A kind of synthetic technology of cefoxitin

A technology for the synthesis of cefoxitin acid, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of high cost, difficulty in obtaining cephalosporanic acid, and low yield, reduce energy consumption and discharge of organic waste water, and be suitable for large-scale industrialization Effects on production, improved yield and product quality

Active Publication Date: 2016-11-16
LIAONING TIANHUA CHEM
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Problems solved by technology

[0006] 1) U.S. Patent US4297488 reports the synthesis of cefoxitin using cephamycin C as a raw material. The process is cumbersome, the yield is low, the cost is high, and the fermentation level of raw material cefoxitin C is low and difficult to obtain, so it has no industrial value
[0007] 2) Chinese patent CN101007812A has reported that with 7-MAC (methoxy cephalosporin) as raw material through 2-thiophene acetylation reaction, hydrolysis reaction and carbamoylation reaction obtain cefoxitin, because the price of 7-MAC is relatively Expensive, the process cost is not dominant
[0008] 3) Chinese patent CN101555252A reported that cefoxitin was obtained from 7-ACA (7-aminocephalosporanic acid) through acylation, methoxylation, hydrolysis and carbamoylation. The main method of industrial production of cefoxitin, but the operation is complicated, the yield is low, and the cost is high
[0009] Due to the starting materials in the existing route, one class is easy to get but complex structure cephamycin C, and the other is simple in structure but difficult to obtain various cephalosporanic acid derivatives; the process method is also relatively loaded down with trivial details, The yield is low and the operation is complicated. Therefore, there is an urgent need for a synthetic process with low raw material cost, simple process route, strong operability, high yield and low cost.

Method used

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  • A kind of synthetic technology of cefoxitin
  • A kind of synthetic technology of cefoxitin
  • A kind of synthetic technology of cefoxitin

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preparation example Construction

[0043] The synthetic method of cefoxitin acid of the present invention comprises the following steps:

[0044] 1) Dissolve 7-ACA in water, adjust the pH with ammonia water to dissolve 7-ACA, then add immobilized penicillin acylase, add methyl 2-thiopheneacetate dropwise, filter the filtrate after the reaction is complete, and add immobilized penicillin acylase Cephalosporin C deacetylesterase continues to react. After the reaction, the filtrate is filtered out, added with activated carbon for decolorization, filtered, then adjusted to pH and crystallized, filtered, and dried to obtain the intermediate 3-deacetyl cephalothinic acid.

[0045] 2) Dissolve the intermediate 3-deacetyl cephalothinic acid obtained in step 1) with a mixed solvent of dichloromethane, methanol and tetrahydrofuran, drop the sodium methoxide solution prepared in advance and cool down after dropping to a certain temperature, and finish the dripping Finally, add tert-butyl hypochlorite dropwise, then keep w...

Embodiment 1

[0047] The synthesis of embodiment 1,3-deacetyl cephalothinic acid

[0048] Put 80 grams of 7-ACA into a stirred flask, add 1000 ml of deionized water, start stirring and adjust the pH with 8% ammonia water to dissolve 7-ACA, control the temperature at 20°C, and put 30 grams of immobilized penicillin into acylation Enzyme, then add 55 grams of methyl 2-thiopheneacetate dropwise, and simultaneously use 8% ammonia water to control the pH6.5~7.0 until the pH no longer changes, and the liquid chromatography detects that the 7-ACA residue is less than 1.0%. Wash the immobilized enzyme with deionized water; add the filtrate to a stirred flask, control the temperature at 20°C, put in 20 grams of immobilized cephalosporin C deacetylesterase to start the reaction, and use 8% ammonia water to control the pH from 7.0 to 7.5 to pH Keep it unchanged for 3 minutes, then the reaction is over, filter and collect the filtrate, add 5 grams of activated carbon to the filtrate and stir to decolor...

Embodiment 2

[0049] Embodiment 2, the synthesis of 7-alpha-methoxy-3-deacetyl cephalothinic acid benzathine salt

[0050] Put 100 grams of 3-deacetyl cephalothinic acid, 1000 ml of dichloromethane, 100 ml of methanol, and 100 ml of tetrahydrofuran into a stirred flask, stir to dissolve, cool down to -85°C with liquid nitrogen, and then add dropwise to prepare in advance Sodium methoxide solution (90 grams of sodium methoxide + 200 milliliters of dichloromethane + 200 milliliters of methanol), control the temperature -83 ~ -87 ° C, dropwise add 35 grams of tert-butyl hypochlorite, and continue the reaction for 1 After 1 hour, add 100 ml of 50% glacial acetic acid solution, stir for 15 minutes and heat up to -50°C, then add 300 ml of 5% sodium chloride solution, heat up to 0-5°C, stir for 10 minutes and let stand to separate layers, the water phase Extract once with 100 ml of dichloromethane, combine the organic phases, add activated carbon for decolorization, filter, add 500 ml of water to ...

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Abstract

The invention provides a novel synthesis method of cefoxitin acid. Cefoxitin acid is used as a raw material for synthesizing cefoxitin sodium and belongs to second-generation cephalosporin. The cefoxitin acid has balanced antibacterial spectra and has a strong antibacterial effect on gram-negative bacteria. Due to the existence of 7alpha methoxy in the cefoxitin acid, the hydrolysis action of the cefoxitin acid on beta-lactamase can be reduced greatly, so that the beta-lactamase can exist stably in the cefoxitin acid. In the invention, 3-deacetylase cefoxitin acid which is an intermediate is produced by adopting an enzyme process through two-step continuous reaction, materials react in a mild reaction condition, and the process is simple and is convenient to operate. By adopting the novel synthesis method, time and labor can be saved, and the yield and quality of the product can be improved. Because the two-step reaction is carried out in a water phase at room temperature, the consumption of energy and the discharge of organic wastewater can be reduced greatly. The novel synthesis method meets the requirements of large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of cephalosporin antibiotics, in particular to a preparation method of cefoxitin acid, which belongs to the field of pharmaceutical chemical synthesis. Background technique [0002] Cefoxitin, chemical name: (6R,7S)-3-carbamoyloxymethyl-7-methoxy-8-oxo-7-[2-(2-thiazolyl)ethyl Amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid having the formula C 16 h 17 N 3 o 7 S 2 , molecular weight is 427.46, and chemical structural formula is as shown in (I): [0003] [0004] Cefoxitin acid is the raw material of synthetic cefoxitin sodium, and cefoxitin sodium is the cefoxitin antibiotic that U.S. Merck Company develops, belongs to the second generation cephalosporin, and its antimicrobial spectrum is balanced, and is particularly effective to Gram-negative bacteria. Strong antibacterial effect, due to the presence of the methoxyl group at the 7α position, it can greatly reduce the hydrolysis of β-l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/57C07D501/04
CPCC07D501/04C07D501/57
Inventor 王亚辉张彦斌齐昱宋辉
Owner LIAONING TIANHUA CHEM
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