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Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane

A technology of diazabicyclo and moxifloxacin, which is applied in organic chemistry methods, chemical instruments and methods, organic racemization, etc., can solve the problems of inconvenient large-scale production, high optical purity, and low content, and achieve the reduction of raw material consumption, Effect of avoiding purification process and reducing production cost

Active Publication Date: 2012-04-11
ZHEJIANG APELOA KANGYU PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The resolving agent that this method uses is more expensive, and consumption is big (molecular weight is big), and resolving agent is unstable under acidic conditions, is unfavorable for improving its recovery rate and causes resolving agent to account for a large proportion in raw material consumption, and separation process The operation is complicated, which brings inconvenience to large-scale production; the optical purity of the product is high, but the content is low, which increases the difficulty of subsequent reaction purification

Method used

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  • Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane
  • Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane
  • Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] 10.00g (40.94mmol) cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane in 250ml reaction flask, add 100ml isopropyl acetate, room temperature Stir until it is completely dissolved, add 4.25g (24.54mmol) N-acetyl-L-leucine, heat up to 70-80°C and react for 40 minutes, then slowly cool down to 40°C, crystals are precipitated, continue to cool down to 25°C, and stir overnight. The next day, filter, wash the reaction bottle with the filtrate, and wash the crystal with 4g × 2 isopropyl acetate to get (1 S ,6 R )-8-Benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane·N-acetyl-L-leucine salt, wet weight 7.80g, reduced pressure at 40°C Drying, weighing 7.75g, theoretical yield 90.69%, optical purity 95.05% ee.

[0053] 7.75g (1 S ,6 R )-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane·N-acetyl-L-leucine salt, recrystallized with 44g of acetonitrile, the obtained crystals 40 The weight was 6.31 g after drying under reduced pressure at ℃, the total yield was 73.84%, and the opti...

Embodiment 2

[0056] (1) prepared in embodiment 1 S ,6 R )-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane N-acetyl-L-leucine salt 6.31g (15.11mmol) suspended 15g di In methyl chloride, add 16g water and 1.5g NaHCO 3 , stirred at 31°C, and when both phases were clear, the organic phase was separated, and the aqueous phase was extracted with 5g×2 dichloromethane. The organic phases were combined, dried over 5g anhydrous sodium sulfate, filtered, washed with 5g dichloromethane, and the resulting filtrate reclaimed dichloromethane under reduced pressure to obtain the product (1 S ,6 R )-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane 3.44g, [α] D 20 = -24.4?? (c=0.005, ethanol), optical purity 99.31%ee.

[0057] 1 HNMR (CDCl 3 , MHz) δppm: 7.23-7.34 (m, 5H), 4.62 (s, 2H), 3.79-3.81 (d, 1H), 2.79-2.85 (dd, 1H), 2.73-2.78 (m,1H), 2.61- 2.67 (m, 1H), 2.16 (br s, 1H), 1.89-1.97 (m, 1H), 1.59-1.68 (m, 1H), 1.45-1.51 (m,2H).

[0058] 13 CNMR (CDCl 3 , MHz) δppm: 177.92, 177.76, 135.83...

Embodiment 3

[0060] Method 46 Preparation (1 S ,6 R )-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane·N-acetyl-L-leucine salt 7.27g (17.41mmol) suspended in 15g toluene , add 16g of water and 1.6g of NaHCO 3 , Stir at 30°C, until the two phases are clear, separate the organic phase, and extract the aqueous phase with 5g×2 toluene. Combine organic phase, 5g anhydrous sodium sulfate drying, filter, wash with 4.5g toluene, gained filtrate reclaims toluene under reduced pressure, obtains product (1 S ,6 R )-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane 4.26g, optical purity: 92.63%ee.

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Abstract

The invention discloses a preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane. Crystallization of (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine diastereomeric salts is formed by Cis-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane and N-acetyl-L-leucine in a splitting solvent and dissociates in a alkaline liquid such as Na2CO3 or NaHCO3. The crystallization is extracted through an organic solvent and decompressed and concentrated through organic phases to obtain (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane. The preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane has low production cost and is simple and convenient to split; moreover, fussy purge process during subsequent reaction is avoided. Products of the preparation method not only have high optical purity, but also have higher content.

Description

technical field [0001] The invention relates to the technical field of production of pharmaceutical intermediates, in particular to a moxifloxacin intermediate (1 S ,6 R )-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane. Background technique [0002] Moxifloxacin is an 8-methoxyfluoroquinolone broad-spectrum antimicrobial drug indicated for the treatment of acute sinusitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia in adults with respiratory infections, and skin and soft tissue infections. It was launched in Germany and the United States in 1999 and in China in 2002. The chemical name of moxifloxacin is 1-cyclopropyl-6-fluoro-8-methoxy-7-[(4a S ,7a S )-octahydro-6 H -pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-1,4-dihydroquine-3-carboxylate hydrochloride. [0003] [0004] A kind of moxifloxacin intermediate (1 S ,6 R )-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane preparation method, specifically: cis-8-benzyl-7,9-dioxo -2,8-diazabicyclo[4...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07B57/00
Inventor 戴鹏张柏林张柯华
Owner ZHEJIANG APELOA KANGYU PHARMA
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