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A kind of synthetic method of 10-carbonyl/hydroxymorphine-6-glucuronide

A glucuronide and synthesis method technology, applied in the field of organic synthesis, can solve the problems of unpublished preparation methods and structural identification information, and no generation of 10-carbonyl/hydroxymorphine-6-glucuronide, etc., achieving simple synthesis method, The effect of high purity and high reaction yield

Active Publication Date: 2021-02-02
YICHANG HUMANWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] But this patent does not disclose the preparation method and structure identification information of these two impurities, the inventor once referred to Die Pharmazie (1984), 39 (10), 687-8 and Pharmazie (1978), 33 (9), 609 The synthesis method of 10-carbonyl / hydroxymorphine carries out the synthesis of the impurity 10-carbonyl / hydroxymorphine-6-glucuronide, but does not generate the product of 10-carbonyl / hydroxymorphine-6-glucuronide

Method used

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  • A kind of synthetic method of 10-carbonyl/hydroxymorphine-6-glucuronide
  • A kind of synthetic method of 10-carbonyl/hydroxymorphine-6-glucuronide
  • A kind of synthetic method of 10-carbonyl/hydroxymorphine-6-glucuronide

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preparation example Construction

[0014] The present invention provides a kind of synthetic method of 10-carbonylmorphine-6-glucuronide, comprising:

[0015] 1) oxidizing the compound of formula (III) to obtain the compound of formula (IV),

[0016]

[0017] Wherein, R is formula (R-1) or formula (R-2),

[0018]

[0019] According to the present invention, the present invention oxidizes the compound of formula (III) structure to obtain the compound of formula (IV) structure, and the oxidizing agent of described oxidation is preferably one or both in chromium trioxide and manganese dioxide, and described Oxidation also includes oxidation aid, and described oxidation aid is trifluoroacetic acid or trifluoromethanesulfonic acid; The solvent of described reaction is methylene chloride or chloroform; The temperature of described reaction is 0~30 ℃, more preferably 10 ~25°C; in order to better carry out the reaction, the present invention preferably reacts at 5-10°C for 1-1.5 hours, and then reacts at 20-25°C...

Embodiment 1

[0049] Preparation of compound shown in embodiment 1 formula (I)

[0050]1) Preparation of compound shown in formula (III)

[0051] Take 14.1g of the dry compound represented by formula (II), dissolve it in 100ml of anhydrous chloroform, add 20g of potassium bicarbonate, add 28g of methyl chloroformate dropwise at room temperature, after the addition is complete, the reaction is completed at 55-60°C and cooled to room temperature , filtered, the filter cake was washed with 100ml chloroform, drained, combined the filtrates, concentrated to dryness, 15ml of ethyl acetate was recrystallized, crystallized at 0-5°C for 16-20h, suction filtered, the filter cake was washed with a small amount of glacial ethyl acetate, Dry at 40-45°C for 6-10 hours to obtain 8.32 g of the compound represented by formula (III). Yield: 55.5%

[0052] 2) Preparation of compound shown in formula (IV)

[0053] Take 7.63g of the compound represented by formula (III), dissolve it in 100ml of dichlorometha...

Embodiment 2

[0062] Preparation of compound shown in embodiment 2 formula (I)

[0063] 1) Preparation of compound shown in formula (III)

[0064] Take 14.1 g of the dry compound represented by formula (II), dissolve it in 100 ml of anhydrous dichloromethane, add 20 g of sodium bicarbonate, add 29.5 g of ethyl chloroformate dropwise at room temperature, and after the addition is complete, the reaction is completed at 40-45°C. Cool to room temperature, filter, wash the filter cake with 100ml of dichloromethane, drain it, combine the filtrates, concentrate to dryness, recrystallize in 15ml of ethyl acetate, crystallize at 0-5°C for 16-20h, suction filter, wash the filter cake with a small amount of ice Wash with ethyl acetate and dry at 40-45°C for 6-10 hours to obtain 8.65 g of the compound represented by formula (III). Yield: 56.6%.

[0065] 2) Preparation of compound shown in formula (IV)

[0066] Take 7.75g of the compound represented by formula (III), dissolve it in 100ml of dichlorom...

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Abstract

The invention provides a kind of synthetic method of 10-carbonyl / hydroxymorphine-6-glucuronide, the method provided by the invention is by oxidizing the compound of formula (III) structure, obtains the compound of formula (IV) structure, and then The compound of formula (IV) structure is converted into 10-carbonylmorphine-6-glucuronide, and it is found that the synthetic method is simple, the reaction yield of each step is high, and the product obtained has high purity, which can be used to prepare high-efficiency liquid phase The standard product for chromatographic detection fills the gap in M6G drug detection.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for synthesizing 10-carbonyl / hydroxymorphine-6-glucuronide. 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, since 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 it can be oxidized in aqueous solution. The oxidation reaction is a free radical reaction. Oxygen in the air, sunlight, ultraviolet radiation or...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H17/00C07H1/00
CPCC07H1/00C07H17/00
Inventor 郭建锋易斌李莉娥李杰杜文涛田峦鸢吕金良朱圣姬曲龙妹汪淼
Owner YICHANG HUMANWELL PHARMA
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