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Synthesis method for aztreonam

A synthetic method, the technology of aztreonam, applied in the direction of organic chemistry, etc., can solve the problems of difficult removal of by-product M, large environmental pollution, difficult disposal of waste liquid, etc., to achieve improved yield and purity, good atom economy, The effect of reducing the amount of waste acid

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

[0007] The atom economy of this method is relatively poor, and the by-product M is difficult to remove, thereby affecting the product quality; in addition, heating and removing the tert-butyl group under strong acidic conditions is easy to destroy the aztreonam β-lactam ring, which affects the yield and quality
If trifluoroacetic acid is used, it is highly toxic and uneconomical, cannot be recycled, and causes great environmental pollution
Chinese invention patent CN101514200 adopts the method of combined use of acetic acid / hydrochloric acid for deprotection, although the reaction temperature is lowered, but the mixed acid makes the waste liquid more difficult to handle

Method used

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  • Synthesis method for aztreonam
  • Synthesis method for aztreonam
  • Synthesis method for aztreonam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] In a 500mL three-necked flask, add 50.7g (0.182mol) of triphenylphosphine oxide (TPPO), 100g of dichloromethane, and add 18.1g (0.061mol) of bis(trichloromethyl)carbonate (BTC ) and 50g of dichloromethane, after the dropwise addition, keep warm for 2 hours to prepare a solution containing dichlorotriphenylphosphine.

Embodiment 2

[0030]In a 500mL three-necked flask, add 50.7g (0.182 mol) triphenylphosphine oxide (TPPO), 100g 1,2-dichloroethane, dropwise add 18.1g (0.061 mol) bis(trichloromethyl ) Carbonate (BTC) and 50g of 1,2-dichloroethane solution, after the dropwise addition, keep warm for 2 hours to prepare a solution containing dichlorotriphenylphosphine.

[0031] (2) 2-[[(Z)-1-(2-amino-4-thiazolyl)-2-chloro-2-oxoethylene]amino]oxy-2-methylpropion hydrochloride ( IV) Preparation

Embodiment 3

[0033] In a 1L four-neck flask, add 50.0g (0.152 mol) of compound (III) and 50g of dichloromethane, and add the dichlorotriphenylphosphine solution prepared in Example 1 dropwise at -15°C, and keep the reaction for 3 hours. Raise the temperature to 0°C, inject HCl gas to saturation, and keep stirring for 1 h. Add 400g of petroleum ether and stir for 30min. After suction filtration, the filter cake was vacuum-dried to obtain 45.4 g of compound (IV), with a yield of 82.3%. The mother liquor was evaporated to remove the solvent, and the solid was recrystallized from 300 g of toluene to recover 46.4 g of triphenylphosphine oxide, with a recovery rate of 91.5%.

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Abstract

The invention provides a synthesis method for aztreonam. The synthesis method for the aztreonam particularly comprises the following steps: preparing 2-[[(Z)-1-(2-amino-4-thiazolyl)-2-chlorine-2-oxo ethylidene]amino]oxygen-2-methyl propionic acid hydrochloride (IV) by using (2-amino thiazolyl-4-yl)-2-(tert-butyl oxycarbonyl)-isopropoxy iminodiacetic acid (III) as a starting material under the action of a BTC / TPPO system and HCl gas; and performing condensation on aztreonam parent nucleus (II) to directly obtain the aztreonam. Compared with the traditional process, the new process has the characteristics as follows: (1) an acyl chloride method is adopted, so damage to beta-lactam ring by strong acid in the traditional process is avoided from the source; (2) residue of 2-mercaptobenzothiazole (M) of the product is eliminated from the source; (3) the used reaction reagent triphenylphosphine oxide (TPPO) can be recycled and is environment-friendly; and (4) in the aztreonam product, the yield is high and the purity is over 99 percent, so important industrialized application prospect is achieved.

Description

(1) Technical field [0001] The invention relates to a method for synthesizing aztreonam, which belongs to the field of medicine and chemical industry. (2) Background technology [0002] Aztreonam is a synthetic monocyclic β-lactam antibiotic disclosed in US4775670, the chemical name is: [2S-[2α,3β(Z)]-2-[[[1-(2- Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylene]amino]oxy On behalf of] -2-methylpropionic acid, molecular formula: C 13 h 17 N 5 o 8 S 2 , molecular weight: 435.44, structural formula (I): [0003] [0004] Aztreonam mainly acts on sensitive aerobic or concurrently anaerobic Gram-negative bacteria and Pseudomonas aeruginosa, such as Escherichia coli, Klebsiella, Serratia, Proteus mirabilis, indole-positive Proteus, citronella Acid bacilli, Haemophilus influenzae, Pseudomonas aeruginosa and other pseudomonas, certain Enterobacter species, Neisseria gonorrhoeae, etc. Clinically, it is mainly used to treat various infections c...

Claims

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Application Information

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IPC IPC(8): C07D417/12
Inventor 郑仙明王光明顾士崇刘会军王敏卢明江
Owner ZHEJIANG HUAFANG PHARMA
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