Method for synthetizing minodronic acid intermediate and preparing minodronic acid by virtue of one-pot process

A technology of minodronic acid, synthesis method, applied in the field of chemistry, capable of solving problems such as danger

Inactive Publication Date: 2015-06-10
BEIJING VENTUREPHARM BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Chinese Journal of Medical Industry 2004, 35(4): 193-194 introduced the use of imidazo[1,2-a]pyridine as its raw material to synthesize compound 5 through a series of reactions, but this method requires the use of highly toxic sodium cyanide, there is a certain danger

Method used

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  • Method for synthetizing minodronic acid intermediate and preparing minodronic acid by virtue of one-pot process
  • Method for synthetizing minodronic acid intermediate and preparing minodronic acid by virtue of one-pot process
  • Method for synthetizing minodronic acid intermediate and preparing minodronic acid by virtue of one-pot process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0010] Example 1: Synthesis of 2-{imidazo[1,2-a]pyridin-3-yl}acetic acid (compound 5)

[0011] Step 1: Add 360 g (3.82 mol) of compound to a 10 L three-necked flask 1 and 3.6 L ethanol, N 2 Protected, stirred in an ice-water bath until the solid was completely dissolved, and controlled the temperature at 0-10 °C; weighed 588 g (4.58 mol) of the compound 2 The reaction system was added dropwise within 1 h, and the temperature of the system rose slightly; after the dropwise addition, the temperature was controlled at 0-10 °C for 2 h, and the reaction progress was monitored by TLC. 2 After the reaction was complete, the reaction was changed to heating and reflux reaction for 6h, and the progress of the reaction was monitored by TLC to obtain the compound 3 .

[0012] Step 2: Change the reaction to an ice-water bath and cool to 0~10 °C; weigh 306 g (7.65 mol) NaOH and add 920 mL ice water to make a solution, and add dropwise to the above reaction system within 30 min after coo...

Embodiment 2

[0016] Example 2: Synthesis of Minodronic Acid (Compound 6)

[0017] Step 1: Prepare a compound with a purity of more than 97% according to the method of Example 1 5 .

[0018] Step 2: Add 1500 mL of chlorobenzene into a 5 L three-necked flask, start adding and stirring, and use nitrogen protection; weigh 60.0 g (0.34 mol) of the compound after 20 min 5 and 84.0 g (1.02 mol) of phosphorous acid were added to the reaction system, and the heating was turned on; when the temperature rose to 90~100 °C, 130 mL (1.37 mol) of phosphorus tribromide was added dropwise to the system within 40 min, and an exhaust gas absorption device was added ; After the dropwise addition was completed, the temperature was controlled at 110-115 °C for reaction, and the progress of the reaction was detected by TLC until the compound 5 After the reaction was complete, the heating was stopped, and the temperature was cooled to room temperature.

[0019] Step 3: A large amount of orange-yellow sol...

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Abstract

The invention relates to a preparation technology of a minodronic acid key intermediate 2-{imidazo[1,2-a]pyridine-3-yl}acetic acid (compound 5), and a monohydrate prepared by synthesizing the minodronic acid (6) by employing the intermediate, purifying and refining. The synthesis of the minodronic acid key intermediate has an important effect on the quality of the minodronic acid. The technology comprises the following steps: firstly, with 2-aminopyridine (1) and trans-4-amino-2-ethyl crotonate (2) as raw materials, synthesizing a high-purity minodronic acid intermediate (5) through the treatment such as hydrolysis and acidification, wherein the reactions are finished by one-pot reaction; and then synthesizing the minodronic acid (6) under the action of phosphorous acid and phosphorus tribromide.

Description

technical field [0001] The invention belongs to the field of chemistry and relates to 2-{imidazo[1,2-a]pyridin-3-yl}acetic acid (compound 5 ), and the synthesis of minodronic acid (compound 6 ). The purpose is to provide a simple, green, high-yield and high-purity process for preparing minodronic acid intermediates and minodronic acid. The following are the structures of minodronic acid intermediates and minodronic acid [0002] Background technique [0003] Minodronic acid is a third-generation bisphosphonate drug for the treatment of hypercalcemia caused by osteoporosis and malignant tumors. It is a new type of heterocyclic bisphosphonic acid compound developed by Yamanouchi Co., Ltd. of Japan. The bone resorption inhibitory activity of this drug is 2 times, 10 times and 100 times that of incadronate sodium, alendronate sodium and pamidronate disodium respectively. . Due to the excellent curative effect and less gastrointestinal side effects of this product, it has...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 粟勇马苏峰郭夏
Owner BEIJING VENTUREPHARM BIOTECH
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