6- -penicillanic acid

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). 

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... 

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... 

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%. 

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

D-a-azidophenylacetamido)penicillanic acid 1-ethoxy-earbonyloxyethyl ester... 

Over the past few years there have been an increasing number of reports of diseases that are becoming resistant to previously effective drug treatments. This resistance is often due to the presence of enzymes that bring about chemical modification of the drug to an inactive form, e.g. /S-lactamase enzymes deactivate (6-lactam antibiotics by their conversion to penicillanic acid. 

Penicillanic acid derivatives are synthetically produced /3-lactamase inhibitors. 

Fig. 5.6 A, Nocardicin A B, 3-aminomonobactamic acid (3-AMA) C, aztreonam D, penicillanic acid sulphone (sodium salt) E, / -bromopenicillamc acid (sodium salt) F, tazobactam G, sulbactam.

Penicillanic acid sulphone (Tig. 5.6D) protects ampicillin flom hydrolysis by staphylococcal Alactamase and some, but not all, of the Mactamases produced by Gram-negative bacteria, but is less potent than clavulanic acid. /3-bromopenicillanic acid (Tig. 5.6E) inhibits some types of Alactamases. 

Tazobactam (Tig. 5.6F) is a penicillanic acid sulphone derivative marketed as a combination with piperacillin. Alone it has poor intrinsic antibacterial activity but is comparable to clavulanic acid in inhibiting /J-lactamase activity. 

Stereocontrolled total syntheses of penicillanic acid S. S -dioxide and 6-aminopenicillanic add from (5)-asparatic add and (i ,i )-tartaric add, respectively, have been reported (Eq. 4.37).45... 

---