Synthetic method of cefoxitin acid

A technology of cefoxitin acid and synthetic method, which is applied in the field of synthesis of cefoxitin acid, and achieves the effects of high yield, easy availability of raw materials, and good quality

Active Publication Date: 2015-03-11
YANCHENG KAIYUAN MEDICINE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is the need to use highly toxic thallium salts

Method used

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  • Synthetic method of cefoxitin acid
  • Synthetic method of cefoxitin acid
  • Synthetic method of cefoxitin acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] The synthesis of embodiment 1 tert-butyl hypochlorite

[0027] Add 37.0g (0.50mol) of tert-butanol and 33.0g (0.55mol) of glacial acetic acid into a 100mL beaker, stir and mix well for later use.

[0028] Add 405.8g (0.60mol) sodium hypochlorite to a 1000mL four-neck flask, dropwise add the prepared mixed solution of tert-butanol and glacial acetic acid, control the temperature during the dropwise addition at 20-25°C, and continue stirring for 2-4 hours after the addition is complete (GC detection tert-butanol<1%). After the reaction is complete, add about 100 mL of 5% sodium hydroxide aqueous solution dropwise, adjust the pH=6.5 to 7.0, stir at room temperature for 5 minutes, separate the liquids, wash the organic phase with 50 mL of 10% sodium chloride aqueous solution, separate the aqueous phase, and the organic phase is light 40.7 g of yellow liquid (tert-butyl hypochlorite), GC purity 96.3%, yield 72.2%.

Embodiment 2

[0029] The synthesis of embodiment 2 methoxy cephalothin benzathine salt

[0030] Put 150mL of methanol and 10.8g (0.20mol) of sodium methoxide into a 500mL four-neck flask, stir to dissolve, and cool down to -20--25°C for later use.

[0031] Put 600mL of dichloromethane, 39.6g (0.10mol) cephalothinic acid, 4.7g (0.01mol) trioctyl ammonium methyl ammonium bisulfate into a 2000mL four-neck flask, stir and cool down to -80~-90°C, dropwise to prepare The methanol solution of sodium methoxide, temperature control during the dropping process -80~-90°C, after the dropwise addition, 13.5g (0.12mol) tert-butyl hypochlorite prepared in the first step was added dropwise, and the temperature was controlled during the dropping process ‐80~‐90°C, after the dropwise addition is completed, control the temperature at ‐80~‐90°C and stir for 0.5~1h to obtain a methoxy compound solution (HPLC detection raw material cephalothinic acid<5%), the reaction is complete.

[0032] Add 9.5g (0.05mol) of...

Embodiment 3

[0049] The synthesis of embodiment 3 cefoxitin acid

[0050] Put 250mL of acetone and 50.5g (0.05mol) of methoxycefalotin benzathine salt into a 500mL four-neck flask, stir to dissolve, and cool down to -30--35°C for later use.

[0051] Add 28.3g (0.20mol) of CSI, control the temperature at ‐30~‐35°C and stir for 0.5~1h, then add 80.0g of 10% disodium hydrogen phosphate aqueous solution, control the temperature at 25~30°C and stir for 0.5~1h. Filter, transfer the filtrate to a 2L four-necked flask, and cool down to 0-5°C for later use.

[0052] Add 1500g of purified water dropwise, after dropping, control the temperature at 0-5°C to stir and crystallize for 1h, filter, beat the filter cake with 150g of purified water for 10 minutes, filter, put the filter cake (crude cefoxitin acid) into a 500mL four-necked flask for later use.

[0053] Add 300g of purified water, stir to cool down to 5-10°C, add about 8.0g of sodium phosphate in batches for alkali dissolution, control the pH...

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Abstract

The invention discloses a synthetic method of cefoxitin acid. Cephalotin acid used as a raw material reacts with prepared tert-butyl hypochlorite in the presence of sodium methylate to obtain a methoxy substance; the methoxy substance is subjected to a hydrolysis reaction and salt formation is carried out in the presence of benzathine to obtain methoxy cefalotin benzathine; methoxy cefalotin benzathine reacts with CSI, and hydrolysis is carried out to obtain a cefoxitin acid crude product; and the cefoxitin acid crude product undergoes the step of recrystallization to finally prepare cefoxitin acid. The synthetic method is simple to operate and is low-cost. By the synthetic method, quality and total yield reach 95.8%. The produced cefoxitin acid is a white solid powder, and purity of the product reaches more than 99.0%. The product has good quality and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing cefoxitin acid. Background technique [0002] Cefoxitin acid, chemical name: (6R,7R)‐3‐carbamoyloxymethyl‐7‐methoxy‐8‐oxo‐7‐[(2-thienyl)acetamido]‐5‐sulfur Hetero-1-azabicyclo[4,2,0]-oct-2-ene-2-carboxylic acid is a semi-synthetic cephamycin antibiotic developed by Merck Company of the United States. Its chemical structural formula is as follows: [0003] [0004] Clinically, the sodium salt of cefoxitin is used to make injections for the treatment of bacterial infections. The drug was first approved for marketing by Japan's Daiichi Pharmaceutical Development Company in August 1979 under the trade name Cenomycin. The antibacterial effect of cefoxitin is similar to that of second-generation cephalosporins, but because its structure contains a 7α-methoxy group, it greatly reduces the hydrolysis and destruction of β-lactamase in bacteria, and i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/57C07D501/04
CPCC07D501/04C07D501/57
Inventor 伊正革徐波刘悉承
Owner YANCHENG KAIYUAN MEDICINE CHEM
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