Preparation method of dezocine impurity A and homologues thereof

A technology of homologue, dezocine, applied in the direction of organic chemistry, etc., to achieve the effect of simple and easy-to-obtain reagents and convenient operation

Active Publication Date: 2019-01-15
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there is no report on the conversion of phenolic substances without hydroxyl groups on the satu...

Method used

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  • Preparation method of dezocine impurity A and homologues thereof
  • Preparation method of dezocine impurity A and homologues thereof
  • Preparation method of dezocine impurity A and homologues thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add 1 g (1.0 equivalent) of dezocine, 0.1 g (0.05 equivalent) of scandium trifluoromethanesulfonate, 1,8-diazabicyclo[5.4.0]-undeca-7 into a 25 mL single-necked round bottom bottle -ene 0.93g (1.5 equivalents), dichloromethane 10mL, 70% tert-butanol peroxide 2.62g (5.0 equivalents), and stirred at room temperature for 5h to stop the reaction. The reaction solution was diluted with 40 mL of dichloromethane, followed by 20 mL of 5% NaOH aqueous solution, 5% Na 2 S 2 o 3 Wash with 20 mL of aqueous solution, separate the liquids, and wash the organic phase with anhydrous Na 2 SO4 2 g was dried, concentrated to dryness under reduced pressure, and the residue was separated by column chromatography to obtain 93 mg of dezocine impurity A as an off-white solid. The NaOH aqueous extract was adjusted to pH 7 with acetic acid, stirred in an ice-water bath for 30 min, filtered, and the filter cake was dried to recover 0.52 g of dezocine. The dezocine charging amount is 1.0g, th...

Embodiment 2

[0025] Add 20.0 g (1.0 equivalent) of dezocine, 2.3 g (0.1 equivalent) of titanium tetraisopropoxide, 6.0 g (0.5 equivalent) and 200 mL of dichloromethane into a 500 mL three-necked flask, and lower the temperature of the reaction solution to -10°C , slowly add 62.0 g (4.0 equivalents) of 80% cumene hydroperoxide dropwise for 2.0 h. After the dropwise addition, the reaction temperature is slowly raised to room temperature for 3 h, and then the reaction temperature is raised to 75° C. for 1 h. Stop the reaction, extract the reaction solution with 70 mL of 5% NaOH aqueous solution, filter the insoluble matter, separate the liquids, extract the organic phase twice with 5% NaOH aqueous solution, 5% NaOH 2 S 2 o 3 Extract once with 200mL of aqueous solution, once with 50mL of saturated saline, use starch-KI test paper to detect that there is no peroxide residue in the organic phase, separate the liquids, and wash the organic phase with anhydrous MgSO 4 5.0 g was dried, concentrat...

Embodiment 3

[0027] Add 2 g (1.0 equivalent) of dezocine (1.0 equivalent), 0.23 g (0.1 equivalent) of titanium tetraisopropoxide, 0.6 g (0.5 equivalent) of DBU, and 10 mL of isopropyl acetate into a 50 mL single port, and lower the temperature of the reaction solution to -10 ° C. Slowly add 6.2 g (4.0 equivalents) of 80% cumene hydroperoxide dropwise, and react at 60° C. for 3 h after the dropwise addition. Stop stirring, extract the reaction solution with 20mL of 5% NaOH aqueous solution, filter the insoluble matter, separate the liquids, and use 10mL of 5% NaOH aqueous solution, 5% NaOH solution for the organic phase successively 2 S 2 o 3 Wash with 30 mL of aqueous solution, use starch-KI test paper to detect that there is no peroxide residue in the organic phase, separate the liquids, concentrate the organic phase to dryness, and separate the residue by column chromatography to obtain 192 mg of dezocine impurity A. Combine the aqueous NaOH extracts, adjust the pH to 7 with acetic aci...

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Abstract

The invention discloses a preparation method of a dezocine impurity A and homologues thereof. The method includes the steps of: taking dezocine and homologues thereof as the raw material, adopting a transition metal as the catalyst and using a peroxide as the oxidizing agent, and carrying out reaction to obtain the dezocine impurity A and homologues thereof. The invention has the advantages that:a new chemical method is provided to convert phenolic substances into epoxides, at the same time the used reagents are simple and easily available, the operation is simple, and parts of the unreactedraw materials can be recovered.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of dezocine impurity A and its homologues. Background technique [0002] Dezocine is a typical opioid alkaloid analgesic, developed by AstraZeneca, and belongs to a synthetic mixed opioid receptor agonist-antagonist. Due to the good tolerance and safety of dezocine, the recognition of the market and medical institutions has been continuously improved, and the clinical demand has continued to increase. Dezocine is less addictive and is used to treat moderate to severe postoperative pain, visceral colic, and pain in patients with advanced cancer. At present, dezocine has been approved for marketing by the State Food and Drug Administration of China, and its synthesis process has been industrialized (CN102503840A). Dezocine is prone to degradation reaction during the stability test, resulting in impurity A, whose chemical structure is as follows:...

Claims

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Application Information

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IPC IPC(8): C07D301/19C07D301/12C07D301/14C07D303/32
CPCC07D301/12C07D301/14C07D301/19C07D303/32
Inventor 李博蔡伟韩林李飞飞陈小青陈亮
Owner YANGTZE RIVER PHARM GRP CO LTD
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