining atorvastatin, which is applied in the refining field of atorvastatin core M4, which can solve the problems of low qualified rate of product refining at one time, affect production efficiency, increase product cost, etc., achieve large production capacity and increase production and good productivity and stability

Pending Publication Date: 2022-03-18
河南豫辰药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] At the same time, during the process of refining the crude product of atorvastatin core M4, the research and development personnel analyzed by HPLC method that there was an unknown impurity (RRT1.15), which was difficult to remove after production, directly affecting the quality of the final product, and leading to The melting point is unqualified, and the pass rate of the product is low in one-time refining. Subsequent rework is required, which directly affects production efficiency and increases product costs.

Method used

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  • Refining method of atorvastatin parent nucleus M4
  • Refining method of atorvastatin parent nucleus M4
  • Refining method of atorvastatin parent nucleus M4

Examples

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Effect test

Embodiment 1

[0052] In the process of refining the crude atorvastatin core M4, it is necessary to add hydrochloric acid or glacial acetic acid to adjust the pH value of the reaction system, and it is necessary to precisely control the amount of hydrochloric acid or glacial acetic acid added. In this example, a DCS that can regulate the pH value is used. Reactor systems to regulate pH, such as figure 1 As shown, the DCS reactor system capable of regulating the pH value includes a reactor 1, a first adding tank 2, a second adding tank 4 and DCS control equipment;

[0053] The first adding tank 2 contains hydrochloric acid, and the second adding tank 4 contains glacial acetic acid;

[0054] The reactor 1 is provided with a stirring shaft and a stirring paddle, and the top cover of the reactor 1 is provided with a first feed port and a second feed port, and the output end of the first feed tank 2 is connected to the top of the reactor 1 through the first feed pipe 11. The first feeding port o...

Embodiment 2

[0070] A method for refining atorvastatin core M4, the specific steps are as follows;

[0071] (1) Add 1600kg of atorvastatin core M4 (i.e. compound VI) crude product 1 to the reactor with a volume of 5000L, then add 4800kg of water, stir and mix, and add dropwise hydrochloric acid to adjust the pH value. The DCS that regulates the pH value controls the reaction kettle system to control the dripping amount of hydrochloric acid, and sets the pH value range to 5.60-6.40. When the pH value is greater than the range value, open the first electric control valve 12 for hydrochloric acid dripping. When the pH value is 5.95, close the first electric control valve 12, stop dripping;

[0072] Then beat at room temperature for 2 hours, centrifuge, dry under reduced pressure, and control the moisture to ≤1%, to obtain 1486kg of atorvastatin mother nucleus M4 crude product 2, which was detected by HPLC, and the content of atorvastatin mother nucleus M4 in crude product 2 was 98.95% %, moi...

Embodiment 3

[0077] A method for refining atorvastatin core M4, the specific steps are as follows;

[0078] (1) Add 1600kg of atorvastatin core M4 (i.e. compound VI) crude product 1 to the reactor with a volume of 5000L, then add 4800kg of water, stir and mix, and add dropwise hydrochloric acid to adjust the pH value. The DCS that regulates the pH value controls the reaction kettle system to control the dripping amount of hydrochloric acid, and sets the pH value range to 5.60-6.40. When the pH value is greater than the range value, open the first electric control valve 12 for hydrochloric acid dripping. When the pH value is 6.10, close the first electric control valve 12, stop dripping;

[0079] Then beat at room temperature for 2 hours, centrifuge, dry under reduced pressure, and control the moisture to ≤1%, to obtain 1481 kg of atorvastatin mother nucleus M4 crude product 2, which was detected by HPLC, and the content of atorvastatin mother nucleus M4 in crude product 2 was 99.15% %, mo...

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Abstract

The invention belongs to the technical field of medicine synthesis processes, and particularly relates to a refining method of atorvastatin parent nucleus M4. The DCS reaction kettle system is adopted to adjust the pH value of the system, so that the target product M4 can be effectively prevented from being damaged under acid-base conditions, unknown impurities are reduced, and the refining qualification rate is increased. According to the method disclosed by the invention, inorganic salts such as potassium carbonate, potassium bicarbonate and potassium chloride in the atorvastatin mother nucleus M4 (namely a compound VI) crude product 1 synthesized by a convergence method can be removed in the pulping process, and a mixed solvent is utilized in the recrystallization process, so that impurities are effectively removed and reduced, and the refining yield is improved. The process disclosed by the invention is simple in post-treatment, large in productivity, and suitable for industrial production, and the obtained product is high in chemical purity, low in impurity content, high in melting point, short in melting range and good in stability, and the recovered solvent and the crystallization mother liquor can be recycled.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis technology, and in particular relates to a method for refining atorvastatin core M4. Background technique [0002] Atorvastatin calcium is a statin blood lipid-lowering drug jointly developed by WarnerLambert Company and Prizer Company of the United States. It can strongly inhibit the activity of hydroxymethylglutaryl-CoA (HMKG-CoA) reductase, significantly reduce total cholesterol and low The content of high-density lipoprotein cholesterol. Because of its small toxic and side effects, unique mechanism of action, and good tolerance, the market application prospect is very broad. [0003] Atorvastatin mother core M4 is a mother ring intermediate for the synthesis of atorvastatin calcium, and its molecular formula is C 26 h 24 FNO 3 , chemical name: 4-fluoro-α-[2-methyl-1-oxypropyl]-γ-oxo-N,β-diphenylbenzenebutyramide, its structural formula is as follows: [0004] [0005] The pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/24C07C235/80
CPCC07C231/24C07C235/80
Inventor 傅收宫海伟李闪闪李锋军魏利强贾玉香徐燕红程丽红
Owner 河南豫辰药业股份有限公司
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