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Novel route for cefathiamidine compounds

A cefathiamidine and compound technology, which is applied in the field of synthesis of cephalosporins and cefathiamidine compounds, can solve the problems of deepening color, low content of crude products, instability under heat and the like, achieves improved purity and yield, and simple synthesis process , the effect of easy separation and purification

Inactive Publication Date: 2010-05-12
HAINAN LINGKANG PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Cefathiamidine has a unique molecular structure of zwitterionic inner salt, which is unstable when exposed to heat, and the product is easy to change color during storage, resulting in darker color
In the synthesis of cefathiamidine, Chinese patent CN1640878A uses bromoacetyl bromide, and bromide ions are likely to remain in the product. In addition, in the condensation reaction, the choice of solvent system is not good, the removal rate of impurities is not high, and the crude product content is low.
U.S. Patent USP3646025 and "Chinese Medicinal Chemical Impurities" 2001, 10, No. 11 both introduced the synthesis method of cefathiamidine, but they are all complicated, not easy to realize, high in cost, difficult to operate and difficult to guarantee quality

Method used

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  • Novel route for cefathiamidine compounds
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  • Novel route for cefathiamidine compounds

Examples

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Effect test

Embodiment 1

[0030] 1. Synthesis of N, N'-Diisopropylamidine Thioacetic Acid

[0031] Add 320 grams of N,N'-diisopropylthiourea and 200 grams of sodium bicarbonate to a mixed solvent of 2 liters of acetone and 500 ml of water, stir for 10 min, then add 278 grams of 2-bromoacetic acid in 500 ml of Acetone solution was stirred and reacted at room temperature for 2 hours, then the pH of the reaction was adjusted to 3 with 2 mol / L hydrochloric acid, then cooled to 0° C., stirred to precipitate a solid, filtered, and dried to obtain 410 g of the product, with a yield of 94%.

[0032] 2, the synthesis of cefathiamidine

[0033] Dissolve 510 grams of triphenylphosphine in 1 liter of 1,2-dichloroethane, add dropwise to 1 liter of 2-dichloroethane containing 550 grams of triphosgene, and keep the reaction temperature at 5°C, after the dropwise addition, react at this temperature for 2 hours, then add the mixture dropwise to 200 grams of N, N'-diisopropylamidinothioacetic acid in 800ml of 1,2-dichl...

Embodiment 2

[0038] 1. Synthesis of N, N'-Diisopropylamidine Thioacetic Acid

[0039] Add 640 grams of N, N'-diisopropylthiourea and 400 grams of sodium bicarbonate to a mixed solvent of 4 liters of acetone and 1000 ml of water, stir for 10 min, then add 1000 ml of 556 grams of 2-bromoacetic acid Acetone solution was stirred and reacted at room temperature for 2 hours, then the pH of the reaction was adjusted to 3.5 with 5 mol / L hydrochloric acid, then cooled to 0° C., stirred to precipitate a solid, filtered, and dried to obtain 813.9 g of the product, with a yield of 93.3%.

[0040] 2, the synthesis of cefathiamidine

[0041] 1020 grams of triphenylphosphine were dissolved in 2 liters of 1,2-ethylene dichloride, and added dropwise to 2 liters of 2-ethylene dichloride containing 1,100 grams of triphosgene, and the reaction temperature was maintained at 4°C, after the dropwise addition, react at this temperature for 2 hours, then add the mixture dropwise to 400 grams of N, N'-diisopropyla...

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Abstract

The invention provides a novel route for cefathiamidine compounds. The new route comprises the following steps of: reacting N,N'-diisopropyl thiourea and sodium bicarbonate, adding 2-bromacetic acid in the mixture for reaction, adding triphosgene and triphenylphosphine oxide serving as catalysts, reacting the product of the previous reaction with N,N'-diisopropyl amidine sulfur radical acetic acid to obtain solution(A), and adding the solution(A) to aqueous solution of 7-ACA dropwise for reaction to obtain the target product. The cefathiamidine compounds prepared by the method have the advantages of higher purity and yield, low-priced raw materials, simple synthesis process, simple equipment and easy separation and purification of products.

Description

technical field [0001] The invention relates to a cephalosporin compound, in particular to a synthesis method of a cefathiamidine compound, and belongs to the technical field of chemical synthesis. Background technique [0002] Cefathiamidine, its chemical name is: (6R,7R)-3[(acetoxy)methyl]-7-[α-(N,N'-diisopropylamidinothio)-acetamido]8- Oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate betaine, molecular formula C 19 h 28 N 4 o 6 S 2 , molecular weight 472.59, structural formula: [0003] [0004] It is a β-lactam antibiotic, the first-generation cephalosporin, and its antibacterial spectrum is similar to that of cephalothin. It has strong antibacterial effect on G+ bacteria, especially has a unique effect on G+ enterococci. A cephalosporin exclusive to cocci. It is mainly used for respiratory tract infection, biliary tract, urinary tract, gynecological diseases, sepsis, pneumonia, meningitis and other infections caused by sensitive bacteria. Sterile crystall...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/28C07D501/06B01J31/02B01J27/20A61P31/04
Inventor 邱民
Owner HAINAN LINGKANG PHARMA CO LTD
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