Piperazine carboxylation

A mixture of 10 g of the above piperazine carboxylate ester, 8 g of phosphorus pentoxide and 20 ml of phosphorus oxychloride is heated under reflux for about 1 day, diluted with 100 ml each of chloroform and benzene and quenched with 200 g of ice. The mixture is made basic with 10% sodium hydroxide. Theorganic layer is Isolated and extracted with 150 ml of dilute hydrochloric acid. The product is precipitated from the aqueous layer by addition of 10% sodium hydroxide, extracted with benzene and dried over potassium carbonate. Recrystallization from benzene-petroleum ether gives 2[Pg.77]

In addition to the racemic drugs discussed in this section, resolutions are also used in the isolation of key building blocks for the pharmaceutical industry. An important class of these intermediates are amino acids, many of which are available as the single isomer from natural sources (see INTRODUCTION). The use of unnatural amino acids and d configured ones are expected to have a greater influence at the biological level. In the drive for molecular diversity and metabolic stability, a number of unnatural amino acids such as the non-pro-teinogenic piperazine carboxylic acid (47) (Fig. 18.18) have been developed. Specifically,... 

Many infinite 2-D assemblies have also been constructed including (but not limited to) piperazine carboxylic acid [108], trithiocyanuricbipyridine [109], pyr-idyloxamide dicarboxylic acid [110], picolylaminocyclohexenone dicarboxylic acid [111], triazine uracil [112], tris-(4-pyridyl)triazine trimesic acid [113], bipyridine ur-eylene dicarboxylic acid [76] and isonicotinamide dicarboxylic acid [93, 114], Scheme 2.5.16. 

Derivatives of 1 -piperazine carboxylic acid have been thoroughly examined for activity against influenza A (strain PR 8) in mice [175]. Of 100 compounds tested, 19 were found active after being given to mice orally in a single maximum well-tolerated dose. Virus was administered intranasally and activity was based on percentage survivors at 14 days after infection. It was found that the structural features of either (XXXII) or (XXXIII) were necessary for activity. 

End groups include amino, dimethylamino, piperazine, carboxyl, ethylene oxide, and hydroxymethylene (Table 8). 

Piperazine NH group of 9-fluoro-10-(l-piperazinyl)-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-<7e]-l,4-benzothiazine-6-carboxylate was reacted with 4-nitrophenylsulfonyl chloride, 2,6-dichloropyrazine, 2,6-dichloropyridine in DMF in the presence of pyridine, and with 4-nitrophenyl isothiocyanate in aqueous acetone in the presence of KOH (01MIP13). A side chain amino group on a 2,3-dihydro-7//-pyrido[l,2,3- fe]-l,4-benzothiazin-7-one skeleton was acylated (OOMIPIO). 

Yet another nonsedating zwitterionic H-1 antihistamine consists of the product from metabolism of the terminal hydroxyl of the potent antihistamine hydroxyzine terminating in hydroxymethyl instead of a carboxylic acid. This compound, cetirzine (123), can be obtained in straightforward fashion by alkylation of the monosubstituted piperazine 120 with halide 121, via the amide 122 [27]. 

A mixture containing 1.33 g of 5,8-dihydro-8-ethyl-2-methylthio-5-oxopyridol [2,3-d]-pyrimidine-6-carboxylic acid, 1,94 g of piperazine hexahydrate and 20 ml of dimethyl sulfoxide was heated at 110°C for 1 hour with stirring. The separated solid was collected by filtration, washed with ethanol, and then dried at Such a temperature that did not rise above 50°C to give 1,57 g of the trihydrate of the product as nearly colorless needles,... 

Monaca et al. (2003) examined the effect of the SSRI citalopram on REMS in 5-HTia and 5-HTib knockout mice. Citalopram suppressed REMS in wild-type and 5-HTib mice but not in 5-HT,A I mutants. The 5-HTja receptor antagonist WAY 100635 prevented the citalopram-induced inhibition of REMS in wild-type and 5-HTib knockout mice. However, pretreatment with the 5-HTib receptor antagonist GR 127935 [2 -methyl-4 -(5-methyl-(l,2,4)oxadiazol-3-yl)-biphenyl-4-carboxylic acid ((4-methoxy-piperazine-l-yl)-phenyl)amide] was ineffective in this respect. It was concluded that the action of citalopram on REMS in the mouse depends exclusively on the activation of 5-HT,A receptors. Notwithstanding this, there is unequivocal evidence showing that administration of selective 5-HTib receptor agonists suppresses REMS in the rat. 

Irradiation of the potassium salt of the substituted cyclopenta[b]pyrrole-2-carboxylic acid 389 results in formation of the central piperazine core of 390 following decarboxylation (Equation 104) <20010L537, 2003JA10664>. 

Carboxylic acids N-(Bromoacetyl)-A -[5- (dimethylamino)naphthalene-l -sulfonyl]piperazine 65... 

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],... 

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. 

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