Piperazines piperazine-2-carboxamides

A number of diarylmethyl alkylpiperazines, such as, for example lidoflazine, have found use as coronary vasodilators for the treatment of angina. The most recent of these interestingly incorporates a 2,6-dichloroaniline moiety reminiscent of antiarrhythmic agents. Treatment of the piperazine carboxamide 124 with acetone leads to formation of the nitrogen analogue of an acetal, the aminal 125. Alkylation of the remaining secondary nitrogen with chloroamide 126 leads to the intermediate 127. Exposure to aqueous acid leads to hydrolysis of the aminal function... 

Rossen K, Sager J, DiMichele LM (1997) An efficient and versatile synthesis of piperazine-2-carboxamides. Tetrahedron Lett 38(18) 3183-3186... 

The directed sorting method will first be illustrated by the preparation of libraries of piperazine-2-carboxamide derivatives.18 The piperazine-2-carboxylic acid scaffold is a pharmacologically important19 center core... 

Fig. 2. Examples of piperazine-2-carboxamide derivatives pharmacologically active.

Representative Sample of the Reagents Used in the 5000-Member 4-Alkyl-piperazine-2-carboxamide Combinatorial Library0... 

Notes (a) Loaded with the Yamaguchi method, (b) Fmoc-amino acid loaded with DIC/ DMAP, deprotected and reacted with bromo-acid. (c) Symmetric diamine loaded on the nitrophenyl carbonate derivative of Wang resin and subsequently reacted with bromo-acid. (d) Piperazine carboxamide scaffold reacted with the nitrophenyl carbonate derivative of Wang resin. 

Alkylation with Piperazine-2-Carboxamide Scaffold to Produce 18... 

It seems appropriate that having earlier discussed applications of MCRs to the synthesis of widely prescribed local anesthetics, that we conclude with more recent applications. One such example is the large-scale synthesis via a piperazine-2-carboxamide 107 [94] (Scheme 11.21) of the HIV protease inhibitor Crixivan 108. 

Chemical Name N,N-Diethyl-4-methyl-l-piperazine-carboxamide citrate... 

Phenol-type resins 13-15 have also been used to prepare LH-RH, enkephalin and bradykinin peptide analogs. Peptides were successfully cleaved by ammonoly-sis (NH3 in MeOH-DMF or DMF, 5-18h) or aminolysis with protected amino acid or peptide esters bearing the free a-amino group [24, 25, 35]. Marshall s mercaptophenol resin (16) has been used to prepare libraries of piperazine-2-carboxamides (consisting of 22 different amines) and 6-carboxybenzopyran-4-ones. Cleavage was performed using an excess of appropriate amines in pyridine for 24 to 48 h [36, 37]. Tetrahydro-P-carboline-3-carboxamides have also been similarly synthesized and released [38]. 

Lonza AG has reported on the use of enantioselective amidases for the resolution of piperazine-2-carboxamide and piperidine-2-carboxamide using whole cell biocatalysts from Klebsiella terrigena, Pseudomonas fluorescence and Burkholderia sp., the last containing an (R)-selective amidase (Scheme 12.2-7)[l 1. Furthermore, several amidases exhibiting high selectivities [either (Sj- or (R)-] towards 2-arylpropiona-... 

The current state of the art involves the use of piperazine compounds which react with diisocyanates to form electrochemically detectable or fluorescent urea derivatives (Eickeler, 1990 Warwick et al., 1981 Schmidtke and Seifert, 1990 Brown et al., 1987 Bagon et al., 1984 Ellwood et al., 1981). Two OSHA methods (nos. 42 and 47) (OSHA, 1989a OSHA, 1989h) describe a derivatization with l-(2-pyridyl)-piper-azine (2PP) to l,6-bis-[4-(2-pyridyl)-l-piperazine-carbamyl]-hexane (HDI-2PP), 2,6-bis-[4-(2-pyridyl)-1 -piperazine-carbamyl]-toluene (2,6-TDI-2PP), 2,4-bis-[4-(2-pyri-dyl)-l-piperazine-carbamyl]-toluene (2,4-TDI-2PP) and N,N -(methylenedipheny-lene)-bis-4-(2-pyridinyl)-l-piperazine-carboxamide (MDI-2PP) on a coated filter, using the combination HPLC/fluorescence for separation and detection, respectively. 

Fifty years of established views of the Ugi reaction have been challenged by results of a theoretical study which suggests, for example, that the intermediate imine is not in equilibrium with its isocyanide adduct." An asymmetric three-component Ugi reaction has applied chiral cyclic imines in synthesis of morpholino- or piperazine-keto-carboxamide derivatives." ... 

The central piperazine core of 396 has been synthesized from reaction of 2-bromobenzofuran-3-one 394 and l-methyl-l//-imidazole-2-carboxamide 395 in acetonitrile at elevated temperatures (Equation 106) <1999H(50)259>. 

Animal glue HMDS Pyrrole 2 carboxamide, diketodipyrrole, pyrrole[1,2 a]piperazine 3,6 dione 28... 

Di(etbylcarboxamide)-piperazine, CiqH 2( 402, may be considered as the parent compd of its hexanitro deriv although not used to prep it 1,4-Di[N(2 -trinitroethylj-carboxamide)-piperazine or N,N -Bis(2,2(2 trinitroethyl) -piperazine-l,4-dicarboxamide,... 

Reactions of 3-substituted 2-(lV-phenylaminomethyl)piperazines with a slight excess of ethyl 2-chloroacetate under reflux afforded mixtures of 9-substituted 2-phenylperhydropyrido[l,2-a]pyrazin-3- and -4-ones, which could be separated by column chromatography [72JCS(P2)1374], When 2-[(3-trifluoromethylphenyl)aminomethyl]piperidine was heated with optically active ethyl 2-chloropropionate (87MIP1 91TA231), or lactic acid ethyl ester methanesulphonate (91TA231), the product was a C-9a epimeric mixture of 2-(3-trifluoromethylphenyl)-4-methylperhydropyrido[l,2-fl]-pyrazin-3-ones. The reaction between yV-methyl-2-piperidine-carboxamide and hydroxymaleic anhydride in pyridine resulted in 2,3-dimethyl-3-hydroxyperhydropyrido[l,2-a]pyrazine-l,4-dione (74CB2804). 

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