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7-amino-3-vinyl cephalosporanic acid preparation method

A technology based on cephalosporanic acid and vinyl, which is applied in the field of preparation of 7-amino-3-vinyl cephalosporanic acid, can solve the problems of poor product purity, many side reactions, and difficulty in solvent recovery, and achieve good quality and high-quality products. The effect of high yield and less waste

Active Publication Date: 2017-03-22
QILU ANTIBIOTICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this process solves the problem of recycling sodium iodide and formaldehyde, the "one pot method" simultaneously undergoes quaternary phosphine and vinylation reactions in a strong alkali environment for a long time, resulting in many side reactions, poor product purity, and crystallization. The purity of GVNE is less than 98%, and the purity of GVNE obtained after the aqueous phase is applied for 5 times is reduced to 96%. Moreover, the mixed solvent of dichloromethane and acetone is used in the reaction, which brings great difficulties to solvent recovery.

Method used

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  • 7-amino-3-vinyl cephalosporanic acid preparation method
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Examples

Experimental program
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Effect test

Embodiment 1

[0035]Add 400ml of chloroform and 400ml of water to the reaction bottle, and add 60g (123.2mmol) of 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (GCLE), 18.5g (123.2mmol) of Sodium iodide and 34g (129.6mmol) triphenylphosphine were maintained at 30-35°C for reaction, and the reaction progress was monitored by HPLC. After 2 hours, the reaction was basically completed. Separate layers, lower the temperature of the lower organic phase to 0-5°C, add 400ml of 1.6% aqueous sodium hydroxide solution (w / w), and keep stirring at 0-5°C for 0.5h. The layers were separated, the upper aqueous phase was retained and used mechanically as the aqueous phase containing sodium iodide, and the lower organic phase was washed with 400ml of water. Add 75ml of 37% formaldehyde aqueous solution (w / w) and 4g of tetrabutylammonium bromide to the organic phase, stir thoroughly at 0-10°C, monitor the reaction progress with HPLC, and the reaction is basically completed after ...

Embodiment 2

[0037] Transfer the aqueous phase containing sodium iodide to be applied mechanically into the reaction flask, adjust the pH to 6-7 with 10% hydrochloric acid, add 400ml of chloroform, 60g (123.2mmol) of 7-phenylacetamido-3-chloromethylcephalosporanic acid p-Methoxybenzyl ester (GCLE), 34g (129.6mmol) triphenylphosphine, maintain the reaction at 30-35°C, monitor the reaction progress with HPLC, and the reaction is basically completed after 2h. Separate layers, lower the temperature of the lower organic phase to 0-5°C, add 400ml of 1.6% aqueous sodium hydroxide solution (w / w), and keep stirring at 0-5°C for 0.5h. The layers were separated, the upper aqueous phase was retained and used mechanically as the aqueous phase containing sodium iodide, and the lower organic phase was washed with 400ml of water. Add 10ml of formaldehyde-containing aqueous phase and 37% formaldehyde aqueous solution (w / w) to the organic phase, stir thoroughly at 0-10°C, monitor the reaction progress with ...

Embodiment 3

[0039] Transfer the sodium iodide-containing aqueous phase to be applied mechanically into the reaction flask, adjust the pH to 6-7 with 10% hydrochloric acid, add 400ml of dichloromethane, 60g (123.2mmol) of 7-phenylacetamido-3-chloromethyl cephalosporin P-methoxybenzyl alkanoate (GCLE) and 34g (129.6mmol) triphenylphosphine were maintained at 30-35°C for the reaction, and the reaction progress was monitored by HPLC. After 2 hours, the reaction was basically completed. Separate layers, lower the temperature of the lower organic phase to 0-5°C, add 400ml of 1.6% aqueous sodium hydroxide solution (w / w), and keep stirring at 0-5°C for 0.5h. The layers were separated, the upper aqueous phase was retained and used mechanically as the aqueous phase containing sodium iodide, and the lower organic phase was washed with 400ml of water. Add 140ml of 20% formaldehyde aqueous solution (w / w) and 4g of tetrabutylammonium bromide to the organic phase, stir thoroughly at 0-10°C, monitor the ...

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Abstract

The invention belongs to the technical field of medicine synthesis, and especially discloses a method for preparing 7-amino-3-vinyl cephalosporanic acid. The preparation method takes GCLE as an initial raw material, the GCLE and sodium iodide and triphenylphosphine are reacted in a mixing system of an organic solvent and water to generate phosphine salt, a certain amount of alkali lye is added in an organic phase for reacting to generate the corresponding phosphorus ylide, excess free alkali in an organic phase is removed through washing, formaldehyde and ylide are added for a wittig reaction, the organic phase is concentrated to a certain weight, phenol is added for removing carboxyl protection, amino protection is removed, crystallization is carried out to obtain 7-AVCA. The synthesis method does not require a mixing organic solvent, can realize recovery of sodium iodide and formaldehyde, has the advantages of high product yield, good quality, no three wastes generation, and environmental protection, and is suitable for large scale industrial production.

Description

[0001] (1) Technical field [0002] The invention belongs to the technical field of medicine synthesis, in particular to a preparation method of 7-amino-3-vinyl cephalosporanic acid. [0003] (2) Background technology [0004] 7-Amino-3-vinylcephalosporanic acid (7-AVCA) chemical name is 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane- 2-ene-2-carboxylic acid is a key intermediate in the synthesis of the third-generation cephalosporins cefixime and cefdinir. Both cefixime and cefdinir are oral cephalosporin antibiotics with broad antibacterial spectrum, strong antibacterial activity, long duration of effective concentration, stability to β-lactamase, and high oral bioavailability, and have been widely used clinically. Have a good market prospect. [0005] [0006] There are many synthetic methods of 7-AVCA in domestic and foreign literature reports. The key to the synthesis is the introduction of the 3-position vinyl group, but the most suitable for industrial promo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/02C07D501/22C07D501/04
Inventor 史韶华侯传山付景龙王欣单红宾王勇进李凤侠汤沸
Owner QILU ANTIBIOTICS PHARMA
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