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Compound of aztreonam and a synthetic method thereof

A synthesis method and technology of aztreonam, applied in the directions of organic chemistry, bulk chemical production, antibacterial drugs, etc., can solve the problems of low sulfuric acid yield, difficult treatment, environmental hazards, etc., and achieve improved reaction yield and product purity. Improve and simplify the effect of processing

Inactive Publication Date: 2009-08-26
HAINAN LINGKANG PHARMA CO LTD
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  • Description
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Problems solved by technology

The problem with the above-mentioned method is that the cost of using trifluoroacetic acid in the reaction is high, and it cannot be recycled, and the yield of sulfuric acid is low, and ring-opening products are generated, and it cannot be recycled and applied mechanically, which is harmful to the environment.
U.S. Patent No. 5,254,681A discloses a method for preparing aztreonam, which includes using 2-(2-amino-4-thiazolyl)-2-(Z)-(alkoxyimino)acetic acid in 1-hydroxyl- Acylation of azetidine in the presence of benzotriazole and dicyclohexylcarbodiimide, the reagents used in this method are toxic and expensive, and they are also difficult to handle

Method used

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  • Compound of aztreonam and a synthetic method thereof
  • Compound of aztreonam and a synthetic method thereof
  • Compound of aztreonam and a synthetic method thereof

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Embodiment 1

[0021] The synthesis of embodiment 1 aztreonam

[0022] Add 100 g (0.56 mol) of (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid into the reaction flask, add 1,4-dioxane Ring 1000 ml and N-methylmorpholine 60 ml (0.6mol), the solution was cooled to 5 ° C, stirred until clear, added 800 ml of (2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl )-isopropoxyiminoacetic acid-2-mercaptobenzothiazolyl ester 268 grams (0.56mol) of the solution of 1,4-dioxane, stirred and reacted for 3 hours, then added 3000 milliliters of acetic acid aqueous solution of pH=5 and 1000 ml of ethyl acetate, stirred for 1 hour, separated into layers, removed the ethyl acetate layer, the ethyl acetate can be recovered and used mechanically, the aqueous phase was added with 10% hydrochloric acid to adjust the pH=1, the mixture was heated to 40°C, and kept for 2 hours, A solid was formed, cooled to room temperature, stirred, the solid was precipitated, left overnight, filtered, washed with water, and dr...

Embodiment 2

[0027] The refining of embodiment 2 aztreonam

[0028] Heat 3000 ml of absolute ethanol to 55°C, add 50 g of aztreonam crude product, stir until dissolved, add 6.04 g of activated carbon, stir and adsorb for 30 minutes, filter while hot, and slowly cool the filtrate to 0°C, precipitate solid, continue stirring for 4 hours, filtered, washed with 50 ml of water, and vacuum-dried at 50°C to obtain 46.2 g of white β-form aztreonam refined product, with a yield of 92.4%, a purity of 99.8%, and mp: 239-241°C.

[0029] Elemental analysis Molecular formula: C 13 h 19 N 5 o 8 S 2

[0030] Theoretical value C: 35.7%, H: 4.4%, N: 16.0%, O: 29.3%, S: 14.6%;

[0031]Experimental values ​​C: 35.5%, H: 4.4%, N: 16.1%, O: 29.4%, S: 14.7%.

[0032] H-NMR (D 2 O): δ6.95 (s, 1H), 4.67 (d, 1H, J=2Hz), 4.82 (qd, 1H, J=7, 2.5Hz), 1.58 (d, 1H, J=7.0Hz).

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Abstract

The invention provides a compound of aztreonam and a synthetic method thereof. In the method, general solvents are used, suitable amines are chosen, (2-aminothiazole-4-group)-2-(tert-butoxycarbonyl)-iminodiacetic acid isopropoxide acid-2-ester mercaptobenzothiazole and (3-S-trans form)-3-amino-4-methyl-2-oxo-1-sulfonic acid azetidine are used as intermediates; therefore, the method simplifies reaction and has good effect on depriving protecting groups by the mixed aqueous solution of acetic acid and hydrochloric acid.

Description

technical field [0001] The invention relates to a synthesis method of aztreonam compound, which belongs to the technical field of medicine. Background technique [0002] Aztreonam is a monocyclic lactam antibiotic disclosed in US 4775670, and its chemical name is: [2S-[2α, 3β(z)]]-2-[[[1-(2-amino-4-thiazole Base)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylene]amino]oxo]-2- Methylpropionic acid, the molecular formula is: C 13 h 19 N 5 o 8 S 2 , molecular weight: 437.44, structural formula: [0003] [0004] Aztreonam is a synthetic monocyclic β-lactam antibiotic with high antibacterial activity against most aerobic Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae, and Oxitobacter Bacillus aerogenes, Bacillus cloacae, Proteus, Serratia, Citrobacter, Shigella and other Enterobacteriaceae bacteria, as well as influenza bacillus, Neisseria gonorrhoeae, Neisseria meningitidis, etc. Pseudomonas also has good antibacterial effect. C...

Claims

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Application Information

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IPC IPC(8): C07D417/12A61P31/04
CPCY02P20/55
Inventor 张锡芬
Owner HAINAN LINGKANG PHARMA CO LTD
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