Semisynthetic Penicillins. I. 2-Biphenylylpenicillins

Abstract

The preparation of a number of penicillins with 2-biphenylyl side chains is described. Some of the substituted 2-biphenylcarboxylic acids used as intermediates were synthesized for the first time or were prepared by new methods. These penicillins were active against penicillin G-resistant as well as penicillin G-susceptible staphylococci.The penicillin nucleus, 6-aminopenicillanic acid, which became available in quantity as a biosynthetic product in 1959,1 has been used as the starting material for the chemical preparation of a great number of "semisynthetic" penicillins.2 Previously, total biosynthesis had been the only commercially feasible method for making penicillins, and, out of the limited number so obtainable, only two, penicillins G and V (benzylpenicillin and phenoxymethylpenicillin, respectively), had found wide clinical use. These two antibiotics are active against many Gram-positive organisms, including "susceptible" staphylococci, but they are not effective against the increasing number of "resistant" strains of staphylococci which are being encountered clinically. In this paper the term "susceptible" is used for those staphylococci which are sensitive to penicillins G and V, and "resistant" for those which are unaffected by high levels (e.g. 500-1000 /ml.) of these antibiotics because they have the ability to produce a lactam-opening penicillinase.3The object of the work described in this and the following papers was to find a penicillin with good activity against both susceptible and resistant staphylococci as defined above. An early semisynthetic product, methicillin4 (2,6-dimethoxyphenylpenicillin), has approximately equal activity against these two classes of organism because it is stable to staphylococcal penicillinase.5 However, this activity is low, pre-(1) F.

Design and Synthesis of New Tetrazolyl- and Carboxy-biphenylylmethyl-quinazolin-4-one Derivatives as Angiotensin II AT1 Receptor Antagonists

“…Trying to push the latter reaction forward by increasing the reaction time gave a mixture of the acid ( V ) and the amide ( IV ). When the hydrolysis was performed using ethylene glycol,15b the acid ( V ) was isolated in good yield. Additionally, acid-catalyzed hydrolysis of the nitrile ( III ) resulted in the formation of V as the sole product in good yield 15c.…”

“…When the hydrolysis was performed using ethylene glycol,15b the acid ( V ) was isolated in good yield. Additionally, acid-catalyzed hydrolysis of the nitrile ( III ) resulted in the formation of V as the sole product in good yield 15c. The spectral and analytical data of III − V matched the reported data for these compounds.…”

Direct diazo-transfer reaction on β-lactam: Synthesis and preliminary biological activities of 6-triazolylpenicillanic acids

“…We selected a subset of terminal alkynes whose closely related carboxylic acid analogs have been shown to support the antimicrobial activities of β-lactams. [38][39][40] Alkynes such as 7, 10h, 10i, and 10k that we could not obtain from commercial sources were synthesized from the corresponding carboxylic acid, through the intermediacy of aldehyde, using the Bestmann-Ohira reagent. [41][42][43] Hydroxyl alkyne 10f and 10l were obtained by a direct Grignard reaction of ethynylmagnesium bromide with the appropriate aldehydes.…”

β-Lactam Antibiotics: Structure-Activity Relationships

“…In fact with a six-membered ring (or a fused ring system of equivalent or greater bulk, e.g., quinacillin) a single ortho substituent of proper type can be sufficient for good penicillinase resistance. Thus o-biphenylylpenicillin (diphenicillin) is stable toward penicillinase but the analogous meta and para analogs, as well as o-biphenylylmethylpenicillin, are susceptible (Tables 3 and 4) (DOLAN et al 1962;HOOVER et al 1964). Other aromatic or heterocyclic ring systems, and even a cyclohexyl ring, can substitute for either benzene ring in o-biphenylylpenicillin, provided they meet specific structural requirements CHOW et al 1966).…”