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 prot

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

Example Embodiment

[0074] Example 1

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

[0076]

[0077] Weigh A: 9.4 g or 0.1 mol of 2-aminopyridine, 20.9 g or 0.1 mol of ethyl 4-bromoacetoacetate and 1.1 g or 0.01 mol of DABCO, and dissolve them in 400 mL of water. Heat to 60-70°C and monitor the reaction by TLC. The reaction is complete in about 1 hour. It was extracted three times with 200 mL of ethyl acetate, the organic layers were combined, 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 with 100 mL of a mixture 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 ...

Example Embodiment

[0089] Example 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, which is 1.36mol, 318g of methyl 4-bromoacetoacetate, which is 1.63mol, and DABCO30.5g, which is 0.272mol, and dissolve in 2.5L of water. Heat to 60-70°C and monitor the reaction by TLC. The reaction is complete in about 1.5 hours. It was extracted 3 times with 2L of ethyl acetate, the organic layers were combined, 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 with 470 mL of a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate was 2:5 to obtain 135 g of 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,1...

Example Embodiment

[0102] Example 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, that is 0.2mol, 42.9g of ethyl 4-bromoacetoacetate, that is 0.22mol, and 20.2g of triethylamine, that is 0.2mol, and dissolve in 380mL of water. It was heated to 60-70°C and the reaction was monitored by TLC. The reaction was complete in about 5 hours. It was extracted 3 times with 150 mL of ethyl acetate, the organic layers were combined, 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 with 100 mL of a mixture 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 light yellow solid, with a yield of 61.2%.

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

[0107]

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

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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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