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A kind of preparation method of dezocine key intermediate

An intermediate, dezocine technology, applied in the field of medicinal chemistry, can solve the problems of high cost of raw materials and preparations, harsh reaction conditions, long synthesis cycle, etc., and achieve the effect of shortening the synthesis cycle, low cost of raw materials, and fewer steps

Active Publication Date: 2017-11-03
WENZHOU MEDICAL UNIV
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  • Abstract
  • Description
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Problems solved by technology

At present, because dezocine has many synthesis steps, cumbersome operation, long synthesis cycle, harsh reaction conditions in some cases, and low safety of individual reactions, the cost of raw materials and preparations is high, resulting in high cost of medication for patients. high

Method used

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  • A kind of preparation method of dezocine key intermediate
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  • A kind of preparation method of dezocine key intermediate

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preparation example Construction

[0019] The preparation method of dezocine key intermediate V of the present invention, its synthetic route is as follows:

[0020]

[0021] Using 7-methoxy-2-tetralone as a raw material, first methylate at the benzylic position, and then carry out alkylation at the ortho position of the carbonyl to obtain the key intermediate V.

Embodiment 1

[0022] Embodiment 1, preparation methylation product II

[0023] Dissolve 7-methoxy-2-tetralone I (17.6g, 0.10mol) in 30ml of dichloromethane, cool the reaction system to 0°C, and add N,N-diisopropyl to the reaction system in batches Ethylamine (13.6ml, 0.1mol), at this temperature, slowly add cooled methyl iodide (6.22ml, 0.1mol) dropwise into it over 20 minutes. After the dropwise addition, the temperature was naturally raised to room temperature, and the reaction was carried out at room temperature for 4 hours. After TLC spotting, the raw material spots basically disappeared. The pH was then adjusted to neutral with saturated ammonium chloride solution, followed by three extractions with 25 ml each of EtOAc. The combined organic phases were washed with saturated sodium chloride, dried over magnesium sulfate, concentrated, and purified by column chromatography to obtain 16.2 g of methylated product II with a yield of 85%.

Embodiment 2

[0024] Example 2, preparation of carbonyl unilateral alkylation products IVa and IVb

[0025] The methylated product II (15.2g, 80mmol) was dissolved in 35ml tetrahydrofuran (THF), the reaction system was cooled to 0°C, and Et was slowly added to the reaction system 3 N (22.2ml, 0.16mol), stirred at this temperature for 30 minutes. Then warm up to room temperature, add dibromopentane III (12.2ml, 88mmol) to the reaction system at this temperature, then heat up to 40-45°C, keep this temperature for 12 hours, monitor by TLC, the methylation raw material basically disappears Finally, the pH value was adjusted to be neutral with 1mol / L hydrochloric acid solution, and then extracted three times with 90ml of ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over sodium sulfate, concentrated under reduced pressure, and passed through a column to obtain carbonyl unilaterally alkylated products IVa and IVb. The combined mass is 22.4g, and th...

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Abstract

The present invention discloses a dezocine key intermediate preparation method, 7-methoxy-2-tetralone is used as a starting material for first benzyl-site methylation and then ortho alkylation of the carbonyl group, the dezocine key intermediate can be prepared by three strategies of stepwise synthesis, two-step and one-pot methods. The dezocine key intermediate preparation method has the advantages of simple synthetic route, less steps, high yield simple operation, great reduction of the synthesis cycle, mild reaction conditions, and improvement of the safety of the technology, the low raw material cost and easy industrialization. The preparation cost is greatly reduced by the simple synthesis method, the patient dosage cost is reduced, the national social security spending can be reduced to some extent, and some of the social and economic benefits are produced.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a key intermediate of dezocine. Background technique [0002] Dezocine, scientific name (-)-[5R-(5α,11α,13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl- 5,11-Methylenebenzocyclodecen-3-ol (CAS No.: 53648-55-8), which belongs to a typical opioid alkaloid analgesic, was developed by AstraZeneca. These drugs work by stimulating opioid receptors. Dezocine has stronger analgesic effect than pentazocine, is a κ receptor agonist, and is also a μ receptor antagonist. Dezocine is less addictive and is suitable for the treatment of moderate to severe pain after surgery, visceral colic and pain in patients with advanced cancer. At present, dezocine raw materials and preparations have been approved for marketing by the State Drug and Food Administration of China. Due to its good tolerance and safety, dezocine has been increasingly rec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C49/755C07C45/61C07C45/68
CPCC07C45/61C07C45/68C07C2602/10C07C2603/80C07C49/755
Inventor 冯建鹏梁广刘志国张亚利蔡跃飘卢孔秦
Owner WENZHOU MEDICAL UNIV
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