3-Cephems

In the search for improved antibacterials not only has the effect produced by the variation of the C-7 amido side chain and the 3 substituent been studied, but so also has the more synthetically challenging question of the effect of changes in the cephem nucleus (194,197,198). Nuclear analogues have been studied since the early 1970s but only the oxacephem class has reached the marketplace. 

The most informative feature of the IR spectra of azetidin-2-ones is generally the /3-lactam carbonyl absorption, the frequency of which is affected by substitution and by fusion of the ring (c/. Table 3). Thus, IR spectra of simple monocyclic /3-lactams generally have absorption maxima in the region 1730-1760 cm while the fused 2- and 3-cephem systems (60) and (61) show IR maxima in the regions 1772-1784 and 1782-1792 cm S respectively (b-72MI50900 p. 318). 

The higher frequencies of the /3-lactam carbonyl absorption in fused systems has been attributed to increased inhibition of amide resonance as the /3-lactam ring becomes less planar (b-72mI50900 p. 303). For the 3-cephems (61) there is also the possibility of enamine resonance which could further reduce the ability of the /3-lactam nitrogen to contribute to amide resonance. 

Isomerization of 3-cephems (27) to 2-cephems (28) takes place in the presence of organic bases (e.g. pyridine) and is most facile when the carboxyl is esterified. Normally an equilibrium mixture of 3 7 (3-cephem/2-cephem) is reached. Since the 2-cephem isomers are not active as antibacterial agents, the rearrangement proved to be an undesirable side reaction that complicated acylation of the C-7 amine under certain conditions. A method for converting such mixtures to the desired 3-cephem isomer involves oxidation with concomitant rearrangement to the 3-cephem sulfoxide followed by reduction. Additions... 

A very efficient one-pot procedure for the production of 3-hydroxy-3-cephems (45) has been developed which gives the desired product in almost 80% overall yield from (43a) which is readily available from penicillin. TTie sequence of reactions is (1) mesylation to give (43b), (2) formation of enamine (43c), (3) bromination to afford (44) and (4) hydroly-sis/cyclization with hydrochloric acid in methanol to afford (45) which, in some cases, crystallizes directly from the reaction mixture (B-82MI51000). 

Scheme 6 depicts a typical penicillin sulfoxide rearrangement (69JA1401). The mechanism probably involves an initial thermal formation of a sulfenic acid which is trapped by the acetic anhydride as the mixed sulfenic-acetic anhydride. Nucleophilic attack by the double bond on the sulfur leads to an episulfonium ion which, depending on the site of acetate attack, can afford either the penam (19) or the cepham (20). Product ratios are dependent on reaction conditions. For example, in another related study acetic anhydride gave predominantly the penam product, while chloroacetic anhydride gave the cepham product (7lJCS(O3540). The rearrangement can also be effected by acid in this case the principal products are the cepham (21) and the cephem (22 Scheme 7). Since these early studies a wide variety of reagents have been found to catalyze the conversion of a penicillin sulfoxide to the cepham/cephem ring system (e.g. 77JOC2887).

Application of the Curtius reaction to the 3-carboxyl of a penicillin has provided intermediates which have been used for the construction of cephem derivatives. As can be seen in Scheme 23, this route allows the selective cleavage of the C(3)—N(4) bond of the thiazolidine ring, thereby allowing a reconstruction of that ring in a different form (72HCA388 and the following three papers). The preparation of a related intermediate is shown in Scheme 24 (76HCA2298). 

Cefazaflur (58) stands out among this group of analogues because it lacks an arylamide C-7 side chain (see cephacetri 1 e for another example).Cefazaflur (58) is synthesized by reaction of 3-(1-methyl-lB[-tetrazol-5-ylthiomethylene)-7-amino-cephem-4-carboxylic acid (56) with trifluoromethylthioacetyl chloride (57). ... 

Chemical Name 7-(D-0 -Phenylglycylamido)-3-chloro-3-cephem-4-carboxylic acid Common Name —... 

Preparation of 7-amino-3-chloro-3-cephem-4-carboxylic acid To a solution of 750 mg (1 55 mmol) of p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride in 20 ml of tetrahydrofuran and 40 ml of methanol was added a suspension of 750 mg of prereduced 5% palladium on carbon catalyst in 20 ml of ethanol and the suspension was hydrogenated under 50 psi of hydrogen at room temperature for 45 minutes. The catalyst was filtered and washed with THF and water. The filtrate and catalyst washes were combined and evaporated to dryness. The residue was dissolved in a water-ethyl acetate mixture and the pH adjusted to pH 3. The insoluble product was filtered and triturated with acetone. The product was then dried to yield 115 mg of 7-amlno-3-chloro-3-cephem-4-carboxylic acid. 

Preparation of 7-(D-0t-phenyigiycyiamido)-3-chioro-3-cephem-4-carboxyiic acid To a suspension of 280 mg (1.2 mmol) of 7-amino-3-chloro-3-cephem-4-carboxylic acid in 14 ml of acetonitrile was added with stirring at room temperature 0.5 ml of N, 0-bis-(trimethylsilyl)acetamide to form the soluble disilylmethyl derivative thereof. The solution was cooled to 0°C and was slowly added to a solution of the mixed anhydride formed by reacting 408 mg (1.5 mmol) of methyl-3-a-carboxybenzylaminocrotonate sodium salt with 161 mg (1.7 mmol) of methyl chloroformate in the presence to 2 drops of N, N-dimethylbenzyl amine in 7 ml of acetonitrile. 

