A method for enzymatically preparing n-bromoacetyl-7-aminocephalosporanic acid

Abstract

The invention belongs to the field of enzyme catalysis and biological pharmacy and discloses a method for preparing N-acetyl bromide-7-aminocephalosporanic acid through enzyme catalysis. The method includes the following steps that 7-aminocephalosporanic acid and acyl donors are added into a buffer solution to be mixed evenly, immobilized penicillin amidase is added for reaction, and N-acetyl bromide-7-aminocephalosporanic acid is obtained through separation after reaction. The method has the advantages of being mild in reaction condition, environmentally friendly, simple in process, high in target product yield and the like.

Description

technical field [0001] The invention belongs to the field of enzyme catalysis and biopharmaceuticals, in particular to a method for preparing N-bromoacetyl-7-aminocephalosporanic acid catalyzed by penicillin acylase. Background technique [0002] Cefathiamidine is my country's first self-developed semi-synthetic cephalosporin. Cefathiamidine is a broad-spectrum antibacterial agent, which has a strong killing effect on most Gram-positive bacteria and some Gram-negative bacteria, especially the killing effect on enterococci exceeds that of similar species used in clinical practice. In addition, cefathiamidine also shows certain curative effect on the infection of methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis (Chinese Journal of Antibiotics, 2005,30(2):107). Clinical studies have shown that cefathiamidine has the characteristics of high blood concentration and good clinical curative effect. In recent years, the market of cefa...

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Problems solved by technology

Or replace bromoacetyl bromide with chloroacetyl chloride, and prepare cefathiamidine through similar chemical acylation and condensation processes (Chinese Journal of Pharmaceutical Industry, 2009, 40 (12): 888; CN 102285999 B; CN 101486718 B), but chlorine The chlorine activity in the acetyl group is low, resulting in a low yield of the second condensation reaction, so in industry, the first step of cefathiamidine synthesis still uses bromoacetyl bromide as an acyl donor

Another method for synthesizing cefathiamidine is to first synthesize side chain 1,3-diisopropylamidino-2-thio-acetic acid hydrochloride, then after activation by Vilsmeier reagent, finally combine with protected The 7-ACA condensation of base, after deprotection, obtains cefathiamidine (Chinese Journal of Medicinal Chemistry, 2001,11 (5): 293; CN 101704827 B); Although the target product yield of this synthetic pathway route is relatively high (56 %), but its operation is complicated and harsh, and the silylating reagent used is expensive, and the cost is higher; and the activation process needs to adopt highly toxic active reagents such as triphosgene and triphenylphosphine, but also toluene, xylene, Highly toxic reagents such as chlorobenzene and dichlorobenzene

Therefore, chemical preparation of cefathiamidine not only requires the use of highly active acyl donors (acyl chlorides or acid bromides), volatile organic solvents and bases, but also requires low-temperature reactions. The reaction conditions are harsh, the process is complicated, and the environment is seriously polluted. Current requirements for sustainable social and environmental development

In addition, the yield of N-bromoacetyl-7-ACA, the key intermediate of cefathiamidine, is usually not ideal, the highest is only 73% (China Modern Applied Pharmacy, 2010 27(2):126)

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