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Asymmetric synthesis method of dezocine key intermediate

A synthesis method and intermediate technology, which is applied in the field of synthesis of key intermediates of dezocine, can solve the problems of low catalyst stereoselectivity, troublesome reaction process, high price, etc., achieve good yield, simple operation, and high preparation method concise effect

Pending Publication Date: 2022-01-07
宁波赜军医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the raw materials used in this method have the disadvantages of being expensive and difficult to prepare
Moreover, the stereoselectivity of the catalyst in the reaction of Chinese patent CN201810078820.0 is not high (82% ee), and the subsequent recrystallization will increase the ee value to 99%. The reaction process is also troublesome and needs to be carried out under dark conditions

Method used

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  • Asymmetric synthesis method of dezocine key intermediate
  • Asymmetric synthesis method of dezocine key intermediate
  • Asymmetric synthesis method of dezocine key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0039] A kind of asymmetric synthetic method of dezocine key intermediate, synthetic route is as follows:

[0040]

[0041](1) Preparation of compound 3

[0042] Under the condition of a dry ice-ethanol bath, control the internal temperature below -60°C, slowly add lithium diisopropylamide solution LDA (16.5mL, 33.0mmol, 2M in THF / Heptane), the addition was completed in about 15min, and the resulting solution was stirred at low temperature for 1h. Afterwards, a THF solution (25 mL) of compound 2 (10 g, 36.0 mmol; refer to the preparation method in Org. Bio. Chem. 2007, 5, 143-150) was added to the reaction system. The system naturally returned to room temperature and reacted for 3h. After the reaction is over, add saturated ammonium chloride solution to the reaction system to quench the reaction, then add ethyl acetate, separate the organic phase, extract the aqueous phase twice with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and filter ...

Embodiment 2

[0057] An asymmetric synthesis method of a key intermediate of dezocine, which is the same as the synthetic route of Example 1, the difference is that the preparation conditions of compound 3 are different, and the preparation of compound 3 is specifically as follows:

[0058] Under the condition of a dry ice-ethanol bath, the internal temperature was controlled below -60°C, and slowly added bis(trimethylsilyl)amide lithium LiHMDS ( 22mL, 22.0mmol, 1M inTHF), the addition was completed in about 15min, and the resulting solution was stirred at low temperature for 1h. After that, a tetrahydrofuran solution (15 mL) of compound 2 (6.72 g, 24.0 mmol) was added to the reaction system. The system naturally returned to room temperature and reacted for 3h. After the reaction is over, add saturated ammonium chloride solution to the reaction system to quench the reaction, then add ethyl acetate, separate the organic phase, extract the aqueous phase twice with ethyl acetate, combine the ...

Embodiment 3

[0060] An asymmetric synthesis method of a key intermediate of dezocine, which is the same as the synthetic route of Example 1, the difference is that the preparation conditions of compound 3 are different, and the preparation of compound 3 is specifically as follows:

[0061] Under the conditions of a dry ice-ethanol bath, control the internal temperature below -60°C, slowly add lithium diisopropylamide solution to cyclooctanone 2 (2.0g, 15.8mmol) in methyltetrahydrofuran (MeTHF) solution (30mL) LDA (8.7mL, 17.4mmol, 2Min THF / Heptane) was added in about 15min, and the resulting solution was stirred at low temperature for 1h. After that, a solution (15 mL) of compound 2 (5.32 g, 19.0 mmol) in methyl tetrahydrofuran was added to the reaction system. The system naturally returned to room temperature and reacted for 3h. After the reaction is over, add saturated ammonium chloride solution to the reaction system to quench the reaction, then add ethyl acetate, separate the organic ...

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Abstract

The invention discloses an asymmetric synthesis method of a dezocine key intermediate. The method comprises the following steps of carrying out nucleophilic reaction on a compound 1 and a compound 2 in an ether solvent C under the condition of alkali A to obtain a compound 3, carrying out coupling reaction on the compound 3 in an aprotic organic solvent D under the action of alkali B, a palladium catalyst and a chiral ligand (R)-BINAP at 80-110 DEG C to obtain a compound 4, wherein the palladium catalyst is selected from any one or more than two of Pd(OAc)2, Pd(dba)2 and Pd2(dba)3, and reacting the compound 4 in an ether solvent F under the action of alkali E and a methylation reagent to obtain a compound 5. The method is simple and easy to operate, the dezocine key intermediate with high optical purity can be obtained, and the method is suitable for industrial production.

Description

technical field [0001] The present invention relates to a synthesis method of a key intermediate of dezocine, in particular to an asymmetric synthesis method of a key intermediate of dezocine. Background technique [0002] Dezocine is a benzo-bridged natural product. This compound is a κ receptor agonist and a μ receptor antagonist. It can play an analgesic effect and is less addictive. It is often used for postoperative analgesia. Pain and pain caused by internal organs and cancer. [0003] [0004] There are three consecutive chiral centers in the structure of dezocine, one of which is a chiral bridgehead quaternary carbon center, which is difficult to synthesize. At present, the synthetic route of dezocine is mainly disclosed in U.S. Patent US4001331 (application date 1973-12-03), which uses 7-methoxyl-1-methyl-2-tetralone as the starting material to synthesize The route is as follows: [0005] [0006] However, racemic dezocine was obtained. [0007] Chinese pa...

Claims

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Application Information

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IPC IPC(8): C07C45/67C07C45/68C07C49/755C07C49/753
CPCC07C45/67C07C45/68C07B2200/07C07C2603/80C07C2601/18C07C49/753C07C49/755Y02P20/55
Inventor 董伟郑新华王红芳贾颖隋赫王睿王舒欢邵伟滔吕红梅
Owner 宁波赜军医药科技有限公司
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