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A kind of refining method of methylnaltrexone bromide

A technology of methylnaltrexone bromide and a refining method, which is applied in the field of chemical drug synthesis, can solve the problems of high nitrogen protection requirements, cumbersome operation, and high equipment cost, and achieve the effect of good sample stability

Active Publication Date: 2021-03-02
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, the nitrogen protection device and solvent degassing device are cumbersome to operate in industrial production, and the equipment cost is high. Therefore, it is very necessary to find a good refining process to replace the refining method in the literature, especially to solve the very high requirements for nitrogen protection. The problem

Method used

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  • A kind of refining method of methylnaltrexone bromide
  • A kind of refining method of methylnaltrexone bromide
  • A kind of refining method of methylnaltrexone bromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0033] Add 120ml of anhydrous methanol, 20ml of purified water, and 100mg of sodium thiosulfate into a 250ml dry three-necked flask, stir to dissolve, mix evenly, add 20g of crude methylnaltrexone bromide, raise the temperature to 70°C and stir to dissolve, and keep stirring for 30min after dissolution. Heat filtration, cool the filtrate to 0-5°C, stir and crystallize for 8-12 hours, filter, collect the filter cake and dry it in vacuum at 40-45°C, with a vacuum degree (negative pressure) of 0.07-0.08MPa, weigh to obtain methyl bromide The refined ketone product was 17.6 g, and the HPLC detection purity was 99.8%.

Embodiment 1b

[0035] Add 120ml of absolute ethanol, 20ml of purified water, and 100mg of sodium thiosulfate into a 250ml dry three-necked flask, stir to dissolve and mix evenly, add 20g of crude methylnaltrexone bromide, heat up to 70°C and stir to dissolve, keep stirring for 30min after dissolving, heat Filtrate, cool the filtrate to 0-5°C, stir and crystallize for 8-12h, filter, collect the filter cake and dry it in vacuum at 40-45°C, with a vacuum degree (negative pressure) of 0.07-0.08MPa, weigh to obtain methylnaltrexone bromide Refined product 18.2g, HPLC detection purity is 99.9%.

Embodiment 1c

[0037] Add 120ml of isopropanol, 20ml of purified water, and 100mg of sodium thiosulfate into a 250ml dry three-necked flask, stir to dissolve and mix evenly, add 20g of crude methylnaltrexone bromide, heat up to 70°C and stir to dissolve, keep stirring for 30min after dissolving, heat Filtrate, cool the filtrate to 0-5°C, stir and crystallize for 8-12h, filter, collect the filter cake and dry it in vacuum at 40-45°C, with a vacuum degree (negative pressure) of 0.07-0.08MPa, weigh to obtain methylnaltrexone bromide Refined product 18.3g, HPLC detection purity is 99.9%.

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Abstract

The invention discloses a refining method for methyhaaltrexone bromide. The refining method comprises the following steps: (1) adding a stabilizing agent into a mixed solvent of low-level alkanol andwater, stirring for dissolving, and uniformly mixing; (2) adding a methyhaaltrexone bromide crude product into the mixture acquired in the step (1), uniformly mixing, rising temperature till fully dissolving solid, stirring and preserving heat; (3) hot filtering, transferring filtrate into a reaction kettle, stirring, cooling and crystallizing; (4) filtering, recycling sediment and drying, therebyacquiring a refined product of methyhaaltrexone bromide. According to the method, no special harsh nitrogen protection is required, and meanwhile, the operation is convenient and simple, and when themethyhaaltrexone bromide is amplified to 1-5kg in batches, the quality of sample is still equivalent to that in laboratory. On this basis, the yield is equivalent to that reported in the literature,and the purity of the methyhaaltrexone bromide sample after being refined according to the technology can reach up to 99.5% or above and even above 99.8%.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis, and in particular relates to a method for refining methylnaltrexone bromide. Background technique [0002] Methylnaltrexone bromide (methylnaltrexone, MNTX) is a selective mu opioid receptor antagonist, acting on opioid receptors in the gastrointestinal tract, and can completely block or partially block the pain induced by morphine analgesics. Intestinal smooth muscle relaxation response, thereby reducing or limiting opioid-induced constipation side effects. At the same time, because methylnaltrexone bromide is a quaternary ammonium salt, it cannot pass through the blood-brain barrier. Due to the above characteristics, methylnaltrexone bromide can be used as a peripherally acting opioid receptor antagonist without affecting opioids. The analgesic effect of the central nervous system improves the constipation effect of opioids. [0003] Naltrexone bromide belongs to morphinone de...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D489/08
CPCC07D489/08
Inventor 罗宏军李国贤徐溶熔尹必喜花鹏徐浩宇蔡伟
Owner YANGTZE RIVER PHARM GRP CO LTD