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Synthetic method of morphine derivative and applications

A synthesis method and technology of derivatives, applied in sugar derivatives, sugar derivatives, preparation of sugar derivatives, etc., can solve the problems that glycosides cannot be seen, cannot obtain pure M3G, cannot be obtained, etc.

Active Publication Date: 2018-04-27
YICHANG HUMANWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, when the inventor repeated the method, he found that under the catalysis of lithium hydroxide, morphine could hardly react with the sugar ring, and HPLC showed that the peaks of morphine were almost all, and the peaks of glycosides were almost invisible; After processing, there is also a large amount of morphine in the product, and after purification, relatively pure M3G cannot be obtained (the HPLC purity of M3G is about 65%, and morphine is 35%)
Therefore, using this method cannot obtain M3G with better purity, nor can it be used as a standard or reference substance

Method used

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  • Synthetic method of morphine derivative and applications
  • Synthetic method of morphine derivative and applications
  • Synthetic method of morphine derivative and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] (1) compound shown in formula II (R 1 for the synthesis of acetyl)

[0063] Take 10g of morphine and add it to acetonitrile, add 7.1g of triethylamine, lower to 0°C, add dropwise 7.5g of acetic anhydride, keep the temperature below 10°C, after dropping, react at 20-30°C for 5 hours, pour the reaction solution into 100ml Chloromethane, neutralized with saturated sodium bicarbonate solution, washed with 50ml of purified water and saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

[0064] (2) compound shown in formula III (R 1 is acetyl) and formula IV compound (R 5 for the synthesis of trifluoroacetyl)

[0065] Dissolve the product obtained in the first step with 150ml of absolute ethanol, add 2.4g of hydroxylamine hydrochloride, react at 20-30°C for 12 hours, concentrate under reduced pressure, add 50ml of water and 120ml of dichloromethane to the concentrate, extract and separate, and dichloromethane...

Embodiment 2

[0073] (1) compound shown in formula II (R 1 for the synthesis of benzoyl)

[0074] Add 10g of morphine into tetrahydrofuran, add 2.8g of sodium hydride, lower to 0°C, add dropwise 10.2g of benzoyl chloride, keep the temperature below 10°C, after the drop is complete, react at 20-30°C for 1 hour, pour the reaction solution into 100ml of dihydrofuran Chloromethane, neutralized with saturated sodium bicarbonate solution, washed with 50ml of purified water and saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

[0075] (2) compound shown in formula III (R 1 Be benzoyl) and formula IV compound (R 5 for the synthesis of trifluoromethanesulfonyl)

[0076] Dissolve the product obtained in the first step with 120ml of anhydrous methanol, add 3.8g of phenylhydrazine, react at 30-40°C for 10 hours, concentrate under reduced pressure, add 50ml of water and 120ml of dichloromethane to the concentrate, extract and separa...

Embodiment 3

[0084] (1) compound shown in formula II (R 1 for the synthesis of 3,5-dinitrobenzoyl)

[0085] Take 10g of morphine and add it to acetone, add 5.5g of pyridine, lower to 0°C, add dropwise 16.2g of 3,5-dinitrobenzoyl chloride, keep the temperature below 10°C, after dropping, react at 10-20°C for 5 hours, and The reaction solution was poured into 100ml of dichloromethane, neutralized with saturated sodium bicarbonate solution, washed with 50ml of purified water and saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

[0086] (2) compound shown in formula III (R 1 is 3,5-dinitrobenzoyl) and formula VI compound (R 5 for the synthesis of trifluoroacetyl)

[0087] Dissolve the product obtained in the first step with 150ml of isopropanol, add 4.8g of anhydrous potassium carbonate, react at 50-60°C for 12 hours, concentrate under reduced pressure, add 50ml of water and 120ml of dichloromethane to the concentrate, ext...

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Abstract

The invention discloses a synthetic method of a morphine derivative. The method employs morphine as an initial raw material, and selective protection and glycosylation are carried out in order to obtain a target product. The HPLC purity of M3G obtained by the synthetic method reaches 99.8%, and the M3G can be used as a reference substance or a standard substance for researching quality of relatedproducts.

Description

technical field [0001] The invention relates to drug synthesis in the field of analgesics, in particular to a synthesis method of morphine derivatives. Background technique [0002] Morphine is metabolized in the body into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), of which M3G accounts for 44% to 45% of metabolites and has no analgesic activity. M3G has greater polarity and is not easy to pass through the blood-brain barrier. However, in the process of preparing M6G, M3G may also be generated, thus affecting the analgesic activity of M6G. [0003] Document 1 Bertold Berrang, et al, synthesis of morphine-3-glucuronide, synthesis communications, 5(3), 231-236 (1975), reported a synthetic method for the synthesis of M3G. Using morphine under the action of lithium hydroxide, reacting with the sugar ring, and then hydrolyzing under the action of lithium hydroxide, M3G is prepared. [0004] However, when the inventor repeated the method, he found that under...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H1/00C07D489/02G01N30/02
CPCC07D489/02C07H1/00C07H17/00G01N30/02Y02P20/55
Inventor 郭建锋符义刚李仕群田峦鸢吕金良曲龙妹李莉娥杜文涛
Owner YICHANG HUMANWELL PHARMA
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