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Method for synthesizing naloxone or naltrexone

A synthesis method and technology of naltrexone, which is applied in the field of pharmaceutical chemistry, can solve the problems of low reaction yield, environmental pollution, and serious injury to synthesis workers, and achieve increased reaction speed, no side reactions, and increased yield Effect

Inactive Publication Date: 2011-01-26
甘肃普安制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The disadvantage of this process is that when the compound generates compound 1, the reaction conditions are not easy to control, side reactions are prone to occur, and the yield of the reaction is not high;
[0008] In the production process from oxycodone to naloxone, the total yield of this process is about 40%, and a large amount of toxic solvents such as chloroform and dichloroethane were used in the previous production process, which is harmful to the synthesis The injury of the staff is relatively large, and it is easy to cause pollution to the environment

Method used

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  • Method for synthesizing naloxone or naltrexone
  • Method for synthesizing naloxone or naltrexone
  • Method for synthesizing naloxone or naltrexone

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Dissolve 10g of thebaine in 100ml of formic acid, keep warm at 20°C, add 33g of m-chloroperoxybenzoic acid dropwise with stirring, keep warm for 5h, replace the system with nitrogen 4 times, add 0.5g of Raney nickel, replace with hydrogen 4 times, wait The system was stable, kept at 30°C, hydrogenated for 10 hours, filtered, the filter cake (the filter cake was the catalyst), washed twice with 10ml of water, the filtrate was adjusted to PH=8-9 with 30% sodium hydroxide solution, filtered, and the filter cake was vacuum-dried. Compound 28.2g was obtained, yield: 81.0%;

[0033] 28.2g of compound was added to the reaction flask, 82ml of acetic anhydride was added, the temperature was raised to 70°C, and after 1 hour of reaction, the system was concentrated to dryness in vacuo to obtain 38.8g of compound, yield: 94.7%;

[0034] Put 38.8g of the compound into the reaction flask, under nitrogen protection, add 90ml of toluene, add 14.7g of chloroformic acid-1-chloroethyl est...

Embodiment 2

[0039] Dissolve 10g of thebaine in 110ml of formic acid, keep warm at 25°C, add 35.2g of m-chloroperoxybenzoic acid dropwise with stirring, keep warm for 3 hours, replace the system with nitrogen for 5 times, add 0.6g of Raney nickel, and replace with hydrogen for 4 times, When the system is stable, keep warm at 25°C, hydrogenate for 12 hours, filter, filter the cake (the filter cake is the catalyst), wash twice with 10ml of water, adjust the filtrate to PH=8-9 with 30% sodium hydroxide solution, filter, and dry the filter cake in vacuum , to obtain compound 28.4g, yield: 82.9%;

[0040] Add 28.4g of compound into the reaction flask, add 84ml of acetic anhydride, raise the temperature to 60°C, and react for 1 hour, then concentrate the system to dryness in vacuo to obtain 38.9g of compound, yield: 93.5%;

[0041] Put 38.9g of the compound into the reaction flask, under nitrogen protection, add 90ml of toluene, add 14.7g of chloroformic acid-1-chloroethyl ester, add 0.9g of pot...

Embodiment 3

[0046] Dissolve 10g of thebaine in 130ml of formic acid, keep warm at 20°C, add 30g of m-chloroperoxybenzoic acid dropwise, keep warm for 7 hours, replace the system with nitrogen for 3 times, add 0.5g of Raney nickel, and replace with hydrogen for 5 times. Stable, keep warm at 30°C, hydrogenate for 10 hours, filter, filter cake (the filter cake is the catalyst), wash twice with 10ml of water, adjust the filtrate to PH=8-9 with 30% sodium hydroxide solution, filter, and vacuum dry the filter cake to obtain Compound 28.0g, yield: 79.0%;

[0047] Add 28.0 g of compound into the reaction flask, add 92 ml of acetic anhydride, raise the temperature to 80°C, and react for 1 hour, then concentrate the system to dryness in vacuo to obtain 38.7 g of compound, yield: 96%;

[0048] Put 38.7g of the compound into the reaction flask, under nitrogen protection, add 87ml of toluene, add 14.7g of chloroformic acid-1-chloroethyl ester, add 0.9g of potassium bicarbonate, heat up to 90°C for 40h...

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Abstract

The invention provides a method for synthesizing naloxone or naltrexone, which comprises the following steps of: dissolving thebaine in formic acid, uniformly stirring, dripping an oxidant, keeping the temperature of between 20 and 40 DEG C for 3 to 7 hours, displacing gas in a reaction vessel by inert gas serving as protective gas for 3 to 5 times, adding a metallic framework catalyst, displacing the gas by hydrogen for 3 to 5 times, keeping the temperature of between 25 and 45 DEG C and stabilizing a system for 7 to 13 hours to obtain a compound 2; reacting the compound 2 with acetic anhydride at the temperature of between 60 and 100 DEG C for 1 to 2 hours to obtain a compound 3; taking the inert gas as the protective gas, adding toluene, chloroformic acid-1-chloroethyl ester and potassium bicarbonate into the compound 3, heating to the temperature of between 75 and 100 DEG C and reacting for 20 to 40 hours, concentrating under reduced pressure until the system is fully dry, adding 10 percent hydrochloric acid, and heating and refluxing for 2 to 6 hours to obtain a compound 4; dissolving the compound 4 and at least one alkylation reagent in an organic solvent 1 and reacting with alkali at the temperature of between 50 and 100 DEG C to obtain a compound 5; and reacting the compound 5 with boron tribromide in an organic solvent 2 at the temperature of between -10 and 40 DEG C for 2 to 4 hours to obtain a compound 6, namely the naloxone or naltrexone.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a new synthetic route of naloxone or naltrexone. Background technique [0002] The main component of naloxone and its chemical name are: 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate [0003] Molecular formula: C 19 h 21 NO 4 [0004] Molecular weight: 327.37 [0005] At present, the synthesis method from oxycodone to naloxone is reported in Beijing Academy of Military Medical Sciences. The synthesis method is as follows: [0006] [0007] The disadvantage of this process is that when the compound generates compound 1, the reaction conditions are not easy to control, side reactions are prone to occur, and the yield of the reaction is not high; [0008] In the production process from oxycodone to naloxone, the total yield of this process is about 40%, and a large amount of toxic solvents such as chloroform and dichloroethane were us...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D489/08
Inventor 祝可锦刘杰王邦荣谢涛臧亚虎郭建常立昕陈大祺
Owner 甘肃普安制药股份有限公司
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