Refining method of methyhaaltrexone bromide

A technology of bromnaltrexone and a purification method, which is applied in the field of chemical drug synthesis, can solve the problems such as the inability of the bromnaltrexone product to meet the purity, and achieves the effects of mild conditions, simple operation and high yield

Inactive Publication Date: 2014-09-03
NEW FOUNDER HLDG DEV LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this method, the traditional recrystallization method is adopted in the refining part, and the disadvantage is that the bromethylnaltrexone product obtained by this method cannot meet the required purity of the high-quality medicinal high-quality methylnaltrexone refined product.

Method used

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  • Refining method of methyhaaltrexone bromide
  • Refining method of methyhaaltrexone bromide
  • Refining method of methyhaaltrexone bromide

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0036] Preparation Example 1: Synthesis of Methylnaltrexone Bromide

[0037] Under the protection of nitrogen, add 11.6g (34.0mmol) naltrexone base, 175mL anhydrous acetone, 23.2mL DMF, 11.4mL (208mmol) methyl bromide into the three-necked flask, turn off the nitrogen, and react in a sealed manner at 25°C for 21 days. After the reaction is completed, reduce the pressure Concentrate the reaction solution to dryness, add 150 mL of acetone to wash, then suction filter, take the filter cake and dry it in vacuum at 80°C for 6 hours to obtain 13.4 g of crude methylnaltrexone bromide, with a yield of 90.17%.

Embodiment 1

[0038] Embodiment 1: the refining of methylnaltrexone bromide

[0039] Add 13.4g of crude methylnaltrexone bromide, 75mL of methanol, and 19mL of pure water into a 250mL four-neck flask, stir and heat to dissolve, add 0.7g of activated carbon for needles after cooling slightly, reflux for 30min, cool to room temperature and stir for 4h, filter, and use for filter cake After washing with methanol and drying, vacuum drying at 80° C. for 6 hours, 10.4 g of a white product (referred to as “brommethylnaltrexone refined product 1”) was obtained, with a yield of 77.61%.

[0040]Above-mentioned 10.4g methylnaltrexone bromide refined product 1 was dissolved with appropriate amount of water and passed through reverse phase silica gel column, first eluted with 1% aqueous methanol solution, then eluted with 5% aqueous methanol solution, and monitored by thin layer chromatography (TLC). When the main component spots appeared in the layer chromatogram, the corresponding eluent was collected...

Embodiment 2

[0042] Embodiment 2: the refining of methylnaltrexone bromide

[0043] Add 13.4g of crude methylnaltrexone bromide, 75mL of methanol, and 19mL of pure water into a 250mL four-neck flask, stir and heat to dissolve, add 0.7g of activated carbon for needles after cooling slightly, reflux for 30min, cool to room temperature and stir for 4h. After filtering, the filter cake was washed with methanol and sucked dry, and dried in vacuum at 80° C. for 6 hours to obtain 10.2 g of a white product (referred to as “brommethylnaltrexone refined product 1”).

[0044] Above-mentioned 10.2g methylnaltrexone bromide refined product 1 is dissolved with appropriate amount of water and passes through reverse phase silica gel column, first with 1% aqueous methanol elution, then with 5% methanol aqueous elution, thin-layer chromatography (TLC) monitoring, when thin When the main component spots appeared in the layer chromatogram, the corresponding eluent was collected, and the collected eluent was c...

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Abstract

The invention provides a refining method of methyhaaltrexone bromide, belonging to the technical field of chemical drug synthesis. According to the refining method, the methyhaaltrexone bromide is separated and purified by inverse silica gel column chromatography, and the procedure of recrystallization on a methyhaaltrexone bromide product by a mixed solvent of methanol and water can be added before and after the inverse silica gel column chromatography. According to the refining method, the conditions are mild, the yield is high, the purity of refined products is high, and the generated product meet the requirement on purification of medical methyhaaltrexone bromide preparation, so that the method is applicable to industrialized mass production.

Description

technical field [0001] The invention relates to a method for refining methylnaltrexone bromide, belonging to the technical field of chemical drug synthesis. Background technique [0002] Methylnaltrexone bromide (methylnaltrexone, MNTX) is a selective mu opioid receptor antagonist, as a quaternary ammonium salt, which limits the ability of methylnaltrexone bromide to cross the blood-brain barrier, making methylnaltrexone Naltrexone acts as a peripherally acting opioid receptor antagonist in tissues such as the gastrointestinal tract; therefore, methylnaltrexone reduces the constipating effects of opioids without affecting the central nervous system effects of opioids. analgesic effect. [0003] Methylnaltrexone bromide has the following characteristics: 1) it acts on peripheral μ receptors, and does not activate opioid receptors in the central nervous system, which may be a competitive antagonist; 2) it is safe, and a series of tests have not found that it has serious toxic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D489/08
Inventor 易崇勤王振国郭欲晓谢小飞
Owner NEW FOUNDER HLDG DEV LLC
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