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Preparation method of D-(-)-alpha-sulbenicillin sodium

A technology of sulbenicillin sodium and sulbenicillin acetic acid, which is applied in the field of preparation of D--α-sulbenicillin sodium, can solve the problem that the conversion rate of production intermediates is not very high, the yield of synthetic products is affected, and the stability is uncertain, etc. problems, to achieve the effect of shortening the synthesis steps, low toxicity and stable properties

Inactive Publication Date: 2018-05-29
HUNAN ER KANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chen Qingping, "Carbonyldiimidazole acylating agent used in the synthesis of cephalosporin" (Journal of China Pharmaceutical University 1988, 19(3): 192-196) used side group acid to react with carbonyldiimidazole in anhydrous Reaction in DMSO, the conversion rate of the production intermediate is not very high, and the stability of the intermediate in the solvent is also uncertain, which will affect the yield of subsequent synthetic products

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Dissolve 100g of sulfophenylacetic acid in a mixed solvent of 500mL of dichloromethane and toluene, the mixing volume ratio of dichloromethane and toluene is 1.5:4.0, stir rapidly, and then add 100mL of triethanolamine until the solution is clear. Cool down to -10°C and add 62.2 g of carbonyldiimidazole, keep it at -10°C for 1.5 hours to prepare a mixed acyl imidazole acylating agent solution, and refrigerate at -15°C for later use.

[0035]Preparation of D-(-)-α-sulfbenicillin sodium: Suspend 35 g (0.16 mol) of 6-APA in 300 mL of water-acetone-isopropanol mixed solution with a volume ratio of 0.5:1:1.5. Cool down to -5°C, and adjust the pH to 8 with triethanolamine water to completely dissolve 6-APA. Under an ice bath, add the mixed acyl imidazole acylating agent solution dropwise to the above solution at a rate of 5% volume per minute. After the drop is complete, keep stirring at 10°C for 45 minutes. The reaction solution was washed with ether (70 mL × 2), and n-buta...

Embodiment 2

[0037] Dissolve 110g of sulfophenylacetic acid in a mixed solvent of 500mL of dichloromethane and toluene, the mixing volume ratio of dichloromethane and toluene is 2.5:4.5, stir rapidly, and then add 100mL of triethanolamine until the solution is clear. Cool down to -10°C and add 56.6g of carbonyldiimidazole, keep it at -10°C for 1.5h to prepare a mixed acyl imidazole acylating agent solution, and refrigerate at -15°C for later use.

[0038] Preparation of D-(-)-α-sulfbenicillin sodium: Suspend 30 g (0.14 mol) of 6-APA in 300 mL of water-acetone-isopropanol mixed solution with a volume ratio of 0.8:1:2.5. Cool down to -5°C, and adjust the pH to 8 with triethanolamine water to completely dissolve 6-APA. Under ice-cooling, add the mixed acyl imidazole acylating agent solution dropwise to the above solution at a rate of 10% volume per minute. After the drop is complete, keep stirring at 10°C for 45 minutes. The reaction solution was washed with diethyl ether (70 mL × 2), and n-...

Embodiment 3

[0040] Dissolve 150g of sulfophenylacetic acid in a mixed solvent of 500mL of dichloromethane and toluene, the mixing volume ratio of dichloromethane and toluene is 1.5:4.0, stir rapidly, and then add 120mL of triethanolamine until the solution is clear. Cool down to -10°C and add 70.6 g of carbonyldiimidazole, keep it at -10°C for 1.5 hours to prepare a mixed acyl imidazole acylating agent solution, and refrigerate at -15°C for later use.

[0041] Preparation of D-(-)-α-sulfbenicillin sodium: Suspend 40 g (0.25 mol) of 6-APA in 300 mL of water-acetone-isopropanol mixed solution with a volume ratio of 1.2:1:2. Cool down to -5°C, and adjust the pH to 8 with triethanolamine water to completely dissolve 6-APA. Under an ice bath, add the mixed acyl imidazole acylating agent solution dropwise to the above solution at a rate of 8% volume per minute. After the drop is complete, keep stirring at 10°C for 45 minutes. The reaction solution was washed with ether (70 mL × 2), and n-butan...

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Abstract

The invention provides a preparation method of D-(-)-alpha-sulbenicillin sodium. The method comprises the following steps: taking alpha-sulfonylphenylacetic acid as an initial raw material, performinga reaction with carbonyl diimidazole to generate an acyl imidazoles acylating agent, and performing condensation with 6-APA to obtain a diastereomer of sulbenicillin; separating D-(-)-alpha-sulbenicillin by a recrystallization method, and forming salt with sodium hydroxide to obtain the D-(-)-alpha-sulbenicillin sodium. During a acid anhydrides preparation process, usage of a severe-toxicity substance is avoided, during a preparation process, recrystallization is used, and the optically pure D-(-)-alpha-sulbenicillin is prepared, cost is saved, operation is simplified, yield is increased, andthe method is in favor of industrial production and environment protection.

Description

technical field [0001] The invention relates to a preparation method of sulfbenicillin sodium, in particular to a preparation method of optically pure D-(-)-α-sulfbenicillin sodium. Background technique [0002] Sulbenicillin sodium, the English name is sulbenicillin disodium, the Chinese chemical name is: (2S, 5R, 6R)-3,3-dimethyl-6-(2-phenyl-2-sulfoacetamido)-7- Oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid disodium salt. [0003] Its molecular formula is C 16 h 16 N 2 Na 2 o 7 S 2 , the molecular weight is 458.42. [0004] Its structural formula is: [0005] [0006] Sulbenicillin sodium is an optically active broad-spectrum semi-synthetic penicillin developed by Japan's Takeda Pharmaceutical Company. Sulbenicillin sodium binds to the penicillin-binding protein on the cell membrane and hinders the synthesis of bacterial cell wall mucopeptides, making it unable to cross-link The resulting cell wall defect, resulting in bacterial cell rupture and death...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/62
CPCC07D499/62
Inventor 帅放文王向峰章家伟
Owner HUNAN ER KANG PHARMA
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