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 nalmefene, can produce on a large scale, make nalmefene simultaneously The content of naltrexone, an impurity in Fenzhong, is less than 0.1%, and the purity of nalmefene is greater than 99.5%, meeting the requirements of injection grade

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Under the protection of nitrogen, 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 here should be fast to prevent water absorption ; 25°C, react for 2 hours, the reaction system is bright yellow, and the reaction time can be adjusted appropriately depending on the scale of the reaction.

[0018] Under the protection of nitrogen, dissolve naltrexone in 200mL THF, pour it directly into the reaction bottle (with a weak temperature rise), then add 100mL THF into the reaction bottle, raise the temperature to 60°C, and keep it warm for 20h. Monitoring and developing agent: methylene chloride volume / methanol volume=30 / 1, HPLC monitoring); after the reaction is complete, cool down to below 25°C, add 200mL of saturated ammonium chloride dropwise under ice bath (slowly add dropwise at the beginning, because Excessive heat re...

Embodiment 2

[0022] Under the protection of nitrogen, add 300mL tetrahydrofuran (THF) into the four-necked flask, add potassium tert-butoxide, stir mechanically, add bromomethyltriphenylphosphine directly into the four-necked flask, and react at 25°C for 1.5h. The reaction system is fresh yellow. Under the protection of nitrogen, dissolve naltrexone in 150mL THF, pour it directly into the reaction flask, add 100mL THF into the reaction flask, raise the temperature to 65°C, and keep it warm for 18h. Methanol=30 / 1, monitored by HPLC), after the reaction is complete, cool down to below 25°C, add 200mL of saturated ammonium chloride dropwise under ice bath, the reaction solution changes from dark yellow turbid system to off-white turbid system, and then turns into brown solution system.

[0023] Add 150mL of purified water to the reaction system, separate the liquid, keep the organic phase, extract the water phase with 300mL, 300mL, and 130mL of methyl tert-butyl ether, combine the organic ph...

Embodiment 3

[0025] Under the protection of nitrogen, 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 (here, the operation speed should be fast to prevent water absorption) , 25°C, reacted for 2.5h, the reaction system was bright yellow. Under the protection of nitrogen, dissolve naltrexone in 250mL THF, pour it directly into the reaction flask, then add 150mL THF into the reaction flask, raise the temperature to 63°C, and keep the reaction for 22h. / methanol=30 / 1, monitored by HPLC), after the reaction is complete, cool down to below 25°C, add 250 mL of saturated ammonium chloride dropwise under ice bath, the reaction solution changes from dark yellow turbid system to gray-white turbid system, and then becomes in Brown solution system.

[0026]Add 200mL of purified water to the reaction system, separate the liquid, keep the organic phase, extract the w...

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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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