Piperazine 1-carboxylic acid ethyl ester

Chlorobenzhydryl chloride Piperazine 1-carboxylic acid ethyl ester 4-tert-Butylbenzyl chloride... 

Catalytic synthesis of l-ethyl>6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-quinoline-3-carboxylic acid ethyl ester (Norfloxacin ethyl ester) (15a). To a dry 15 mL recovery flask equipped with a reflux condenser was added 13 (150 mg, 0.5 mmole), (R)-binap (10 mg, 0.017 mmole), cesium carbonate (360 mg, 0.950 mmole), piperazine (215 mg, 2.5 mmole), Pd2(dba)3 (10 mg, 0.010 mmole), and 1.5 mL of DMF. The reaction vessel was purged with nitrogen and heated to reflux. After three hours, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by thin-layer chromatography on a 500 micron silica gel preparative plate with an elution mixture of chloroform methanol water ammonia (80 20 2 0.2) to give 101 mg of 15a as an off-white solid in 58% yield and, separately, 29 mg of 17 as a light brown solid in 22% yield. Using this procedure, the yield of 15a... 

Reacting 3-chloro-4-fluoroaniline and ethyl ethoxymethylenmalonate gives the snbsti-tntion prodnct (33.2.15), which upon heating in diphenyl ester cyclizes into ethyl ester of 6-flnoro-7-chloro-l,4-dihydro-3-quinolin-4-on-carboxylic acid (33.2.16). Direct treatment of the prodnct with ethyl iodide in the presence of triethylamine and snbseqnent hydrolysis with a base gives l-ethyl-6-flnoro-7-chloro-l,4-dihydro-3-qninolin-4-on-carboxylic acid (33.2.17). Reacting this with piperazine gives norfloxacin (33.2.18) [70-75]. 

The synthesis of fluoroquinoline antibacterials almost invariably involves substitution of the chlorofluoroquinolone with an amine as the final step (Scheme 1). Thus, the above model studies indicate excellent potential for the palladium-catalyzed amination reaction to succeed. However, initial attempts to couple the chlorofluoroquinolone derivative 2 with piperazine using the Pd2dba3/binap catalyst system and NaOtBu in toluene solvent resulted only in the recovery of unreacted starting material. Changing to more polar solvents (DMSO, DMF) or the addition of iodide salts (in an attempt to generate the iodo derivative) had no effect. It was believed that the insolubility of the carboxylic acid 2 played a role in its failure to react and that the ethyl ester would be a more productive substrate. Conveniently, the ethyl ester of 2 is an intermediate in the standard synthesis of Norfloxacin, thus, the synthesis of 13 was readily accomplished (eq 2). ... 

Ethyl l-cyclopropyl-4-oxo-7-phenylsulfonyl-6-trifluoromethyl-l,4-dihydro-l,8-naphthyridine-3-carboxylate (7) gave the crude ester (8, R = Et) (piperazine, MeCN, 20°C), characterized after saponification to l-cyclopropyl-4-oxo-7-(piperazin-l-yl)-6-trifluoromethyl-l,4-dihydro-1,8-naphthyri dine-3-car-boxylic acid (8, R = H) (NaOH, EtOH 37% overall).1167... 

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