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Method for reducing 8-benzyl-2,8-diazabicyclo[4,3,0]nonane and chiral isomer thereof

A technology for diazabicyclo and chiral isomers is applied in the field of reduction of 8-benzyl-2,8-diazabicyclo[4,3,0]nonane and its chiral isomers, It can solve the problems of dangerous use, unfavorable industrialization, and expensive lithium aluminum hydride, so as to reduce production costs and improve safety.

Inactive Publication Date: 2009-12-02
ZHEJIANG LIAOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Both of the above two methods involve a reduction step, and both use lithium aluminum hydride as the reducing agent. Since lithium aluminum hydride is expensive and dangerous to use, it is not conducive to industrial production, thus lacking market competitiveness.

Method used

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  • Method for reducing 8-benzyl-2,8-diazabicyclo[4,3,0]nonane and chiral isomer thereof
  • Method for reducing 8-benzyl-2,8-diazabicyclo[4,3,0]nonane and chiral isomer thereof
  • Method for reducing 8-benzyl-2,8-diazabicyclo[4,3,0]nonane and chiral isomer thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Add 24.4g (0.1mol) of 8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and about 400mL of mixed solvent into a 1000ml three-necked reaction flask (mixed solvent The composition is 250ml of acetonitrile and 150ml of isopropanol), heat up to 60°C, add 16.5g (0.11mol) of D-tartaric acid, after all the solids are dissolved, slowly cool down to 30°C, a large amount of crystals are precipitated, and keep at 30°C Stir for 2 hours, filter, rinse once with a small amount of mixed solvent, and dry to obtain (1S,6R)8-benzyl-7,9-dioxo2,8-diazabicyclo[4,3,0] D-tartrate of nonane 16.3g (0.04137mol), the yield is 41.4%, [a] D 23 =-59.3° (C=0.5, 1N HCl), optical purity 99.2%ee.

Embodiment 2

[0027] (1S, 6R) 8-benzyl-7,9-dioxo 2,8-diazabicyclo[4,3,0]nonane D-tartrate 17.5g ( 0.0444mol) into a 500ml reaction flask, add 50ml of deionized water and 100ml of toluene, cool to below 10°C, slowly add 10% sodium carbonate aqueous solution dropwise, adjust pH=9, then keep stirring for 0.5 hours, let stand and separate, Separate the water layer, wash the organic layer once with 50ml deionized water, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain 9.5g (0.04398mol) of oily matter, the yield is 99.1%, [a 】 D 23 =-23.5° (C=5, ethanol)

Embodiment 3

[0029]Add (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane prepared according to the method in Example 2 into a 500ml three-necked reaction flask 24.4g (0.1mol) of alkane and 200ml of tetrahydrofuran were cooled to 0°C, 12.1g (0.32mol) of sodium borohydride was added, kept stirring at 0°C for 2 hours, and then 41.97g (0.3 mol), keep the temperature at 0-5°C during the dropwise addition, after the dropwise addition, continue the heat preservation reaction for 2 hours, then raise the temperature to 40°C heat preservation reaction for 6 hours, after the reaction is completed, cool to room temperature, and add the reaction solution dropwise to 100ml 2N HCl In the solution, after the dropwise addition, continue to stir for 0.5 hours, filter to remove the white solid salt, concentrate the filtrate under reduced pressure, then add 200ml of toluene and 100ml of 2N aqueous sodium hydroxide solution to it, stir for 0.5 hours, let stand, and separate the water layer , the toluene...

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Abstract

The invention discloses a method for reducing 8-benzyl-2,8-diazabicyclo[4,3,0]nonane and a chiral isomer thereof. The method comprises the steps of: taking 8-benzyl-7,9-dioxo2,8-diazabicyclo[4,3,0]nonane or (1S,6R)-8-benzyl-7,9-dioxo2,8-diazabicyclo[4,3,0]nonane as a raw material, and adopting a metal borohydride / BF3 reduction system for reduction to obtain a corresponding product, namely the 8-benzyl-2,8-diazabicyclo[4,3,0]nonane or (S,S)-8-benzyl-2,8-diazabicyclo[4,3,0]nonane. The method adopts the metal borohydride / BF3 reduction system for reduction, avoids the use of an expensive and dangerous reagent, namely lithium aluminum hydride, reduces production cost, improves the safety of the operation, and provides a safe and economical production method for industrial mass production of a moxifloxacin intermediate, namely the (S,S)-8-benzyl-2,8-diazabicyclo[4,3,0]nonane.

Description

1. Technical field [0001] The invention relates to a reduction method of 8-benzyl-2,8-diazabicyclo[4,3,0]nonane and its chiral isomer. 2. Background technology [0002] (S, S)-8-benzyl-2,8-diazabicyclo[4,3,0]nonane has a structure as shown in formula (III), which is the fourth-generation fluoroquinolone antibacterial drug moxifloxacin The key intermediate, moxifloxacin, has a broad antibacterial spectrum and low drug resistance rate. It has strong antibacterial activity against common respiratory pathogens, and has a long half-life, strong tissue penetration, and bidirectional excretion in the liver and kidney. It has good pharmacokinetics. Kinetic properties and good safety and tolerance, easy to take once a day, is a new generation of quinolone antibacterial drugs ideal for the treatment of COPD and AECB. The chemical name of moxifloxacin is 1-cyclopropyl-7-(S,S)-2,8-diazo-bicyclo[4,3,0]non-8-yl-6-fluoro-1,4- Dihydro-4-oxo-3 quinoline carboxylic acid, its hydrochloride f...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 屠雄飞
Owner ZHEJIANG LIAOYUAN PHARM CO LTD
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