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Preparation method of minodronic acid for treating osteoporosis

A technology of minodronic acid and osteoporosis, applied in the field of medicine and chemical industry, can solve the problems of slow reaction speed, low yield, harsh conditions, etc., and achieve the effects of increased reaction speed, uniform reaction and improved yield

Inactive Publication Date: 2016-08-10
邱善晓 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The purpose of the present invention is to overcome the defects of slow reaction speed, low yield and harsh conditions in the above-mentioned existing methods for preparing minodronic acid, and provide a method for preparing minodronic acid for treating osteoporosis

Method used

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  • Preparation method of minodronic acid for treating osteoporosis
  • Preparation method of minodronic acid for treating osteoporosis
  • Preparation method of minodronic acid for treating osteoporosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] A preparation method of minodronic acid for treating osteoporosis, the method comprises the following steps:

[0030] (1) 10.7g (30mmol) of the compound shown in formula I, 32.3g (250mmol) of DIEA and 20.9g (100mmol) of 4-bromo-ethyl acetoacetate were added in a 200ml flask filled with THF, stirred at room temperature for 30 minutes, Then 11.7g (125mmol) of 2-aminopyridine was added to the reaction solution, and the reaction was stirred at 45°C for 3.5 hours. TLC monitored the complete reaction of 4-bromo-ethyl acetoacetate, filtered, concentrated under reduced pressure, added water, and extracted with ethyl acetate. (50mL×3 times), washed with saturated brine (50mL×3 times), combined the organic phases, removed the solvent under reduced pressure, and dried to obtain ethyl 2-(imidazo[1,2-α]pyridin-3-yl)acetate 19.7g, yield 96.4%, purity 98.19%.

[0031]

[0032] (2) 2-(imidazo[1,2-α]pyridin-3-yl) ethyl acetate obtained in step (1) and 8.1g of lithium hydroxide in a ...

Embodiment 2

[0035] A preparation method of minodronic acid for treating osteoporosis, the method comprises the following steps:

[0036] (1) 14.3g (40mmol) of compound shown in formula I, 25.8g (200mmol) of DIEA and 20.9g (100mmol) of 4-bromo-ethyl acetoacetate were added in a 200ml flask equipped with THF, stirred at room temperature for 30 minutes, Then 11.7g (125mmol) of 2-aminopyridine was added to the reaction solution, and the reaction was stirred at 40°C for 3.5 hours. TLC monitored the complete reaction of 4-bromo-ethyl acetoacetate, filtered, concentrated under reduced pressure, added water, and extracted with ethyl acetate. (50mL×3 times), washed with saturated brine (50mL×3 times), combined the organic phases, removed the solvent under reduced pressure, and dried to obtain ethyl 2-(imidazo[1,2-α]pyridin-3-yl)acetate 19.3g, yield 94.5%, purity 97.68%.

[0037](2) 2-(imidazo[1,2-α]pyridin-3-yl) ethyl acetate obtained in step (1) and 6.8g of lithium hydroxide in a mixed solvent o...

Embodiment 3

[0040] A preparation method of minodronic acid for treating osteoporosis, the method comprises the following steps:

[0041] (1) 14.3g (40mmol) of the compound shown in formula I, 38.8g (300mmol) of DIEA and 20.9g (100mmol) of 4-bromo-ethyl acetoacetate were added to a 200ml flask filled with THF, stirred at room temperature for 30 minutes, Then 11.7g (125mmol) of 2-aminopyridine was added to the reaction solution, and the reaction was stirred at 50°C for 3.5 hours. TLC monitored the complete reaction of 4-bromo-ethyl acetoacetate, filtered, concentrated under reduced pressure, added water, extracted with ethyl acetate (50mL×3 times), washed with saturated brine (50mL×3 times), combined the organic phases, removed the solvent under reduced pressure, and dried to obtain ethyl 2-(imidazo[1,2-α]pyridin-3-yl)acetate 19.1g, yield 93.7%, purity 97.9%.

[0042] (2) 2-(imidazo[1,2-α]pyridin-3-yl) ethyl acetate obtained in step (1) and 8.9g of lithium hydroxide in a mixed solvent of 1...

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Abstract

The invention discloses a preparation method of minodronic acid for treating osteoporosis .The preparation method comprises the following steps that 1, 4-bromine ethyl acetoacetate and 2-aminopyridine perform contact reaction in the present of a compound shown in a formula (I) and DIEA to obtain 2-(imidazo[1,2-alpha] pyridine-3-yl) ethyl acetate; 2, the 2-(imidazo[1,2-alpha] pyridine-3-yl) ethyl acetate obtained in the step 1 is hydrolyzed under the alkaline condition to obtain 2-(imidazo[1,2-alpha]pyridine-3-yl)acetic acid; 3, the 2-(imidazo[1,2-alpha]pyridine-3-yl)acetic acid obtained in the step 2 is subjected to phosphorylation to obtain the minodronic acid .The method can greatly improve the yield of the minodronic acid and is mild in condition and higher in reaction speed .

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of minodronic acid for treating osteoporosis. Background technique [0002] Minodronic acid (minodronic acid), listed in Japan in January 2009, its chemical name is [1-hydroxy-2-(imidazo[1,2-α]pyridin-3-yl)-ethylene] 1,1-bisphosphonic acid. Minophosphate is used to treat osteoporosis and hypercalcemia caused by osteoporosis and malignant tumors. The drug has high anti-bone resorption activity, and also has antagonizing effect on osteolysis caused by myeloma and tumors. [0003] At present, there are many methods for the synthesis of minodronic acid. However, in the method for preparing minodronic acid, there are still disadvantages such as harsh reaction conditions, long reaction time and low reaction yield, which seriously restrict the application of minodronic acid. [0004] Document (Chem Pharm Bull, 1998,46 (11), p1703) disclos...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 陈令浩
Owner 邱善晓
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