Method for preparing 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid

A 2-a, imidazolo technology, applied in the field of medicinal chemistry, can solve the problems of the environment, hazards to operators and equipment, strong irritation and volatility, unfavorable industrial production, etc., to achieve good raw material stability, short reaction steps, and easy operation simple effect

Inactive Publication Date: 2011-02-16
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In Chinese patent CN101531681A, succinic acid monoethyl chloride is used as a raw material, and the target product 2-[imidazo(1,2-a)pyridin-3-yl]acetic acid is prepared through 4 steps of reaction, wherein a highly corrosive , strong irritant and volatile bromine and trimethylchlorosilane, the specific chemical reactions are as follows, this method will also cause greater harm to the environment, operators and equipment, and is not conducive to industrial production

Method used

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  • Method for preparing 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid
  • Method for preparing 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0025] (1) Preparation of 2-[imidazo(1,2-a)pyridin-3-yl]methyl acetate

[0026] Dissolve 56.5g (0.60mol) of 2-aminopyridine in 550ml of ethanol, cool to about 0-5°C, add 78ml of triethylamine (0.55mol), then slowly add 75.3g of methyl 4-chloroacetoacetate dropwise (0.50mol), dropwise finished within 1.5h. After 20 hours of reaction, the reaction liquid was evaporated to dryness under reduced pressure, and the residue was dissolved in 500 ml of chloroform, separated by silica gel chromatography, concentrated and crystallized, and the crude product was recrystallized with ethyl acetate to obtain 50.4 g of a white solid, namely Methyl 2-[imidazo(1,2-a)pyridin-3-yl]acetate, yield 53% (relative to methyl 4-chloroacetoacetate);

[0027] (2) Preparation of 2-[imidazo(1,2-a)pyridin-3-yl]acetic acid

[0028] 19g (0.10mol) of 2-[imidazo(1,2-a)pyridin-3-yl]methyl acetate was dissolved in 500ml of methanol, 20g of potassium hydroxide was added, the temperature was raised to reflux, HPLC...

Embodiment 2

[0030] (1) Preparation of 2-[imidazo(1,2-a)pyridin-3-yl]methyl acetate

[0031] Dissolve 56.5g (0.60mol) of 2-aminopyridine in 550ml of ethanol, cool to about 0-5°C, add 78ml of triethylamine (0.55mol), and slowly add 75.3g (0.50mol) of methyl 4-chloroacetoacetate dropwise. mol), the dripping was completed within 1.5h. After 6 hours of reaction, the reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 500ml of chloroform, separated by silica gel chromatography, concentrated and crystallized, and the crude product was recrystallized with ethyl acetate to obtain 33.3g of white solid, namely Methyl 2-[imidazo(1,2-a)pyridin-3-yl]acetate, yield 35% (relative to methyl 4-chloroacetoacetate);

[0032] (2) Preparation of 2-[imidazo(1,2-a)pyridin-3-yl]acetic acid

[0033] Dissolve 19g (0.10mol) of methyl 2-[imidazo(1,2-a)pyridin-3-yl]acetate in 500ml of ethanol, add 20g of potassium hydroxide, heat up to reflux, and after HPLC monitors ...

Embodiment 3

[0035] (1) Preparation of 2-[imidazo(1,2-a)pyridin-3-yl]ethyl acetate

[0036] Dissolve 56.5g (0.60mol) of 2-aminopyridine in 550ml of dioxane, cool to about 0-5°C, add 78ml of triethylamine (0.55mol), slowly add 4-chloroacetoacetate ethyl 82.3 g (0.50mol), dripped within 1.5h. After 20 hours of reaction, the reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 500 ml of chloroform, separated by silica gel chromatography, concentrated and crystallized, and the crude product was recrystallized with ethanol to obtain 52.0 g of white solid, namely 2 -[imidazo(1,2-a)pyridin-3-yl]ethyl acetate, yield 51% (relative to ethyl 4-chloroacetoacetate);

[0037] (2) Preparation of 2-[imidazo(1,2-a)pyridin-3-yl]acetic acid

[0038] Dissolve 19g (0.10mol) of methyl 2-[imidazo(1,2-a)pyridin-3-yl]acetate in 500ml of methanol, add 22g of sodium hydroxide, heat up to reflux, and after HPLC monitors that the reaction is complete, depressurize Con...

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Abstract

The invention provides a method for preparing 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid, which comprises the following steps of: reacting 4-chloro-acetoacetic acid ester and 2-aminopyridine in an organic solvent in the presence of an acid binding agent to obtain 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid ester; and hydrolyzing the 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid under the acid or alkaline condition to obtain the 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid. In the method, raw materials have high stability and low price and are readily available; deadly toxic cyanides or high corrosion and unstable bromides are not used; the reaction step is short; the operation is simple; the method is safe and environment-friendly; special equipment is not needed; and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing an anti-osteoporosis drug Minodronate (Minodronate) intermediate 2-[imidazo(1,2-a)pyridin-3-yl]acetic acid . Background technique [0002] Minodronate is a novel heterocyclic bisphosphonate compound developed by Japan Yamanouchi Co., Ltd., which is used to treat hypercalcemia caused by osteoporosis and malignant tumors. It was first approved for listing in Japan on January 21, 2009, and the trade names were Recalbon (Ono Pharmaceuticals) and Bonoteo (Astellas Pharmaceuticals). 2-[imidazo(1,2-a)pyridin-3-yl]acetic acid is an important intermediate in the synthesis of minodronic acid. [0003] The synthesis method of minodronic acid has been reported in European patent EP0354806, but there is no report on the synthesis method of 2-[imidazo(1,2-a)pyridin-3-yl]acetic acid in this patent. In non-patent literature: Chinese Journal of Pharmace...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 赵世明罗振福
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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