Method for continuously preparing rosuvastatin intermediate by micro-channel modular reaction device

A microchannel module, rosuvastatin technology, applied in chemical recovery, organic chemistry and other directions, can solve the problems of low yield, difficult to purify, many by-products, etc., and achieve high yield, easy operation, and less side reactions. Effect

Active Publication Date: 2019-05-24
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Purpose of the invention: In view of the shortcomings in the synthesis and preparation process of the existing statin hypolipidemic drug rosuvastatin, such as low yield, many by-products, and difficulty in purification, the present invention provides a modular reaction device using microchannels The method for continuously preparing the intermediate of rosuvastatin has the advantages of simple and fast operation, high yield, low production cost, good application prospect and production value of industrialized method

Method used

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  • Method for continuously preparing rosuvastatin intermediate by micro-channel modular reaction device
  • Method for continuously preparing rosuvastatin intermediate by micro-channel modular reaction device
  • Method for continuously preparing rosuvastatin intermediate by micro-channel modular reaction device

Examples

Experimental program
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Effect test

Embodiment 1

[0046] (1) In the microchannel reaction device, the isopropanol solution (11.5mL) of p-fluorobenzaldehyde (0.04mol) and the isopropanol solution (0.135mL) of acetic acid catalyst (0.135mL), methyl isobutyrylacetate (0.04mol) Solution (11.5mL) and catalytic amount of piperidine (0.225mL) were pumped into the first mixer 3 from pump A1 and pump B2 respectively, the flow rate of pump A1 was 0.38mL / min, and the flow rate of pump B2 was 0.38mL / min min. After fully mixing, enter the first microreactor 4. The volume of the first microreactor 4 is 40mL, the reaction residence time is 30min, and the reaction temperature is 30°C. The obtained reaction effluent is 2-(4-fluorophenyl)methylene - Methyl 3-oxo-4-methylpentanoate (ZD-1).

[0047] (2) along with the reaction solution that step (1) obtains flows into the second mixer 6, flow velocity is 1.24mL / min, S-methylisothiouronium sulfate (2.08mol) is added into equimolar amount of saturated sodium bicarbonate ( 2.08mol) free isopropan...

Embodiment 2

[0060] The operation is the same as in Example 1, the only difference is:

[0061] In step (1), the reaction temperature in the first microreactor is 20°C, and finally 2-(4-fluorophenyl)methylene-3-oxo-4-methylpentanoic acid methyl ester (ZD- 1) The reaction effluent has a yield of 75%.

Embodiment 3

[0063] The operation is the same as in Example 1, the only difference is:

[0064] In step (1), the reaction temperature in the first microreactor is 40°C, and finally 2-(4-fluorophenyl)methylene-3-oxo-4-methylpentanoic acid methyl ester (ZD- 1) The reaction effluent has a yield of 80%.

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Abstract

The invention discloses a method for continuously preparing a rosuvastatin intermediate by a micro-channel modular reaction device. The method includes the steps: performing reaction on isopropanol solution of fluorobenzaldehyde and isopropanol solution of isobutyrylacetic acid methyl ester in a first micro-reactor under catalysis of acetic acid and piperidine to generate a first product; performing reaction on the first product and isopropanol solution with free S-methyl isothiourea salt in a second micro-reactor to generate a second product; performing reaction on the second product, acetonesolution of potassium permanganate and acetic acid in a third micro-reactor to generate a third product; performing reaction on the third product and methylamine ethanol solution in a fourth micro-reactor to obtain the rosuvastatin intermediate. The rosuvastatin intermediate is low in toxicity, less in pollution, low in production cost, good in quality, high in profit, green and environmentally friendly and efficient in energy and has industry enlargement potential.

Description

technical field [0001] The invention relates to a method for preparing an intermediate of statin blood lipid-lowering drug rosuvastatin, in particular to a method for preparing an important intermediate of rosuvastatin 4-(4-fluorophenyl)- Method for methyl 6-isopropyl-2-(methylamino)pyrimidine-5-carboxylate. Background technique [0002] Rosuvastatin, chemical name (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methyl-methylsulfonyl-amino)- Pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic acid, which is a selective hydroxymethylglutaryl coenzyme (HMG-CoA) reductase inhibitor, competes for HMG-CoA reductase, Thereby reducing cholesterol biosynthesis and causing increased clearance of cholesterol from the blood. The main site of action of rosuvastatin is the liver-the target organ for lowering cholesterol. It increases the number of receptors on the surface of liver LDL cells, promotes the absorption and catabolism of LDL, and inhibits the hepatic synthesis of VLDL, thereby reduci...

Claims

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Application Information

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IPC IPC(8): C07D239/42
CPCY02P20/584
Inventor 杨照刘亮王志祥方正
Owner CHINA PHARM UNIV
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