Synthesis of chloramphenicol

Chloramphenicol has been sueeessfully synthesized by different methods and the present global demand of this drug is adequately met exclusively by chemical synthesis. The synthesis put forward by Long et al. (1949) is diseussed below  

Typhoid fever and similar salmonellal infections are usually considered the prime indications for the use of chloramphenicol. It is also employed in acute infections due to Heamophilus influenzae, including meningitis attributed to ampicillin-resistant strains. It also find its enormous applications in topical infections of eye and skin. It has also been used to eradicate vibrios from patients with cholera. It is employed for rickettsial infections like typhus and Rocky Mountain spottedfever. 

Chloramphenicol is particularly recommended for the management and treatment of serious infections produced by the strains of both Gram-positive and Gram-negative organism that have developed eventually resistance to either ampicillin or penicillin G, for instance H. influenzae, Salmonella typhi, S. pneumoniae, B. fragilis, and N. meningitidis. 

It is used topically extensively for the superficial conjunctival infections and blepharitis essentially caused by coli, H. influenzae, Moraxella lacunata, Streptococcus hemolyticus, andS aureus. However, it is still the drug of choice for the typhoid fever. 

Mechanism of Action. The drug has specifically the ability to penetrate right into the central nervous system (CNS) therefore, it is still an important alternative therapy for meningitis. The major course for the metabolism of chloramphenicol essentially involves the formation of the 3-o-glucuronide. 

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Dichloroacetic acid is used in the synthesis of chloramphenicol [56-75-7] and aHantoin [97-59-6]. Dichloroacetic acid has vimcidal and fungicidal activity. It was found to be active against several staphylococci (36). The oral toxicity is low the LD q in rats is 4.48 g/kg. It can, however, cause caustic bums of the skin and eyes and the vapors are very irritating and injurious (28). 

George S, Narina SV, Sudalai A (2006) A Short Enantioselective Synthesis of (-(-Chloramphenicol and (+)-Thiamphenicol Using Tethered Aminohydroxylation. Tetrahedron 62 10202... 

Jiang has expanded the Carreira method of alkyne addition to aldehydes to include other ligands and Zn(II) salts (Eq. 13) [17]. Thus use of stoichiometric quantities of Zn(II) difluoromethane sulfonate salt and (lS,2S)-3-(tert-butyldi-methylsilyloxy)-2-N,N-dimethylamino-l-(p-nitrophenyl)propane-l-ol (3) in the addition reaction can afford propargylic alcohols in high ee. Difluoromethanesul-fonic acid is prepared from 3,3,4-,4-tetrafluoro[1.2]oxathietane the amino alcohol has been used in the synthesis of chloramphenicol and is also readily accessible. Application of a combination of this same amino alcohol ligand with Zn(OTf)2 has also been shown to afford products in high yield and ee in addition reactions (Eq. 14) [18]. 

Besides the group of psychotropic compounds, we must quote here the antibiotics as drugs where a rapid recent development of techniques can be observed. D.c. polarographic techniques for the determination of chloramphenicol [242], tetracycline [243] and streptomycin [244] are available. The polarographic determination of penicillin G potassium salt is only indirect and is preceded by the introduction of a nitroso group [245]. The synthesis of chloramphenicol comprises the chemical reduc-... 

From the point of view of importance and chemical feasibility, chloramphenicol (Figure 9) presented an excellent subject for structural modification. It was the first truly broad-spectrum antibiotic isolated, and its structure and total synthesis were both reported two years after the discovery was announced (40, 41, 42). The synthesis of chloramphenicol analogs proved to be one of the great disappointments of early chemical research in the antibiotic field. Hundreds of analogs were synthesized, but none was found superior to the parent drug in terms either of antimicrobial activity or therapeutic index (43). The palmitate and hemisuccinate esters have provided superior dosage forms for oral and parenteral use. One synthetic analog, thiamphenicol (44) has achieved limited use in human and veterinary medicine. 

The possibility of chloramphenicol detected in food samples collected in national monitoring programs in the early 2000s being attributed to environmental exposure was the subject of a 2004 review. Two aspects—natural synthesis of chloramphenicol in soil and the persistence of chloramphenicol in the environment after historical veterinary use—were considered. The review found that although the possibility of food being occasionally contaminated... 

A particularly important application of this method is in the synthesis of chloramphenicol (by Roussell-Uclaf), an antityphoid drug, in which resolution of the DL-threo base (reaction 9.4) is accomplished by its dissolution in aqueous HCl from which the less soluble o-chloramphenicol HCl preferentially crystallizes. To the mother liquor which now contains excess L-compound, an equal quantity of oL-base is added when the L-chloramphenicol HCl preferentially crystallizes. This process is repeated several times to obtain the d and l forms alternately in pure forms. 

Example 9.4 Complete asymmetric synthesis of —)-chloramphenicol, (l/ ,2/ )-TM 9.2 is outlined in Scheme 9.6. An exemplary application of chiral organocatalysts is present in symmetric catalytic cyclization to aziridine 4 in the key step of the synthesis [11, 12]. Scheme 9.7 presents the detailed mechanism of chemo- and stereoselective rearrangement of chiral aziridine daivative 4 in the final intermediate 5. 

Observe that the former presented retrosynthesis and non-stereoselective synthesis of racemic chloramphenicol have no relation to this asymmetric synthesis of —)-chloramphenicol. It is an often-encountered situation in plaiming the synthesis of complex chiral molecules, although it does not detract from the value of ret-rosynthetic consideration. Unavailability of the chiral variant of certain reactions prompts synthetic organic chemists to explore other routes besides the one suggested by retrosynthesis and to discover new, original solutions. Analysis of the sertraline molecule in the next section offers impressive support of this statement. 

