Piperazine and derivs

Piperazine and Derivatives. See Diethylene-diamine and Derivatives in Vol 5, D1230-R to D1231-R. An addnl ref is A.T. Blomquist, OSRD 4134 (1944), 7 68... 

Piperazines and derivatives are archaetypical scaffolds and can be considered as efficient, however, structurally simple peptidomimics. The scaffolds combine conformational rigidity with peptide-like spacial placement of amino acid side chains or isosteres thereof. Moreover, piperazines can be used to confine compounds with beneficial properties such as water solubihty. Piperazines are therefore in the center of synthetic interest and many different synthetic pathways have been designed [16-19]. A preferred way to synthesize different piperazine scaffolds with plenty of variabihty provides MCR chemistry. Several piperazine scaffolds are currently only accessible by isocyanide-based MCR. Likely they could be assembled by sequential synthesis as well however, the synthetic efficiency, the diversity, and the size of the alternative chemical space will be inferior. The application of... 

They are described in Vol.5 of Encycl,pp D1299-R D1300-L, under Dike to piperazine and Derivatives... 

Dihydroxy dime thyldioxy piperazine and deriv 5D1291... 

With piperazine and derivatives Co(1,4-C4HioN2)(CH3COO)2 room 4.90 Gouy 74M7... 

The synthesis of ethylenediamine (EDA) from ethanolamine (EA) with ammonia over acidic t3pes of zeolite catalyst was investigated. Among the zeolites tested in this study, the protonic form of mordenite catalyst that was treated with EDTA (H-EDTA-MOR) showed the highest activity and selectivity for the formation of EA at 603 K, W/F=200 g h mol, and NH3/ =50. The reaction proved to be highly selective for EA over H-EDTA-MOR, with small amounts of ethyleneimine (El) and piperazine (PA) derivatives as the side products. IR spectroscopic data provide evidence that the protonated El is the chemical intermediate for the reaction. The reaction for Uie formation of EDA from EA and ammonia required stronger acidic sites in the mordenite channels for hi er yield and selectivity. 

Benzhydrylamine Derivatives Attachment of piperazine nitrogen directly to a benzhydryl carbon leads to a pair of compounds which show vasodilator activity, and which should be useful in disease states marked by impaired blood circulation. Reaction of piperonyl chloride (18) with a mixture of piperazine and piperazine dihydrochloride leads to the monoalkylation product (19). (It may be supposed that the mixture of free base and salt equilibrates to the monobasic salt, thus making the second amine less nucleophilic.) Alkylation of 19 by means of benzhydryl chloride then... 

Hsin, L.-W., Dersch, C.M., Baumann, M.H. et al. (2002) Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents chiral hydroxyl-containing derivatives of l-[2-[bis (4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and l-[2-(diphenylmethoxy)ethyl]-4-(3-phe-nylpropyl)piperazine. Journal of Medicinal Chemistry, 45 (6), 1321-1329. 

Thiadiazole 57 reacts with cyclic secondary amines such as piperidine, piperazine, and morpholine to afford the substituted derivatives 64 in 80-85% yield (Equation 13) <2005EJM1346>. Under similar conditions, thiadiazole 57 reacts with hydrazine hydrate to give the thiadiazolhydrazine 65 in 97% yield <2004BML5967>. 

The synthesis of the representative compound of this series, 1,4-dihydro-l-ethyl-6-fluoro (or 6-H)-4-oxo-7-(piperazin-l-yl)thieno[2/,3/ 4,5]thieno[3,2-b]pyridine-3-carboxylic acid (81), follows the same procedure as that utilized for compound 76. Namely, the 3-thienylacrylic acid (77) reacts with thionyl chloride to form the thieno Sjthiophene -carboxyl chloride (78). Reaction of this compound with monomethyl malonate and n-butyllithium gives rise to the acetoacetate derivative (79). Transformation of compound 79 to the thieno[2 3f 4,5]thieno[3,2-b]pyhdone-3-carboxy ic acid derivative (80) proceeds in three steps in the same manner as that shown for compound 75 in Scheme 15. Complexation of compound 75 with boron trifluoride etherate, followed by reaction with piperazine and decomplexation, results in the formation of the target compound (81), as shown in Scheme 16. The 6-desfluoro derivative of 81 does not show antibacterial activity in vitro. 

