6-Aminopenicillanic acid synthesis

In subsequent studies,22 Sheehan et al. demonstrated that the action of diisopropylcarbodiimide on penicilloate 24, prepared by protection of the free primary amino group in 23 with trityl chloride (see Scheme 6b), results in the formation of the desired -lactam 25 in a very respectable yield of 67 %. In this most successful transformation, the competing azlactonization reaction is prevented by the use of a trityl group (Ph3C) to protect the C-6 amino function. Hydrogenolysis of the benzyl ester function in 25, followed by removal of the trityl protecting group with dilute aqueous HC1, furnishes 6-aminopenicillanic acid (26), a versatile intermediate for the synthesis of natural and unnatural penicillins. 

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

Figure 6.18 Chemical synthesis of amoxicillin from 6-aminopenicillanic acid via the Dane Salt of 4-hydroxyphenylglycine.

These defects have spurred attempts to prepare analogs. The techniques used have been (1) natural fermentation (in which the penicillin-producing fungus is allowed to grow on a variety of complex natural nutrients from which it selects acids for incorporation into the side chain), (2) biosynthetic production (in which the fermentation medium is deliberately supplemented with unnatural precursors from which the fungus selects components for the synthesis of "unnatural" penicillins), (3) semisynthetic production (in which 6-aminopenicillanic acid (2) is obtained by a process involving fermentation, and suitably activated acids are subsequently reacted chemically with 6-APA to form penicillins with new side chains) and (4) total synthesis (potentially the most powerful method for making deep-seated structural modifications but which is at present unable to compete economically with the other methods). 

N-Aminooxazolidone, 228 6-Aminopenicillanic acid (6-APA), 409, 410 Aminophenazole, 248 p-Aminophenol, 111 Aminophylline, see theophylline Amlnopromazine, 390 Aminopropylon, 234 2-Aminopyrimidine synthesis, 127, 128... 

The optimum yield of a condensation product is obtained at the pH where Ka has a maximum. For peptide synthesis with serine proteases this coincides with the pH where the enzyme kinetic properties have their maxima. For the synthesis of penicillins with penicillin amidase, or esters with serine proteases or esterases, the pH of maximum product yield is much lower than the pH optimum of the enzymes. For penicillin amidase the pH stability is also markedly reduced at pH 4-5. Thus, in these cases, thermodynamically controlled processes for the synthesis of the condensation products are not favorable. When these enzymes are used as catalysts in thermodynamically controlled hydrolysis reactions an increase in pH increases the product yield. Penicilhn hydrolysis is generally carried out at pH about 8.0, where the enzyme has its optimum. At this pH the equiUbrium yield of hydrolysis product is about 97%. It could be further increased by increasing the pH. Due to the limited stability of the enzyme and the product 6-aminopenicillanic acid at pH>8, a higher pH is not used in the biotechnological process. 

On the other hand, the discovery of the parent amine 6-aminopenicillanic acid (9.40, 6-APA) in fermentation products constituted a major breakthrough in penicillin synthesis. 

Chemists from the Sankyo Co. reported the use of 6-bromopenicillanate 28, easily obtained from 6-aminopenicillanic acid, in a multistep synthesis of (3RAR)-4-acetoxy-3- (R)- -((/-hutyldimethylsilyl)oxy)ethyl]-2-azctidinonc (31)97, a pivotal intermediate for the synthesis of 1-/9-methyl carbapenem antibiotics (equation 23)98. After cleavage of the thiazolidine ring of 28 with trimethyloxonium tetralluoroborate, the intermediate 29 was subjected to a Reformatsky condensation with acetaldehyde, catalysed by diethyla-luminium chloride. The 8-(S) stereocentre in 30, formed in 50% d.e., was inverted under Mitsunobo conditions to approach the target molecule 31. 

The second most important group of immobilized enzymes is still the penicillin G and V acylases. These are used in the pharmaceutical industry to make the intermediate 6-aminopenicillanic acid [551-16-6] (6-APA), which in turn is used to manufacture semisynthetic penicillins, in particular ampicillin [69-53-4] and amoxicillin [26787-78-0]. This is a remarkable example of how a complex chemical synthesis can be replaced with a simple enzymatic one ... 

Investigating the kinetically controlled synthesis of the /flactam antibiotic amoxicillin from 6-aminopenicillanic acid and D-p-hydroxyphenylglycine methyl ester in a solid suspension system in which the reaction nevertheless occurred in the liquid phase, Diender et al. found that the pH value and dissolved concentrations took a very different course at different initial substrate amounts (Diender, 2000). These results were described reasonably well by the model based on mass and charge balances, pH-dependent solubilities of the reactants, and enzyme kinetics. 

Sulbactam sodium is semi-synthetic antibiotic of penicillinic group. Start material for it s synthesis is 6-aminopenicillanic acid. First 6-aminopenicillanic acid was isolated in 1957 year from benzylpenicilline as resalt of treating of it by penicillinaze. Benzylpenicilline is produced by microorganism of genus Streptomyces. 

Another example of ozonolysis being used in the production of penem-type antibiotics, which are regarded as a hybrid between penicillins and cephalosporins, has been demonstrated by Osborne and colleagues82 who describe the convenient and chiral synthesis of the triazolymethylene penem 85, from 6-aminopenicillanic acid (6-APA) (86), an inexpensive and readily available chiral synthon. The multi-step synthesis incorporates a key synthetic step involving the ozonolytic cleavage of a double bond in 87 to produce an amide 88 (Scheme 11.23). 

The penicillins [pen i SILL in] are the most widely effective antibiotics and are among the least toxic drugs known the major adverse reaction to penicillins is hypersensitivity. The members of this family differ from one another in the R substituent attached to the 6-aminopenicillanic acid residue. The nature of this side chain affects their antimicrobial spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes (P-lactamases). Figure 30.1 shows the main structural features of the penicillins. Figure 30.2 shows the classification of agents affecting cell wall synthesis. 

As indicated, the synthesis of pencillin V (ref.31) afforded certain intermediates which were later converted to 6-aminopenicillanic acid (ref.34) but the low yield could not enable the process to compete with the fermentation route, since the synthesis of Penicilin V commenced with valine it could of course in the present context Itself be viewed as an aspect of semi-synthesis. Although loss of chirality occurred at an early stage due to the formation of an oxazolone which gave racemic penicillamine and the final product had to be resolved with loss of the chiral value of the starting material, the remarkable steps involved are shown. 

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