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Method for preparing D (-)-sulbenicillin sodium

A technology of sulbenicillin sodium and sulbenicillin, which is applied in the direction of organic chemistry, can solve the problems of high production cost, poor solubility, and difficult industrialization, so as to avoid poor control of pH value, reduce the generation of impurities, and facilitate industrialization Effect

Active Publication Date: 2014-07-30
山东安信制药有限公司
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0017] In the above synthesis method, route 1 directly produces sulfbenicillin by reacting D(-)-sulfophenylacetyl chloride with 6-APA. In this method, due to the poor solubility of D(-)-sulfophenylacetyl chloride, the reaction yield low, with many impurities, and industrialization is difficult; in route 2, the intermediate is made into a mixed anhydride generated by pivaloyl chloride, and 6-APA is silane-protected at the same time, and then reacted with the mixed anhydride to improve the intermediate. Solubility problem, at the same time, after the acetylation of 6-APA, the activity of its condensation reaction is enhanced, and the generation of impurities is reduced, but the acidity of the exposed sulfonic acid group in the route is strong, and the solubility needs to be further improved. At the same time, due to the use of pivaloyl chloride, More expensive reagents such as BSA have higher production costs; in Route 3, ethyl iodide is used to protect the sulfonic acid group, which increases the solubility of the subsequent intermediate, but the sulfbenicillin obtained by the direct reaction of the acyl chloride generated with 6-APA, Impurities are still high, and ethyl iodide reagent is used at the same time, the price is high, and the production cost is increased

Method used

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  • Method for preparing D (-)-sulbenicillin sodium
  • Method for preparing D (-)-sulbenicillin sodium
  • Method for preparing D (-)-sulbenicillin sodium

Examples

Experimental program
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Embodiment 1

[0032] Embodiment 1: the preparation of compound a

[0033] Dissolve 100g (0.463mol) D(-)-sulfophenylacetic acid in 1000ml toluene, slowly add 150.9g chlorosulfonic acid (1.30mol) dropwise at room temperature, keep warm for 1.5 hours after the dropwise addition, and distill toluene under reduced pressure. Add 800ml of petroleum ether, stir for 0.5 hours, filter, and dry at 40-50°C for 4 hours to obtain 115.0g of compound a, with a yield of 98.1%, HPLC content of 98.6%, m.p: 65-68°C, ESI (m / z): 253.1.

Embodiment 2

[0034] Embodiment 2: the preparation of the compound b of acetyl protection

[0035] 100g of intermediate a (0.395mol) prepared in Example 1 was dissolved in 600ml of dichloromethane, and the dichloromethane solution of acetic anhydride was added dropwise at room temperature [dissolve 120.0g of acetic anhydride (1.175mol) in 100ml of dichloromethane in methane], react at room temperature for 1.0 hour after adding, after TLC detects that the reaction is complete, distill the solvent under reduced pressure, add 600ml of petroleum ether, stir for 0.5 hour, filter, and dry to obtain 115.4g of compound b protected by acetyl group, the yield 97.3%, HPLC content 98.1%, m.p: 87-90°C, ESI (m / z): 300.

Embodiment 3

[0036] Embodiment 3: the preparation of D (-)-sulfabenicillin sodium

[0037] Dissolve 100g of intermediate b (0.333mol) obtained in Example 2 in 600ml of dichloromethane, lower the temperature to 0~5°C, add 79.2g (0.366mol) of 6-APA in batches, and keep warm for 1.5 hours after the addition. After the TLC detection reaction was complete, dichloromethane was evaporated under reduced pressure, 300ml of water was added, 10% sulfuric acid was added dropwise under stirring to adjust the pH to 1.5~2.0, stirred for 1 hour, 400ml of n-butanol was added to extract once, and after standing for stratification Then add 400ml of n-butanol for extraction once, combine the organic phases, add 150ml of water to wash once, then add 200ml of water, control the temperature at 0~5°C, add dropwise 5% sodium bicarbonate solution to adjust the pH to 6.5-7.0, static After separation, the organic phase was washed with 50ml of water, the layers were allowed to stand, the aqueous phases were combined, ...

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Abstract

The invention discloses a method for preparing D(-)-sulbenicillin sodium, belongs to the technical field of medicine. The method comprises the following steps that D(-)-sulfophenylacetic acid and chlorosulfonic acid react to generate a compound a, and the compound a and anhydride react to generate a compound b; then the compound b and 6-APA react to obtain D(-)-sulbenicillin; and the D(-)-sulbenicillin and alkali react and then are subjected to freeze-drying to obtain the D(-)-sulbenicillin sodium. Sulfo group and carboxyl group are generated into a mixed anhydride mode at the same time through an intermediate b prepared by the preparation method, the polarity is small, and the solubility in an organic solvent is good. Meanwhile, as the highly-acidic sulfo group is protected, the problem that the pH value in the reaction process is difficultly controlled is solved. The efficiency is increased, and the impurity generation is reduced. The sulbenicillin sodium prepared by the method has high yield and good quality and is easier to industrialize.

Description

technical field [0001] The invention relates to a preparation method of D(-)-sulfbenicillin sodium, which belongs to the technical field of medicine. Background technique [0002] Sulbenicillin sodium, chemical name: (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 weight: 458.42; molecular formula: C 16 h 16 N 2 Na 2 o 7 S 2 , the structural formula is: [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 effect. This product also has antibacterial activity against hemolytic Streptococcus, Streptococcus pneumoniae and staphylococci that do not produce penicillinase. This ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/62C07D499/14
Inventor 杨庆坤张雷雷周先国李哲杨波勇吴柯张兆珍董廷华李保勇
Owner 山东安信制药有限公司
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