Cephalosporin acids

Removal of the ester group afforded the cephalosporin acid (205). 7-Amino- and 7-acylaminocephalosporin esters directly substituted at position 3 with a secondary acyclic amino group or a cyclic secondary amino group were reduced in dry solvents with diborane to yield 3-unsubstituted 3-cephems. The same 3-aminocephalosporins were reacted with an alkyl or aryl Grignard reagent to afford the corresponding 3-alkyl- or 3-aryl-3-cephem esters (U.S. Patent 4,065,618). 

The reactivity of ketenimines such as 146 is related to substituent R. Ketenimines were isolable when R was phenyl or alkyl. In contrast, ketenimines wherein R was halogen, thienyl, phenylthio, methylthio, or methylsulfonyl were sufficiently reactive to afford iminoethers (147) at -78°C in the presence of excess lithium methoxide. The trimethyl-chlorosilane-quinoline procedure satisfactorily converted all these substituted iminoethers to amides in good yields. The overall sequence proved amenable for use with cephalosporin acids, by prior protection of the carboxyl group as a silyl ester. Extension of this method to the penicillin series permitted the preparation of 6a-methoxyketenimine 149 and 6a-methoxyimino ether 150 from the corresponding methyl 6p-(2-chlorophenyl)acetamido and fi -dichloroacetamidopenicillanates, respectively. No further transformations of these substances were reported. 

Wittig reagents," decarbonylation," oxidation, oxime formation, and fluorination, to afford a variety of novel cephalosporins. Acid (73 c), also prepared from (65), in which the carboxy-group has been translocated to the abnormal C-3 position, has been reported to have only weak antibacterial activity. Recently, a more direct synthesis of 3-halogenomethyl-cephalosporins (74) and (75) has been described in which a boron trihalide effected the replacement of the 3-acetoxy-group by a halogen atom. Similarly, (75 X = OAc or... 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

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). 

Chloroacetoacetic esters are important industrial intermediates used especially for the synthesis of the aniinothia2olylacetic acid side chain of modem cephalosporins (see Antibiotics, P-LACTAMS-cephalosporins). For a review of the chemistry of 4-chloroacetoacetates see Reference 112. 

In a similar way, several cephalosporins have been hydrolyzed to 7-aminodeacetoxycephalosporanic acid (72), and nocardicin C to 6-aminonocardicinic acid (73). Penicillin G amidase from Pscherichia coli has been used in an efficient resolution of a racemic cis intermediate required for a preparation of the synthon required for synthesis of the antibiotic Loracarbef (74). The racemic intermediate (21) underwent selective acylation to yield the cis derivative (22) in 44% yield the product displayed a 97% enantiomeric excess (ee). 

Protection of carboxyflc acids and sulfenic acids requires efficient sdyl donors, eg, BSA, MTSA, and bis(ttimeth5isdyl)urea [18297-63-7] (BSU). BSU is often prepared in situ from hexamethyldisda2ane and urea to yield over 90% of the sdylated derivative in synthesis of cephalosporins (5). 

Steroid Antibiotics. The steroid antibiotics are a stmcturaHy diverse class of steroids that have a common biological function, ie, antibacterial, antifungal, antiviral, or antitumor activities. This group of compounds can overlap with other steroid classes Hsted above. Eusidic acid [6990-06-3] (67), helvohc acid [29400-42-8] (68), and cephalosporin [13258-72-5] (69) exemplify a set of antibacterial steroids that contain a prolanostane skeleton with an... 

Pharmaceuticals and Agrochemicals. Thioglycohc acid and its esters are useful as a raw material to obtain biologically active molecules. In cephalosporine syntheses, (4-pyridyl)thioacetic acid [10351 -19-8] (65) and trifluoromethane (ethyl) thioglycolate [75-92-9] (66) are used as intermediates. Methyl-3-ainino-2-thiophene carboxylate can be used as intermediate for herbicidal sulfonylureas (67) and various thiophenic stmctures (68). 

In the period up to 1970 most P-lactam research was concerned with the penicillin and cephalosporin group of antibiotics (1). Since that time, however, a wide variety of new mono- and bicychc P-lactam stmctures have been described. The carbapenems, characterized by the presence of the bicychc ting systems (1, X = CH2) originated from natural sources the penem ring (1, X = S) and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are 7-oxo-(R)-l-a2abicyclo[3.2.0]hept-2-ene-2-carboxyhc acid [78854-41-8] CyH NO, and 7-oxo-(R)-4-thia-l-a2abicyclo[3.2.0]hept-2-ene-2-carboxylic a.cid [69126-94-9], C H NO S, respectively. 

In the case of thienamycin (Fig. lb) the absolute stereochemistry at C-5 was unambiguously deterrnined from the ene-lactam (16). The resultant (R)-aspartic acid (17) demonstrated that the absolute stereochemistry at C-5 of thienamycin is (R), corresponding to that found in the C-5 position of both penicillins and cephalosporins. Confirmation of the stereochemical assignments in both thienamycin (2) and the olivanic acid MM 13902 (3, n = 0) has been confirmed by x-ray crystallography (19,21,22). The stmctural determination of the nonsulfated derivatives from S. olivaceus (23), PS-5 (5) (5), the carpetimycins (6), and the asparenomycins (7) followed a similar pattern. 

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. 

Most cephalospoiin antibiotics are white, off-white, tan, oi pale yeUow sohds that are usually amorphous, but can sometimes be obtained crystalline. The cephalosporins do not usually have sharp melting points, but rather decompose upon heating at elevated temperatures. The acid strength, p of the... 

Isolation. Isolation procedures rely primarily on solubiHty, adsorption, and ionic characteristics of the P-lactam antibiotic to separate it from the large number of other components present in the fermentation mixture. The penicillins ate monobasic catboxyHc acids which lend themselves to solvent extraction techniques (154). Pencillin V, because of its improved acid stabiHty over other penicillins, can be precipitated dkecdy from broth filtrates by addition of dilute sulfuric acid (154,156). The separation process for cephalosporin C is more complex because the amphoteric nature of cephalosporin C precludes dkect extraction into organic solvents. This antibiotic is isolated through the use of a combination of ion-exchange and precipitation procedures (157). The use of neutral, macroporous resins such as XAD-2 or XAD-4, allows for a more rapid elimination of impurities in the initial steps of the isolation (158). The isolation procedure for cephamycin C also involves a series of ion exchange treatments (103). 

---