1 -Benzyl-4- piperazine

Piperazine, N-alkylation with benzyl chloride, 42, 19 Piperazine, 1-benzyl-, 42,19 Piperidine, addition to ethylene, 43, 45 as catalyst for Claisen-Schmidt condensation, 41, 40 Piperidine, 1-ethyl-, 43, 45 Piperidine, 1-(2-naphthyl)-, 40,74 Pivalic acid, oxidative coupling to a,a,-a, a -tetramethyladipic add, 40, 92... 

V-mono substituted or protected piperazines benzyl bromides, bromoacet-amides, a-bromo ketones11 pyridyl, benzothiazolyl [86, 1211... 

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

Incorporation of the P-amino acid amide from 25 into piperazine hit 26 improved DPP-4 inhibition by more than 80-fold and led to the discovery of 32 (Table 17.5) [46], The 2-fluorophenyl effect on DPP-4 potency was again observed with compound 33 however, this compound showed very high clearance and no oral bioavailability in the rat. More simplified truncated compounds 34 and 35 showed decreased DPP-4 potency by 10-fold compared to 33, and the removal of the benzyl group resulted in a more significant loss of DPP-4 activity (36). Unfortunately, while 34 showed good... 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

Fisher, M. J., Backer, R. T., Collado, L, et al. (2005) Privileged structure based ligands for melanocortin receptors—substituted benzylic piperazine derivatives. Bioorg. Med. Chem. Lett. 15, 4973-4978. 

Derivatization of a-aminosuberic acid to produce selectively protected derivatives such as Z-L-Asu(OtBu)-OH 16 is performed as outlined in Scheme 6. Using Z-l-Asu-OH 13 as starting material, conversion into a-benzyl ester 14 by treatment with Bzl-Br, followed by reaction with isobutene/H2S04 and saponification of the benzyl ester 15 leads to the desired product 16 as the piperazine salt.124 ... 

To avoid formation of piperazine-2,5-diones the use of mild acid labile N -protecting groups such as Trt or Ddz for the penultimate amino acid residue have been proposed in the case of the tris(alkoxy)benzyl linker, and subsequent acylation of the dipeptide as TFA salt. 

The most direct way of testing the possibility that reaction of an ingested amine with nitrite can give rise to sufficient of a carcinogenic N-nitroso compound to induce tumors has been to feed the amine and nitrite simultaneously to animals for most of their lifespan. The first successful experiment of this type was that of Sander and BUrkle ( ), using the amine methyl benzyl amine, which when fed to rats with nitrite induced esophageal tumors, the same tumor induced in rats by feeding nitrosomethyl benzyl amine. Similar experiments were carried out in mice with piperazine (24), and in rats with heptamethyleneimine (25). 

The piperazine-substituted pyrimido[5,4-< ][l,2,4]triazine 103 undergoes selective reaction with benzylic halides to provide the benzylic piperazinyl analogues 104 <2003BML2895> as shown in Equation (15). The products are protein tyrosine phosphatase inhibitors. 

Compound Name Phosphorus, Red Phosphorus, White Phosphorus Oxychloride Phosphorus Oxychloride Calcium Phosphide Phthalic Anhydride Isophthalic Acid Phthalic Anhydride Benzyl N-Butyl Phthalate Di-N-Amyl Phthalate Dibutyl Phthalate Diethyl Phthalate Diheptyl Phthalate Diiscoecyl Phthalate Di-N-Amyl Phthalate Diootyl Phthalate Diiscoedyl Phthalate Phthalic Anhydride Chloropicrin, Liquid Cyclohexanone Piperazine Piperazine Nitralin... 

The 2,3-dichloro-4-hydroxyphenyl derivative of aripiprazole was prepared to confirm the structure of a primary metabolite of aripiprazole (Scheme 21). The synthesis began with the protection of 4-bromo-2,3-dichlorophenol as its benzyl ether 71. Palladium-catalyzed amination of 71 with piperazine proceeded regioselectively in excellent yield. Alkylation of the piperazine 72 with 69 in the presence of K2CO3 and... 

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