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High-purity minodronic acid and preparation method thereof

A bisphosphonic acid and phosphorylation technology, which is applied to the field of high-purity minodronic acid and its preparation, can solve the problems of many reaction steps, difficult product purification, large environmental pollution, etc., and achieves reduction of reaction steps, difficulty reduction, The effect of strong reaction controllability

Active Publication Date: 2009-09-16
AVENTIS PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method is dangerous to operate due to the use of the highly toxic substance sodium cyanide
At the same time, there are many side reactions, and the generated products are difficult to purify
Moreover, there are many steps in the reaction, the operation is cumbersome, and the environmental pollution is relatively large.

Method used

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  • High-purity minodronic acid and preparation method thereof
  • High-purity minodronic acid and preparation method thereof
  • High-purity minodronic acid and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0040] 1, the preparation of ethyl 4-formyl butyrate (III)

[0041] N 2 Under protection, succinic acid monoethyl chloride (16.5g, 0.1mol) was dissolved in dried THF (1L), cooled to -80°C, and LiAlH(OC 4 h 9 -t) THF (1L) solution of (38g, 0.15mol), dripping is completed, stirred at low temperature for 5h, the reaction is completed, the reaction solution is poured into a large amount of ice water, extracted with ethyl acetate (600ml×3), combined with ethyl acetate, Dry, filter, and concentrate to obtain 7.9 g of yellow liquid, with a yield of 61%.

[0042] Preparation of 2.3-bromo-4-formyl butyric acid ethyl ester (IV)

[0043] Compound (III) (7.9g, 0.06mol) and trimethylchlorosilane (7.8g, 0.072mol) were added to the reaction flask, the temperature was lowered to 0°C, and triethylamine (6g, 0.06mol) was added dropwise. After dropping, the temperature was raised to reflux, and after 4 hours it was cooled to room temperature, 200ml of chloroform was added, and a solution of ...

Embodiment 2

[0051] 1, the preparation of ethyl 4-formyl butyrate (IV)

[0052] N 2 Under protection, succinic acid monoethyl chloride (16.5g, 0.1mol) was dissolved in dried DMF (1L), cooled to -80°C, and LiAlH(OC 4 h 9 -t) DMF (1L) solution of (38g, 0.15mol), dripping is completed, stirred at low temperature for 5h, the reaction is completed, the reaction solution is poured into a large amount of ice water, extracted with ethyl acetate (600ml×3), combined with ethyl acetate, Dry, filter, and concentrate to obtain 7.9 g of yellow liquid, with a yield of 61%.

[0053]The preparation of 2.3-bromo-4-formyl butyric acid ethyl ester (V)

[0054] Compound (IV) (7.9 g, 0.06 mol) and bromotrimethylsilane (11 g, 0.072 mol) were added to the reaction flask, the temperature was lowered to 0° C., and triethylamine (6 g, 0.06 mol) was added dropwise. After dropping, the temperature was raised to reflux, and after 4 hours it was cooled to room temperature, 200ml of chloroform was added, and a soluti...

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PUM

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Abstract

The invention discloses a high-purity 1-hydroxyl-2-(imidazo(1,2-a) pyridine-3-group) ethylidene-1, 1-diphosphonic acid and a preparation method thereof. The target product of the invention can be applied to the treatment of osteoporosis and hypercalcemia caused by malignant tumor, with higher safety and effectiveness. The preparation method has mild reaction condition and simple post treatment, and can obtain high-purity final products and is easier to implement industrialized production.

Description

technical field [0001] The present invention relates to the preparation method of 1-hydroxyl-2-{imidazo[1,2-a]pyridin-3-yl}ethylene-1,1-bisphosphonic acid (compound of formula I), which can be used for Treatment of osteoporosis and hypercalcemia. Background technique [0002] Minodronic acid is a new type of heterocyclic bisphosphonic acid compound developed by Japan Yamanouchi Company. It is currently undergoing Phase III clinical trials for the treatment of osteoporosis and osteoporosis and malignant tumors. Hypercalcemia, its bone resorption inhibitory activity is 2 times, 10 times and 100 times that of incadronate disodium, alendronate sodium and pamidronate disodium, respectively. The synthetic method of minodronic acid is respectively reported in EP0354806 (disclosure date: 1990-02-14), and its chemical name is 1-hydroxyl-2-{imidazo[1,2-a]pyridin-3-yl} Ethylene-1,1-bisphosphonic acid. The structural formula is as follows: [0003] [0004] EP0354806 (disclosure ...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61P19/10A61P3/14
Inventor 杨利民
Owner AVENTIS PHARMA HAINAN
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