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Synthesis method of biapenem

A synthesis method and compound technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of complicated operation, low yield, unstable solution, etc., and achieve the effect of high product purity and simple operation.

Inactive Publication Date: 2007-03-14
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The solution of carbapenems is extremely unstable, 10-20% will be degraded during the concentration process, the operation is cumbersome, the yield is not high, and it is not easy to scale up production

Method used

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  • Synthesis method of biapenem
  • Synthesis method of biapenem

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Experimental program
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Effect test

Embodiment 1

[0021] 30g (63mmol) of 6-[(4R, 5R, 6S)-2-(benzyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1 -Azabicyclo[3,2,0]hept-2-en-3-yl]thio-6,7-dihydro-5H-pyrazolo[1,2-α][1,2,4 ] Triazol-4-ium chloride, add 150ml tert-butanol, 50ml ethyl acetate, 450ml 0.30mol / L magnesium chloride buffer solution (pH=5.5), stirring and dissolving, the weight content of adding 10g palladium is 10% palladium Carbon, controlled hydrogenation pressure 5Kg / m 2 , react at 25°C for 3h, filter, wash the aqueous phase with ethyl acetate 300ml×2, add acetone 500ml, stir at -10°C for 2h, filter, wash the solid with acetone 30ml×2, and dry under reduced pressure to obtain parapenem 16.5 g, (yield: 75%, purity: 97.0%).

[0022] In this embodiment, R in the compound of general formula I is PhCH 2 .

Embodiment 2

[0024] 30g (63mmol) of 6-[(4R, 5R, 6S)-2-(benzyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1 -Azabicyclo[3,2,0]hept-2-en-3-yl]thio-6,7-dihydro-5H-pyrazolo[1,2-α][1,2,4 ] triazol-4-ium chloride, add 150ml THF, 450ml0.30mol / L sodium acetate damping fluid (pH=5.5), stirring and dissolving, adding the weight content of 1.5g palladium hydroxide is 20% palladium hydroxide carbon , control hydrogenation pressure 10Kg / m 2 , react at 25°C for 2.5h, filter, wash the aqueous phase with ethyl acetate 300ml×2, add acetone 500ml, stir at -10°C for 2h, filter, wash the solid with acetone 30ml×2, and dry under reduced pressure to obtain baper Nan 15.4g, (yield: 70%, purity: 97.5%).

[0025] In this embodiment, R in the compound of general formula I is PhCH 2 .

Embodiment 3

[0027] 30g (57.5mmol) of 6-[(4R, 5R, 6S)-2-(4-nitrobenzyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7 -Oxo-1-azabicyclo[3,2,0]hept-2-en-3-yl]thio-6,7-dihydro-5H-pyrazolo[1,2-α][ 1,2,4] triazol-4-ium chloride, add isopropanol 150ml, 0.35mol / L zinc acetate buffer salt (pH=6.0) 450ml, stir to dissolve, add platinum carbon (10%) 5g, Control hydrogenation pressure 3Kg / m 2 , reacted at 0°C for 4.0h, filtered, added 400ml of acetone to the filtrate, stirred at -10°C for 1h, precipitated crystals, filtered, washed the solid with acetone 30ml×2, dried under reduced pressure to obtain 12g of parapenem, (yield : 60%, purity: 98.5%).

[0028] In this embodiment, R in the compound of general formula I is 4-O 2 NPhCH 2 .

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Abstract

The present invention discloses process of synthesizing Biapenem. The synthesis process includes the following steps: the hydrogenation reaction of the compound shown in expression I to eliminate protecting group inside buffer solution or the mixed liquid of buffer solution and organic solvent in the presence of catalyst of Pd or Pt containing compound; and the subsequent collection of Biapenem from the reaction product. The synthesis process is simple, high in product purity and suitable for industrial production.

Description

technical field [0001] The present invention relates to a synthesis method of diapenem. Background technique [0002] Diapenem is a new generation of carbapenem antibiotics, its chemical name is: 6-[(4R,5R,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]- 4-Methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-en-3-yl]thio-6,7-dihydro-5H-pyrazolo[1 , 2-α][1,2,4]triazol-4-ium inner salt. Diapenem has the pharmacological activity of general carbapenem antibiotics, has a broad antibacterial spectrum, and its antibacterial activity is similar to that of imipenem and meropenem (Acdridge.K, Morice M, et al, antimicrob Agent.Chemother, 1994, 38( 4): 889-890). The activity against intestinal bacteria is stronger than that of imipenem, and its antibacterial activity against non-fermenting gram-negative bacteria, especially Pseudomonas aeruginosa and gentamicin-resistant (GM) Pseudomonas aeruginosa, is 2 times stronger than that of imipenem (Takek Nishino et al., Chenotherapy, 1994, 42(4): 64-66). [0003...

Claims

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Application Information

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IPC IPC(8): C07D519/00C07D487/04C07D477/00
CPCY02P20/55
Inventor 刘相奎袁哲东朱雪焱杨玉雷
Owner SHANGHAI INST OF PHARMA IND
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