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Preparation method of 5-[4-[2-(5-ethyl-2-pyridine)ethoxy] benzylidene]-2,4thiazolidine diketone

A technology of thiazolidinedione and benzylidene, which is applied in the field of pioglitazone intermediates, can solve the problems of unstable yield and quality, safe production, relatively high air humidity requirements, and difficult drying of moisture, etc., to shorten the reaction cycle , Simplified operation, reduced air humidity requirements

Inactive Publication Date: 2005-02-16
HUADONG MEDICINE +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] There are some defects in the preparation of compound I by this method, because in the reaction process of this method, the requirement to moisture in the reaction system is very high, and the moisture and air humidity in the raw material have a greater impact on the reaction, potassium p-hydroxybenzaldehyde In the preparation of salt, water is generated, and the temperature during drying should not be too high, which makes it difficult to dry the water. However, it is easy to absorb moisture during the separation of p-hydroxybenzaldehyde potassium salt from the reaction system and the drying process. The requirements are relatively high, which will have a greater impact on the follow-up response in areas with a lot of rain or high air humidity
In addition, isopropyl ether is used as a solvent in the preparation of p-hydroxybenzaldehyde potassium salt, which requires high explosion-proof requirements for the production site; the existence of these defects makes the reaction reproducibility of this method poor, and the yield and quality are unstable and also There will be problems in production safety

Method used

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  • Preparation method of 5-[4-[2-(5-ethyl-2-pyridine)ethoxy] benzylidene]-2,4thiazolidine diketone
  • Preparation method of 5-[4-[2-(5-ethyl-2-pyridine)ethoxy] benzylidene]-2,4thiazolidine diketone
  • Preparation method of 5-[4-[2-(5-ethyl-2-pyridine)ethoxy] benzylidene]-2,4thiazolidine diketone

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preparation example Construction

[0039] (ii) preparation reaction of potassium salt V

[0040] P-Hydroxybenzaldehyde IV, ethanol, and ROK are put into a reactor, and the reaction is obtained by raising the temperature and stirring.

[0041] (iii) Substitution reaction

[0042] The ethanol solution of the potassium salt is pumped into the sulfonylation reactor, stirred and heated, and the end point of the reaction is monitored by TLC. After the reaction is completed, it is concentrated, washed, dried, and concentrated to dryness to obtain a substitute.

[0043] (iv) Condensation reaction

[0044] Add ethanol and thiazolidinedione to Substitute VI, stir to raise the temperature, and monitor the end point of the reaction with TLC. After the reaction is completed, freeze and freeze overnight, centrifuge, and dry in vacuum to obtain Compound I.

Embodiment 1

[0047] Sulfonylation reaction

[0048] (5-ethyl-2-pyridyl) ethanol II 10Kg (64.5mol), triethylamine 8Kg, dichloromethane 150 liters into the reaction tank, ice-salt bath cooling, methanesulfonyl chloride 10Kg (86.7mol) was added dropwise under stirring ), react at room temperature for 6 hours after the dropwise addition, add 50 liters of water to wash twice, and dry the dichloromethane phase with anhydrous magnesium sulfate. Suction filtration, and the filtrate was concentrated to dryness under reduced pressure.

[0049] Preparation and Substitution Reaction of Potassium Salt V

[0050] Add 12Kg (100mol) of p-hydroxybenzaldehyde IV, 100 liters of ethanol, and 8.4Kg (120mol) of potassium methylate into the reaction tank, stir and react at room temperature for 10 hours, add sulfonyl compound III to the reaction solution, heat up to reflux for 5 hours under stirring , concentrated to dryness under reduced pressure, added 300 liters of ethyl acetate and stirred to dissolve, wash...

Embodiment 2

[0054] Sulfonylation reaction

[0055] (5-ethyl-2-pyridyl) ethanol II 10Kg (64.5mol), triethylamine 8Kg, dichloromethane 150 liters into the reaction tank, ice-salt bath cooling, methanesulfonyl chloride 10Kg (86.7mol) was added dropwise under stirring ), react at room temperature for 6 hours after the dropwise addition, add 50 liters of water to wash twice, and dry the dichloromethane phase with anhydrous magnesium sulfate. Suction filtration, and the filtrate was concentrated to dryness under reduced pressure.

[0056] Preparation of Potassium Salt V Substitution Reaction

[0057] Add 12Kg (100mol) of p-hydroxybenzaldehyde IV, 100 liters of ethanol, 16Kg (160mol) of potassium tert-butoxide into the reaction tank, stir and react at 50°C for 5 hours, add sulfonylated compound into the reaction solution, heat up to reflux for 5 hours under stirring , concentrated to dryness under reduced pressure, added 300 liters of ethyl acetate and stirred to dissolve, washed twice with 30...

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Abstract

An improved process for preparing 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]phenylmethylene]- 2,4 thiazolidin edione includes such steps as sulfonylation reaction of (5-ethyl-2-pyridyl) alcohol to obtain sulfonyl compound, reaction of p-hydroxy benzaldehyde on ROK to obtain p-hydroxy benzaldehyde potassium salt, substitution reaction between the two above resultants, and condensation reaction between the substituted compound, thiazoledione and alcohol to obtain the product.

Description

technical field [0001] The present invention relates to intermediates of pioglitazone, more specifically to 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene]-2,4thiazolidinedione method of preparation. technical background [0002] Pioglitazone hydrochloride is a new generation of thiazolidinediones diabetes treatment drug, structural formula such as 5-[4-[2-(5-ethyl-2-pyridyl) ethoxy] benzylidene]- 2,4 Thiazolidinedione (hereinafter referred to as compound I) is an important intermediate of pioglitazone hydrochloride. There are many preparation methods of Compound I, but all of them have some defects and cannot be applied to industrial production. For example, the European patent "Method for producing ethers" (Method for producing ethers, EP506273, published on September 30, 1992) discloses a method for preparing compound I, and its preparation steps are: [0003] (1) Sulfonylation reaction: (5-ethyl-2-pyridyl) sulfonylation reaction of ethanol II...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12
Inventor 胡祖耀郑直
Owner HUADONG MEDICINE
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