Preparation method of dezocine impurities

A technology of dezocine and impurities, applied in the field of medicine, can solve the problem of no standard product sales, etc., and achieve the effects of improving clinical drug safety, high yield and improving drug safety

Active Publication Date: 2020-05-19
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Through literature search, there is no literature report on the synthesis method of this compound, and there is no standard product on the market.

Method used

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  • Preparation method of dezocine impurities
  • Preparation method of dezocine impurities
  • Preparation method of dezocine impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Formula 1 compound (5.0g, 19.3mmol) and 60ml of 1,2-dichloroethane were added to a 250ml reaction flask, and N-chlorosuccinimide (3.8g, 28.95mmol) was slowly added dropwise at room temperature, stirred Reaction 3h. DBU (2 mL) was added, the temperature was raised to 40°C-50°C, and the reaction was completed after 12 hours of reaction. Add water (75mL) to the reaction flask, filter with a Buchner filter, remove the solids, wash with saturated brine, dry and spin dry to obtain the crude compound of formula 2 (4.8g, light yellow solid), which can be used directly without further purification react in the next step.

[0048] Dissolve the compound of formula 2 (4.8g) in dichloromethane (55mL), slowly add aluminum chloride (5.13g, 38.6mmol), then dropwise add thiophenol (4.24g, 38.6mmol), and heat up to 30-350°C, keep warm for 6h. Cool the reaction system in an ice bath to about 0°C, slowly add ammonia water dropwise to quench the reaction until the pH>7, keep the system t...

Embodiment 2

[0051] The compound of formula 1 (5.0g, 19.3mmol) and 60ml of 1,2-dichloroethane were added to a 250ml reaction flask, and N-bromosuccinimide (4.05g, 23.16mmol) was slowly added dropwise at room temperature, stirred Reaction 2h. Triethylamine (2 mL) was added, the temperature was raised to 50°C-60°C, and the reaction ended after 18 hours of reaction. Add water (75mL) to the reaction flask, filter with a Buchner filter, remove the solid matter, wash with saturated brine, dry and spin dry to obtain the crude compound of formula 2 (4.9g, light yellow solid), which is used directly without further purification react in the next step.

[0052] The compound of formula 2 (4.9 g) was dissolved in dichloromethane (55 mL), and aluminum chloride (7.7 g, 57.9 mmol) was added slowly, followed by ethanethiol (3.58 g, 57.9 mmol). After the addition, the temperature was raised to 30-35°C, and the reaction was kept for 4 hours. Cool the reaction system in an ice bath to about 0°C, slowly ad...

Embodiment 3

[0054] Formula 1 compound (5.0g, 19.3mmol) and 80ml of 1,2-dichloroethane were added to a 250ml reaction flask, and N-iodosuccinimide (7.3g, 32.81mmol) was slowly added dropwise at room temperature, stirred Reaction 1.5h. Pyridine (2 mL) was added, the temperature was raised to 50°C-60°C, and the reaction was completed after 18 hours of reaction. Add water (100mL) to the reaction flask, filter with a Buchner filter, remove the solid matter, wash with saturated brine, dry and spin dry to obtain the crude compound of formula 2 (4.7g, light yellow solid), which is used directly without further purification react in the next step.

[0055] The compound of formula 2 (4.7g) was dissolved in 1,2-dichloroethane (55mL), ethanethiol (3.58g, 57.9mmol) was added, and aluminum chloride (7.7g, 57.9mmol) was added slowly. After the addition, the temperature was raised to 35-40°C, and the reaction was kept for 2 hours. Cool the reaction system in an ice bath to about 0°C, slowly add ammoni...

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Abstract

The invention discloses a preparation method of a dezocine impurity. (5R,11S,13S)-3-methoxy-5-methyl-5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methylbenzocyclononene-13-amine is used as an initial raw material to efficiently synthesize and prepare (5R,11S)-3-hydroxy-5-methyl-5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methylbenzocyclononene-13-imine. The preparation method has the advantages of simple operation, easily available raw materials, mild reaction conditions, high product purity and high yield, and is suitable for large-scale preparation. The synthesized impurity can be used for qualitative and quantitative analysis of impurities, so the medication safety of dezocine can be improved.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically relates to a method for preparing impurities produced during the preparation of dezocine injection. Background technique [0002] Dezocine is a powerful opioid analgesic that mainly acts on μ receptors and κ receptors, and can relieve pain caused by postoperative surgery and cancer. Clinical studies have proved that the analgesic intensity, onset time and duration of action of dezocine injection are comparable to morphine, and the tolerance is good, and the tendency of drug abuse is lower than that of morphine. Animal experiments have shown that the physical dependence of dezocine is significantly lower than that of morphine hydrochloride in terms of the degree of urging and natural withdrawal reactions in mice and rats, and it will not increase with the increase of the dose, but will decrease to some extent. [0003] Dezocine, English name Dezocine, chemical name (-)-[5R-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C249/02C07C251/20
CPCC07C249/02C07C2603/80C07C251/20
Inventor 肖志超徐浩宇蔡伟要世伟孙春艳吕慧敏刘景龙张海波
Owner YANGTZE RIVER PHARM GRP CO LTD
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