Amoxicillin, synthesis

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). 

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 ... 

A different approach has been used for the synthesis of amoxicillin (Figure 6.18). Based on the application of the inexpensive Dane salt of 4-hydroxyphenylglydne, a process has been developed giving the required compound in almost quantitative yield. 

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

Mechanism of Action Amoxicillin inhibits bacterial cell wall synthesis, while clavula-nate inhibits bacterial beta-lactamase. Therapeutic Effect Amoxicillin is bactericidal in susceptible microorganisms. Clavulanateprotects amoxicillin from enzymatiedeg-radation. 

D-p-Hydroxyphenylglycine is an important component of certain semi-synthetic antibiotics such as the semi-synthetic cephalosporins cefadroxil and cefatrizine and the semi-synthetic penicillin amoxicillin, with a combined world market in excess of 3 x 10 /a. Synthesis was possible from DL-5-monosubstituted hydantoins (cyclic ureides of amino acids) provided that a selective D-hydantoinase could be found, which would be competitive with chemical methods. 

It has also been tested whether this approach could work for the synthesis of the beta-lactam antibiotic amoxicillin [46]. First, a number of organic and inorganic... 

Therefore, a solid-to-solid synthesis of amoxicillin in aqueous solution is not feasible. 

Examples of enzyme inhibitors that can be used as drugs Enzyme inhibitors can be used as drugs, inhibiting either intracellular or extracellular reactions. For example, the p-lactam antibiotics, such as penicillin and amoxicillin, act by inhibiting one or more of the enzymes of bacterial cell wall synthesis. 

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. 

Dr. David Johnson (1975-1982). Of all my senior managers, Dave Johnson was the one who knew most about organic chemistry and synthesis. He was a hard-driving chemist with a nose for practical solutions to process development problems. Being a student of Professor John Sheehan, his knowledge of (3-lactam chemistry was extensive. Indeed he was called on to represent Bristol-Myers in its many patent battles with Beecham in which Bristol-Myers staked out its own patent position covering ampicillin and amoxicillin trihydrates.8... 

Amoxicillin is one of the most widely used antibiotics in the penicillin family. The discovery and synthesis of such antibiotics in the twentieth century have made routine the treatment of infections that were formerly fatal. You were likely given some amoxicillin to treat an ear infection when you were a child. The penicillin antibiotics are discussed in Chapter 22. 

More recently, a biocatalytic manufacturing route was developed in which deacylation was accomplished by penicillin G acylase in water at room temperature, requiring no protection and deprotection (Scheme 8.9) [58]. Moreover, through reaction engineering, penicillin G acylase also catalyzes the acylation of 6-APA with either amino esters or aminoamides to produce a wide range of semi-synthetic P-lactam antibiotics such as amoxicillin and ampicillin. A similar approach could be applied to the synthesis of the 7-ADCA derivatives cefaclor, cephalexin, and cefadroxil. 

Amoxicillin/ Antibiotic Inhibits bacterial cell wall synthesis... 

Chemferm is one of among several companies which apply penicillin acylase for the kinetically controlled industrial synthesis of semisynthetic antibiotics in aqueous environments (Scheme 37) [109-111]. Ampicillin (119) and amoxicillin (120) can be obtained by the enzyme-catalyzed condensation of 6-aminopenicillic acid (6-APA, 117) with the amide or ester of D-(-)-4-hydrox-yphenylglycine and D-(-)-phenylglycine, respectively. In a similar way, cephalexin (121) can be obtained by reaction of D-(-)-phenylglycine with 7-aminodesacetoxycephalosporanic acid (7-ADCA, 118). Penicillin acylase from diverse microbial strains such as E. colU Klyveromyces citrophiluy and Bacillus megabacterium was successfully applied for this transformation and was used in its immobilized form based on a gelatin carrier. The immobilization allows an easy separation from the reaction medium and the reuse of the enzyme for at least 50 cycles. Impressive characteristics of this transformation are yields >90%, a selectivity of >95%, and an optical purity of >99% ee. The industrial manufacture takes place in repetitive batch reactors at many locations worldwide with an annual production volume of 2,000 t. 

The so-called Dane-anhydride route for the synthesis of semi-synthetic / -lactam antibiotics can be used practically for aU members of this class of compounds, and may be exemplified here for amoxicillin. (D)-4-Hydroxyphenylglycine is treated first with the potassium salt of ethyl acetoacetate and then with pivaloyl chloride. This results in the Dane-anhydride, which may easily be coupled with 6-aminopeniciUanic acid. 

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