Penicillin semisynthetic

Chemical or enzymatic hydrolysis of this compound allows to obtain large quantities of 7-aminocephalosporanic acid. A number of semisynthetic beta-lactam cephalosporin antibiotics were created by acylating the amino group of the last with various acid derivatives (analogous to the semisynthetic penicillin series) and currently there are about 25,000 of them, of which about 100 are used in medicine. Unlike penicillins, semisynthetic cephalosporins are synthesized not only by expanding the spectrum of various acids by which 7-aminocephalosporanic acid is acylated, but also by internal modifications of aminocephalosporanic nucleus (Rj and Rj). 

Other Reactions. The reaction of Thydioxybenzaldehyde with sodium cyanide and ammonium chloride, Strecker synthesis, yields /J-hydroxyphenylglycine [938-97-6] a key intermediate in the manufacture of semisynthetic penicillins and cephalosporins (see Antibiotics, p-LACTAMs). 

Pharmaceuticals. -Hydroxybenzaldehyde is often a convenient intermediate in the manufacture of pharmaceuticals (qv). For example, 2-(p-hydroxyphenyl)glycine can be prepared in a two-step synthesis starting with -hydroxybenzaldehyde (86). This amino acid is an important commercial intermediate in the preparation of the semisynthetic penicillin, amoxicillin (see ANTIBIOTICS, P-LACTAMs). Many cephalosporin-type antibiotics can be made by this route as well (87). The antiemetic trimethobenzamide [138-56-7] is convenientiy prepared from -hydroxybenzaldehyde (88) (see Gastrointestinal agents). 

Most of the new commercial antibiotics have resulted from semisynthetic studies. New cephalosporkis, a number of which are synthesized by acylation of fermentation-derived 7-amkiocephalosporanic acid, are an example. Two orally active cephalosporkis called cefroxadine and cephalexin are produced by a synthetic ring-expansion of penicillin V. 

The penicillins as natural and semisynthetic agents are used primarily against susceptible Pasteurella sp., staphylococci, streptococci, clostridia, and CoTynebacterium sp. Penicillin is widely used for therapeutic purposes against these organisms and in animal feeds as a growth promoter. The latter effect is considered to be a result of subtie and reversible effects on the gastrointestinal microflora. 

AH cephalosporins found in nature (Tables 1 and 2) have the D-a-aminoadipic acid 7-acyl side chain (21). AH of these compounds can be classified as having rather low specific activity. A substantial amount of the early work in the cephalosporin area was unsuccessfiiHy directed toward replacing the aminoadipic acid side chain or modifying it appropriately by fermentation or enzymatic processes (6,22). A milestone ia the development of cephalosporins occurred in 1960 with the discovery of a practical chemical process to remove the side chain to afford 7-ACA (1) (1). Several related processes were subsequendy developed (22,23). The ready avaHabHity of 7-ACA opened the way to thousands of new semisynthetic cephalosporins. The cephalosporin stmcture offers more opportunities for chemical modification than does that of penicillins There are two side chains that especiaHy lend themselves to chemical manipulation the 7-acylamino and 3-acetoxymethyl substituents. 

Worldwide retail antibiotic sales in 1986 were approximately 11 biUion of which penicillins comprised approximately 2.5 biUion (66). Preparations containing ampicillin are estimated at 800 million whereas those containing amoxicillin are estimated at 1,020 million. Total sales include sales of ampicillin esters and the iireidopenicillins derived from ampicillin. Total sales of penicillins, including semisynthetic penicillins in the United States in 1987, were 25 million (67). Sales of amoxicillin, the largest single selling penicillin, were approximately 350 million. 

The cost of 6-APA, ampicillin, and amoxicillin is invariably linked to that of penicillin G. 6-APA remains one of the cheapest raw starting materials available for the preparation of semisynthetic penicillins and other related P-lactam antibiotics. 

The second most important group of immobilized enzymes is stiU the penicillin G and V acylases. These are used in the pharmaceutical industry to make the intermediate 6-aminopenici11anic acid [551-16-6] (6-APA), which in turn is used to manufacture semisynthetic penicillins, in particular ampicilHn [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 ... 

Pharmacologically useful isoxazoles (B-82MI41600) include antibacterial sulfonamides (614), (615) and (616), semisynthetic penicillins (617), (618), (619) and (620), semisynthetic cephalosporin (621), anabolic steroid (622), the monoamine oxidase inhibitor (623) (used in psychotherapy), antiinflammatory agent (624) and antitumor agent (625). 

Although the last step in the preparation of a semisynthetic penicillin may appear to be a straightforward acylation of 6-APA, the wealth of functionality and reactivity of the 3-lactam requires highly specialized conditions for achieving this transformation. 

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

Semisynthetic. In 1959, scientists at Beecham Researeh Laboratories sueceeded in isolating the penicillin nucleus, 6-aminopenicillanie aeid (6-APA Fig. 5.1 A R represents H). During the commercial production of benzylpenicillin, phenylacetic (phenylethanoic) acid (C6H5.CH2.COOH) is added to the medium in whieh the Penicillium mould is growing (see Chapter 7). This substance is a precursor of the side... 

