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Synthetic method of lipid-lowering drug ciprofibrate

A technology of blood lipid-lowering drug and synthesis method, which is applied in the field of synthesis of blood lipid-lowering drug ciprofibrate, which can solve the problems of insufficient stability of raw material styrene, uneasy properties of hydroxystyrene, and insufficient mild reaction conditions, etc., and achieve post-processing steps The effect of simplicity, strong economy, and short reaction route

Active Publication Date: 2017-07-07
NANJING UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disadvantages: The raw material p-hydroxystyrene is not easy to obtain commercially and its properties are unstable, so it is often used as an intermediate; the other two steps of the reaction require the introduction of excess alkali, and the reaction conditions are not mild enough
Disadvantages: Although the reaction raw materials are simple and the conditions are relatively mild, the reaction route is lengthy, which reduces the yield, and the raw material styrene is not stable enough (easy to self-polymerize), which limits its application

Method used

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  • Synthetic method of lipid-lowering drug ciprofibrate

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preparation example Construction

[0032] The invention provides a synthesis method of ciprofibrate. The route uses p-hydroxybenzaldehyde as a raw material to obtain a final product through Knoevenagel-decarboxylation reaction, Bargllini reaction and olefin insertion reaction. In the Knoevenagel-decarboxylation cascade reaction, a mixed solvent is used to replace the traditional single solvent, which effectively reduces the reaction time and promotes the conversion of intermediate products; in the olefin insertion reaction, TiCl4 / Mg / CCl4 is used to replace the traditional carbene addition System to build a three-membered ring, avoiding the use of a strong base, the reaction is carried out at a lower temperature, the conditions are mild, and the energy consumption is reduced. Specific steps include:

[0033] (1) p-Hydroxybenzaldehyde (I), generates p-hydroxystyrene (II) through heating and alkali catalysis with malonic acid in a mixed solvent;

[0034] (2) p-hydroxystyrene (II) and acetone, chloroform, and alkali...

Embodiment 1

[0042] (1) Synthesis of p-hydroxystyrene (II)

[0043] Dissolve 50g of p-hydroxybenzaldehyde (I) in 250mL of toluene, add 85g of malonic acid and 41.5mL of diethylamine, heat to reflux at 150°C, and divide the water with a water separator. After reacting for 2 hours, separate the oily product, then add 250ml of DMF, continue to heat up to 150°C, react for 2 hours, cool the reaction liquid, adjust the pH to 3-4 with 1mol / L dilute hydrochloric acid in an ice bath, and extract with ethyl acetate. Organic phase saturated with NaHCO 3 solution washing, saturated NaCl solution washing, anhydrous Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure to obtain 46.0 g of crude p-hydroxystyrene (II) oil, with a yield of 94.6%.

[0044] (2) Synthesis of 2-methyl-2-(4-vinylphenoxy)propionic acid (III)

[0045] Dissolve 10g of p-hydroxystyrene (II) in 70mL of acetone, add 9.9g of NaOH and 2.6g of tetra-n-butylammonium bromide, and heat at 40°C to make it reflux s...

Embodiment 2

[0050] (1) Synthesis of p-hydroxystyrene (II)

[0051] Dissolve 50g of p-hydroxybenzaldehyde (I) in 500mL of 1:1 (v / v) DMF / toluene, add 85g of malonic acid and 41.5mL of diethylamine, heat to reflux at 150°C, and divide the water with a water separator. After reacting for 4 hours, the reaction solution was cooled, and the pH was adjusted to 3-4 with 1mol / L dilute hydrochloric acid in an ice bath, extracted with ethyl acetate, and the organic phase was washed with saturated NaHCO 3 solution washing, saturated NaCl solution washing, anhydrous Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure to obtain 46.0 g of the crude p-hydroxystyrene (II) oil, with a yield of 93.5%.

[0052] (2) Synthesis of 2-methyl-2-(4-vinylphenoxy)propionic acid (III)

[0053] Dissolve 10g of p-hydroxystyrene (II) in 70mL of acetone, add 9.9g of NaOH and 2.6g of tetra-n-butylammonium bromide, and heat at 40°C to make it reflux stably; dissolve 29.8g of chloroform in about 10...

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Abstract

The invention provides a synthetic method of lipid-lowering drug ciprofibrate. The synthetic method comprises the following steps: catalyzing reaction of p-hydroxy benzaldehyde and propane diacid in a mixed solvent by virtue of alkali, so as to generate p-hydroxystyrene; catalyzing reaction of p-hydroxystyrene, acetone, chloroform and alkali by virtue of a phase transfer catalyst, so as to generate an intermediate 2-methyl-2-(4-vinylphenoxy)propionic acid; and reacting 2-methyl-2-(4-vinylphenoxy)propionic acid with TiCl4, Mg and CCl4, so as to generate ciprofibrate. The synthetic method has the beneficial effects that the reaction route is short, the raw materials are cheap and easily available, reaction conditions are mild, the energy consumption is reduced, and the production cost is lowered; the post-processing step is simple, the emission of three wastes is reduced, and the method is environment-friendly and safe. Compared with routes of predecessors, the synthetic method has the advantages that the reaction selectivity and conversion rate of the route are relatively high, the wasting of the raw materials is reduced, and the economical efficiency is relatively high.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing blood lipid-lowering drug ciprofibrate. Background technique [0002] Fibrate drugs, also known as phenoxyaromatic acid drugs, refer to a class of lipid-lowering drugs including gemfibrozil, clofibrate, fenofibrate, bezafibrate, and ciprofibrate. This type of drug is absorbed quickly and completely after oral administration, and the drug concentration in plasma can be detected within 1 to 2 hours after taking the drug, and has a high binding rate to plasma protein. The half-life of fibrates ranges from a few hours to 24 hours. Ciprofibrate has the effect of lowering blood lipids. By improving the distribution of cholesterol, it can reduce the deposition of CH and LDL on the blood vessel wall. [0003] Patent CN201310237441.9 uses p-hydroxystyrene as the starting material to construct the carboxyl terminal in one step through the Barg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/363C07C59/72
CPCC07C37/20C07C51/00C07C51/363C07C59/72C07C39/20C07C59/68
Inventor 苏贤斌范佳辉李裴竹徐萧和
Owner NANJING UNIV OF TECH
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