6- -penicillanic

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

Substitution of the -methyl group of penicillanic acid sulfone has also been extensively investigated. The cyclopropyl sulfone (25, R = R = H,... 

The 6-methoxymethylene penicillanic acid [93040-42-7] (31, R = CH OCH (2)-isomer, R" = R " = 3) designed to mimic the amino acrylate species found usiag clavulanic acid and sulbactam. Upon the reaction of this compound with the enzyme, the potential exists for further Michael addition to inactivate the enzyme. The compound is indeed a -lactamase inhibitor but no synergy data have been reported. The related imine stmcture... 

The circular dichroism curves for a variety of penicillanic acid derivatives have been published and discussed (B-77MI51100) and have been used to support extended Hiickel MO calculations (77T711). 

Substitution at C(5) of the penicillanic ring system has been relatively little explored. The 5a-phenyl analog has been prepared by total synthesis as shown in Scheme 26 75JMC486). It was interesting that epimerization (step iv) occurs without side chain silylation (cf. Section 5.11.3.8.4). 

A direct substitution at the 5-position of the intact penicillanic acid ring system has been reported as shown in Scheme 27 (79CC485). 

Halogen atoms in the 6-position of penicillanic acid are readily removed under reducing conditions (Scheme 33). Methyl 6,6-dibromopenicillanate is converted first to the 6a-bromo... 

The 6a-halo- and 6,6-dihalo-penicillanates have been shown to undergo halogen-metal exchange to form enolates which can then react with acetaldehyde to form 6-(l-hydroxyethyOpenicillanates (Scheme 34) (77JOC2960, 79TL3805). From (41) the isomeric products were obtained in the ratio (48) (49) (50) = 24 49 27. From (42) the isomeric products were obtained in the ratio (51) (52) (53) = 39 1.5 60. Product ratios were very... 

When 6-APA is diazotized in the absence of an anion more nucleophilic than water, or when a 6-diazopenicillanate is treated with aqueous nonnucleophilic acid, 6o -hydroxy-penicillanates are produced (67HCA1327, 74JOC1444). Esters of these compounds can be formed either by acylation, or by thermal rearrangement of the corresponding N-... 

A very direct, one-step procedure for the preparation of a particular 6a-methoxy-penicillanate, which also presumably goes through a 6-acylimino intermediate, has been described (Scheme 47) (81AG(E)808). Note that this route does not even require blocking of the 3-carboxyl. 

Methylfurazancarboxylic acid chloride was transformed into the corresponding acetic acid 66, which was used for the preparation of penicillanic acid derivatives (Scheme 46) (67USP3322751). 

The preparation of isothiazolidin-3-one 5-oxide and 5,5-dioxide derivatives of azetidin-3-ones was described (99EUP100069), starting from penicillanic acid sulfoxide amides in the presence of halogenating agents in anhydrous inert solvents or even without them. Through rearrangement and oxidation with conventional methods, compounds 73 could be obtained. For some derivatives the usefulness, as intermediates for the preparation of novel p-lactam analogs or active substances in formulations for antimicrobial therapy, is claimed. 

N-diben2yloxycarbonyl-p-oxy-dl-a -aminophen.ylacetamido)-penicillanic acid so liberated was extracted into diethyl ether (50 ml and 2 portions of 30 ml). The ether phase was washed with water (3 x 5 ml) and the water washings were discarded. 

Chloro-6-fluorobenzaldoxime Methyl acetoacetate 6-Amino-penicillanic acid Sodium hydroxide... 

A solution of the amide chloride (4.6 g) in dry, alcohol-free chloroform (20 ml) was added slowly to a solution of trimethylsilyl 6-amino-penicillanate (7.2 g) and triethylamine (3.5 ml) in dry, alcohol-free chloroform (50 ml) with stirring and cooling to -70°C. The temperature was raised to 0°C during 1V4 hours. The solution was evaporated to dryness in vacua and the residue was triturated with dry ether (200 ml). The precipitate was filtered off and washed with dry ether. The filtrate was diluted with ether (200 ml). 2-Butanol (2.8 ml) was added dropwise with stirring and cooling to0°C. The stirring was continued for A hour at 0°C, whereupon the precipitate was filtered off, washed with ether and dried. It was a white, amorphous powder, soluble in water. 

The soiution was treated with 0.01 mol of formaldehyde in aqueous solution, with agitation. The solution was then filtered to eliminate traces of insoluble product and the filtrate was lyophilized. Sodium 6-[ D(-)-alpha-(methylene-amino-phenylacetamido)] -penicillanate was obtained. 

Common Name 6-(5-methyl-3-phenyl-2-isoxazoline-4-carboxamido)penicillanic acid, sodium salt 5-methy -3-phenyl-4-isoxazolylpenicillin, sodium salt... 

Chemical Name Sodium salt of 6-[D(—)-0i-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-phenylacetamido] penicillanic acid... 

D(—)-a-amlnophenylacetamido] penicillanic acid Trimethylsilyl chloride Sodium 2-ethyl hexanoate... 

To this acid was then added 1 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride (from the reaction of N-ethylethylenediamine and diethyl oxalate to give 2,3-dioxo-4-ethyl-piperazine which Is then reacted with phosgene) and the resulting mixture was reacted at 15°C to 20°C for 2 hours. After the reaction, a deposited triethylamine hydrochloride was separated by filtration, and the filtrate was incorporated with 0.4 g of n-butanol to deposit crystals. The deposited crystals were collected by filtration to obtain 1.25 g of white crystals of 6-[ D(—l-Ct-(4-ethyl-2,3-dioxo-1 -piperazinocarbonylaminolphenylacetamido] penicillanic acid. Into a solution of these crystals in 30 ml of tetrahydrofuran was dropped a solution of 0.38 g of a sodium salt of 2-ethyl-hexanoic acid in 10 ml of tetrahydrofuran, upon which white crystals were deposited. The deposited crystals were collected by filtration, sufficiently washed with tetrahydrofuran and then dried to obtain 1.25 g of sodium salt of 6-[D(—)-a-(4-ethyl-2,3-di-0X0-1-piperazinocarbonylaminolphenylacetamido] penicillanic acid, melting point 183°C to 185°C (decomposition), yield 90%. 

A fine suspension of 25.18 grams (0.05 mol) of potassium salt of enamine protected ampicillin and 10.65 grams (0.05 mol) 3-bromophthalide were reacted in a 1 2 mixture of acetone/ethyl acetate (1,500 ml) for 24 hours. After filtration the organic layer was washed twice with 250 ml portions of 1 N sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Addition of ether crystallized the phthalide enamine protected a-aminophenylacetamido penicillanate in 85% yield. 

D(-)-0i-(Aminophenylacetamido)l penicillanic acid (Ampicillin) Metampicillin sodium Piperacillin sodium a-Aminophenyl acetic acid Ampicillin... 

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