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Method for producing minodronic acid monohydrate by using water as solvent

A minodronic acid monohydrate and solvent technology, which is applied in the field of minodronic acid hydrate production, can solve the problems of inconvenient production process and increased cost, achieve significant economic value, low production cost, and improve the effect of drug purity

Inactive Publication Date: 2015-12-02
ZHONGSHAN HAIHONG MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] Although this process overcomes the production of chemical isomers, it needs to go through two steps of protection and deprotection, which will undoubtedly increase the cost and bring inconvenience to the production process

Method used

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  • Method for producing minodronic acid monohydrate by using water as solvent
  • Method for producing minodronic acid monohydrate by using water as solvent
  • Method for producing minodronic acid monohydrate by using water as solvent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Step a: Preparation of ethyl 2-[imidazo(1,2-a)pyridin-3-yl]acetate (B)

[0076]

[0077] Weigh A: 9.4g or 0.1mol of 2-aminopyridine, 20.9g or 0.1mol of ethyl 4-bromoacetoacetate and 1.1g or 0.01mol of DABCO, and dissolve them in 400mL of water. Heat to 60-70°C, monitor the reaction by TLC, and the reaction is complete in about 1 hour. Extracted three times with 200 mL of ethyl acetate, combined the organic layers, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was recrystallized from a mixture of 100 mL of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate was 1:3 to obtain 18 g of light yellow solid with a yield of 88.1%.

[0078] ESI-MS:[M+H] + =205.1

[0079] NMR data: 1 H-NMR (CDCl 3 ,400MHz): δ(ppm)=8.06(d,J=6.8Hz,1H),7.62(d,J=8.8Hz,1H),7.56(s,1H),7.20(t,1H),4.14-4.20 (dd, J=7.2Hz, 2H), 3.94(s, ...

Embodiment 2

[0090] Step a: Preparation of methyl 2-[imidazo(1,2-a)pyridin-3-yl]acetate (B)

[0091]

[0092]Weigh A: 128g of 2-aminopyridine, namely 1.36mol, 318g of methyl 4-bromoacetoacetate, namely 1.63mol, and 30.5g of DABCO, namely 0.272mol, and dissolve them in 2.5L of water. Heating to 60-70°C, monitoring the reaction by TLC, the reaction was complete in about 1.5 hours. Extracted 3 times with 2 L of ethyl acetate, combined the organic layers, washed with 750 mL of saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was recrystallized from a mixture of 470 mL of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate was 2:5, to obtain 135 g of a light yellow solid with a yield of 52.2%.

[0093] ESI-MS:[M+H] + =191.1

[0094] NMR data: 1 H-NMR (CDCl 3 ,400MHz): δ(ppm)=8.06(d,J=6.8Hz,1H),7.62(d,J=8.8Hz,1H),7.56(s,1H),7.20(t,1H),4.25(s...

Embodiment 3

[0103] Step a: Preparation of ethyl 2-[imidazo(1,2-a)pyridin-3-yl]acetate (B)

[0104]

[0105] Weigh A: 18.8g of 2-aminopyridine, namely 0.2mol, 42.9g of ethyl 4-bromoacetoacetate, namely 0.22mol, and 20.2g of triethylamine, namely 0.2mol, and dissolve them in 380mL of water. Heating to 60-70°C, monitoring the reaction by TLC, the reaction was complete in about 5 hours. Extracted three times with 150 mL of ethyl acetate, combined the organic layers, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was recrystallized from a mixture of 100 mL of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate was 1:3, to obtain 25.2 g of a light yellow solid with a yield of 61.2%.

[0106] Step b: Preparation of 2-[imidazo(1,2-a)pyridin-3-yl]ethyl acetate (C)

[0107]

[0108] Dissolve B: 75 g of ethyl 2-(imidazo[1,2-a]pyrid...

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Abstract

The present invention discloses a method for producing a minodronic acid monohydrate by using water as a solvent. According to the method, ethyl 4-bromoacetoacetate or methyl 4-bromoacetoacetate is adopted as a raw material and reacts with 2-aminopyridine by adopting water as a solvent under the effect of a catalytic amount of an organic alkali so as to highly-selectively obtain 2-(imidazo[1,2-a]pyridine-3-yl)ethyl acetate, the 2-(imidazo[1,2-a]pyridine-3-yl)ethyl acetate (methyl acetate) is hydrolyzed with an alkali solution to obtain 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid, the 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid, phosphorous acid and phosphorus trichloride react to obtain minodronic acid, and refining is performed to obtain the minodronic acid monohydrate. According to the present invention, the process has characteristics of simple reaction operation, easily available raw materials, easy post-treatment, high yield, application of the water as the solvent, and environmental protection, and is suitable for mass production.

Description

technical field [0001] The invention relates to a method for producing minodronic acid hydrate with water as a solvent, belonging to the technical field of chemical synthesis. Background technique [0002] Osteoporosis is a systemic metabolic bone disease, which is a disease of unbalanced bone formation and bone resorption, which is characterized by bone loss and fine structure destruction of bone tissue, resulting in increased bone fragility and fractures. disease. Bisphosphonates reduce osteoclast activity, direct or induce osteocytes, and produce osteoclast inhibitory factors. [0003] Minodronic acid developed by Astellas is a third-generation azaaryl bisphosphonate derivative that can be used as oral and injectable preparations. Pharmacological experiments show that its anti-bone resorption activity is 2, 10, and 100 times that of incadronate disodium disodium incadronate, alendronate sodium alendronate, and pamidronate disodium disodium pamidronate. [0004] Minodro...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 兰小兵杨青海
Owner ZHONGSHAN HAIHONG MEDICINE CO LTD
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