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Refining method of 4-phenylaminopiperidine analgesic

A technology of anilinopiperidine and a purification method, applied in directions such as organic chemistry, can solve problems such as being unsuitable for industrialized production, time-consuming, labor-intensive cost, low acid salt yield, etc., achieving simple and easy-to-obtain reagents, reducing production costs, and techniques simple effect

Active Publication Date: 2011-05-18
YICHANG HUMANWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the existing preparation technologies on raw materials are obtained through 6-8 steps of organic synthesis to obtain the fentanyl or its derivatives and then directly form a salt to obtain its acid salt. Due to the multi-step synthesis, the free base contains more impurities. After being prepared into the target acid salt, it also contains a lot of impurities, and it is difficult to remove related impurities by continuing to refine. In addition, fentanyl or its derivatives are purified by column and other methods, and then prepared into acid salt. This method improves the purity, but the method is cumbersome and time-consuming and labor-intensive, and the cost is high, and the yield of the final acid salt is low, which is not suitable for industrial production

Method used

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  • Refining method of 4-phenylaminopiperidine analgesic
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  • Refining method of 4-phenylaminopiperidine analgesic

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Mix 10 g of crude fentanyl, 6 g of methanesulfonic acid, and 30 ml of methanol to obtain fentanyl mesylate.

[0037] Fentanyl mesylate is added to ethanol at 1:3 by weight (g): volume (ml), stirred and heated to reflux, adding 0.05 times the weight of fentanyl mesylate for decolorization with activated carbon, after filtration The filtrate was cooled and crystallized, and filtered to obtain the refined product of fentanyl mesylate.

[0038] Fentanyl mesylate was dissolved in water according to weight (g): volume (ml) = 1:20, and alkali was added to neutralize to pH 10, and a white solid was precipitated to obtain fentanyl base. Add citric acid to the fentanyl base solution (the solvent is a lower aliphatic alcohol below C7, the same below), to obtain 12.4 g of fentanyl citrate, with a crude yield of 79%.

[0039] Dissolve 12.4 g of fentanyl citrate in 87 ml of ethanol-ether (volume ratio 6:5) mixed solution, heat up to reflux, add 0.03 times of activated carbon for dec...

Embodiment 2

[0041] Mix 10 g of crude fentanyl, 5 g of oxalic acid, and 30 ml of methanol to obtain fentanyl oxalate.

[0042] Add fentanyl oxalate to ethanol at a weight (g): volume (ml) ratio of 1:5, stir and raise the temperature to reflux, add activated carbon 0.05 times the weight of fentanyl oxalate for decolorization, filter and crystallize the filtrate by cooling , filtered to obtain refined fentanyl oxalate.

[0043] Add fentanyl oxalate to water according to weight (g): volume (ml) = 1:20 to dissolve, add alkali to neutralize to pH 10, and precipitate white solid to obtain fentanyl base. Add citric acid to the fentanyl base solution to obtain fentanyl citrate, 13.2 g, with a crude yield of 84%. .

[0044] Dissolve 13.2 g of crude fentanyl citrate in 145 ml of methanol-ether (volume ratio 1:0.5) mixed solution, heat up to reflux, add 0.03 times of activated carbon for decolorization and recrystallization, and obtain 12.0 g of refined fentanyl citrate. Yield 90%.

Embodiment 3

[0046] Mix 10 g of crude remifentanil, 5 g of oxalic acid, and 23 ml of ethanol to obtain remifentanil oxalate.

[0047] Add remifentanil oxalate into ethanol at a weight (g): volume (ml) ratio of 1:3, stir and raise the temperature to reflux, add 0.05 times of activated carbon for decolorization, and filter the filtrate to cool and crystallize, and filter to obtain remifentanil Refined oxalate.

[0048] Remifentanil oxalate was added to water to dissolve at weight (g): volume (ml) = 1:13, and alkali was added to neutralize to pH 10, and a white solid was precipitated, which was the base of remifentanil. Concentrated hydrochloric acid was added dropwise to the base solution of remifentanil to obtain 9.0 g of remifentanil hydrochloride, and the yield of the crude product was 63%. .

[0049] Dissolve 9.0 g of remifentanil hydrochloride crude product in 90 ml of methanol-acetone (volume ratio 1:1) mixed solution, raise the temperature to reflux, add 0.03 times of activated carb...

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Abstract

The invention discloses a refining method of 4-phenylaminopiperidine analgesic, comprising the following steps of firstly preparing an acid salt from the 4-phenylaminopiperidine analgesic, purifying the acid salt after recrystallization, alkalizing the salt again to obtain free basic groups, adding another acid to the mixture to obtain another acid salt, re-crystallizing and refining the obtainedanother acid salt by a second solvent to obtain the acid salt. According to the invention, the process is simple, the used agents are simply and easily obtained, and only twice salifying operation and recrystallization operation are needed; and by utilizing the refining method, the content of impurities is remarkably reduced, the purity reaches the weight standard associated with the pharmacopoeia, the purity and the yield of fentanyl compound acid salts prepared from fentanyl compound free basic groups are remarkably improved, the production cost is reduced, and the production efficiency is remarkably improved.

Description

technical field [0001] The invention relates to a method for refining 4-anilinopiperidine analgesics. Background technique [0002] Fentanyl, remifentanil, sufentanil, alfentanil and other series of compounds are 4-anilinopiperidine analgesics, which are mostly used as acid salts such as hydrochloride or citrate , a narcotic analgesic that acts on mu opioid receptors. Most of the existing preparation technologies on raw materials are obtained through 6-8 steps of organic synthesis to obtain the fentanyl or its derivatives and then directly form a salt to obtain its acid salt. Due to the multi-step synthesis, the free base contains more impurities. After being prepared into the target acid salt, it also contains a lot of impurities, and it is difficult to remove related impurities by continuing to refine. In addition, fentanyl or its derivatives are purified by column and other methods, and then prepared into acid salt. This method improves the purity, but the method is cum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58C07D211/66C07D409/06C07D401/06
Inventor 曾华荣郑华章符义刚李莉娥钟丽君
Owner YICHANG HUMANWELL PHARMA
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