Synthesis method for 7-neophedan-3-chloromethyl cephalosporanic p-methoxy benzyl ester

A technology of chloromethyl cephalosporanic acid and p-methoxybenzyl ester, which is applied in the field of pharmaceutical synthesis, can solve the problems of too many dichlorotrichloro compounds, difficult to realize industrialization, complicated equipment, etc., and achieves simple equipment operation and simplified operation. , the effect of investment reduction

Inactive Publication Date: 2009-05-13
上海五洲药业股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0023] 3. Electrolytic chlorination requires complex equipment, but dichloromethane, sodium hypochlorite and other chlorinating agents are used to form too many dichloro and trichloro compounds
[0024] 4. Difficult to handle after closed ring, dimethyl formamide, dichloromethane, ethanol are used in a large number of various solvents, it is difficult to realize industrialization

Method used

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  • Synthesis method for 7-neophedan-3-chloromethyl cephalosporanic p-methoxy benzyl ester
  • Synthesis method for 7-neophedan-3-chloromethyl cephalosporanic p-methoxy benzyl ester
  • Synthesis method for 7-neophedan-3-chloromethyl cephalosporanic p-methoxy benzyl ester

Examples

Experimental program
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Effect test

example 1

[0073] Example 1 Chloro

[0074] 60g of p-methoxybenzyl alcohol (0.43mmol), add 300ml of toluene, cool to -10°C, add 3g of tetrabutylammonium bromide (0.009mmol), 1g of zinc chloride (0.007mmol), at -10~0°C Next, 150ml of 30% hydrochloric acid (1.444mmol) was added dropwise for about 0.5h, while maintaining the reaction for 1h, the hydrochloric acid layer was removed, and the p-methoxybenzyl chloride solution was set aside.

[0075] 1. Esterification

[0076] Add 150g (0.40mmol) of penicillin G potassium, 15g (0.046mmol) of tetrabutylammonium bromide, and 72ml of DMF to the above-mentioned p-methoxybenzyl chloride solution, keep stirring at 30-32°C for 10-12 hours, and add 300ml of water Stand to separate layers, remove the water layer (containing DMF), and leave the penicillin p-methoxybenzyl ester toluene solution for future use.

[0077] 2. Oxidation

[0078] The above toluene solution of penicillin p-methoxybenzyl ester was cooled to -10~-5°C, 150ml (0.43mmol) of 22±2% ...

example 2

[0089] 1. Chlorine

[0090] 60g of p-methoxybenzyl alcohol (0.43mmol), add 300ml of toluene, cool to 0°C, add 3g of tetrabutylammonium bromide (0.009mmol), 1g of zinc chloride (0.007mmol), at 0~10°C, 150ml of 30% hydrochloric acid (1.444mmol) was added dropwise for about 0.5h, while maintaining the reaction for 1h, the hydrochloric acid layer was removed, and the p-methoxybenzyl chloride layer was set aside.

[0091] 2. Esterification

[0092] Add 150g (0.40mmol) of potassium penicillin G (0.40mmol), 15g (0.046mmol) of tetrabutylammonium bromide, and 72ml of DMF to the above-mentioned toluene layer, keep stirring at 25-30°C for 10-12 hours, add 300ml of water and let it stand for stratification. (containing DMF), and the toluene layer of penicillin p-methoxybenzyl ester for later use.

[0093] 3. Oxidation

[0094] The above toluene solution of penicillin p-methoxybenzyl ester was cooled to -20~-10°C, and 150ml (0.43mmol) of 22±2% peracetic acid was added dropwise for about...

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Abstract

The invention provides a method for synthesizing 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (GCLE). The method produces the GCLE by taking methoxybenzyl alcohol as a raw material through steps such as esterification and oxidation, ring opening and exchange, chlorization and ring closure and so on. The method has the advantages that the method has a simplified solvent and easy recovery, obviously improves the quality, ensures that the content is more than or equal to 95 percent, reduces the cost, has convenient operation, and is easy for industrialized production.

Description

Technical field: [0001] The invention relates to drug synthesis, in particular to a synthesis method of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (abbreviated as GCLE). Background technique: [0002] 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (GCLE for short) is an important antibiotic raw material, and it is one of the important semi-synthetic antibiotic mother nuclei, and another after 7ACA and 7ADCA The new mother nucleus can be used as a lead compound to prepare a new generation of cephalosporins containing double bonds at the C3 position, thiomethyl groups, and quaternary ammonium salts. Such as cefixime, cefprozil, ceftazidime. Because its 3 bits are -CH 2 Cl base, and more active, easier to synthesize new cephalosporins. [0003] The production method of relevant 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (GCLE) mainly contains: [0004] 1. About the synthesis of pe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/24
Inventor 孙海全
Owner 上海五洲药业股份有限公司
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