The mixture was stirred at ice bath temperature for 2 hours, 1 ml of methanol was added and the mixture was filtered to remove insoluble impurities. Two milliliters of water were added to the filtrate and the pH was adjusted momentarily to pH 1.5, to effect removal of theenamine block, and then to pH 4.5 with triethylamine. After stirring for an additional hour at ice bath temperature the reaction product,7-(D-0 -phenylglycylamido)-3-chloro-3-cephem-4-carboxylic acid (zwitterion) precipitated from the reaction mixture as a crystalline solid. 

Amino-3-methyl-3-cephem-4-carboxylic acid Manufacturing Process... 

On the other hand, 1 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid was suspended in 20 ml of methanol, and 1.4 g of triethylamine was added thereto to be dissolved, and 0,4 ml of acetic acid was further added thereto. This solution was cooled to -20°C and the mixed acid anhydride prepared previously was added thereto. After the mixture was reacted at -20°C for 1 hour, the temperature of the reaction mixture was raised to 0°C over a period of 1 hour, and the mixture was reacted for 3 hours at the same temperature. 

After the reaction, 1 ml of water was added to the reaction mixture, and the mixture was adjusted to a pH of 1,0 with concentrated hydrochloric acid while being cooled, and then stirred for 30 minutes. The insoluble matters were filtered off, and the filtrate was adjusted to a pH of 5.5 with triethylamine. This solution was concentrated under reduced pressure, and the residue was diluted with 20 ml of acetone to precipitate white crystals. The crystals were collected by filtration and washed with ethanol to obtain 1.46 g of white crystals of7-[D(-)-0 -emino-(4-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylicacid having a decomposition point of 197°C. 

Chemical Name Sodium 7-(D-2-formyloxy-2-phenylacetamldo)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate... 

Amino-3-(1 -methyl-1 H-tetrazol-5-yI-thiomethyI)-3-cephem-4-carboxylic acid... 

To 13 of ethyl acetate were added 85.1 g (2.59 mols) of 7-emino-3-(1 -methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and 1,361 g (10.37 mols) of monotrimethylsilyl acetamide, and the mixture was stirred at 50°C until a clear solution was obtained. The solution was cooled to 20°C and 514 g (2.59 mols) of 0-formyl mandeloyl chloride was added at a rate such that the temperature of the reaction solution was maintained between about 20°C to 25°C with ice-cooling. 

The reaction mixture was stirred for 1.5 hours at about room temperature after the addition of the mandeloyl chloride was completed. Five liters of water were then added to the reaction mixture and the diluted mixture was stirred for about 10 minutes. The organic layer was separated and was washed twice with water. The combined washes are extracted with 1.5 of ethyl acetate and the extract is combined with the washed organic layer, The whole was dried over magnesium sulfate, filtered and evaporated in vacuo on a 25°C water bath to yield 1,460 g of product,7-(D-2-formyloxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthlomethyl)-3-cephem-4-carboxyllc acid, as a yellow foam. 

The product was dissolved in 5 of acetone and the solution was mixed with a solution of 430 g (2.59 mols) of sodium 2-ethylhexanoate in 5.4 of acetone. The combined solutions were seeded and stirred in an ice bath for 1.5 hours. The crystalline precipitate of sodium 7-(D-2-formyloxy-2-phenylacetamido)-3-(1 -methyl-1 H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate was filtered and washed with 5 of acetone. The crystalline salt was dried overnight in a vacuum oven at 40°C to yield 1,060 g (80%) of product, melting at 182°C to 184°C. 

A suspension of 37.3 g (0.1 mol) of 7/3-amino-3-methoxy-3-cephem-4-carboxylic acid hydrochloride dioxanate in 500 ml methylene chloride is stirred for 15 minutes at room temperature under an argon atmosphere and treated with 57.2 ml (0.23 mol) of bis-(trimethylsilyl)-acetamide. After 45 minutes the faintly yellow slightly turbid solution is cooled to 0°C and treated within 10 minutes with 31.2 g (0.15 mol) of D-Ct-amino-Ct-d, 4-cyclohexadienyl (acetyl chloride hydrochloride. Thirty minutes thereafter 15 ml (about 0.21 mol) of propylene oxide is added and the mixture is further stirred for 1 hour at 0°C. A cooled mixture of 20 ml of absolute methanol in 200 ml of methylene chloride is added within 30 minutes, after another 30 minutes the precipitate is filtered off under exclusion of moisture, washed with methylene chloride and dried under reduced pressure at room temperature. The obtained hygroscopic crystals of the hydrochloride of 7j3-[D-a-(1,4-cyclohexadienyl)acetylamino] -... 

Diphenylmethyl 7j3-amino-7a-methoxy-3-(1 -methyltetrazol-B-yD-thiomethyl-l -oxa-dethia-3-cephem-4-carboxylate Aluminum chloride Sodium-2-ethylhexanoate... 

To a stirred suspension of p-(p-methoxvbenzyloxy)-phenylmalonic acid (125 mg) in methylene chloride (3 ml) are added triethylamine (55 All) and oxalyl chloride (26 AH) at -15°C, and the suspension is stirred for 40 minutes at 0°C. The mixture Is added to a solution of diphenylmethyl 7 -amino-7a-methoxy-3-(1 -methyltetrazol-5-yl)thiomethyl-1 -oxadethia-3-cephem-4methylene chloride (3 ml) and pyridine (63 AH), and the mixture is stirred for 30 minutes at 0°C. The reaction mixture is diluted with ethyl acetate, washed with aqueous 2 N-hydrochloric acid and water, dried over sodium sulfate, and concentrated to give crude product (212 mg), which Is chromatographed on silica gel (20 g) and... 

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