Imipenem monohydrate

Imipenem monohydrate, a member of the carbapenem class of antibiotics isolated from the soil organism Streptomyces cattleya[1], is an intravenous β-lactam antibiotic effective against a wide range of Gram-positive and Gram-negative bacteria, including several multi-drug resistant bacterial species. Imipenem acts as cell wall-targeting antibiotic[2][3].

With 6-aminopenicillanic acid (6-APA) as raw material. Mix dichloromethane, bromine, sulfuric acid, and sodium nitrite, and add 6-APA. After the reaction is completed, neutralize with sodium bisulfite aqueous solution. The organic layer was separated and washed with saturated sodium chloride to obtain 6, 6-dibromopenicillanic acid (I) in a yield of 89%. Add (I) to a methanol solution of acetyl chloride and react for 6h to obtain methyl 6, 6-dibromopenicillinate (II) with a yield of 91%. Dissolve (Ⅱ) in tetrahydrofuran, add methylmagnesium iodide dropwise at -78℃, add acetaldehyde after 40min, react for 10min, add saturated aqueous ammonium chloride solution to terminate the reaction, extract, concentrate, and separate by HPLC to obtain compound (Ⅲ ). Compound (Ⅲ), ether, zinc powder and 1mol/L. Ammonium acetate, react at room temperature for 1h. Filtration, extraction, concentration, and HPLC separation gave compound (IV) in 92% yield. Compound (IV), dimethylformamide, imidazole and tert-butyl silicon chloride were stirred overnight. Diethyl ether was diluted and extracted, washed and concentrated to obtain compound (V) with a yield of 98%. Compound (V), glacial acetic acid and mercury acetate were reacted at 90°C for 1 hour. Cool, filter, concentrate and add ethyl acetate. Filtration, washing the filtrate and concentrating to obtain compound (IV) with a yield of 75%. Compound (Ⅵ), acetone, NaIO4 (containing a small amount of KMnO4) aqueous solution and 0.033mol/L phosphate buffer (pH=7.0), reacted at room temperature overnight. After filtration, the filtrate was concentrated to half, saturated with sodium chloride, and extracted with ethyl acetate several times. The extract was washed and concentrated to obtain compound (VII) with a yield of 70%. Compound (VII), ZnCl2 and dichloromethane are mixed, dropwise adding 2-diazo-3-tert-butyldimethylsiloxy-3-butenoic acid p-nitrobenzyl ester in dichloromethane solution, and reacting for another 1h . Dilute with ethyl acetate, wash with water, dry, concentrate, and separate with VIC to obtain compound (VIII), yield 80%. Compound (Ⅷ) was dissolved in methanol, 1 mol/L, hydrochloric acid was added, and reacted for 6 h to obtain compound (XI) in 95% yield. Compound (IX), ethyl acetate and a trace of Rh2(Oac)4 were refluxed for 10 min. Filtration and concentration gave compound (X) in 99% yield. Compound (X), anhydrous acetonitrile and diisopropylethylamine are mixed, and diphenyl chloride chloride is added dropwise. After the reaction is completed, it is concentrated to dryness to obtain compound (XI) with a yield of 85%. Compound (Ⅺ) was dissolved in acetonitrile, diisopropylethylamine was added dropwise, and then N-[(p-nitrobenzyloxy)carbonyl]aminoethanethiol in anhydrous acetonitrile solution was added dropwise below 0°C for 2 hours. After TLC separation, compound (XII) was obtained with a yield of 51%. Compound (XII) is dissolved in tetrahydrofuran, and added with phosphate buffer. 10% palladium-charcoal, hydrogenated to obtain thiamphenicol. Add benzyloxymethylimine hydrochloride at low temperature, filter and separate to obtain imipenem in 10.1% yield. $The following compound reacts with alkylthiosilicon, and then hydrogenated to obtain imipenem.

An extremely broad-spectrum semi-synthetic antibiotic