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Preparation method of methyhaaltrexone bromide

A technology of methylnaltrexone bromide and naltrexone base, which is applied in the field of chemical drug synthesis, can solve the problems of high boiling point of dimethylformamide, impact on the quality of the final product, and excessive dimethylformamide, so as to reduce production costs , easy to refine, to ensure the effect of the reaction

Active Publication Date: 2014-07-23
NEW FOUNDER HLDG DEV LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The shortcoming of this method is: the amount of dimethylformamide as the aprotic dipolar solvent is too little, only accounts for 1% of solvent system, and naltrexone base can not be dissolved in the solvent completely, causes the incomplete reaction
The disadvantage of this method is: the amount of dimethylformamide as an aprotic dipolar solvent is too much, first of all, the cost is too high, and the price of dimethylformamide is much higher than that of acetone, making this method unsuitable for industry Application; secondly, dimethylformamide has a high boiling point and is not easy to remove from the final product. Removing dimethylformamide from the final product requires high temperature and energy, which has a great impact on the quality of the final product

Method used

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  • Preparation method of methyhaaltrexone bromide
  • Preparation method of methyhaaltrexone bromide
  • Preparation method of methyhaaltrexone bromide

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Under nitrogen protection, add 11.6g (34.0mmol) naltrexone base, 175mL anhydrous acetone, 23.2mL (23.2mL DMF), 11.4mL (208mmol) methyl bromide to the three-necked flask, turn off the nitrogen, and react in a closed atmosphere at 25°C for 21 days. After the reaction is completed, reduce the pressure. The reaction solution was concentrated to dryness, washed with 150 mL of acetone, and the filter cake was collected by suction filtration, and vacuum-dried at 80° C. for 6 h to obtain 13.4 g of bromonaltrexone product with a yield of 90.17%.

Embodiment 2

[0030] Under nitrogen protection, add 80.0 g of naltrexone base, 1200 mL of anhydrous acetone, 160.0 mL of DMF, 78.5 mL of methyl bromide to the three-necked flask, turn off the nitrogen, and seal the reaction at 25°C for 21 days. After the reaction is completed, the reaction solution is concentrated under reduced pressure to dryness, and added After washing with 1000 mL of acetone, the filter cake was collected by suction filtration, and vacuum-dried at 80 °C for 6 h to obtain 90.7 g of methylnaltrexone product with a yield of 88.5%.

Embodiment 3

[0032] 65.3g of naltrexone base, 990mL of anhydrous acetone, 130.6mL of DMF, 64.2mL of methyl bromide were added to the three-necked flask, and the reaction was airtight at 25°C for 21 days. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and 800mL of acetone was added for washing and suction filtration. The filter cake was dried under vacuum at 80°C for 6 hours to obtain 74.4 g of methylnaltrexone bromide product with a yield of 89.0%.

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Abstract

The invention provides a preparation method of methyhaaltrexone bromide, belonging to the technical field of chemical drug synthesis. The method allows naltrexone base to contact methyl bromide in an anhydrous solvent system, wherein the solvent system contains 10-16% (by volume) dipolar protophobic solvent. The preparation method of methyhaaltrexone bromide disclosed by the invention has simple operation, mild reaction condition, low cost, complete reaction and high yield, so that the method is suitable for industrialized production.

Description

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

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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