Hf and H Receptors. Histamine exerts its actions by binding to receptors on cell membranes. Two types of histamine receptors, the Hi and H2 receptors, are known specific agonists and antagonists exist for each of these receptors. Black et al. (55) differentiated H and H2 receptors with the compounds, 2-methylhistamine and 4 methylhistamine. 2-Methylhistamine is active on tissues with H receptors 4-methylhistamine is active on tissues with H2 receptors. Classical antihistaminic drugs were developed in the 1930 s these compounds block H but not H2 receptors. Among the clinically used H -blockers are derivatives of ethanolamine, ethylenediamine, alkylamine, piperazine and phenothiazine (32). These agents are valuable in the treatment of... 

Fig. 1 Basic piperazine and ketopiperazine scaffolds and the number of commercial available derivatives according to substructure search from eMolecules [1]...

Finally, ortho aminoesters have been used to produce 7-deazaxanthines. For example ethyl 2-amino-5-phenyl-l//-pyrrole-3-carboxylate is first treated with 2-chloroethyl isocyanate in refluxing toluene. The resulting urea derivative is then allowed to react with l-(2-methoxyphenyl)piperazine and cyclized to the expected pyrrolo[2,3-,7 pyrimidin-2,4(177,377)-dione <2006BMCL150>. 

The hemocompatibility of poly(amido-amine) polyelectrolyte complexes was recently studied by Xi, Zhang and coworkers [499, 500]. The poly(amido-amine) was based on piperazine and methylene bisacrylamide, and the polyelectrolyte complexes were obtained from the reaction of poly(amido-amine) with alginic acid, carboxymethyl cellulose or poly(methacrylic acid). Complexes of polyamido-amine and alginic acid with a 1 2 ratio gave the best hemocompatibility. Finally, the blood compatibility of polyelectrolyte complexes based on anionic and cationic cellulose derivatives were studied by Ito et al. [338], In vivo, good blood compatibility of complexes formed from quaternary hy-droxyethyl cellulose reacted with carboxymethyl cellulose and cellulose sulfate was observed. 

Diphenylpiperazine and derivs 5 D1474—D1475 N.N -bis (4-nitrosophenyl)-piperazine 5 D1474 N -bis (2,4,6-trinitrophenyl) piperazines 5 D1475... 

The usefulness of piperazine and its derivatives for the preparation of polyamides has been known for some time, and it is one of the few disecondary diamines which can be employed to prepare high-melting polycondensates. Piperazine polyamides are especially useful as hot melt adhesives (68USP3377303), since they display unusually good adhesion to vinyl-based polymers such as poly(vinyl chloride). Piperazine is also the preferred diamine for the preparation of thermoplastic polyamides which exhibit the combined properties of low melt viscosity, high softening point and impact resistance at low temperatures (80USP4218351). 

N.-Y. Shih, Imidazolyl-Alkyl-Piperazine and -Diazepine Derivatives as Histamine H3 Agonists/Antagonists, PCT Int. Patent Appl. WO 93/12093 (1993). 

In this development, both amino moieties are differentially protected and thus, incorporation of these amino acids into peptide chains either at the a- or p-position is possible. This procedure has also been applied to the synthesis of piperazine-2-carboxylic acids and derived peptides [135], Scheme 51. For example, the bicyclic a-hydroxy (S-lactam 161, upon ring expansion and subsequent coupling of the resulting NCA 162 with a-amino esters, affords 163 in good yield. 

The synthesis of linker-head intermediate 16, illustrated in Scheme 3.2.5, began with Boc-tranexamic acid 15 [29] which, on amide coupling with Cbz-piperazine and EDC, again followed by palladium-catalyzed hydrogenation of the Cbz group as in the latter case, furnished derivative 16. 

Diarylpyrrole derivatives Catalyst pharmacophore Had difficulty predicting N-methyl piperazine and thiomorpholine derivatives. No numerical prediction data were presented Biava et al. (47)... 

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