Of 6-aminopenicillanic acid

To this there is added dropwise with continued cooling and stirring a solution of ethyl chlorocarbonate (0.1 mol). After approximately 10 minutes, the acylating mixture is cooled to about -5°C and then is slowly added to a stirred ice-cold mixture of 6-aminopenicillanic acid 0.1 mol), 3% sodium bicarbonate solution (0.1 mol) and acetone. This reaction mixture is allowed to attain room temperature, stirred for an additional thirty minutes at this temperature and then is extracted with ether. 

The known methods for the preparation of D- -)-a-aminobenzylpenicillin by the acylation of 6-aminopenicillanic acid result in the preparation of aqueous mixtures which contain, in addition to the desired penicillin, unreacted 6-aminopenicillanic acid, hydrolyzed acylat-ing agent, and products of side reactions such as the products of the acylating agent reacted with itself and/or with the desired penicillin, as well as other impurities. 

Example 1 ot-AzidobenzylpenicWin via the Mixed Anhydride — A solution of o-azido-phenylacetic acid (8.9 grams, 0.05 mol) of triethylamine (5.1 grams, 0.05 mol) in 50 ml of dry dimethylformamide was stirred and chilled below -5°C. At this temperature ethyl chloroformate (4.7 ml) was added in portions so that the temperature was never above -5°C. After the mixture had been stirred for 20 minutes, dry acetone (100 ml), chilled to -5°C, was added in one portion, immediately followed by an ice-cold solution of 6-aminopenicillanic acid (10.8 grams, 0.05 mol) and triethylamine (5.1 grams, 0.05 mol) in 100 ml of water, and the stirring was continued for VA hours at 0°C. 

B) Acylation of 6-Aminopenicillanic Acid To a solution of the aryl halocarbonyl ketene (0.1 mol) in methylene chloride (sufficient to provide a clear solution and generally from about 5 to 10 ml per gram of ketene) there is added the proper alcohol RjOH (0.1 mol), in this case 5-indanyl alcohol. The reaction mixture is maintained under an atmosphere of nitrogen and stirred for a period of from 20 minutes to 3 hours, care being taken to exclude moisture. The temperature may range from about -70° to about -20°C. The infrared spectrum of the mixture is then taken to determine and confirm the presence of the ketene ester. A solution of 6-aminopenicillanic acid-triethylamine salt (0.1 mol) in methylene chloride (50 ml) is added and the mixture stirred at -70° to -20°C for 10 minutes. The cooling bath is then removed and the reaction mixture stirred continuously and allowed to warm to room temperature. 

A suspension of 6-aminopenicillanic acid (36.4 grams) in water was adjusted to pH 7.2 by the addition of N aqueous sodium hydroxide and the resulting solution was treated with a solution of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (46.1 grams) in isobutyl methyl ketone. The mixture was stirred vigorously for hours and then filtered through Dicalite. The layers were separated and the isobutyl methyl ketone layer was shaken with saturated brine. Then, precipitation of the sodium salt only took place after dilution of the mixture with ether. In this way there was obtained 60.7 grams of the penicillin sodium salt having a purity of 88% as determined by alkalimetric assay. 

To a stirred suspension of 6-aminopenicillanic acid (540 g) in dry alcohol-free chloroform (3.75 liters) was added dry triethylamine (697 ml), and the mixture stirred for 10 minutes at room temperature. It was then cooled in a bath of crushed Ice while a solution of 2,6-dimethoxybenzoyl chloride (500 g) in dry alcohol-free chloroform (3.75 liters) was added in a steady stream over 20 minutes. When all the acid chloride had been added the cooling bath was removed and the mixture stirred for 1 hour at room temperature. The mixture was stirred vigorously and sufficient dilute hydrochloride acid (2.3 liters of 0.87 N) was added to give an aqueous layer of pH 2.5. The mixture was filtered, the layers separated, and only the chloroform layer was retained. 

The acid chloride obtained as described above was dissolved in dry acetone (10 ml) and added in a steady stream to a stirred solution of 6-aminopenicillanic acid (1.08 g, 5 mmol) in a mixture of N sodium bicarbonate (15 ml) and acetone (5 ml). After the initial reaction the reaction mixture was stirred at room temperature for 45 minutes, then washed with ether (3 X 25 ml). Acidification of the aqueous solution with N hydrochloric acid (11 ml) to pH 2 and extraction with ether (3 x 15 ml) gave an ethereal extract which was decolorized with a mixture of activated charcoal and magnesium sulfate for 5 minutes. 

Scheme 6. Azlactonization of intermediate 5 (a) and synthesis of 6-aminopenicillanic acid (b).

The structure of the natural isomer of 6-aminopenicillanic acid is shown. You are asked to draw the structure of its enantiomer and its 6-epimer. 

Pieces of various routes to moxalactam have been published from which the following may be assembled as one of the plausible pathways. The benzhydrol ester of 6-aminopenicillanic acid ( ) is -chlorinated and treated with base whereupon the intermediate sulfenyl chloride fragments (to ). Next, displacement with propargyl alcohol in the presence of zinc chloride gives predominantly the stereochemistry represented by dia-stereoisomer The side chain is protected as the phenyl-... 

Various derivatives of 6-aminopenicillanic acid (e.g., 454) and 7-aminocephalosporanic acid (e.g., 455) have been prepared and examined as possible antibacterials. ... 

Figure 1.15. Structure of 6-aminopenicillanic acid (a) generalized penicillin structure (b) and side-groups present in two natural penicillins and two semisynthetic penicillins (c)...

Facilitated transport of penicilHn-G in a SLM system using tetrabutyl ammonium hydrogen sulfate and various amines as carriers and dichloromethane, butyl acetate, etc., as the solvents has been reported [57,58]. Tertiary and secondary amines were found to be more efficient carriers in view of their easy accessibility for back extraction, the extraction being faciUtated by co-transport of a proton. The effects of flow rates, carrier concentrations, initial penicilHn-G concentration, and pH of feed and stripping phases on transport rate of penicillin-G was investigated. Under optimized pH conditions, i. e., extraction at pH 6.0-6.5 and re-extraction at pH 7.0, no decomposition of peniciUin-G occurred. The same SLM system has been applied for selective separation of penicilHn-G from a mixture containing phenyl acetic acid with a maximum separation factor of 1.8 under a liquid membrane diffusion controlled mechanism [59]. Tsikas et al. [60] studied the combined extraction of peniciUin-G and enzymatic hydrolysis of 6-aminopenicillanic acid (6-APA) in a hollow fiber carrier (Amberlite LA-2) mediated SLM system. 

B) Acylation of 6-Aminopenicillanic Acid To a solution of the aryl halocarbonyl ketene (0.1 mol) in methylene chloride (sufficient to provide a clear solution and generally from about 5 to 10 ml per gram of ketene) there is added the proper alcohol R2OH (0.1 mol), in this case 5-indanyl alcohol. 

A solution of 19.2 g (0.096 mole) of a-methoxy-4-chlorophenyl acetic acid in 200 ml of acetone is cooled in an ice bath to 0°C. To the cooled solution is added 10.2 g (0.1 mole) of triethylamine in 100 ml of acetone. The temperature of the reaction mixture is maintained at 10°C and a solution of 11.0 g (0.1 mole) of ethylchloroformate in 45 ml of acetone is added dropwise with agitation so as to maintain a final reaction temperature of -5°C. To this mixture is then slowly added with stirring a solution of 23.8 g (0.11 mole) of 6-aminopenicillanic acid in 40 ml of water and 15 ml of triethylamine. Upon completion of the addition, the mixture is stirred while attaining room... 

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