A kind of preparation method of dezocine impurity c

A technology of dezocine and impurities, which is applied in the field of medicinal chemistry, can solve problems such as difficult preparations, and achieve the effect of simple and efficient synthesis

Active Publication Date: 2021-11-09
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the presence of phenolic hydroxyl groups and amino groups in dezocine impurity C, it is difficult to prepare this impurity using conventional prior art

Method used

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  • A kind of preparation method of dezocine impurity c
  • A kind of preparation method of dezocine impurity c
  • A kind of preparation method of dezocine impurity c

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Synthesis of dezocine impurity C: dissolve dezocine impurity A (10.1 mg, namely R=H in formula (II)) in CH 2 Cl 2 (1mL), reduce the reaction temperature to -78°C with dry ice, add BF 3 (0.05mL, 33% ether solution, about 7.0 equivalents), after the addition, the reaction temperature was slowly raised to -20°C for 60 minutes, the reaction was stopped, and 5% NaHCO was added to the reaction solution 3 The aqueous solution is neutralized to neutral, the liquid is separated, and the aqueous phase is re-used with CH 2 Cl 2 (2 mL) was extracted twice, the organic phases were combined and then column chromatographed to obtain 5.3 mg of dezocine impurity C (formula I) as a white solid with a yield of 52%. The ratio of the amount (unit: mL) of the reaction solvent dichloromethane to the amount (unit: g) of dezocine impurity A is about 100:1. H NMR spectrum (DMSO-d 6 ,500MHz)δ8.29(s,1H),7.83(d,J=8.5Hz,1H),6.83(d,J=2.0Hz,1H),6.77(dd,J=8.5,2.0Hz,1H), 3.40(d,J=7.5Hz,1H),2.85(dd...

Embodiment 2

[0037] Synthesis of dezocine impurity C: dissolve dezocine impurity A (10.2 mg, ie R=H in formula (II)) in 10% sulfuric acid aqueous solution (0.2 mL, H 2 SO 4 The equivalent of about 6.0), after 5 minutes, dilute the reaction solution with 2mL of ice water, wash with 5% NaHCO 3 The aqueous solution is neutralized to neutral, adding CH 2 Cl 2 (5mL) was extracted twice, and the organic phases were combined and subjected to column chromatography to obtain 4.6mg of dezocine impurity C, a white solid, with a yield of 45%. The ratio of the amount (unit: mL) of the reaction solvent sulfuric acid aqueous solution to the amount (unit: g) of dezocine impurity A is about 20:1. The characterization data of dezocine impurity C are the same as in Example 1.

Embodiment 3

[0039] Synthesis of Dezocine Impurity C: Dissolve Dezocine Impurity A (30.4 mg, ie R=H in formula (II)) in dioxane (1 mL), add ZnO (0.1 g, 10.5 equivalents), and heat After reacting at 90°C for 6 hours, it was concentrated to remove the solvent and separated by column chromatography to obtain 24.6 mg of dezocine impurity C (Formula I) as a white solid with a yield of 81%. The ratio of the amount (unit: mL) of the reaction solvent dioxane to the amount (unit: g) of dezocine impurity A is 33:1. The characterization data of dezocine impurity C are the same as in Example 1.

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Abstract

The invention discloses a preparation method of dezocine impurity C, which uses dezocine impurity A and its homologues as raw materials, undergoes a rearrangement reaction in the presence of a catalyst, and separates and prepares dezocine impurity C. The advantage of the present invention is that: using dezocine impurity A with epoxy structure or its homologues as raw materials, the simple and efficient synthesis of dezocine impurity C is realized by utilizing the rearrangement reaction of epoxides, and the reagents used are simple and easy to obtain , easy to operate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of dezocine impurity C. Background technique [0002] Dezocine is a synthetic mixed opioid receptor agonist-antagonist alkaloid analgesic with good tolerance and safety. Its approval is constantly improving and its clinical demand is gradually increasing. . Compared with opioid analgesics such as morphine, dezocine has the advantage of being less addictive, and it is clinically used for the treatment of 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 (CN 102503840 A). [0003] Dezocine is a phenolic compound, which is prone to a small amount of degradation during long-term storage and may produce impurity C. Its chemical structure is as follo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C221/00C07C225/20C07D301/19C07D303/36
CPCC07C221/00C07D301/19C07D303/36C07C2603/80C07C225/20
Inventor 李博蔡伟徐镜人陈小青韩林陈亮宣景安李浩冬刘景龙刘晶
Owner YANGTZE RIVER PHARM GRP CO LTD
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