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A kind of preparation method of diazabicyclic compound

A technology for diazabicyclic compounds, which is applied in the field of preparation of diazabicyclic compounds, and can solve the problems of insufficient optical purity, low yield, and high cost of moxifloxacin hydrochloride intermediates

Active Publication Date: 2016-05-18
大连永达苏利药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to overcome the defects that the optical purity of the moxifloxacin hydrochloride intermediate prepared by the existing preparation method is not high enough, the yield is low, the cost is high and it is not suitable for industrialized large-scale production, and a method is provided. A kind of preparation method of diazabicyclic compound

Method used

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  • A kind of preparation method of diazabicyclic compound
  • A kind of preparation method of diazabicyclic compound
  • A kind of preparation method of diazabicyclic compound

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Put 20g of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane into a 250mL reaction bottle, add 150mL of isopropanol, stir until it is completely dissolved, Add 2.5g of acetic acid and 10g of (S)-p-toluenesulfonylanisine, heat up to reflux, then slowly cool down to room temperature, and stir overnight. The next day, filter to obtain crystals, wash with a small amount of isopropanol to obtain (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane *(S)-p-toluenesulfonyl glucuroninate was recrystallized from isopropanol to obtain 17.7 g of white solid, with a yield of 79% and an optical purity of 99.5% ee.

Embodiment 2

[0042] Put 5g of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane into a 100mL reaction bottle, add 50mL of n-butanol, stir until it is completely dissolved, Add 1 g of water and 3.2 g of (S)-p-toluenesulfonylanisine, raise the temperature to 80°C, then slowly cool down to room temperature, and stir overnight. The next day, filter to obtain crystals, wash with a small amount of isopropanol to obtain (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane *(S)-4.4g of p-toluenesulfonyl phenylosinate, yield 78%, optical purity 96.5%ee.

Embodiment 3

[0044] Put 5g of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane in a 100mL reaction bottle, add 50mL of isopropanol, stir until it is completely dissolved, Add 0.5g of acetic acid and 3.3g of (S)-benzenesulfonylphenylosysine, raise the temperature to 80°C, then slowly cool down to room temperature, and stir overnight. The next day, filter to obtain crystals, wash with a small amount of isopropanol to obtain (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane Alkane*(S)-toluenesulfonyl phenylininate was recrystallized from isopropanol to obtain 4.2 g of a white solid with a yield of 75% and an optical purity of 97.5% ee.

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Abstract

The present invention discloses a diazabicyclo compound preparation method. The preparation method of a compound represented by a formula (IIIa) comprises the step of in a solvent, carrying out a salt forming reaction on a compound represented by a formula I and a resolution agent, wherein the resolution agent is a compound represented by a formula (IIa). The preparation method of a compound represented by a formula (IIIb) comprises the step of in a solvent, carrying out a salt forming reaction on the compound represented by the formula I and a resolution agent, wherein the resolution agent is a compound represented by a formula (IIb). In the compound IIa and / or IIb, R is C1-C20 alkyl, or C6-C10 aryl substituted by one or more selected from following substituents or unsubstituted C6-C10 aryl, halogen, or C1-C4 alkyl substituted by halogen or unsubstituted C1-C4 alkyl. The diazabicyclo compound prepared by the preparation method of the present invention has characteristics of high optical purity, high yield and low cost, and is suitable for industrial production. The formulas (I), (IIa), (IIb), (IIIa) and (IIIb) are shown as follows.

Description

technical field [0001] The invention relates to a preparation method of diazabicyclic compounds. Background technique [0002] Moxifloxacin hydrochloride, whose structural formula is shown below, is a fourth-generation 8-methoxyquinolone antibacterial drug used for the treatment of acute sinusitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia, and skin and soft tissue infections . Moxifloxacin has a broad antibacterial spectrum, long half-life, strong tissue penetration, bidirectional excretion in liver and kidney, good pharmacokinetics, good safety and tolerance. Moxifloxacin was launched in Germany and the United States in 1999, and in China in 2002. [0003] [0004] German Bayer Company disclosed moxifloxacin intermediate (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane in patent EP550903 in 1993 The patent discloses the chemical resolution of 8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane through D-tartaric acid or L-tartaric ac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07B57/00
CPCC07B57/00C07B2200/07C07D471/04
Inventor 韦元曹庆华
Owner 大连永达苏利药业有限公司