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Asymmetric Synthesis of (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, low efficiency, and high cost, and achieve the effects of high yield, low process cost, and simple method

Active Publication Date: 2022-03-01
WUHAN UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 of (s,s)-2,8-diazabicyclo[4,3,0]nonane
  • Asymmetric Synthesis of (s,s)-2,8-diazabicyclo[4,3,0]nonane
  • Asymmetric Synthesis of (s,s)-2,8-diazabicyclo[4,3,0]nonane

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Experimental program
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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 of (S, S)-2,8-diazabicyclo[4,3,0]nonane, using N-benzyl-butenedimide as raw material, and N-p-toluenesulfonyl-N`-propeniminohydrazine (Ⅱ) in the presence of chiral square amide catalyst (Ⅲ) through asymmetric [2+4] addition reaction to obtain 8-benzyl-2-p-toluene Sulfonamido-7,9-dioxo-(1S,6R)-2,8-diazabicyclo[4,3,0]-3-ene nonane, followed by recrystallization, reduction, acid-catalyzed hydrolysis, The reduction step affords (S,S)‑2,8‑diazabicyclo[4,3,0]nonane. The synthesis method of the invention is simple, the yield of the asymmetric catalytic product is high, the enantioselectivity of the product after recrystallization can be as high as 90%, the condition is mild, the operation is simple, the production cost is low, and it can be used in industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular 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 Patents(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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