Aztreonam preparation method

A technology of aztreonam and amino, which is applied in the field of preparation of aztreonam compounds, can solve the problems of unfavorable industrial production, expensive raw materials, cumbersome steps, etc., and achieve the effects of stable source of raw materials, high purity, and simple operation

Inactive Publication Date: 2014-07-09
FUAN PHARM (GRP) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In summary, the above-mentioned preparation method of aztreonam has cumbersome steps, expensive raw materials, low conversion rate and other defects, which are unfavorable for industrialized production

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 12

[0037] Example 1 [2S-[2α,3β(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1- Preparation of tert-butyl sulfo-3-azetidinyl)amino]-2-oxoethylene]amino]oxo]-2-methylpropanoate

[0038] Mix 5 g of (S)-3-amino-2-oxo-1-azetidinesulfonic acid with (Z)-2-amino-a-[(1-tert-butoxycarbonyl-1-methylethoxy 14.61 g of benzothiazolethiol imino-4-thiazolyl acetate was put into the reaction flask, dissolved in 500 mL of acetone, and 4.3 mL of triethylamine was added at room temperature, stirred for 2.5 hours, cooled to 0°C, and added dropwise Trifluoroacetic acid, adjust the pH value to 4.5, then stir for 1.5 hours, filter, and dry the filter cake to obtain [3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)- [(1-tert-butoxycarbonyl-1-methylethoxy)imino]-acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid 11g, product The rate is 79%.

Embodiment 2

[0039] The preparation of embodiment 2 aztreonam

[0040] [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)-[(1-tert-butoxycarbonyl-1-methylethoxy)imino] -Acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid 5g was dissolved in 20mL of formic acid, added 30mL of anisole, cooled to 0°C, slowly added dropwise 2mol of dilute hydrochloric acid / L15mL, raised to room temperature after completion, stirred for 2 hours, then added ethyl acetate, continued to stir for 0.5 hours, filtered, washed the filter cake with ethyl acetate, dried to obtain 4 g of aztreonam crude product, yield 90%.

Embodiment 3

[0041] The refining of embodiment 3 aztreonam

[0042] Add 5g of crude product aztreonam into 5mL of deionized water, heat and stir to dissolve, add activated carbon for adsorption, filter, cool off, add 45mL of ethanol, cool to 5-10°C, stir, precipitate solid, filter, wash with absolute ethanol, Dried to obtain 4.5g of aztreonam compound refined product, yield 90%, HPLC purity 99.5%,

[0043] Chromatographic conditions:

[0044] Column: C 18 Column, 250×4.6mm, 5μm

[0045] Mobile phase: use 0.05mol / L potassium dihydrogen phosphate solution (adjust pH value to 3.0 with phosphoric acid)-acetonitrile (90:10) as mobile phase A, use 0.05mol / L potassium dihydrogen phosphate solution (adjust pH value with phosphoric acid) to 3.0) - acetonitrile (60:40) as mobile phase B; elute isocratically with mobile phase A first, and immediately perform linear gradient elution as shown in the table below after the aztreonam peak is eluted.

[0046]

[0047] Detection wavelength: 270nm

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Abstract

The present invention relates to an aztreonam compound preparation method, which comprises the following operation steps: (1) dissolving and mixing a compound represented by a formula (I) and a compound represented by a formula (II) with an organic solvent, adding an alkali at a room temperature, carrying out a complete stirring reaction, cooling to a temperature of -20-10 DEG C, adding trifluoroacetic acid in a dropwise manner, stirring, filtering, and drying the filter cake to obtain a compound represented by a formula (III); and dissolving the compound represented by the formula (III) in formic acid, adding anisole, cooling to a temperature of -20-10 DEG C, adding hydrochloric acid in a dropwise manner, stirring, adding ethyl acetate, stirring, filtering, washing the filter cake with ethyl acetate, and drying to obtain the aztreonam compound represented by a formula (IV). Compared with the aztreonam compound preparation method in the prior art, the aztreonam compound preparation method of the present invention has characteristics of stable raw material source, low price, low cost, short reaction period, simple operation, high yield, less three-waste, environmental pollution reduction and high product purity, and is suitable for industrial production. The formula I, II, III and IV are as the follows.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and specifically relates to a preparation method of aztreonam compound. Background technique [0002] Aztreonam is a monocyclic β-lactam antibiotic developed by Bristol-Myers Squibb (BMS). It is clinically used to treat various infections caused by sensitive aerobic Gram-negative bacteria, such as: urinary tract infection, lower respiratory tract infection, sepsis, intra-abdominal infection, gynecological infection, postoperative wounds and burns, ulcers and other skin and soft tissue infections. It is also used to treat the above-mentioned types of infections in nosocomial infections (such as nosocomial infections in immunocompromised patients). The compound is disclosed in U.S. Patent No. 4,775,670, and its chemical name is: [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)-[(1-carboxylic acid-1 -methylethoxy)imino]-acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, the mol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 蒋晨洪荣川郭子维
Owner FUAN PHARM (GRP) CO LTD
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