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Stereo-selective synthesis method of 6beta-hydroxymorphine derivative

A technology of stereoselectivity and synthesis method, which is applied in the preparation of sugar derivatives, sugar derivatives, and sugar derivatives, etc., can solve the problems of drug safety hazards, difficult removal of impurities, and low quality of M6G products.

Active Publication Date: 2019-10-08
YICHANG HUMANWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] M6G itself is relatively stable, but in the process of synthesizing M6G, due to the easy reversal of the configuration during the glycosylation reaction, it is easy to generate the compound impurity shown in formula (I-2), and the impurity is difficult to remove in the subsequent purification process, resulting in The quality of M6G products is not high, which has caused great hidden dangers to the drug safety of the people.
This structure has not been reported in the literature

Method used

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  • Stereo-selective synthesis method of 6beta-hydroxymorphine derivative
  • Stereo-selective synthesis method of 6beta-hydroxymorphine derivative
  • Stereo-selective synthesis method of 6beta-hydroxymorphine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] Morphine-6-β-O-β-D-glucuronide

[0114] S1: Add 33.4g (0.05mol) of morphine sulfate, 4g (0.1mol) of sodium hydroxide, 350mL of acetonitrile and 100ml of water into a 1L three-necked flask equipped with a thermometer, cool down to 10°C for reaction, and dropwise add 10.8g (0.05mol) 3,5-Dinitrobenzoyl chloride. After the dropwise addition, slowly return to room temperature and react for 5 hours. After the reaction is complete, pour the reaction solution into 500ml of ethyl acetate, separate the layers, extract the water layer twice with 200ml of ethyl acetate, combine the ethyl acetate layers, wash with 5% aqueous sodium bicarbonate until neutral, saturated chlorination Wash once with sodium, dry ethyl acetate overnight with anhydrous magnesium sulfate, filter, concentrate under reduced pressure at 45 ° C, and recrystallize the residue with ethanol to obtain 20.4 g of a white solid, namely the compound of formula II (R 1 is 3,5-dinitrobenzoyl, R 3 For methyl), yield: 8...

Embodiment 2

[0126] The preparation of embodiment 2 6-beta-hydroxymorphine

[0127]S1: Add 33.4g (0.05mol) of morphine sulfate, 4g (0.1mol) of sodium hydroxide, 350mL of acetonitrile and 100ml of water into a 1L three-necked flask equipped with a thermometer, cool down to 10°C for reaction, and add 5.3g (0.05mol) dropwise Isobutyryl chloride. After the dropwise addition, slowly return to room temperature and react for 5 hours. After the reaction is complete, pour the reaction solution into 500ml of ethyl acetate, separate the layers, extract the water layer twice with 200ml of ethyl acetate, combine the ethyl acetate layers, wash with 5% aqueous sodium bicarbonate until neutral, saturated chlorination Wash once with sodium, dry ethyl acetate overnight with anhydrous magnesium sulfate, filter, concentrate under reduced pressure at 45 ° C, and recrystallize the residue with ethanol to obtain 16.4 g of a white solid, namely the compound of formula II (R 1 is isobutyryl, R 3 For methyl), yi...

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Abstract

The invention discloses a stereo-selective synthesis method of a 6beta-hydroxymorphine derivative. The synthesis method comprises the following steps: (i) reducing a compound of a formula VI to a compound of a formula VII by sodium borohydride in a hydrophilic organic solvent in the presence of a catalytic amount of a C1-C4 alkanoic acid; and (ii) separating the compound of the formula VII obtained in the step (i) to obtain a compound of a formula VIII, wherein definitions of substituents in the formula VI, the formula VII and the formula VIII are detailed in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a stereoselective synthesis method of 6β-hydroxymorphine derivatives. Background technique [0002] Morphine-6-glucuronide (M6G) is the main metabolite of morphine, and its mechanism of action is similar to that of other opioids. It is a central nervous system μ-receptor opioid agonist. Compared with morphine, the analgesic effect of M6G is slower but lasts longer, and the side effects are milder, especially the incidence of nausea, vomiting and respiratory depression is lower. In addition, because morphine glucuronide is not metabolized by the liver, compared with other opioids, it has obvious advantages for patients with hepatic insufficiency. The structural formula is as follows: [0003] [0004] M6G itself is relatively stable, but in the process of synthesizing M6G, due to the easy reversal of the configuration during the glycosylation reaction, it is easy ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D489/02C07H17/04C07H1/00
CPCC07D489/02C07H1/00C07H17/04
Inventor 周皓郭建锋易斌李莉娥田峦鸢吕金良李禹琼汪淼李仕群杜文涛朱圣姬
Owner YICHANG HUMANWELL PHARMA
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