Method for preparing nalmefene compound

A compound, the technology of nalmefene, which is applied in the field of medicine, can solve safety problems and other problems, and achieve good practicability, good economic benefits and social effects, and the effect of improving safety and product yield

Inactive Publication Date: 2012-07-18
NANJING YOKO PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Purpose of the invention: for the deficiencies in the prior art, the purpose of the invention is to provide a kind of method for preparing nalmefene compound, to solve the safety problem existing in the preparation of existing n

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0016] Example 1

[0017] Under nitrogen protection, add 400 mL of tetrahydrofuran (THF) into the four-necked flask, add potassium tert-butoxide, stir mechanically, and directly add bromomethyltriphenylphosphine into the four-necked flask. The operation speed is preferably fast here to prevent water absorption. ; 25 ℃, the reaction 2h, the reaction system is bright yellow, the reaction time, depending on the size of the reaction can be adjusted appropriately.

[0018] Under nitrogen protection, dissolve naltrexone in 200 mL of THF, pour it directly into the reaction flask, (there is a weak temperature rise), then add 100 mL of THF into the reaction flask, heat it up to 60 °C, and keep the reaction for 20 h, (dot plate Monitoring and developing agent: volume of dichloromethane / volume of methanol = 30 / 1, HPLC monitoring); after the reaction is complete, cool down to below 25 °C, and add 200 mL of saturated ammonium chloride dropwise under an ice bath (begin to slowly add dropwis...

Example Embodiment

[0021] Example 2

[0022] Under nitrogen protection, 300 mL of tetrahydrofuran (THF) was added to a four-necked flask, potassium tert-butoxide was added, and mechanically stirred, bromomethyltriphenylphosphine was directly added to the four-necked flask, and reacted at 25°C for 1.5 h. The reaction system was fresh. yellow. Under nitrogen protection, naltrexone was dissolved in 150 mL of THF, directly poured into the reaction flask, 100 mL of THF was added to the reaction flask, the temperature was raised to 65 °C, and the reaction was kept for 18 h, (dot plate monitoring, developing solvent: dichloromethane / Methanol = 30 / 1, monitored by HPLC), after the reaction was completed, the temperature was lowered to below 25 °C, and 200 mL of saturated ammonium chloride was added dropwise under an ice bath. The reaction solution changed from a dark yellow turbid system to a gray-white turbid system, and then changed to brown. solution system.

[0023] Add 150 mL of purified water to...

Example Embodiment

[0024] Example 3

[0025] Under nitrogen protection, add 500 mL of tetrahydrofuran (THF) into the four-necked flask, add potassium tert-butoxide, stir mechanically, and directly add bromomethyltriphenylphosphine into the four-necked flask (the operation speed should be fast here to prevent water absorption) , 25 ℃, the reaction 2.5h, the reaction system is bright yellow. Under nitrogen protection, naltrexone was dissolved in 250 mL of THF, directly poured into the reaction flask, then 150 mL of THF was added to the reaction flask, the temperature was raised to 63 °C, and the reaction was incubated for 22 h, (dot plate monitoring, developing solvent: dichloromethane / methanol=30 / 1, monitored by HPLC), after the reaction was completed, the temperature was lowered to below 25 °C, and 250 mL of saturated ammonium chloride was added dropwise under an ice bath. The reaction solution changed from a dark yellow turbid system to an off-white turbid system, and then changed to Brown so...

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PUM

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Abstract

The invention discloses a method for preparing a nalmefene compound, which comprises the steps as follows: a conventional method is adopted to prepare the nalmefene compound at first so as to obtain a brown solution reaction system, and then the brown solution reaction system is extracted and purified by adopting methyl tert-butyl ether to obtain dried off-white nalmefene solids; and then ethyl acetate is adopted to obtain the white solid nalmefene compound through refining. The method has the advantages as follows: (1) methyl tert-butyl ether is applied creatively during the preparation process of nalmefene, ether that is explosive solvent in the traditional technology is abandoned, and safety and product yield coefficient are improved greatly during the preparation process; and (2) ethyl acetate is adopted to refine nalmefene for the first time, so that the content of naltrexone that is impurities is less than 0.1 percent, the purity of nalmefene is more than 99.5 percent, the requirements of injection grade can be achieved, the problem that naltrexone that is main impurities in the traditional technology exceeds standard can be well solved, product quality and safety can be improved, excellent practicability is achieved, and excellent economic benefits and social effects can be realized.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a method for preparing nalmefene compounds. Background technique [0002] Nalmefene (nalmefene), as a specific morphine receptor blocker, is a naltrexone analog with a 6-methylene group. The drug was synthesized in 1975 and launched in 1995. Alternatives to Loxone. Nalmefene is a pure opioid receptor antagonist, which has no intrinsic activity itself, but can competitively antagonize μ, κ, and δ opioid receptors, and has the strongest affinity with μ receptors. Pharmacodynamic studies have shown that nalmefene has a longer duration of action than naloxone, has the characteristics of multiple administration routes, high bioavailability, and small adverse reactions; it does not produce respiratory depression, psychotomimetic or miotic effects; it does not Develop tolerance, physical dependence and potential for abuse. It has been used to antagonize the symptoms of ...

Claims

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Application Information

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IPC IPC(8): C07D489/08
Inventor 高建兴张峰陆修涛曹燕锋姜东成
Owner NANJING YOKO PHARMA GRP CO LTD
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