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Process for producing racemic cis-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonyl hydride

A diazabicyclo and dioxo technology, which is applied in the field of preparation of fine chemical products, can solve the problems of intense reaction conditions and complex operations, and achieve the effects of simple treatment, high reaction yield and fast dehydrogenation reaction speed

Inactive Publication Date: 2009-05-13
EAST CHINA NORMAL UNIV
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  • Application Information

AI Technical Summary

Problems solved by technology

It is then reduced to racemic cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane by high-pressure hydrogenation, thereby overcoming the prior art Existing defects such as intense reaction conditions and complicated operation

Method used

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  • Process for producing racemic cis-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonyl hydride
  • Process for producing racemic cis-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonyl hydride
  • Process for producing racemic cis-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonyl hydride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The first step, dehydrogenation of (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane: add 5g to 1000ml single-necked bottle (1R,6S)-8-Benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (e.e. value 83%), 25g manganese dioxide, 120g tetrahydrofuran, oil The bath was heated to 60°C for 10 hours. Cool down to room temperature, recover manganese dioxide (filter residue) by suction filtration, and remove the solvent from the filtrate: add 100ml of dichloromethane to dissolve, wash with a small amount of 5% dilute hydrochloric acid, dry over anhydrous sodium sulfate, and remove the solvent to obtain 4.6g of dark yellow solid. The yield of 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine was 93%. Mp.: 106~108℃; 1 H NMR (CDCl 3 ): δ ppm: 1.86 (2H, m), 2.34 (2H, t, J=6Hz), 3.36 (2H, t, J=5Hz), 4.60 (2H, s), 7.26~7.35 (5H, m).

[0031] The second step, high-pressure hydrogenation of 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine: 60g6-benzyl-5 , ...

Embodiment 2

[0033] The first step, dehydrogenation of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane:

[0034]Add 0.5g (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (e.e. value 98%) in 100ml single-necked bottle, 2.5g of manganese dioxide and 10g of toluene were heated in an oil bath to reflux at 110°C for 7 hours. Cool down to room temperature, recover manganese dioxide by suction filtration, and remove the solvent from the filtrate: add 10ml of dichloromethane to dissolve, wash with a small amount of 5% dilute hydrochloric acid, dry over anhydrous sodium sulfate, and remove the solvent to obtain 0.45g of dark yellow solid 6-benzyl Base-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine, the yield was 91%. The melting point and NMR data are the same as those of 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine in Example 1.

[0035] The second step, high-pressure hydrogenation of 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine: 20g6-benzyl...

Embodiment 3

[0037] The first step, dehydrogenation of (1R,6S)8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane:

[0038] Add 0.5g (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (e.e. value 90%) in 100ml single-necked bottle, 2.5g of manganese dioxide and 2g of cyclohexane were heated in an oil bath to 80°C and refluxed for 5 hours. Cool down to room temperature, recover manganese dioxide by suction filtration, remove the solvent from the filtrate, add 10ml of dichloromethane to dissolve, wash with a small amount of 5% dilute hydrochloric acid, dry over anhydrous sodium sulfate, and remove the solvent to obtain 0.47g of 6-benzyl as a dark yellow solid Base-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine, the yield was 95%. The melting point and NMR data are the same as those of 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine in Example 1.

[0039] The second step, high-pressure hydrogenation of 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-b]pyridine: 20g6-...

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Abstract

The invention discloses a method for preparing racemic cis-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo[4.3.0]nonane, which relates to a racemization method for (1R,6S)-cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane. Firstly, the (1R,6S)-cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is refluxed for 3 to 10h in the presence of a manganese dioxide catalyst and a dehydrogenation solvent at a temperature of between 60 and 110 DEG C for an oxydehydrogenation reaction, and then obtained 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrido[3,4-b]pyridine reacts for 5 to 10 h in the presence of a Pd / C or PtO2 catalyst and a hydrogenation solvent at a temperature of between 70 and 100 DEG C at the pressure of between 5 and 9MPa and is reduced into the racemic cis-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo[4.3.0]nonane. The method has the advantages of simple process, quick reaction, more than 90 percent of two-step overall yield, mild conditions, simple treatment after the reaction, no secondary reactions, and reutilized catalyst, and meets the requirement of environmental protection. The obtained product is the racemic cis-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo[4.3.0]nonane, fully avoids the generation of trans-products, can be directly used for optical resolution, and remarkably improves the utilization rate of raw materials.

Description

technical field [0001] A process for the preparation of racemic cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane involving a (1R,6S)-cis 8- The invention relates to a racemization method of benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, which belongs to the technical field of preparation of fine chemical products such as medicine. Background technique [0002] Chiral cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is a synthetic antibacterial drug such as the fourth generation of new extended-spectrum fluoroquinolone antibacterial drugs- Moxifloxacin (EP-550903), antifungal drugs (JP-2005-97298) and food additives are key intermediates of fine chemicals, which are more and more widely used in industry. At present, it is most widely used in the synthesis of (S, S)-2,8-diazabicyclo[4.3.0]nonane. [0003] [0004] It can be seen from the above formula that only (1S,6R)-cis 8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is actually used. And its enantiomer (1R,...

Claims

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Application Information

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IPC IPC(8): C07D471/04B01J23/34
CPCY02P20/584
Inventor 邹新琢蔡惠华郑祖彪
Owner EAST CHINA NORMAL UNIV
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