Polar piperazines

A number of reductive procedures have found general applicability. a-Azidoketones may be reduced catalytically to the dihydropyrazines (80OPP265) and a direct conversion of a-azidoketones to pyrazines by treatment with triphenylphosphine in benzene (Scheme 55) has been reported to proceed in moderate to good yields (69LA(727)23l). Similarly, a-nitroketones may be reduced to the a-aminoketones which dimerize spontaneously (69USP3453279). The products from this reaction are pyrazines and piperazines and an intermolecular redox reaction between the initially formed dihydropyrazines may explain their formation. Normally, if the reaction is carried out in aqueous acetic acid the pyrazine predominates, but in less polar solvents over-reduction results in extensive piperazine formation. 

Replacement of the methyl group of the piperazine-substituted phenothiazines by some more polar group such as hydroxyethyl fragment leads to a further small increase in potency. It should be noted at this point that all phenothiazines manifest a series of side effects. The given set of these varies, however, with the side chains. The availability of the great variety of such structural variations makes it more likely that some drug will be found that a given individual will tolerate. 

Kwakman et al. [65] described the synthesis of a new dansyl derivative for carboxylic acids. The label, N- (bromoacetyl)-A -[5-(dimethylamino)naphthalene-l-sulfonyl]-piperazine, reacted with both aliphatic and aromatic carboxylic acids in less than 30 min. Excess reagent was converted to a relatively polar compound and subsequently separated from the derivatives on a silica cartridge. A separation of carboxylic acid enantiomers was performed after labeling with either of three chiral labels and the applicability of the method was demonstrated by determinations of racemic ibuprofen in rat plasma and human urine [66], Other examples of labels used to derivatize carboxylic acids are 3-aminoperylene [67], various coumarin compounds [68], 9-anthracenemethanol [69], 6,7-dimethoxy-l-methyl-2(lH)-quinoxalinone-3-propionylcarboxylic acid hydrazide (quinoxalinone) [70], and a quinolizinocoumarin derivative termed Lumarin 4 [71],... 

Since acrylamide-based monoliths generally represent polar support materials, they are predominately also used for separation in normal-phase mode. For that purpose, monolithic polymers were prepared by polymerization of mixtures containing piperazine diacrylamide as cross-linking agent and methacrylamide, A-isopropylacrylamide or 2-hydroxyethyl methacrylate, and vinylsulfo-nic acid as monomers. 

The replacement of the polar head group of a range of piperazines by a 2-methylimidazo[4,5-f]pyridine group provided efficient orally active platelet-activating factor antagonists, for example, compounds 191-193 <1996JME487>. 

Quinolone carboxylic acid antibacterials are synthetic compounds whose basic nuclear structure includes a quinolone ring and a carboxylic acid group. Fluoroquinolones are second-generation quinolones that contain in their molecule a fluorine and a piperazine ring. Quinolones are amphoteric compounds slightly soluble in polar solvents such as water, and insoluble in nonpolar solvents such as benzene and hexane. Most of these drugs are fluorescent and are quite stable in aqueous solution toward light, except miloxacin, which is reported to be unstable. 

In order to simplify the previous preparation method, a more straightforward procedure was later developed by the same group [30], The polymerization mixture consisted of an aqueous solution of acrylamide A, piperazine diacrylamide 111, and vinylsulfonic acid 12 with added stearyl methacrylate 2 or butyl methacrylate 1A to control the hydrophobicity of the gel. Since neither of these non-polar monomers is soluble in water, a surfactant was added to the mixture, followed by sonication to form an emulsion of the hydrophobic monomer in the aqueous solution. Once initiated, the mixture was immediately drawn into an acryloylsilanized capillary, where the polymerization was completed. The presence of the strongly acidic sulfonic acid functionalities afforded EOF that remained constant over a broad pH range. 

This effect of solvent polarity on the product distribution is in agreement with the proposed reaction scheme. A solvent such as acetone favors a reaction involving charge destruction, such as the alkyl halide formation from the aziridinium ion with the counter ion. Thus acetone favors piperazine formation. A solvent of high polarity favors charge stabilization or charge transfer such as the polymerization steps. Therefore, polymer or piperazine derivatives can be prepared by the proper choice of solvent. 

The more reactive 2-chloro-3-fluoropyridine (89) is aminated readily by piperazine in boiling -butanol to give —60% of 90 (83JMC16%). The presence of a polar cyano group allows the 2-chloro-3-cyanopyridine (72) to be aminated already at I00°C by methylamine to 2-methylamino-3-cyanopyridine (91) in 63% yield (85SC10I3). An additional 6-chloro group, as in 92, leads, upon amination with ammonia to a mixture of the corresponding amino compounds 93 and 94. With the weakly basic aniline in the... 

Cleavage of the A -Fmoc derivatives is fast with primary (cyclohexylamine, ethanolamine) and secondary amines such as piperidine or piperazine (Table 3), but substantially slower with tertiary amines (TEA, DIPEA).P5] The reaction is faster in polar solvents (DMF, NMP) than in apolar solvents (CH2CI2). 

Separation of relatively pure para-cresol from mixed cresols using an organic solvent and thereafter formation of a solid crystalline complex with the solvent has been reported. Piperazine and DABCO (diazabicyclo-octane) have been found to be very effective as extracting agents in this process of separation. There is very little effect of m-cresol in this process. The values of separation factor approach infinity as 100% p-cresol-base complex is crystallized. The yield of p-cresol was impressive with some aliphatic polar solvents, but... 

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