Cefepime

colorless Powder

A fourth-generation cephalosporin antibacterial agent that is used in the treatment of infections, including those of the abdomen, urinary tract, respiratory tract, and skin. It is effective against PSEUDOMONAS AERUGINOSA and may also be used in the empiric treatment of FEBRILE NEUTROPENIA.

Method 1: The total yield can reach 25%. 7-Amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid benzhydryl ester hydrochloride (I, 50g, 0.11mol) was suspended in a mixture of 400ml ethyl acetate and 150ml water, in ice Under cooling in the bath, add 200ml of lmol/L sodium hydroxide solution. After the addition, continue to stir for 30 minutes to obtain a clear two-phase solution. The ethyl acetate layer was separated. Wash with 300ml water and dry with 100g anhydrous sodium sulfate. The ethyl acetate solution (without removing sodium sulfate) and benzaldehyde (14.2 g, 0.13 mol) were stirred together at room temperature for 2 h. The insoluble matter (ie sodium sulfate) was removed by filtration, the filtrate was concentrated under reduced pressure to about 200ml, and 400rnl of n-pentane was added to precipitate the precipitate. It was collected by filtration to obtain 47.6 g of compound (II) with a yield of 86%. The filtrate was concentrated to about 100ml, 300ml of n-pentane was added, and the precipitate was collected by filtration to obtain another 4.6g of compound (II) with a yield of 8%. The total amount is 52.2g, the yield is 94%, the light yellow prismatic crystals, the melting point is 110-111°C. Compound (II) (52g, 0.10rml) was dissolved in 1L of carbon tetrachloride, and under stirring, a solution of sodium iodide (18.6g, 0.12mol) dissolved in 200ml of acetone was added dropwise. After the addition, continue to stir at room temperature for 40 minutes. Filter with Dicalite, wash the filtrate with 750ml saturated sodium thiosulfate aqueous solution and sodium chloride aqueous solution (2×700ml) successively, dry with 100g anhydrous sodium sulfate, and filter. A small portion of the filtrate is concentrated to dryness to obtain compound (III). The compound is unstable at room temperature and can only be stored for a few days, with a purity of 65% (measured by HPLC). Part of the filtrate is directly used in the next reaction without separating compound (III). The filtrate was cooled to 0°C, and under stirring, a solution of N-methylpyrrolidine (11.8g, 0.11mol) dissolved in 50ml carbon tetrachloride was added dropwise in 30 min. After stirring for 1 hour at 0-5°C, the precipitated precipitate was collected by filtration, washed with 300ml carbon tetrachloride, and dried in vacuum in the presence of phosphorus pentoxide. 70 g of compound (IV) with a melting point of 120°C (decomposition) was obtained. Compound (IV) (68g, purity 60%), 68ml 98% formic acid and 42ml concentrated hydrochloric acid were stirred together at room temperature for 1h. Under vigorous stirring, the reaction solution was poured into 2.5 L of acetone. The formed precipitate was collected by filtration and dried to obtain 30 g of hygroscopic solid. The solid was dissolved in 300 ml of water, 1.5L of acetone was added, and 13.7 g of compound (V) was crystallized as colorless prismatic crystals, with a melting point of 165°C (decomposition), and the yield was 37% based on compound (II). Compound (V) (13.7 g, 37 mmol) was dissolved in 140 ml of water and 280 ml of dimethylformamide, and sodium bicarbonate (6.2 g, 74 mmol) was added in portions within 5 min under ice cooling and stirring to obtain a clear solution. Then add active ester compound (VI) (17.7g, 55.5mmo1), after stirring at room temperature for 1h, use 5ml2mol/L. Sulfuric acid acidified to Ph=3. Filter out the insoluble matter and wash with 10ml water. The filtrate and washing liquid were combined, and 3L of acetone was poured under vigorous stirring to produce a precipitate. The precipitate was collected by filtration and dried to obtain 20.6 g of crude cefpiime sulfate with a purity of 85% (HPLC). Dissolve the crude product in 120ml of water, add 40ml of 2mol/L sulfuric acid, add a few pieces of cefpiime sulfate crystals, and place in the refrigerator for 2h. Collect the formed crystalline powder by filtration, and use 40ml 0.5mol/L in turn. Wash with sulfuric acid and 200ml acetone and dry. 15.0 g of cefepime sulfate was obtained, the yield was 70%, and the melting point was 210°C (decomposition). Method 2: Connect the side chain at position 7 first, and then react at position 3. Compound (I) (2.29g, 5.07mmol) was dissolved in 57ml of acetonitrile, and N, O-bis(trimethylsilyl)acetamide (4.09g, 16.6mmol) was reacted for 50min at room temperature to obtain a clear solution. Add an acid chloride solution. The acid chloride solution was prepared from (Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (VII, 2.04g, 4.60mmol) and phosphorus pentachloride (1.15). g, 5.52mmol) prepared in 20ml dichloromethane. After the addition of the acid chloride solution, stir at room temperature for 30 min. Pour into 200ml of cold water and extract with ethyl acetate (3×100ml). The extracts were combined, washed with an aqueous sodium chloride solution, dried, and evaporated. The residue (4g) was chromatographed on a silica gel column, and eluted with 10:1 and 3:1 toluene and ethyl acetate. Obtained 2.61 g of compound (VIII) in amorphous powder form with a yield of 74% and a melting point of 130°C. Compound (VIII) (1.50 g, 1.79 mmol) and sodium iodide (1.34 g, 8.93 mmol) were stirred in 30 ml of methyl ethyl ketone for 1 h at room temperature. The solvent was evaporated, the residue was dissolved in 100ml ethyl acetate, washed with water, sodium thiosulfate aqueous solution and sodium chloride aqueous solution in turn, dried and evaporated. 1.47g of compound (IX) in amorphous powder form was obtained, with a yield of 89% and a melting point of 120°C (decomposition). Starting from compound (IX), there are many ways to obtain cefpiime. However, these methods require complicated HPLC separation processes. One of them is introduced as follows: Compound (IX) (5.0 g, 5.3.7 mmol) is dissolved in 500 ml of ether, N-methylpyrrolidine (915 mg, 11.5 mmol) is added, and the mixture is stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration, washed with ether (2×100 ml), and dried under vacuum to obtain 3.38 g of compound (X). After the filtrate was placed at room temperature for 1 h, another 610 mg of compound (X) was obtained. The total yield is 73%. 3.99g compound (X) and 20ml 90% trifluoroacetic acid, react at room temperature for 1h. Evaporated in vacuo, and the residue was impregnated with 200 ml of ether to obtain 3.03 g of solid. The solid is composed of cefepime and its isomers (2.6:1). Through complicated HPLC separation, 7.573 mg of colorless powder of cefepime can be obtained, with a yield of 22% [calculated as compound (IX)].

The fourth generation cephalosporin. Its antibacterial spectrum has been further expanded, and it has strong antibacterial activity against various Gram-positive and negative bacteria, including Bacillus, Pseudomonas aeruginosa, and other non-fermentable bacillus, Haemophilus, and Staphylococcus. It is used for various infections caused by sensitive bacteria, mainly for respiratory infections caused by maintenance infections such as Staphylococcus aureus, Enterobacter and Pseudomonas aeruginosa.

Molecular Weight:480.6
XLogP3:-0.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:6
Exact Mass:480.12496023
Monoisotopic Mass:480.12496023
Topological Polar Surface Area:204
Heavy Atom Count:32
Complexity:869
Undefined Atom Stereocenter Count:2
Undefined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes