Synthesis of antimicrobial agents. IV. synthesis of 1‐hydroxypiperazine dihydrochloride and its applications to pyridone carboxylic acid antibacterial agents

Abstract

1‐Hydroxypiperazine dihydrochloride 7 was prepared and it was applied to the syntheses of new pyridone carboxylic acid antibacterial agents (PCA‐antibacterial agents). 1‐Cyclopropyl‐6,8‐difluoro‐1,4‐dihydro‐7‐(4‐hydroxypiperazin‐1‐yl)‐4‐oxoquinoline‐3‐carboxylic acid 13 showed the most potent antibacterial activity.

Synthesis of antimicrobial agents. 5. In vivo metabolism of 7-(4-hydroxypiperazin-1-yl)quinolones

“…On the other hand, after oral administration of the 4-hydroxy-3-methylpiperazinyl compound 4 to mice, 4 and its dehydroxylated derivative 8 were both present, and the mean AUC value of 4 was approximately 4-fold lower than that of 8. In rats, the AUC values of these compounds were reversed, with the AUC of 8 being approximately twice that of 4, as shown in Figure 2.…”

“…The 6,7,8-trifluoro derivative 6,4 7-(4-hydroxypiperazin-1-yl) derivative 3,4 and compounds 7-9® were prepared according to literature procedures. The hydroxylated and 11 with m-chloroperbenzoic acid in chloroform at room temperature afforded the IV-oxides, which spontaneously rearranged to 4 and 5, respectively, by a reverse Michael addition.6 Therefore, the unstable N-oxides were not isolated.…”

“…These findings led us to synthesize 7-(substituted 4-hydroxypiperazin-l-yl)quinolines and to study the structuremetabolism relationship of the quinolones, particularly the influence of substituents at the «-position of the 4-hydroxyl group. This paper describes the syntheses of 7-(4-hydroxypiperazin-l-yl) derivative 3, 7-(4-hydroxy-3-methylpiperazin-l-yl) derivative 4, and 7-(4-hydroxy-3,5-dimethylpiperazin-1 -yl) derivative 5 and the conversion of these compounds (3,4,5) to the corresponding piperazinyl compounds (7,8,9) after oral administration to mice and rats.…”

Product Class 5: Hydroxylamines

“…CPh 2 OH CH 2 1 9 6 [342] H O 2 9 3 [342] H C H 2 2 7 2 [342] CONH(CH 2 ) 8 Me CH 2 1 9 3 [342] CO 2 Me CH 2 1 9 6 [342] CO 2 CH 2 CH=CH 2 CH 2 1 9 0 [342] N-Oxides from 3-(dialkylamino)propanoic acid esters or 3-(dialkylamino)propanenitriles [217,[343][344][345][346] undergo thermal Cope elimination to afford (cyclic) N,N-dialkylhydroxylamines. For example, morpholin-4-ol (260, X = O) and piperidin-1-ol (260, X = CH 2 ) are prepared by this method in reasonable yields (Scheme 96).…”

“…On cooling, N-[(tetrahydropyran-2-yl)oxy]phthalimide was removed by filtration; yield: 25.2 g (quant); The precipitated AgBr was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed (silica gel, CH 2 Cl 2 ) to give N-(1-adamantyloxy)phthalimide(344). A mixture of equimolar amounts of 344 and NH 2 NH 2 •H 2 O in EtOH was refluxed for 1 h, and then diluted with 5% Na 2 CO 3 soln; the re-40.5.2 Acyclic O-Alkyl-, O,N-Dialkyl-, and Trialkylhydroxylamines sulting precipitate was removed by filtration.…”