1- Ethoxycarbonyl-4- piperazine

The preparation of 1 -(5-fluoropyrimidin-2-yl)piperazine moiety of 169 is depicted in Scheme 12.25. Heating 2-chloro-5-fluoro-4-(meihylthio)pyrimidine (prepared from 5-fluorouracil) with A-(ethoxycarbonyl)piperazine in acetonitrile afforded 170. The latter was converted into 171 by desulfurization, followed by acid hydrolysis of the carbamate moiety. 

Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid (0.29 mmol) dissolved in 2 ml DMF was treated with A-ethylmorpholine (1.16 mmol), 1 -pyridin-4-ylmethyl-piperazine (0.29 mmol), and 0-((cyano(ethoxycarbonyl)methylene)amino)-l, 1,3,3-tetramethyluronium tetrafluoroborate (0.3 mmol), then stirred 60 minutes at ambient temperature. The mixture was concentrated, then dissolved in CH2C12, washed three times with saturated NaHC03 solution, dried with Na2S04, and reconcentrated. The residue was purified by chromatography with silica gel using n-heptane/EtOAc, 1 1, then EtOAc, and finally EtOAc/methyl alcohol, 10 1, and 102 mg product isolated. MS ES+, m/z = 500 (M+)... 

Condensations of chloroacetyl chloride (and similar compounds) with substituted ethylenediamines to give 1,4-disubstituted piperazin-2-ones have been described, and a number of 4-alkyl(or aralkyl)- -arylpiperazin-2-ones has been prepared either by catalytic debenzylation or pyrolytic debenzylation (or demethylation) of I,l-dialkyl(or l,l-diaralkyl)-3-oxo-4-arylpiperazinium halides (1609). 3-Ethoxy-carbonylmethylene-6-methylpiperazin-2-one has been synthesized by the reaction of diethyl acetylenedicarboxylate with propylenediamine (1610), and treatment of diethyl fumarate with propylenediamine has been shown to give 3-ethoxycarbonyl-methyl-6-methylpiperazin-2-one, also prepared from the diethyl ester of N- 2 -hydroxyiminopropyl)aspartic acid (84) (1611). 

Ionization constants of 2-carboxypiperazine and the three dicarboxylic acids have been determined (1684), and the nucleophilic reactivity of piperazine compared to other amines in reactions with l-chloro-2,4-dinitrobenzene has been measured (1685). The rate of quaternization of l-ethoxycarbonyl-4-methylpiperazine with allyl bromide (/ = 2.25 1/mol min) and methyl iodide (10A = 1.22) have been measured in acetone-water solution (1686). The composition and structure of the 2-methylpiperazine-carbon disulfide complex has been investigated it was a mixture of l-dithiocarboxy-3-methylpiperazine (138) and the 2-methylpiperazine salt of l,4-bis(dithiocarboxy)-2-methylpiperazine (1687). 

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