Racemization method of (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8- diazabicyclo (4, 3, 0) nonane

A diazabicyclo and dioxo technology, applied in the field of medicine, can solve the problems of high energy consumption, heavy metal pollution, environmental pollution, etc., and achieve the effect of mild reaction conditions, no metal participation, and simple process

Inactive Publication Date: 2014-05-14
SHAOXING UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method requires the use of a large excess of MnO 2 (MnO 2 The molar ratio to raw material is up to 15:1), a large amount of MnO 2 The use of this method makes the atomic economy of the method not ideal, which is not conducive to the control of "three wastes", easily pollutes the environment, and may also cause heavy metal pollution to the product or subsequent products
On the other hand, the reaction also needs to be carried out under heating and reflux, and the energy consumption required by the process is relatively high

Method used

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  • Racemization method of (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8- diazabicyclo (4, 3, 0) nonane
  • Racemization method of (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8- diazabicyclo (4, 3, 0) nonane
  • Racemization method of (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8- diazabicyclo (4, 3, 0) nonane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Oxidative dehydrogenation of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane: Add 12.2g of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane (II), 50mL dimethyl sulfoxide, 15.4g ( 1.2 equivalents) iodine element and oxygen balloon (1 bar), stirring at room temperature for 10 hours. After the reaction was completed, 100 mL of aqueous sodium thiosulfate solution with a concentration of 1 mol / L was added, the aqueous phase was extracted twice with 200 mL of ethyl acetate, the organic phases were combined and washed several times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11.0 g dark yellow solid. through 1 H-NMR analysis, this solid is highly pure 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine, and the productive rate is 91 %. product structure, 1 H-NMR and 13 C-NMR is as follows:

[0034]

[0035] 1 H-NMR (CDCl 3 ,400MHz)δppm7.29-7.22(m,5H),5.10(br s,1H),4.60(s,2H),...

Embodiment 2

[0038] Oxidative dehydrogenation of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane: Add 12.2g of (1R,6S)-8-Benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, 50 mL dimethylsulfoxide and 23.0 g (1.2 eq.) Simple iodine and oxygen balloons (1bar), stirred at room temperature for 10 hours. After the reaction was completed, 50 mL of saturated sodium thiosulfate aqueous solution was added, and the aqueous phase was extracted twice with 100 mL of ethyl acetate. The combined organic phases were washed several times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11.2 g of a dark yellow solid. through 1 H-NMR analysis, this solid is highly pure 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine, and the productive rate is 92 %.

Embodiment 3

[0040] Oxidative dehydrogenation of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane: Add 12.2g of (1R,6S)-8-Benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, 100mL ethyl acetate, 15.4g (1.2 equivalents) iodine and an oxygen bulb (1 bar), stirring at 40°C for 10 hours. After the reaction was completed, 100 mL of aqueous sodium thiosulfate solution with a concentration of 1 mol / L was added, the aqueous phase was extracted twice with 100 mL of ethyl acetate, the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8.5 g Dark yellow solid. through 1 According to H-NMR analysis, the solid was 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine, and the yield was 70%.

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Abstract

The invention relates to the field of a medical technology, and discloses a racemization method of (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8- diazabicyclo (4, 3, 0) nonane. The method comprises the steps of (1) in ether solvent or polar aprotic solvent, carrying out oxidative dehydrogenation on the (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo (4, 3, 0) nonane by taking elemental iodine and oxygen as co-oxidant to prepare 6-benzyl-5, 7-dioxo-1, 2, 3, 4-tetrahydron-pyrrolo (3, 4-b) pyrrole; (2) in ester solvent or alcohol solvent, carrying out catalytic hydrogenation on oxidative product by taking Pd/ Al2O3 as a catalyst to obtain the racemic cis-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo (4, 3, 0) nonane. The method is simple in technology, convenient to operate, mild in reaction conditions, etc.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a method for converting (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane A method for the racemization of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane. Background technique [0002] Moxifloxacin (Moxifloxacin) is the fourth-generation quinolone antibacterial drug developed by Bayer Company in Germany. Its trade name is "Bay Fule", and it is a chiral drug. The drug has an ultra-broad antibacterial spectrum. It not only retains the high activity against Gram aerobic bacteria, but also has very strong antibacterial activity against anaerobic bacteria, mycoplasma, chlamydia, etc., especially against Escherichia coli and Streptomyces aureus Antibiotic-resistant strains showed strong activity. Clinically, moxifloxacin is used for the treatment of upper and lower respiratory tract infections (such as: acute exacerbation of chronic bronchitis, acute sinusitis, communit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 陈风江冯高峰麻倩倩何静耀
Owner SHAOXING UNIVERSITY
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