Sulbenicillin sodium compound and new preparation method thereof

Abstract

The invention relates to a sulbenicillin sodium compound and a new preparation method thereof. A racemic body containing not less than 75% of D-sulbenicillin sodium and not more than 25% of L-sulbenicillin sodium is obtained by a recrystallization method through the differences of dissolubilities of the D-sulbenicillin sodium and the L-sulbenicillin sodium in a mixed solvent of methanol and isopropyl alcohol. The invention has the advantages of simple reaction process, easy operation, low cost, and high product purity.

Description

technical field

[0001] The invention relates to a sulbenicillin sodium compound and a new preparation method thereof, belonging to the technical field of medicine. Background technique

[0002] Sulbenicillin sodium, the 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, molecular formula C 16 h 16 N 2 Na 2 o 7 S 2 , molecular weight 458.42, structural formula:

[0003]

[0004] Sulbenicillin sodium is a broad-spectrum semi-synthetic penicillin antibiotic, which is effective against Enterobacteriaceae such as Escherichia coli, Proteus, Enterobacter, Citrobacter, Salmonella and Shigella, as well as Pseudomonas aeruginosa Bacteria, Haemophilus influenzae, Neisseria and other Gram-negative bacteria have antibacterial activity; it also has antibacterial activity against hemolytic streptococcus, Streptococcus pneumoniae and staphylococcus that does not produce penicillinase; ...

Examples

Embodiment 1

[0026] The synthesis of embodiment 1α-sulfophenylacetyl chloride

[0027] Put 216g (1mol) of α-sulfophenylacetic acid into 400ml of anhydrous diethyl ether, stir well, slowly add 357g (3mol) of thionyl chloride dropwise, after the dropwise completion, add 20ml of triethylamine, at 40°C Stir the reaction for 20 hours, then evaporate diethyl ether and excess thionyl chloride under reduced pressure below 40°C, add 200ml of ether to the residue, evaporate the ether after fully stirring, then add 1000ml of petroleum ether, shake fully, and store at -25°C Freeze for 24 hours, pour off the supernatant, and add 1000ml of dry dichloromethane to the residue to dissolve.

Embodiment 2D

[0028] The synthesis of embodiment 2DL-sulfabenicillin sodium

[0029] Dissolve 216g (1mol) of 6-APA in 2000ml of dichloromethane, slowly add 290ml of triethylamine dropwise under vigorous stirring, then vigorously stir at about 10°C until the solids are completely dissolved, then drop slowly below 0°C Add the dichloromethane solution of α-sulfophenylacetyl chloride obtained in the step, and maintain the pH=7.5 of the reaction with triethylamine at the same time. After dropping, stir and react at room temperature for 2 hours, and pour the reaction solution into 2500ml of ice-water mixture , stirred, allowed to stand for layering, decolorized the water layer with activated carbon, then added 2500ml of n-butanol, adjusted the pH of the reaction solution to 1.5 with 5% sulfuric acid under stirring, collected the organic phase, and used 1000ml of n-butanol for the water layer Alcohol extraction, combined organic phases, and then adding saturated aqueous sodium carbonate to adjust ...

Embodiment 3

[0030] The synthesis of embodiment 3 sulbenicillin sodium

[0031] 300g of DL-sulfbenicillin sodium was added to the reaction flask, then 1500ml of methanol and isopropanol mixed solvent (1:3), heated to reflux for 2 hours, then cooled to room temperature, stirred for 3 hours, and filtered to obtain a white 105 g of solid (D-sulbenicillin sodium: L-sulbenicillin sodium = 3:1), yield 70%.

[0032] [α] 20 : +179°~+181°.

