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Asymmetric synthesis method for (S,S)-2,8-diazabicyclo[4,3,0]nonane

A diazabicyclo and synthesis method technology, applied in the field of medicinal chemistry, can solve the problems of low resolution yield, high cost, low efficiency, etc., and achieve the effect of improving chirality induction

Active Publication Date: 2019-10-11
WUHAN UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] This route is long, and resolution yield is low (only about 20%), and most of dimethyl piperidine dicarboxylate is used for reconversion utilization, and efficiency is low, and cost is high
[0020] In summary, there are many drawbacks in the prior art method for synthesizing (S,S)-2,8-diazabicyclo[4,3,0]nonane, so a simple, safe, efficient and low-cost production method is to be explored is very necessary

Method used

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  • Asymmetric synthesis method for (S,S)-2,8-diazabicyclo[4,3,0]nonane
  • Asymmetric synthesis method for (S,S)-2,8-diazabicyclo[4,3,0]nonane
  • Asymmetric synthesis method for (S,S)-2,8-diazabicyclo[4,3,0]nonane

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] The asymmetric synthesis method of (S, S)-2,8-diazabicyclo[4,3,0]nonane is realized through the following steps:

[0058] 1) 8-benzyl-2-p-toluenesulfonamido-7,9-dioxo-(1S,6R)-2,8-diazabicyclo[4,3,0]-3-ene nonane ( Ⅳ) Preparation

[0059] Add 1.87g (0.01mol) N-benzyl-butene imide (I) (FW=187), 0.45g square amide (Ⅲa) (0.001mol), 2.42g N-p-toluene to a 25ml single-necked bottle Sulfonyl-N`-propeniminohydrazine (Ⅱ) (FW=224) (0.0108mol), 15mL of dry dichloromethane, reacted at -20°C, TLC followed the reaction for 10 hours, after the reaction was complete, concentrated under reduced pressure The solvent was removed and the residue was used for recrystallization.

[0060] Optical purity analysis of the residue: HPLC Chiralcel AD-H column, 250×4.6mm

[0061] UV detection wavelength λ=210nm

[0062] Mobile phase: n-hexane:isopropanol=9:1 (v:v), filter through a 0.45μm filter membrane and degas before use

[0063] Flow rate: 1.0mL / min

[0064] Injection volume: 5μL

[006...

Embodiment 2

[0097] The asymmetric synthesis method of (S, S)-2,8-diazabicyclo[4,3,0]nonane is realized through the following steps:

[0098] 1) 8-benzyl-2-p-toluenesulfonamido-7,9-dioxo-(1S,6R)-2,8-diazabicyclo[4,3,0]-3-ene nonane ( Ⅳ) Preparation

[0099] Add 1.87g (0.01mol) N-benzyl-butenedimide (I) (FW=187), 0.48g square amide (Ⅲb) (0.001mol), 2.42g N-p-toluene to a 25ml single-necked bottle Sulfonyl-N`-propeniminohydrazine (II) (FW=224) (0.0108mol), 15mL of dry dichloromethane, reacted at -20°C, TLC followed the reaction for 10 hours, after the reaction was complete, concentrated under reduced pressure and removed The solvent was removed and the residue was used for recrystallization.

[0100] The optical purity of the residue was analyzed ee% = 87.8%.

[0101] The residue was dissolved in 20 mL of ethyl acetate, heated to reflux until completely dissolved, cooled to 25° C. to precipitate a solid, filtered, and dried to obtain 3.6 g, with a yield of 87.6%.

[0102] Optical purity ...

Embodiment 3

[0111] The asymmetric synthesis method of (S, S)-2,8-diazabicyclo[4,3,0]nonane is realized through the following steps:

[0112] 1) 8-Benzyl-2-p-toluenesulfonamido-7,9-dioxo-(1S,6S)-2,8-diazabicyclo[4,3,0]-3-enenonanedi Preparation of acid salt (Ⅳ)

[0113] Add 1.87g N-benzyl-butenedimide (I) (FW=187, 0.01mol), 0.49g square amide (Ⅲc) (0.001mol), 2.42g N-p-toluenesulfonate to a 25ml single-necked bottle Acyl-N`-propeniminohydrazine (II) (FW=224) (0.0108mol), 15mL of dry dichloromethane, reacted at -20°C, TLC followed the reaction for 10 hours, after the reaction was completed, concentrated under reduced pressure to remove The solvent was removed and the residue was used for recrystallization.

[0114] The optical purity of the residue was analyzed ee% = 93.8%.

[0115] The residue was dissolved in 20 mL of ethyl acetate, heated to reflux until completely dissolved, cooled to 25° C. to precipitate a solid, filtered, and dried to obtain 3.6 g, with a yield of 87.6%.

[0116]...

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Abstract

The invention relates to an asymmetric synthesis method for (S,S)-2,8-diazabicyclo[4,3,0]nonane. N-benzyl-butene imidodicarbonic diamide is taken as a raw material, in presence of a chiral squaramidecatalyst (III), the N-benzyl-butene imidodicarbonic diamide and N-para-toluene sulfonyl-N'-propylene imidogen hydrazine (II) are subjected to an asymmetric [2+4] addition reaction, and 8-benzyl-2-para-toluene sulfonamide-7,9-dioxo-(1S,6R)-2,8-diazabicyclo[4,3,0]-3-alkene nonane is obtained; through the steps of recrystallization, reduction, acid-catalyzed hydrolysis and reduction, the (S,S)-2,8-diazabicyclo[4,3,0]nonane is obtained. The synthesis method is simple, the yield of the asymmetric catalysis product is high, the enantioselectivity of the product through recrystallization can reach 90% or above, and the asymmetric synthesis method is mild in condition, simple to implement, low in production cost and capable of being used for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to an asymmetric synthesis method of (S,S)-2,8-diazabicyclo[4,3,0]nonane. Background technique [0002] (S,S)-2,8-Diazabicyclo[4,3,0]nonane is an important raw material for the synthesis of moxifloxacin. Moxifloxacin has been used in clinical practice. Moxifloxacin belongs to the fourth generation of quinolones. Bacteria have strong antibacterial effect, so it is of great significance to study the effective synthesis method of (S,S)-2,8-diazabicyclo[4,3,0]nonane. [0003] The preparation method of (S,S)-2,8-diazabicyclo[4,3,0]nonane is reported in the literature (WO9415938) using 2,3-dipicolinic acid as raw material, by resolving different chiral The method preparation of amine, method route is as follows: [0004] [0005] This route is costly and polluting due to the fact that another isomer recovery method has not been reported. [0006] Literature (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 申永存邹颖李天成梁夏瑜
Owner WUHAN UNIV OF TECH
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