In pharmaceutical appHcations, the selectivity of sodium borohydride is ideally suited for conversion of high value iatermediates, such as steroids (qv), ia multistep syntheses. It is used ia the manufacture of a broad spectmm of products such as analgesics, antiarthritics, antibiotics (qv), prostaglandins (qv), and central nervous system suppressants. Typical examples of commercial aldehyde reductions are found ia the manufacture of vitamin A (29) (see Vitamins) and dihydrostreptomycia (30). An acyl azide is reduced ia the synthesis of the antibiotic chloramphenicol (31) and a carbon—carbon double bond is reduced ia an iatermediate ia the manufacture of the analgesic Talwia (32). 

This is by far the most versatile route to the synthesis of ester-substituted aziridines, especially as the benzhydryl group can easily be cleaved by hydrogenolysis. Wulff has applied this methodology to a short asymmetric synthesis of the antibiotic (-)-chloramphenicol in four steps from p-nitrobenzaldehyde (Scheme 1.34) [61]. In this case it was found that treatment of the aziridine 111 with excess dichloroacetic acid gave the hydroxy acetamide directly, so no separate deprotection step was required. 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

Ribosomal Protein Synthesis Inhibitors. Figure 5 Nucleotides at the binding sites of chloramphenicol, erythromycin and clindamycin at the peptidyl transferase center. The nucleotides that are within 4.4 A of the antibiotics chloramphenicol, erythromycin and clindamycin in 50S-antibiotic complexes are indicated with the letters C, E, and L, respectively, on the secondary structure of the peptidyl transferase loop region of 23S rRNA (the sequence shown is that of E. coll). The sites of drug resistance in one or more peptidyl transferase antibiotics due to base changes (solid circles) and lack of modification (solid square) are indicated. Nucleotides that display altered chemical reactivity in the presence of one or more peptidyl transferase antibiotics are boxed. 

A famous example of the use of nitro compounds in synthesis was the original synthesis of the antibiotic chloramphenicol (8), which is still used to treat tropical diseases. This synthesis also confirmed the structure of chloramphenicol and established that the (-)-thrco compound was the biologically active stereoisomer. 

Of the fonr possible optical isomers of chloramphenicol, only the o-threo form is active. This antibiotic selectively inhibits protein synthesis in bacterial ribosomes by binding to the 50S subunit in the region of the A site involving the 23 S rRNA. The normal binding of the aminoacyl-tRNA in the A site is affected by chloramphenicol in such a... 

Feedback inhibition of amino acid transporters by amino acids synthesized by the cells might be responsible for the well known fact that blocking protein synthesis by cycloheximide in Saccharomyces cerevisiae inhibits the uptake of most amino acids [56]. Indeed, under these conditions, endogenous amino acids continue to accumulate. This situation, which precludes studying amino acid transport in yeast in the presence of inhibitors of protein synthesis, is very different from that observed in bacteria, where amino acid uptake is commonly measured in the presence of chloramphenicol in order to isolate the uptake process from further metabolism of accumulated substances. In yeast, when nitrogen starvation rather than cycloheximide is used to block protein synthesis, this leads to very high uptake activity. This fact supports the feedback inhibition interpretation of the observed cycloheximide effect. 

Chemical synthesis of racemates and subsequent resolution via crystallization of diastereomeric salts is employed in the preparation of rf-biotin and tocopherol (vitamins), dexchlorpheniramine (antihistaminic), levomepromazine (neuroleptic), levorphanol (analgesic), and naproxen (antiphlogistic), to note some examples4, threo-2-Amino-1 -(4-nitro-phenyl)-l,3-propanediol, an intermediate in the production of chloramphenicol, is resolved by crystallization with entrainment or via crystallization of the salt with camphorsulfonic acid4. Enzymatic resolutions are increasingly employed, normally via deacetylation of racemic acetates. This method has recently been used in the synthesis of carbacyclin derivatives5. 

Mechanism of Action of Florfenicol. The inhibitory activities of chloramphenicol (1, R = NCh). thiamphenicol (1, R = SO2CH3), and florfenicol (2) against a sensitive E cofi strain have been studied. In two different liquid media, both chloramphenicol and florfenicol allowed only 20-30% residual growth at a drug concentration of 2 mg/L, whereas a thiaiuplieiiicul concentration of 25 mg/L was required to produce a similar effect. Florfenicol was also found to be a selective inhibitor of prokaryotic cells. At concentrations of 1 mg/L chloramphenicol and florfenicol, and at a concentration of 25 mg/L, thiamphenicol, inhibited protein synthesis. 

On the other hand, drugs may inhibit the metabolism of other drugs. For example, allopurinol (a xanthine oxidase inhibitor that inhibits the synthesis of uric acid) increases the effectiveness of anticoagulants by inhibiting their metabolism. Chloramphenicol (a potent inhibitor of microsomal protein synthesis) and cimetidine (an H2-receptor blocker used in acid-pepsin disease) have similar properties. In addition, drugs may compete with each other in metabolic reactions. In methyl alcohol (methanol) poisoning, ethyl alcohol may be given intravenously to avert methanol-induced blindness and minimize the severe acidosis. Ethyl alcohol competes with methyl alcohol for... 

As well as being applicable to the glycosylation of monohydroxy compounds, the reaction has been used to disubstitute diols such as chloramphenicol (84), to give products of sequential substitution such as 86, and hence saturated glycosylated compounds. In a different type of application, the resolution of the racemate of compound 85 can be accomplished by glycosylation and separation of the diastereomers to afford the illustrated enantiomer which was required for work on the synthesis of taxol. 

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