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The synthetic method of naloxone hydrochloride

A technology of naloxone hydrochloride and its compound, which is applied in the field of medicine, can solve problems such as low yield, great harm to synthetic workers, and environmental pollution, and achieve the effects of low impurity content, increased reaction speed, and excellent product quality

Active Publication Date: 2016-05-18
CHENGDU TIANTAISHAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The deficiency of this technology is that this technology is when compound generates compound 1, and reaction condition is not easy to control, easily takes place side reaction, and the yield of reaction is not high; This technology is in the production process from oxycodone to naloxone, always The yield is about 40%, and a large amount of toxic solvents such as chloroform and dichloroethane have been used in the previous production process, which will cause great harm to the synthesis staff and easily cause pollution to the environment

Method used

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  • The synthetic method of naloxone hydrochloride
  • The synthetic method of naloxone hydrochloride
  • The synthetic method of naloxone hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0071] Embodiment 1: Preparation of naloxone hydrochloride in dihydrate form

[0072] Step 1: Dissolve 10g of thebaine in 100ml of formic acid, keep warm at 20°C, stir and add 33g of m-chloroperoxybenzoic acid dropwise, after keeping warm for 5 hours, replace the system with nitrogen 4 times, add 0.5g of Raney nickel, and replace with hydrogen for 4 Once the system is stable, keep warm at 30°C, hydrogenate for 10 hours, filter, filter the cake (the filter cake is the catalyst), wash twice with 10ml of water, adjust the pH of the filtrate to 8-9 with 30% sodium hydroxide solution, filter, and vacuum the filter cake Dry to obtain compound 2, 8.12g;

[0073] Step 2: Add 8.12g of the compound obtained in the previous step into a reaction flask, add 82ml of acetic anhydride, heat up to 70°C, and react for 1 hour, then concentrate the system to dryness in vacuo to obtain Compound 3, 8.91g;

[0074] Step 3: Put 8.91g of the compound obtained in the previous step into the reaction f...

Embodiment 2

[0079] Embodiment 2: Preparation of naloxone hydrochloride in dihydrate form

[0080] Step 1: Dissolve 10g of thebaine in 110ml of formic acid, keep warm at 25°C, stir and add 35.2g of m-chloroperoxybenzoic acid dropwise, after keeping warm for 3 hours, replace the system with nitrogen for 5 times, add 0.6g of Raney nickel, and replace with hydrogen 4 times, wait for the system to be stable, keep warm at 25°C, hydrogenate for 12 hours, filter, filter cake (the filter cake is the catalyst), wash 2 times with 10ml water, adjust the pH of the filtrate to 8-9 with 30% sodium hydroxide solution, filter, and filter the cake Vacuum drying to obtain compound 2, 8.31g;

[0081] Step 2: Add 8.31 g of the compound obtained in the previous step into a reaction flask, add 84 ml of acetic anhydride, raise the temperature to 60°C, and react for 1 hour, then concentrate the system to dryness in vacuo to obtain Compound 3, 8.78 g;

[0082] Step 3: Put 8.78g of the compound obtained in the p...

Embodiment 3

[0087] Embodiment 3: Preparation of naloxone hydrochloride in dihydrate form

[0088] Step 1: 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 , when the system is stable, keep warm at 30°C, hydrogenate for 10 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 Dry to obtain compound 2, 8.05g;

[0089] Step 2: Add 8.05 g of the compound obtained in the previous step into a reaction flask, add 92 ml of acetic anhydride, heat up to 80°C, and react for 1 hour, then concentrate the system to dryness in vacuo to obtain Compound 3, 8.73 g;

[0090] Step 3: Put 8.73g of the compound obtained in the previous step into a reaction flask...

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Abstract

The invention belongs to the technical field of medicament synthesis, and relates to a synthetic method of naloxone hydrochloride. The method comprises the following steps: by adopting thebaine as a starting material, oxidizing and then reducing thebaine to obtain a compound 2, reacting the compound 2 with acetic anhydride to obtain an ester compound 3, then removing methyl and performing hydrolysis to obtain a compound 4, reacting the compound 4 with an alkylating reagent (such as the reagent selected from chloropropene, bromopropene, iodopropylene or the combination thereof), performing allylation on the Nth bit of a mother nucleus structure to obtain a compound 5, then removing methyl to obtain naloxone free alkali, then forming acid addition salts with hydrochloric acid, and then refining to obtain naloxone hydrochloride which can be used as a medicinal raw material medicament. By adopting the method disclosed by the invention, a high-quality medicinal raw material medicament can be prepared.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular to a naloxone hydrochloride compound, in particular to a synthesis method of the naloxone hydrochloride compound. Background technique [0002] Naloxone hydrochloride, whose English name is NaloxoneHydrochloride, is the hydrochloride dihydrate of naloxone base, and its chemical name is: 17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan- 6-keto hydrochloride dihydrate, its chemical structure is: [0003] [0004] Naloxone hydrochloride is white crystal or crystalline powder, easily soluble in water, soluble in methanol, almost insoluble in chloroform or ether. [0005] Naloxone is a pure opioid receptor antagonist with no intrinsic activity itself. However, it can competitively antagonize various opioid receptors and has a strong affinity for μ receptors. Naloxone takes effect quickly and has a strong antagonistic effect. Naloxone also reverses all effects of opioid agonists, incl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D489/08
CPCC07D489/08
Inventor 方专王敬江威张莲莲余茹赵东明
Owner CHENGDU TIANTAISHAN PHARMA
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