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Method for preparing pioglitazone

A pyrrolitazone and pyridyl technology, applied in the field of preparation of pyrrolitazone, can solve the problems of high preparation cost, low cyclization yield and the like, and achieve the effects of good product quality, simple reaction operation, and easy reaction control

Inactive Publication Date: 2012-07-04
SHANDONG JINCHENG PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The common disadvantage of these techniques for preparing piroglitazone is that the cyclization yield is low, and the molar yield based on the amino compound IV is between 20% and 45%, and the preparation cost is high.

Method used

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  • Method for preparing pioglitazone
  • Method for preparing pioglitazone
  • Method for preparing pioglitazone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] (a) Preparation of bromide III: In a 1000ml three-necked flask, a magnetic stirrer, a thermometer and a reflux condenser were installed, and 24.2g (0.10mol) of 4-[2-(5-ethyl-2-pyridyl) ethyl was added Oxygen] aniline (amino compound IV), add 150ml methanol and 21.9g (0.13mol) hydrobromic acid (48%), add dropwise 50ml aqueous solution of 7.6g (0.11mol) sodium nitrite at 0~5 ℃, keep warm After 1 hour, 50.4 g (0.59 mol) of acrylic acid and 1.43 g (0.01 mol) of cuprous oxide were added and reacted at 50° C. for 2 hours. After the reaction, 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl}acrylic acid (bromide III) was obtained;

[0042] (b) Preparation of thiothiazolidinedione compound II: the bromide III prepared in step (a) is added to sodium acetate to adjust the pH value=6.8~7.0 to obtain 2-bromo-3-{4-[2-(5 -Ethyl-2-pyridyl)-ethoxy]phenyl}acrylic acid (bromide III) sodium salt aqueous solution, extracted with ethyl acetate, added 12.1g (0.11mol) ammonium dithiocarbama...

Embodiment 2

[0045] (a) Preparation of bromide III: In a 1000ml three-necked flask, a magnetic stirrer, a thermometer and a reflux condenser were installed, and 24.2g (0.10mol) of 4-[2-(5-ethyl-2-pyridyl) ethyl was added Oxygen] aniline (amino compound IV), add 58ml ethanol and 21.9g (0.13mol) hydrobromic acid (48%), add dropwise 50ml aqueous solution of 6.9g (0.10mol) sodium nitrite at 0~5 ℃, keep warm After 2 hours, 43.0 g (0.5 mol) of acrylic acid and 1.14 g (0.008 mol) of cuprous oxide were added and reacted at 30° C. for 6 hours. After the reaction, 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl}acrylic acid (bromide III) was obtained;

[0046] (b) Preparation of thiothiazolidinedione compound II: the bromide III prepared in step (a) is added to sodium acetate to adjust the pH value=6.8~7.0 to obtain 2-bromo-3-{4-[2-(5 -Ethyl-2-pyridyl)-ethoxy]phenyl}acrylic acid (bromide III) sodium salt aqueous solution, extraction with ethyl acetate, adding 11.0g (0.10mol) ammonium dithiocarbam...

Embodiment 3

[0049] (a) Preparation of bromide III: In a 1000ml three-necked flask, a magnetic stirrer, a thermometer and a reflux condenser were installed, and 24.2g (0.10mol) of 4-[2-(5-ethyl-2-pyridyl) ethyl was added Oxygen] aniline (amino compound IV), add 194ml isopropanol and 21.9g (0.13mol) hydrobromic acid (48%), add dropwise 50ml aqueous solution of 8.3g (0.12mol) sodium nitrite at 0~5 ℃, After heat preservation for 1 hour, 86.1 g (1.0 mol) of acrylic acid and 1.72 g (0.012 mol) of cuprous oxide were added and reacted at 80° C. for 2 hours. After the reaction, 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl}acrylic acid (bromide III) was obtained;

[0050] (b) Preparation of thiothiazolidinedione compound II: the bromide III prepared in step (a) is added to sodium acetate to adjust the pH value=6.8~7.0 to obtain 2-bromo-3-{4-[2-(5 -Ethyl-2-pyridyl)-ethoxyl]phenyl}acrylic acid (bromide III) sodium salt aqueous solution, extraction with ethyl acetate, adding 12.1g (0.11mol) ammo...

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Abstract

The invention relates to a method for preparing pioglitazone. The method comprises the following steps of: treating an amino compound IV (4-[2-(5-ethyl-2-pyridyl) ethoxy] phenylamine) by using hydrobromic acid and sodium nitrite, adding acrylic acid and cuprous oxide for reaction to obtain a bromide III (2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-ethoxy] phenyl} acrylic acid); reacting the bromide III and ammonium dithiocarbamate to obtain sulfothiazolidine diketone II (5-{4-[2-(5-ethyl-2-pyridyl)-ethoxy] benzyl}-2-thiocarbonyl-4-thiazolidone); and adding hydroxylamine hydrochloride for condensation, and hydrolyzing with hydrochloric acid to obtain the pioglitazone I (5-{4-[2-(5-ethyl-2-pyridyl)-ethoxy] benzyl}-2,4-thiazolidinedione). According to the technical scheme, the operation is simple, and the reaction is easy to control; and the yield of the product can reach 62 percent, the quality is good, and the purity reaches 99.5 percent (HPLC).

Description

technical field [0001] The invention relates to a preparation method of a medicine for treating type II diabetes, in particular to a preparation method of piroglitazone. Background technique [0002] Pioglitazone is developed and produced by Takeda Chemical Co., Ltd., Japan, and is used to improve and control blood sugar and is a drug for treating type II diabetes. [0003] Pyroglitazone, Chinese name: 5-{4-[2-(5-Ethyl-2-pyridine)-ethoxy]-phenyl}-2,4-thiazolidinedione hydrochloride, white or White crystalline powder, the molecular structure is as follows: [0004] [0005] Patent WO2009133576 discloses the technology of preparing piroglitazone, 4-[2-(5-ethyl-2-pyridyl)ethoxy]aniline (amino compound IV) reacts with sodium nitrite, hydrochloric acid and methyl acrylate , ring closure with thiourea, and hydrolysis to prepare piroglitazone. The disadvantage of this technology is mainly that the yield is low, only 31.3%. [0006] Indian patents IN2002MA00647, IN2005MU01255...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12
Inventor 赵叶青李湛江刘刚刘承平徐立臣
Owner SHANDONG JINCHENG PHARMA & CHEM