Synthetic method of Carumonam sodium

A synthesis method and organic solvent technology are applied in the synthesis field of calumonant sodium, can solve the problems of complicated steps, low yield and the like, and achieve the effects of simple operation, lower production cost, and avoidance of protection and deprotection

Inactive Publication Date: 2013-04-17
ZHEJIANG HUAFANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this process, both the amino group and the carboxyl group of the side chain acid of carumonan need to be protected, and after condensation with the β-lactam core, two deprotections are required to obtain lukamonan, which is cumbersome and has a low yield

Method used

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  • Synthetic method of Carumonam sodium
  • Synthetic method of Carumonam sodium
  • Synthetic method of Carumonam sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] In a 500mL three-neck flask, add (3S-trans)-3-amino-2-(carbamoyloxymethyl)-4-oxoazetidinesulfonic acid (23.9g, 0.1mol), dichloro 180mL of methane was stirred and dissolved, the temperature was lowered to 0-5°C, and triethylamine (40g, 0.4mol) was started to be added dropwise, while (Z)-2-(1-(2-aminothiazol-4-yl)- 2-Chloro-2-oxoethyleneaminooxy) acetic acid hydrochloride (30.0g, 0.1mol), control the reaction temperature at 0-5°C, pH to 7-8, after adding, keep warm at 0-5°C React for 3 hours, add 300g of purified water, stir for 15 minutes, statically separate into layers to obtain a water layer, add 2g of activated carbon to the water layer, stir for 20 minutes to decolorize, filter with suction, and adjust the pH value of the filtrate with 37.5wt% concentrated hydrochloric acid at 0-5°C 1.5 to 2.0, keep warm and stir for crystallization for 2 hours, filter with suction to get the wet product of Kalumonan.

[0046] In a 1000mL three-necked flask, add sodium acetate (18....

Embodiment 2

[0048] In a 500mL three-necked flask, add (3S-trans)-3-amino-2-(carbamoyloxymethyl)-4-oxoazetidinesulfonic acid (23.9g, 0.1mol), ethyl acetate 180ml of the ester was stirred and dissolved, the temperature was lowered to -5~0°C, and pyridine (23.7g, 0.3mol) was added dropwise, while (Z)-2-(1-(2-aminothiazol-4-yl)- 2-Chloro-2-oxoethyleneaminooxy) acetic acid hydrochloride (45.0g, 0.15mol), control the reaction temperature -5~0℃, pH to about 5~6, after adding, -5~ The reaction was carried out at 0°C for 3 hours, and the post-treatment was the same as in Example 1 to obtain the wet product of Kalumonan.

[0049] In a 1000mL three-neck flask, add sodium hydroxide (11.2g, 0.28mol) and 100ml of purified water, stir to dissolve, add the wet product of calumonan obtained above, stir and react at 0-10°C for 3 hours, add absolute ethanol dropwise 500ml, cooled to -20~-15°C, stirred and crystallized for 2 hours, suction filtered, and the filter cake was vacuum-dried at 40°C to obtain 36....

Embodiment 3

[0051] In a 500mL three-neck flask, add (3S-trans)-3-amino-2-(carbamoyloxymethyl)-4-oxoazetidinesulfonic acid (23.9g, 0.1mol), dichloro 180ml of methane was stirred and dissolved, the temperature was lowered to -20~-15°C, piperidine (31.6g, 0.4mol) was added dropwise, and (Z)-2-(1-(2-aminothiazol-4-yl )-2-Chloro-2-oxoethyleneaminooxy)acetic acid hydrochloride (36.0g, 0.12mol), control the reaction temperature -20~-15℃, pH to about 8~9, after adding, -20~-15°C heat preservation reaction for 3 hours, post-treatment as in Example 1, to obtain Kalumonan wet product.

[0052] In a 1000mL three-neck flask, add sodium carbonate (53g, 0.5mol) and 130ml of purified water, stir to dissolve, add the wet product of carumonan obtained above, stir and react at 40-50°C for 1 hour, add dropwise 300ml of tetrahydrofuran, and cool down to Stir and crystallize at -5 to 0°C for 2 hours, filter with suction, and vacuum-dry the filter cake at 60°C to obtain 37.3 g of calumonan sodium, with a yield...

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Abstract

The invention provides a synthetic method of Carumonam sodium, which can be specifically expressed as condensing 2-[[(Z)-1-(2-amino-4-thiazolyl)-2-chlorine-2-oxygen generation ethylidene]amino]oxygen-2-methyl acrylic acid hydrochloride and (3S-anti-form)-3-amino-2-(carbamoyl group oxygen methyl)-4-nitrogen heterocyclic oxygen generation butane sulfonic acid to obtain the Carumonam sodium directly, and further reacting the Carumonam sodium with inorganic base to obtain sodium salt. Compared with a traditional technique, the synthetic method has the following characteristics: (1), the damage of strong acid to beta-lactam ring in the traditional technique is avoided from the source by adopting chloride method; (2), the residual of 2-mercapto benzothiazole (M) in the product is eliminated from the source; and (3), the product yield of the Carumonam sodium is high, and the purity is more than 99 percent, so that the synthetic method has an important industrial application prospect.

Description

(1) Technical field [0001] The invention relates to a method for synthesizing carumonam sodium, which belongs to the technical field of medicine. (2) Background technology [0002] Carumonan sodium is a new monocyclic β-lactam antibiotic, its chemical name is: [[(Z)-[2-[[(2S,3S)-2-[[(carbonylamino)oxy ]methyl]-4-oxo-1-thioxo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-carbonylethyl]amino]oxy] - Acetic acid, disodium salt. [0003] Molecular formula: C 12 h 13 N 6 Na 2 o 10 S 2 . Molecular weight: 510.37. The structural formula is shown in formula (IV): [0004] [0005] Calumonan’s trade name is Amasulin, which was launched in Japan in 1988 and is mainly used in the treatment of Escherichia coli, Citrobacter, Klebsiella, Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa Infections caused by Bacillus and Haemophilus influenzae, respiratory tract infection, urinary system infection, cholangitis, cholecystitis, peritonitis and sepsis have received high cli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
Inventor 郑仙明王光明王敏卢明江钟为慧陈凯苏为科
Owner ZHEJIANG HUAFANG PHARMA
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