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Method for preparing minodronic acid intermediate

A technology of hydrochloric acid and acetic acid, applied in directions such as organic chemistry, can solve the problems of low bromination yield, unsuitable for industrial production, large amount of solvent, etc., and achieves the effects of excellent product quality, cheap raw materials, and simple operation.

Active Publication Date: 2011-11-23
广东宏远集团药业有限公司
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  • Application Information

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Problems solved by technology

This method requires a low temperature reaction of -80°C, the amount of solvent is large, and the bromination yield is low, so it is not suitable for industrial production
[0015] The above three preparation methods all have deficiencies in varying degrees, but the key intermediate I is used in the process. Therefore, it is necessary to find a method for the synthesis of intermediate I that can be safely and easily controlled

Method used

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  • Method for preparing minodronic acid intermediate
  • Method for preparing minodronic acid intermediate
  • Method for preparing minodronic acid intermediate

Examples

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Effect test

Embodiment 1

[0032] Preparation of Diethyl 2-(imidazo[1,2-a]pyridin-3-yl)malonate(III)

[0033] Dissolve 50ml of diethyl malonate in 1L of absolute ethanol, add 30g of sodium ethoxide and stir at room temperature for 2h, add 50g of 3-bromo-imidazo[1,2-a]pyridine (II), and reflux for 4h. The reaction solution was poured into a large amount of ice water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and air-dried at 60°C to obtain 58 g of a yellow solid with a yield of 82.8%. Preparation of 2-(imidazo[1,2-a]pyridin-3-yl)acetic acid (I)

[0034] Add 58g of intermediate (III) into the reaction flask, add 348ml of concentrated hydrochloric acid, raise the temperature to 120°C and stir for 6h to complete the reaction. The reaction solution was concentrated under reduced pressure to obtain 27.5 g of khaki solid (I), with a yield of 75.3%.

Embodiment 2

[0036] Recrystallization of 2-(imidazo[1,2-a]pyridin-3-yl)acetic acid (I)

[0037] Add 27.5g of intermediate I crude product to the reaction flask, add 550ml of methanol, heat to dissolve, filter while hot, cool and crystallize the filtrate, and filter with suction to obtain 23.8g of off-white solid with a yield of 86.5% and a melting point of 236°C-238°C.

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Abstract

The invention relates to the field of medicine synthesis, in particular to a method for preparing a minodronic acid intermediate 2-(imidazo[1,2-a]pyridin-3-yl)acetic acid (I). The method is characterized by comprising the following steps of: performing condensation on 3-bromoimidazo[1,2-a]pyridine (II) and diethyl malonate to obtain 2-(imidazo[1,2-a]pyridin-3-yl)diethyl malonate (III); and hydrolyzing and performing decarboxylation to obtain the 2-(imidazo[1,2-a]pyridin-3-yl)acetic acid (I). The method has the advantages of cheap and readily available raw materials, a few reaction steps, simple operation, high product quality, low cost, suitability for industrial production and the like.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of minodronic acid intermediate 2-(imidazo[1,2-a]pyridin-3-yl)acetic acid (I). Background technique [0002] Minodronic acid is a third-generation azaaryl bisphosphonate derivative with the chemical name [1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidene] Bisphosphonic acid monohydrate, its anti-bone resorption activity is 100-1000 times higher than pamidronate sodium, and can antagonize the osteolysis caused by myeloma and tumor. Clinically used to treat osteoporosis. Its chemical structure is as follows: [0003] [0004] There are many synthetic methods of minodronic acid reported in the literature: [0005] Method 1: The synthetic method disclosed in Chinese Journal of Pharmaceutical Industry 2004, 35(4): 193-194 and document J Med.Chem, 1969, 12(1): 122-126 is as follows: [0006] [0007] The method takes 2-imidazo[1,2-a]pyridine as raw material...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 何广卫李丰王银虎
Owner 广东宏远集团药业有限公司
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