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Preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane

A technology of diazabicyclo and nonane, applied in the field of preparation of -2,8-diazabicyclo[4,3,0]nonane, which can solve the problem of high cost of moxifloxacin and achieve low cost , Raw materials are cheap and easy to get, and the effect is easy to operate

Active Publication Date: 2016-05-11
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] What the present invention is to solve is the problem of high cost of moxifloxacin, thereby providing an effective and economical synthetic route to prepare (S, S)-2,8-diazabicyclo[4,3 ,0] the preparation method of nonane, which avoids the use of expensive resolving agent, greatly reduces the process cost; the intermediate in the whole process does not need to be purified, the crude product is directly used, the process is simple, the total yield is high and the product chirality Purity up to 99%

Method used

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  • Preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane
  • Preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane
  • Preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] step 1

[0083]

[0084] Dissolve the compound formula I (150.0g, 0.9mol) in methanol (1500ml), stir at room temperature for 30min, then add concentrated sulfuric acid (110.5g, 1.125mol) dropwise, the addition is completed in about half an hour, heat to 85°C, and react overnight .

[0085] The methanol was spin-dried under reduced pressure, and then the concentrated solution was slowly poured into an aqueous solution of sodium carbonate, a large amount of gas was released. Adjust the pH to 7-8, extract with dichloromethane (1500ml*2), dry over anhydrous sodium sulfate, and spin dry under reduced pressure to obtain 166.9g of a light yellow solid with a yield of 95%.

[0086] The experimental results are as follows:

[0087] (1) Purity: 98.6%

[0088] (2) 1 HNMR (CDCl 3 300M): such as figure 1 shown.

[0089] From the experimental results, it can be seen that the structure of the product is correct, which is shown in the target product formula II

[0090] Ste...

Embodiment 2

[0151] step 1

[0152]

[0153] Compound formula I (200g, 1.2mol) was dissolved in methanol (3000ml), stirred at room temperature for 30min, then concentrated sulfuric acid (117.6g, 1.2mol) was added dropwise, and the addition was completed in about half an hour, heated to 70°C, and reacted overnight.

[0154] The methanol was spin-dried under reduced pressure, and then the concentrated solution was slowly poured into an aqueous solution of sodium carbonate, a large amount of gas was released. Adjust the pH to 7-8, extract with dichloromethane (1500ml*2), dry over anhydrous sodium sulfate, and spin dry under reduced pressure to obtain 225.3g of a light yellow solid with a purity of 98.5% and a yield of 96.2%.

[0155] Step 2:

[0156]

[0157] Formula II (200 g, 1.02 mol) and toluene (1000 mL) were added into the autoclave, and Pd / C (10.0 g, 5% w / w) was slowly added under nitrogen. After replacing the nitrogen in the autoclave for 3 times, it was heated to 90° C. and t...

Embodiment 3

[0185] step 1

[0186]

[0187] Compound formula I (80g, 0.48mol) was dissolved in methanol (400ml), stirred at room temperature for 30min, then concentrated sulfuric acid (94.1g, 0.96mol) was added dropwise, and the addition was completed in about half an hour, heated to 60°C, and reacted overnight.

[0188] The methanol was spin-dried under reduced pressure, and then the concentrated solution was slowly poured into an aqueous solution of sodium carbonate, a large amount of gas was released. Adjust the pH to 7-8, extract with dichloromethane (1000ml*2), dry over anhydrous sodium sulfate, and spin dry under reduced pressure to obtain 89.7g of a light yellow solid with a purity of 99% and a yield of 95.8%.

[0189] Step 2:

[0190]

[0191] Formula II (80 g, 0.41 mol) and toluene (800 mL) were added into the autoclave, and Pd / C (6.4 g, 8% w / w) was slowly added under nitrogen. After replacing the nitrogen in the autoclave for 3 times, it was heated to 100° C., and the hy...

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Abstract

The invention discloses a preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane and belongs to the field of the preparation method of a moxifloxacin intermediate. The preparation method comprises eight processes. A resolving process is carried out in initial of the preparation method, in the third process, an ester is resolved to form a chiral intermediate and then through a simple chemical reaction, the (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane is prepared. The invention provides the preparation method utilizing an effective and economic synthesis route to prepare the high-chiral purity (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane. The preparation method is free of an expensive resolving agent and greatly reduces a process cost. In the whole technology, the intermediate is not purified and the crude product can be directly used. The preparation method has simple processes and a high overall yield and can produce the product with chiral purity of 99%.

Description

Technical field: [0001] The invention belongs to a method for preparing a moxifloxacin intermediate, in particular to a method for preparing (S,S)-2,8-diazabicyclo[4,3,0]nonane. technical background: [0002] Moxifloxacin is a new type of quinolone drug with spectrum antibacterial activity, especially effective against antibiotic-resistant strains such as Streptomyces aureus, Enterococcus and Escherichia coli, and its activity is equal to or higher than that of currently used Similar drugs such as ofloxacin, levofloxacin and so on. Such high activity is due to the fact that the chemical structure of moxifloxacin is significantly different from other fluoroquinolones. (S,S)-2,8-Diazabicyclo[4,3,0]nonane is the 7-position side chain of moxifloxacin, and is the key intermediate for the synthesis of moxifloxacin. The main part of the cost of cifloxacin. At present, the scale of chiral side chain production of moxifloxacin by domestic enterprises is not large, mainly because t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 李文森
Owner HEADING NANJING PHARMTECH CO LTD
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