title: Synthesis and chromatographic enantioresolution of anti-HIV quinolone derivatives.
abstract: The successful enantioseparation of five 6-desfluoroquinolones with three polysaccharide-based stationary phases (namely, the cellulose-based Chiralpak IB and the two amylose-based Chiralpak AD-H and Lux Amylose-2) is herein described. The investigated species differ for the nature of substituents and/or the position of the stereogenic centre on the quinolone scaffold. The effect on the enantioseparation performance exerted by the different morphology of the cellulose-based and amylose-based polymers, was systematically evaluated for all compounds. In this frame, the impact of alternative alcoholic (ethanol, 2-ethoxyethanol, methanol, 2-propanol) and acidic (acetic, methanesulfonic and trifluoroacetic acid) modifiers as well as of a "non-standard" solvent (chloroform), was investigated in normal phase conditions along with the stereo-electronic peculiarities of the selected polymers. While 7-[4-(1,3-benzothiazol-2-yl)-2-methyl-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (1) was enantioresolved with conventional normal-phase conditions by means of the largely employed amylose-based Chiralpak AD-H column, the recruitment of a bulky alcohol (2-ethoxyethanol) succeeded in the enantioresolution of 6-amino-1-methyl-7-[2-methyl-4-(2-pyridinyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (2) and 6-amino-1-[1-(hydroxymethyl)propyl]-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (3) with the same column. The use of the amylose-based Lux Amylose-2 column, carrying both an electro-withdrawing (chlorine) and an electro-donating (methyl) group on the carbamate residue, allowed to get 6-amino-1-methyl-4-oxo-7-[3-(2-pyridinyl)-1-pyrrolidinyl]-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride (4) enanantioresolved, and 6-amino-1-methyl-4-oxo-7-(3-pyridin-2-ylpiperidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (5) enantioseparated.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Perugia, Italy. natalini@chimfarm.unipg.it
authors.forename: Benedetto
authors.initials: B
authors.lastname: Natalini
authors.forename: Roccaldo
authors.initials: R
authors.lastname: Sardella
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.forename: Federica
authors.initials: F
authors.lastname: Ianni
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
mesh_terms: D019342:Acetic Acid / Q000737:chemistry; D000688:Amylose / Q000031:analogs & derivatives / Q000737:chemistry; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002482:Cellulose / Q000737:chemistry; D002725:Chloroform / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000295:instrumentation / Q000379:methods*; D000431:Ethanol / Q000737:chemistry; D006678:HIV / Q000187:drug effects; D006801:Humans; D008698:Mesylates / Q000737:chemistry; D000432:Methanol / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D048448:Phenylcarbamates / Q000737:chemistry; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014269:Trifluoroacetic Acid / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D008698:Mesylates; D048448:Phenylcarbamates; D015363:Quinolones; C045880:methanesulfonic acid; C080033:Chiralpak AD; D000431:Ethanol; D002725:Chloroform; D002482:Cellulose; D000688:Amylose; D014269:Trifluoroacetic Acid; D019342:Acetic Acid; D000432:Methanol