The manufacture of benzylpenicillin (penieillin G, originally just penicillin ) is chosen as a model for the antibiotic production process. It is the most renowned of antibioties and is the first to have been manufactured in bulk. It is still universally prescribed and is also in demand as input material for semisynthetic antibiotics (Chapter 5). Developments associated with the penicillin fermentation process have been a significant factor in the development of modem bioteehnology. It was a further 30 years, i.e. not until the 1970s, before there were signifieant new advances in industrial fermentations. 

Like benzylpenieillin, penicillin V is still widely used in its own right but can also be used as a starting material for the manufacture of the semisynthetic penicillins, none of which can be made by direct fermentation. 

It is possible to convert penicillin V or benzylpenieillin to a cephalosporin by chemical ring expansion. The first-generation cephalosporin cephalexin, for example, can be made in this way. Most cephalosporins used in clinical practice, however, are semisynthetics produced from the fermentation product cephalosporin C. 

Hydrolysis of penicillin mediated by penicillinase that has motivated attempts to alter its strnctnre (e.g., in semisynthetic penicillins). 

Fig. 2.2 illustrates the three types of chemicals by reference to the production of the semisynthetic penicillin antibiotic, ampicillin. 

Kanegafuchi Chemical Industries produce D-p-hydroxyphenyl glycine, which is a key raw material for the semisynthetic penicillins ampicillin and amoxycillin. Here, an enantioselective hydantoinase is applied to convert the hydantoin to the D-p-hydroxyphenyl glycine. The quantitative conversion of the amide hydrolysis is achieved because of the in situ racemization of the unreacted hydantoins. Under the conditions of enzymatic hydrolysis, the starting material readily racemizes. Therefore, this process enables the stereospecific preparation of various amino acids at a conversion of 100% [38]. 

The answer is b. (Hardman, pp 1077—1086.) Piperacillin is a broad-spectrum, semisynthetic penicillin for parenteral use. Its spectrum of activity includes various Gram-positive and Gram-negative organisms including Pseudomonas. The indications for piperacillin are similar to those for car-benicillin, ticarcillin, and mezlocillin, with the primary use being sus-... 

As streptococcal cellulitis is indistinguishable clinically from staphylococcal cellulitis, administration of a semisynthetic penicillin (nafrillin or oxacillin) or first-generation cephalosporin (cefazolin) is recommended until a definitive diagnosis, by skin or blood cultures, can be made (Table 47-4). If documented to be a mild cellulitis secondary to streptococci, oral penicillin VK, or intramuscular procaine penicillin may be administered. More severe streptococcal infections should be treated with IV antibiotics (such as ceftriaxone 50 to 100 mg/kg as a single dose). 

Aminoglycosidee + penicillin G 100,000-200,000 unit kg/day IV in four divided doses or a semisynthetic penicillin (nafcillin 150-200 mg/kg/day [not to exceed 12 g/24 hours] IV in four to six equally divided doses) depending on isolation of staphylococci or streptococa ... 

Queener, S. Swartz, R. (1979) Penicillins biosynthetic and semisynthetic, Economic Microbiology, 3, Academic Press, 35-123. 

Penicillinacylase is used industrially to catalyze the hydrolytic removal of the side chain in naturally occurring penicillins such as benzylpenicillin (4.49) and phenoxymethylpenicillin (4.50). The nucleus 6-aminopenicillic acid (4.48) is then used as the starting material for the preparation of semisynthetic penicillins. Appropriate acylation of the 6-NH2 group leads to )3-lactamase-stable and broad-spectrum penicillins. 

The bacterium Staphylococcus aureus, which is a major cause of infection in the developed countries, is now resistant to most antibiotics. It is usually present on the skin, where it causes no problems, but it can invade the body through cuts and wounds, including those caused by surgery. These bacteria are now prevalent in many hospitals, so that infection is a major problem for the medical staff in hospitals. The resistant bacterium is known as methicillin-resistant Staphylococcus aureus (MRSA). It is also known in the mass media as the super bug . Penicillin kiUs bacteria because the P-lactam group in the antibiotic inhibits a reaction that is essential for bacterial ceU wall production. Consequently, the bacteria cannot proliferate. Resistance to penicillin in many bacteria is due to production of an enzyme, p-lactamase, that degrades P-lactams. The antibiotic methicillin is one of a group of semisynthetic penicillins in which the P-lactam group is not... 

Scheme 6.7). Penicillin G amidase from Mcaligenes faecalis, which is used in the manufacture of semisynthetic penicillins and cephalosporins, was used in both steps to afford a one-pot cascade process [21]. The acylation was performed in an aqueous medium at pH 10-11 and, after separation of the remaining amine enantiomer, the acylated amine was hydrolyzed with the same enzyme by lowering the pH to 7. 

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