[0033] IR(KBr)ν: 2965 (phCH, stretching), 1767 (lactamC=O), 1673 (-CONH-), 1608 (-COO-), 1527, 1404, 1316, 1214, 1047 (-SO 3 H), 697cm -1 ;

[0034] 1 HNMR (D 2 O) δ: 1.409 (6H, t-CH 3 ×2), 4.130 (1H, d, -CH-COONa), 4.983 (1H, d, Ar-CH-C=O), 5.446 (2H, m, lactam C-H), 7.442 (5H, m, Ar-H ).

technical field

[0001] The invention relates to a sulbenicillin sodium compound and a new preparation method thereof, belonging to the technical field of medicine. Background technique

[0002] Sulbenicillin sodium, the 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, molecular formula C 16 h 16 N 2 Na 2 o 7 S 2 , molecular weight 458.42, structural formula:

[0003]

[0004] Sulbenicillin sodium is a broad-spectrum semi-synthetic penicillin antibiotic, which is effective against Enterobacteriaceae such as Escherichia coli, Proteus, Enterobacter, Citrobacter, Salmonella and Shigella, as well as Pseudomonas aeruginosa Bacteria, Haemophilus influenzae, Neisseria and other Gram-negative bacteria have antibacterial activity; it also has antibacterial activity against hemolytic streptococcus, Streptococcus pneumoniae and staphylococcus that does not produce penicillinase; ...

Examples

Embodiment 1

[0026] The synthesis of embodiment 1α-sulfophenylacetyl chloride

[0027] Put 216g (1mol) of α-sulfophenylacetic acid into 400ml of anhydrous diethyl ether, stir well, slowly add 357g (3mol) of thionyl chloride dropwise, after the dropwise completion, add 20ml of triethylamine, at 40°C Stir the reaction for 20 hours, then evaporate diethyl ether and excess thionyl chloride under reduced pressure below 40°C, add 200ml of ether to the residue, evaporate the ether after fully stirring, then add 1000ml of petroleum ether, shake fully, and store at -25°C Freeze for 24 hours, pour off the supernatant, and add 1000ml of dry dichloromethane to the residue to dissolve.

Embodiment 2D

[0028] The synthesis of embodiment 2DL-sulfabenicillin sodium

[0029] Dissolve 216g (1mol) of 6-APA in 2000ml of dichloromethane, slowly add 290ml of triethylamine dropwise under vigorous stirring, then vigorously stir at about 10°C until the solids are completely dissolved, then drop slowly below 0°C Add the dichloromethane solution of α-sulfophenylacetyl chloride obtained in the step, and maintain the pH=7.5 of the reaction with triethylamine at the same time. After dropping, stir and react at room temperature for 2 hours, and pour the reaction solution into 2500ml of ice-water mixture , stirred, allowed to stand for layering, decolorized the water layer with activated carbon, then added 2500ml of n-butanol, adjusted the pH of the reaction solution to 1.5 with 5% sulfuric acid under stirring, collected the organic phase, and used 1000ml of n-butanol for the water layer Alcohol extraction, combined organic phases, and then adding saturated aqueous sodium carbonate to adjust ...

Embodiment 3

[0030] The synthesis of embodiment 3 sulbenicillin sodium

[0031] 300g of DL-sulfbenicillin sodium was added to the reaction flask, then 1500ml of methanol and isopropanol mixed solvent (1:3), heated to reflux for 2 hours, then cooled to room temperature, stirred for 3 hours, and filtered to obtain a white 105 g of solid (D-sulbenicillin sodium: L-sulbenicillin sodium = 3:1), yield 70%.

[0032] [α] 20 : +179°~+181°.

[0033] IR(KBr)ν: 2965 (phCH, stretching), 1767 (lactamC=O), 1673 (-CONH-), 1608 (-COO-), 1527, 1404, 1316, 1214, 1047 (-SO 3 H), 697cm -1 ;

[0034] 1 HNMR (D 2 O) δ: 1.409 (6H, t-CH 3 ×2), 4.130 (1H, d, -CH-COONa), 4.983 (1H, d, Ar-CH-C=O), 5.446 (2H, m, lactam C-H), 7.442 (5H, m, Ar-H ).

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