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Synthesis method for sulbactam

A technology of sulbactamic acid and its synthetic method, which is applied in the field of sulbactamic acid synthesis, can solve the problems of unsuitability for large-scale industrial production, unstable quality of finished products, high cost of raw materials, etc., and achieve outstanding substantive characteristics, turbidity and Good purity and improved total yield

Inactive Publication Date: 2012-07-04
YIYUAN XINQUAN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] For the reported synthetic methods (US 4420426[P], 1983; US 4590073[P], 1986), there are mainly shortcomings such as relatively high cost of raw materials, complicated operation, many side reactions, low reaction yield, and unstable quality of finished products. , not suitable for large-scale industrial production

Method used

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  • Synthesis method for sulbactam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] (1) Add 500mL of ethyl acetate and 172.3g (1mol) of 47wt% hydrobromic acid into a 1000mL three-necked flask, stir and cool down to 0°C, then add 64g (0.4mol) of bromine and 6.9g (0.1mol) of sodium nitrite , and kept stirring, after dissolving, add 6-APA21.6g (0.1mol) in batches, control the reaction temperature at 4°C for 5h, then add 1mol.L -1 NaHSO 3 Neutralize the excess bromine until the reaction solution is milky yellow, let it stand and separate the layers, extract the aqueous layer twice with 100mL of ethyl acetate and combine the organic layer, then wash with 100mL of water, 100mL of 7% NaHCO 3 aqueous solution, saturated NaCl solution (50ml × 2) was washed until the organic layer was colorless, and the solvent was evaporated under reduced pressure to obtain 34.1 g of 6,6-dibromopenicillanic acid with a yield of 95% (according to 6-APA, the yield =Dry product weight / (6-APA substance quantity×359)).

[0019] (2) Dissolve 34.1g (0.095mol) of 6,6-dibromopenicilla...

Embodiment 2

[0022] (1) Add 600mL of ethyl acetate and 206.8g (1.2mol) of hydrobromic acid of 47wt% in a 1000mL three-necked flask, stir and cool down to 0°C, add 76.8g (0.48mol) of bromine and 8.28g (0.12mol) of sulfide Sodium nitrate, stirring continuously, add 25.9g (0.12mol) of 6-APA in batches after dissolving, control the reaction temperature at 4°C for 5h, then add dropwise 1mol·L -1 NaHSO 3 Neutralize the excess bromine until the reaction solution is milky yellow, let it stand and separate the layers, extract the aqueous layer twice with 100mL of ethyl acetate and combine the organic layer, then wash with 100mL of water, 100mL of 7% NaHCO 3 Aqueous solution, saturated NaCl solution (50ml * 2) wash until the organic layer is colorless, evaporate solvent under reduced pressure to obtain 6,6-dibromopenicillanic acid 41.2g, yield is 95.6% (according to 6-APA, yield =Dry product weight / (6-APA substance quantity×359)).

[0023] (2) Dissolve 41.2g (0.115mol) of 6,6-dibromopenicillanic a...

Embodiment 3

[0026] (1) Add 500mL of ethyl acetate and 172.3g (1mol) of 47wt% hydrobromic acid into a 1000mL three-necked flask, stir and cool down to 0°C, then add 64g (0.4mol) of bromine and 6.9g (0.1mol) of sodium nitrite , and kept stirring, after dissolving, add 21.6g (0.1mol) of 6-APA in batches, control the reaction temperature at 0°C for 3h, then add 1mol·L -l NaHSO 3 Neutralize the excess bromine until the reaction solution is milky yellow, let it stand and separate the layers, extract the aqueous layer twice with 100mL of ethyl acetate and combine the organic layer, then wash with 100mL of water, 100mL of 7% NaHCO 3 aqueous solution, saturated NaCl solution (50ml × 2) was washed until the organic layer was colorless, and the solvent was evaporated under reduced pressure to obtain 33g of 6,6-dibromopenicillanic acid with a yield of 92% (based on 6-APA, the yield = Dry product weight / (6-APA substance quantity×359)).

[0027] (2) Dissolve 33g (0.092mol) of 6,6-dibromopenicillanic ...

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Abstract

The invention belongs to the field of chemical synthesis, and specifically to a synthesis method for sulbactam. According to the method, 6-APA is adopted as a raw material, and bromine is adopted as a brominating agent to carry out a diazotization-bromination reaction; the resulting material is oxidized into sulfone through potassium permanganate; finally the sulfone is subjected to hydrogenation reduction in the presence of a catalyst to prepare the sulbactam, wherein the total yield of the product is 75%. The main characteristics of the method of the invention are that: in the step (1), hydrobromic acid is adopted as the medium so as to increase the reaction conversion rate; in the step (2), a phase transfer catalyst is introduced, and a brominated quaternary ammonium salt is adopted to catalyze the two-phase reaction, such that characteristics of high yield, recovery of the catalyst, and the like are provided; in the step (3), Raney nickel is adopted as the catalyst to catalyze the hydrogenation reduction reaction so as to improve the purity and the total yield of the product. Compared to the traditional process, the method of the present invention has the following advantages that: the process conditions are reasonable, the operation is safe and reliable, the production cost is low, and great practical values and economic benefits are provided.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a synthetic method of sulbactamic acid. Background technique [0002] Sulbactamic acid, the chemical name is (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-4,4-di oxide. It was first developed by Pfizer Research Laboratory in the United States. It has the characteristics of relatively stable properties, easy preparation, obvious effect and high cost performance. It is a pharmaceutical intermediate with high application value when used in combination with β-lactam antibiotics. [0003] The traditional synthetic technique of sulbactamic acid (Suren Husinec, et.al.[J] Collection of Czechoslovak Chemical Communications, 1989,54,1370) mainly contains two kinds: the first is based on 6-aminopenicillanic acid (6 -APA) as the starting material, carry out diazotization and bromination reactions with sodium nitrite and bromine in the organic phase of ethyl ace...

Claims

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Application Information

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IPC IPC(8): C07D499/86C07D499/04
Inventor 王孟
Owner YIYUAN XINQUAN CHEM
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