Sulbactam sodium preparation method

The technology of sulbactam sodium and sulbactam acid is applied in the field of β-lactamase inhibitor synthesis, which can solve the problems of high raw material cost, high bromide ion content and high processing cost, and achieves high reaction yield and simple operation. , the effect of reducing by-products

Inactive Publication Date: 2017-05-24
淄博鑫泉医药技术服务有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In the reported synthetic method, the first step in the preparation process of sulbactam acid all adopts the method of diazotization and bromine substitution to prepare bromopenicillanic acid, followed by hydrogen or metal reducing agent (magnesium powder, zinc powder)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Add purified water (220ml) to a three-necked flask, add 98% concentrated sulfuric acid (12g, 0.12mol), stir, cool to -5°C, add 6-APA (21.62g, 0.1mol), stir until dissolved; Add 10% sodium nitrite aqueous solution (82.8g, 0.12mol) dropwise, control the temperature at -7±1℃, add dropwise for 2h, keep it for 1h after dripping; add ethyl acetate (220ml), ethanol (50ml), copper Powder (1.9g, 0.03mol), add 50% hypophosphorous acid (15.84g, 0.12mol) dropwise, control the temperature at 5±1℃, add dropwise for 1h, keep warm and stir for 1h; filter after the end of warming, stand still, separate, acetic acid Extract the aqueous phase with ethyl ester and combine the organic phases;

[0032] (2) Cool the organic phase in step (1) to 5°C, add glacial acetic acid (12g, 0.2mol), 3% sulfuric acid aqueous solution (196g, 0.06mol), cool down; maintain the temperature at 7°C, add high manganese in batches Potassium acid (18.96g, 0.12mol), add in 30min, then keep for 2h; after the incub...

Embodiment 2

[0035] (1) Add purified water (320ml) to a three-necked flask, add 98% concentrated sulfuric acid (30g, 0.3mol), stir, and cool to -5°C, add 6-APA (21.62g, 0.1mol), and stir until dissolved; Add 10% sodium nitrite aqueous solution (207g, 0.3mol) dropwise, control the temperature to -2±1℃, add dropwise for 2h, keep the temperature for 4h after dripping; add ethyl acetate (320ml), ethanol (50ml), copper powder (9.53g, 0.15mol), add 50% hypophosphorous acid (66g, 0.5mol) dropwise, control the temperature at 7°C, add dropwise for 1h, keep stirring for 3h; filter after the end of incubation, stand still, separate the liquids, and extract the water with ethyl acetate Phase, combined organic phase;

[0036] (2) Cool the organic phase in step (1) to 5°C, add glacial acetic acid (30g, 0.5mol), 3% sulfuric acid aqueous solution (326.6g, 0.1mol), and cool down; maintain the temperature at 8°C and add high Potassium manganate (47.4g, 0.3mol), add in 30min, then keep for 2h; after the incuba...

Embodiment 3

[0039] (1) Add purified water (390ml) into a three-necked flask, add 38% concentrated hydrochloric acid (7.3g, 0.2mol), stir, cool to -5°C, add 6-APA (32.44g, 0.15mol), stir until dissolved ; Add 10% aqueous sodium nitrite (138g, 0.2mol) dropwise, control the temperature at -5°C, add dropwise for 2h, keep it for 3h after dripping; add dichloromethane (330ml), ethanol (50ml), copper powder ( 9.53g, 0.15mol), add 50% hypophosphorous acid (59.4g, 0.45mol) dropwise, control the temperature at 5°C, add dropwise for 1h, keep warm and stir for 2h; after the end of incubation, filter, stand still, separate liquids, dichloromethane extract water Phase, combined organic phase;

[0040] (2) Cool the organic phase in step (1) to 5°C, add glacial acetic acid (30g, 0.5mol), 3% sulfuric acid aqueous solution (196g, 0.06mol), cool down; maintain the temperature at 8°C, add high manganese in batches Potassium acid (47.41g, 0.3mol), add in 30min, then keep for 2h; after the incubation, add 20% hy...

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Abstract

The invention relates to a sulbactam sodium preparation method belongs to the technical field of synthesis of beta-lactamase inhibitors. The sulbactam sodium preparation method comprises the steps that 6-amino penicillanic acid (6-APA) is used as a raw material, reacts in strong acid and a sodium nitrite water solution, then reacts under the effects of copper powder and hypophosphorous acid, and then a target product sulbactam sodium is prepared through oxidation and substitution reaction. The reaction process is simple in operation, the method includes few reaction steps, a by-product is reduced, the final reaction yield is high, the treatment difficulty and cost after wastewater production are reduced, the pressure of environmental protection is reduced for enterprises, the product production cost is reduced, and the sulbactam sodium preparation method is suitable for industrial production.

Description

Technical field [0001] The invention relates to a preparation method of sulbactam sodium, and belongs to the technical field of β-lactamase inhibitor synthesis. Background technique [0002] Sulbactam sodium, chemical name: (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate -4,4-Dioxide. The structural formula is: [0003] [0004] Sulbactam sodium is a synthetic irreversible competitive β-lactamase inhibitor. It was first developed by the Pfizer laboratory in the United States. It is usually combined with penicillins and cephalosporins to avoid β-lactams. Enzyme destruction strengthens the antibacterial activity and is suitable for infections of the respiratory system, urinary system, skin and soft tissues. [0005] Sulbactam sodium is prepared by forming a salt with sulbactam acid and sodium salt. The synthesis of sulbactam acid takes 6-APA as a raw material and is prepared by diazotization, bromination substitution, oxidation, and reduction. There are tw...

Claims

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Application Information

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IPC IPC(8): C07D499/86
CPCC07D499/86
Inventor 唐锋张立明刘成学
Owner 淄博鑫泉医药技术服务有限公司
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