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Process for salifying naloxone hydrochloride

A technology of naloxone hydrochloride and a preparation process, applied in the field of medicine and chemical industry, can solve the problems of changing cohesion, inability to accurately measure the amount of HCl, low purity, etc., so as to reduce the generation of impurities, improve the quality content, improve product quality and Yield effect

Inactive Publication Date: 2011-09-07
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the naloxone base used to form a salt in the aforementioned literature is all extracted with chloroform after steaming out DMF (dimethylformamide) after the previous step of allylation, after steaming out the chloroform, then pass through silica gel column chromatography , the gel-like thing that obtains after concentrating, its purity is relatively low, therefore can't measure the consumption of HCl accurately when forming salt, for making naloxone base form salt thoroughly, adopt excessive HCl, add in naloxone base There are many impurities, which lead to the phenomenon of becoming a cohesive group when forming salt

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] The intermediate 14-hydroxynormorphone and allyl bromide were subjected to an allylation reaction using DMF as a solvent, and 500ml of the allylation reaction liquid was placed in a rotary evaporator, and the solvent was evaporated under reduced pressure, and the residual liquid was Add 50ml of water and 200ml of chloroform to extract the naloxone base generated by the reaction. After the aqueous layer is extracted twice with 100ml of chloroform, the chloroform extracts are combined and decolorized with activated carbon. The mother liquor is evaporated under reduced pressure to remove the chloroform to obtain syrupy naloxone base . Add 50ml of toluene to the above raffinate at 50°C, stir for 3 hours, then cool down to 5°C, keep stirring at 0-5°C for 2 hours. Filter, wash with a small amount of ice-cold toluene, and dry under reduced pressure at 50°C to obtain 35 g of beige naloxone base crystals with a content of 98.3%.

[0017] Dissolve 35 g of the obtained naloxone b...

Embodiment 2

[0019] The treatment process of 500ml allylation reaction solution was the same as in Example 1 to obtain naloxone base. Add 50ml of cyclohexane at 30°C, stir for 3 hours, then cool down to 5°C, keep stirring at 0-5°C for 2 hours. Filter, wash with a small amount of ice-cold cyclohexane, and dry under reduced pressure at 50°C to obtain 33 g of beige naloxone base crystals with a content of 98.0%.

[0020] Dissolve 33 g of naloxone base in 188 ml of acetone, and add 18.8 ml of a DMF solution containing 19.5% HCl dropwise under nitrogen protection, and the temperature of the reaction solution cannot exceed 60° C. during the dropwise addition. After the dropwise addition, keep the temperature at 40-50°C for 3 hours, then lower the temperature to 0-5°C, and keep the temperature for 2 hours to complete the crystallization. Filter, wash with cold acetone, suction filter, and dry under reduced pressure at 50°C to obtain 34 g of naloxone hydrochloride (anhydrous), with a content of 9...

Embodiment 3

[0022] The treatment process of 500ml allylation reaction solution was the same as in Example 1 to obtain naloxone base. Add 50ml of toluene, stir at 85°C for 3 hours, then cool down to 5°C, keep stirring at 0-5°C for 2 hours. Filter, wash with a small amount of ice-cold toluene, and dry under reduced pressure at 50°C to obtain 34 g of beige naloxone base crystals with a content of 98.1%.

[0023] Dissolve 34g of naloxone base in 150ml of methanol, and add 11.6ml of 36% concentrated hydrochloric acid dropwise under the protection of nitrogen. The temperature of the reaction solution cannot exceed 60°C during the dropwise addition. After the dropwise addition, keep the temperature at 40-50°C for 3 hours, then lower the temperature to 0-5°C, and keep the temperature for 2 hours to complete the crystallization. Filter, wash with cold methanol, suction filter, and dry under reduced pressure at 50°C to obtain 32 g of naloxone hydrochloride (anhydrous), with a content of 99.0%.

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PUM

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Abstract

The invention belongs to the pharmaceutical and chemical field and particularly relates to a process for salifying naloxone hydrochloride, which comprises the following steps: carrying out allylation reaction on intermediates of 14-hydroxy normorphine ketone and allyl bromide in DMF (dimethyl rormamide) which is used as a solvent, processing allylation reaction solution to obtain naloxone base, refining the naloxone base, and carrying out salifying reaction. Because the naloxone base is refined, the mass content of the naloxone base is increased, less impurities are generated, the accurate amount of HCl (hydrogen chloride) used for salifying is ensured, the colloidal agglomeration during salifying is avoided, the product quality and yield are improved, the column chromatography process is omitted, the production efficiency is improved, and the cost is reduced.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation process for forming a salt of naloxone hydrochloride. Background technique [0002] The preparation process of naloxone hydrochloride salification has been introduced in many documents, such as dissolving naloxone base in ethanol solution and adding hydrochloric acid or HCl ethanol solution to form a salt, dissolving naloxone base in ether and dropping Add HCl ethanol solution to form a salt, etc. However, in these methods, when salt is formed, crystallization occurs first, and then colloidal bonding becomes agglomerated and cannot be post-treated. [0003] We have found on the basis of a large number of experiments that the reason why the above-mentioned salt-forming method becomes a colloid when forming a salt is mainly due to the excessive amount of HCl used. Because the naloxone base used to form a salt in the aforementioned literature...

Claims

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Application Information

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IPC IPC(8): C07D489/08
Inventor 王军陈梅李敏之
Owner SHANDONG XINHUA PHARMA CO LTD
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