Piperazine chlorination

The activation of nucleophilic substitution was also demonstrated for 4-chloro-7-nitrobenzofurazan 232. Thus, chlorine is easily replaced by piperazine <2001JME3378> or aminopropylene (Scheme 57) <2004TL3625>. 

Several classes of antibiotics, e.g., tetracyclines [86], fluoroquinolones [87, 88], and p-lactams [89] were observed to react with chemical oxidants such as chlorine dioxide (CIO2) and free chlorine. Oxidation with CIO2 yields hydroxylated and oxygenated products in the case of tetracyclines, and leads to dealkylation, hydroxylation, and intramolecular ring closure at the piperazine moiety of the fluoroquinolones [86, 88]. 

NS-300 Membrane. The NS-300 membrane evolved from an effort at North Star to form an interfacial poly(piperazine Isophthala-mide) membrane. Credali and coworkers had demonstrated chlorine-resistant poly(piperazineamide) membranes in the asymmetric form (20). The NS-lOO, NS-200, and PA-300 membranes were all readily attacked by low levels of chlorine in reverse osmosis feedwaters. In the pursuit of a chlorine-resistant, nonbiodegra-dable thin-fiim-composite membrane, our efforts to develop interfaclally formed piperazine isophthalamide and terephthalamide membranes were partially successful in that membranes were made with salt rejections as high as 98 percent in seawater tests. 

Formation of thiolactam 276 and its direct amination with N-methyl piperazine (1994JHC1053) is one of the routes to piprerazines 277 (Scheme 59, Section 3.2.3 (1992AF896, 2002JHC163)). Alternatively, 7-fluorobenzo[l7]thieno[2,3-/][l,4]oxaze-pin-10(9H)-one 279 undergoes chlorination and sequential amination to 277. 

Treatment of piperazine-2,5-diones, unsubstituted on the nitrogen atoms, with phosphorous oxychloride results in chlorination with simultaneous aromatization by loss of two hydrogen atoms [82JCS(P1)953] as shown in Scheme 16. 

The synthesis for the starting material (76-1) for another of these a-2 blockers is quite analogous to that used for the dimethexoxy quinazohne (74-3). In this case, the remaining chlorine is displaced with the complete prefabricated side chain, the piperazine urethane (76-2). There is thus obtained trimazocin (76-3) [85]. 

The preparation of the A -desmethyl analogue, amoxapine (39-7), illustrates an alternate approach in which the oxygen ether linkage is formed last. Reaction of the imidazolide (39-2) from 2,4-dichlorobenzoic acid (39-1) and carbonyldiimidazole with ort/zo-aminophenol (39-3) gives the benzamide (39-4). This is then converted to its imino chloride (39-5) with the ubiquitous phosphorus oxychloride. Treatment of the product with piperazine leads to the amidine (39-6), probably by an addition-elimination sequence. Copper catalyzed displacement of chlorine by phenoxide closes the ring there is thus obtained amoxapine (39-7) [40]. 

Yet another approach to these compounds consists of substituting the piperazine ring onto the preformed heterocyclic moiety. Ullman condensation of the substituted thiosalyciclic acid (40-1) with ort/zo-chloronitrobenzene results in the displacement of chlorine by thiophenoxide and the formation of the thioether (40-2). The nitro group in this last intermediate is then reduced to an aniline (40-3) the resulting amino acid is then cyclized thermally to the lactam (40-4). Treatment of that with phosphorus oxychloride gives the imino chloride (40-5). Reaction with N-methylpiperazine leads to the replacement of chlorine by nitrogen and the formation of clothiapine (40-6) [39]. 

The starting material (48-1) for a pyrrazolopyridazine can be obtained by treating the corresponding enol, which is simply the condensation product of methylmaleic anhydride and hydrazine, with phosphorus oxychloride. Reaction with piperazine leads to the displacement of the sterically more accessible chlorine to afford the alkylation product (48-2). Treatment with hydrazine leads to the replacement of the remaining halogen and the formation of (48-3). The missing carbon is, in this case, supplied by formamide to afford zindotrine (48-4) [51], a compound that shows activity as a bronchodilator. 

In pursuit of a chlorine-resistant, non-biodegradable thin-film-composite membrane, Cadotte et al. 97 )03,104 fabricated interfacially the poly(piperazineamide) membrane (NS-300). The interfacially formed piperazine isophthalamide and terephthalamide membranes exhibited high salt rejection (98 %) in sea water tests but their flux was low (Table 8). The replacing of the isophthaloyl chloride with its triacyl chloride analog, trimesoyl chloride improved vastly the flux of the membrane but its seawater salt rejection was low — in the range of 60 70 % (55). The trimesoyl... 

Kawaguchi et al.105) in Teijin Ltd. prepared a similar polyamide composite membrane from piperazine, trimesoyl chloride, and isophthaloyl chloride on a polysulfone support. The membrane exhibited high chlorine-resistance and excellent pressure-resistance. When used for reverse osmosis of an aqueous solution of 0.5% NaCl and NaOCl (available Cl 4 5 ppm) at pH 6.5 7.0, 25 °C, and 42,5 kg/cm2, the water permeation was 1400 and 13301/m2 - day and desalination was 93.4% and 95.7% after 2 and 100 hr, respectively. 

For a few years after the development of the first interfacial composite membranes, it was believed that the amine portion of the reaction chemistry had to be polymeric to obtain good membranes. This is not the case, and the monomeric amines, piperazine and phenylenediamine, have been used to form membranes with very good properties. Interfacial composite membranes based on urea or amide bonds are subject to degradation by chlorine attack, but the rate of degradation of the membrane is slowed significantly if tertiary aromatic amines are used and the membranes are highly crosslinked. Chemistries based on all-aromatic or piperazine structures are moderately chlorine tolerant and can withstand very low level exposure to chlorine for prolonged periods or exposure to ppm levels... 

Watanabe s group at Tosoh Corporation reported the coupling of a chlorine-substituted indole and piperazine using a 24/Pd-based catalyst, Eq. (167) [134]. The indole substrate, which was prepare via a novel palladium-catalyzed cycliza-tion, was aminated in 94% yield. 

Gas phase chlorination of piperazine in carbon tetrachloride has been shown to give tetrachloropyrazine (605), and treatment of 1,4-bis(chlorocarbonyl)piperazine... 

Other chlorinations have been effected with phosphorus pentachloride alone as follows piperazine-2,5-dione in carbon tetrachloride to 2,5-dichloro-3,6-dihydropyrazine (847, 849) [but at 250°/24hours to tetrachloropyrazine (850, 851)] 2[Pg.102]

Chlorinations of nuclear and extranuclear hydroxyl groups by thionyl chloride have been described in the following piperazines l,4-diformyl-2,3,5,6-tetrahydroxy (thionyl chloride and pyridine at reflux) (895), 2,3,5,6-tetrahydroxy-l,4-bis-(methanesulfonyl) (895), 2-hydroxymethyl-l,4-di( )methyl (thionyl chloride in carbon tetrachloride at 70°) (1649), 2-(2 -hydroxyethyl) (1671), and l-benzyl-4-(2 -hydroxyethyl) (1723). Treatment of 2-hydroxymethyl-1,4-ditosylpiperazine with dibromotriphenylphosphorane gave 2-bromomethyl-l,4-ditosylpiperazine (1650). 

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