Cephalosporin 3-amino

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). 

Chemical Modification. The chemistry and synthetic strategies used in the commercial synthesis of cephalosporins have been reviewed (87) and can be broadly divided into ( /) Selection of starting material penicillin precursors must be rearranged to the cephalosporin nucleus (2) cleavage of the acyl side chain of the precursor (2) synthesis of the C-7 and C-3 side-chain precursors (4) acylation of the C-7 amino function to introduce the desked acylamino side chain (5) kitroduction of the C-3 substituent and 6) protection and/or activation of functional groups that may be requked. 

In the synthesis of ceftazidime (40) (Fig. 8), the protected, preassembled arninothiazole side chain [68672-66-2] (60) is coupled to a protected 7-ACA first and the C-3 displacement step carried out last. By way of contrast, in the synthesis of ceftriaxone (39) (Fig. 9), the preformed C-3 substituent is introduced onto the cephalosporin nucleus in the first step and then the acyl-amino side chain is introduced. This last step is noteworthy for two reasons in that it demonstrates the use of an activated thio ester in the coupling step and that no protecting group chemistry is requited (192,193). 

Early attempts to produce cephalosporin analogs by varying the 7-acylamino substituent were frustrated because, in contrast to previous experience with penicillins, a good method for producing the necessary 7-amino compound (33a) could not be found. This problem was finally solved when it was discovered that diazotization of the a-aminoadipyl residue produces an iminolactone (33b) which can be hydrolyzed to the free amine in good yield. Subsequently an improved procedure was developed which involves silylation of the carboxyl groups followed by reaction with phosphorus pentachloride to yield iminochloride (33c)... 

Scientists at Merck developed a cephalosporin synthesis based on the addition of azidoacetyl chloride to 1,3-thiazines (56). Although this gives the incorrect 7a -epimer (57), it could be equilibrated to a mixture of 7-amino epimers (see Section 5.10.3.3) from which the desired 7/3-isomer could be separated and further elaborated to cephalosporins (B-82MI51001). 

The bulky triphenylmethyl group has been used to protect a variety of amines such as amino acids, penicillins, and cephalosporins. Esters of N-trityl a-amino acids are shielded from hydrolysis and require forcing conditions for cleavage. The a-proton s also shielded from deprotonation, which means that esters elsewhere in the molecule can be selectively deprotonated. 

Benzenesulfenamide and a number of substituted benzenesulfenamides (compounds B, C, and D) have been prepared to protect the 7-amino group in cephalosporins. They are cleaved by sodium iodide (CH3OH, CH2CI2, AcOH, 0°, 20 min, 53% yield from sulfenamide B)."... 

Analogous to azloci11i n-mezloci11i n, acylation of the amino group of 2-phenyl glycine containing cephalosporins is consistent with antipseudomonal activity. There are many... 

Biotechnological processes may be divided into fermentation processes and biotransformations. In a fermentation process, products are formed from components in the fermentation broth, as primary or secondary metabolites, by microorganisms or higher cells. Product examples are amino acids, vitamins, or antibiotics such as penicillin or cephalosporin. In these cases, co-solvents are sometimes used for in situ product extraction. 

Class D enzymes (Mr of about 27,000) exhibit a high activity versus isoxazolyl penicillins, such as oxacillin and are referred to as the OXA-family. Surprisingly, the amino group of the SXXK lysine residues is carboxylated in the most active forms of the enzymes. Penicillins are generally better substrates than cephalosporins but mutations have been found which confer extended activity spectra to these enzymes. 

Beim Cephalosporin sowie 7-Amino-cephalosporinsaurc wird unter C-O-Spaltung und Allyl-Verschiebung eine exo-Methylen-Gruppe erhalten1 ... 

In addition to the amides described in ref. [72], further examples prepared by means of CDI from amino compounds of the cephalosporin or penicillin type, and various heterocyclic carboxylic acids, are reported in ref [86] and [87] and ref. [88] and [89], respectively. 

The antibiotic cephalosporin derivative 48 has been reported it was prepared by the coupling reaction of the 1,2,4-thiadiazole acid chloride derivative 46 with the amino cephalosporin derivative 47. Similar cephalosporin derivatives were mentioned in CHEC-II(1996) (Equation 13) <2001JAN364>. 

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