Piperazine-2,6-diones preparation

Amino-2-methoxyphenyl)perhydropyrido[l,2-tf]pyrazine was prepared from a 2-(5-nitro-2-methoxyphenyl)-3-one derivative by catalytic hydrogenation over Pd/C catalyst, followed by the reduction of the 3-oxo group by treatment with BH3-THF complex <1999WO99/042465>. A nitro group was reduced to an amino group in 2-[4-(3-nitrophenyl)piperazin-l-yl]butyl]perhydropyrido[l,2-tf]pyrazine-l,4-dione <2001JME186>, in 8-hydroxy-... 

Although the formation of symmetric piperazine-2,5-diones is a well documented transformation (93AHC187), the unsymmetric -ones have been prepared from AAs or their amides with acyl halides, such as pyruvoyl chloride (81RTC73) and a-bromopropionyl bromide (91H923). 

Piperazine-2,5-diones can be symmetric or asymmetric. Symmetric DKPs are readily obtained by heating amino acid esters,1179-181 whereas asymmetric DKPs are obtained directly from the related dipeptides under basic or, more properly, acid catalysis, or by cyclocondensation of dipeptide esters.1182-185 As an alternative procedure hexafluoroacetone can be used to protect/activate the amino acid for the synthesis of symmetric DKPs or of the second amino acid residue for synthesis of the dipeptide ester and subsequent direct cyclocondensation to DKPs.1186 The use of active esters for the cyclocondensation is less appropriate since it may lead to epimerization when a chiral amino acid is involved as the carboxy component in the cyclization reaction. Resin-bound DKPs as scaffolds for further on-resin transformations are readily prepared using the backbone amide linker (BAL) approach, where the amino acid ester is attached to the BAL resin by its a-amino group and then acylated with a Fmoc-protected amino acid by the HATU procedure, N -deprotection leads to on-resin DKP formation1172 (see Section 6.8.3.2.2.3). 

The piperazin-2,5-dione 6 is easily prepared from (5)-1 -phenylethylamine and chloroacetyl chloride in a two-step sequence5 6. Base-induced enolization followed by alkylation6 furnishes an easily separable mixture of diastereomers 7 and 8 in 90- 95 % yield with d.r. 55 45 to 90 10 7. 

Piperazine-2,5-diones, in which both amino acid units are primary, lead to bislactim ethers on O-alkylation with Meerwein s reagents. No selectivity in this reaction has been demonstrated so far. Such bislactim ethers (171) have been prepared and extensively used by Schollkopf and his school [79AG(E)863, and later papers]. During the preparation of these bislactim ethers, neutralization of the initially formed bis-tetrafluoroborate salt is carried out with phosphate buffer to avoid racemization. 

Piperazine-2,5-diones and related lactim ethers are covered by S. Rajappa and M. V. Natekar of the National Chemical Laboratory, Pune, India. Their chapter represents the first comprehensive review of these highly important intermediates for the preparation of a wide variety of natural products. 

Boger and co-workers successfully used the intramolecular Ullmann reaction to prepare 23, an intermediate in their total synthesis of piperazinomycin (4) (Scheme 6). In this case, the C9 center of the piperazine-2,5-dione substrate did not epimerize, and the cyclization proceeded smoothly and in high yield 2 ... 

This tripeptide was a key intermediate in an attempted preparation of c[3-(benzyloxymethyl)-2-nitrobenzoyl-Thr-D-Val-Pro-Sar-(Me)Val-] by the [2+3]-segment condensation strategy peptide and cyclization between Sar and (Me)Val. This side reaction was circumvented by using the dipeptide H-D-Val-Pro-OtBu in a [3+2]-segment condensation strategy. Contrary to its benzyl ester, this dipeptide did not form the piperazine-2,5-dione because of presence of the bulky tert-butyl ester.[165 1661 Cyclization was performed between Pro and Sar. 

There is the 3 methods for preparing of 8-azaspiro(4.5)decane-7,9-dione, 8-(4-(4-(2-pyrimidinyl)-l-piperazinyl)butyl) monohydrochloride (U.S. Patent 3,717,634). One of them is follows a mixture of 0.1 mole of the substituted glutaric anhydride, 0.1 mole of l-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (U.S. Pat. 3,398151), and 300 ml of pyridine was refluxed until imide formation was completed. The degree of reaction was readily followed by taking an aliquot portion of the reaction mixture, removing the solvent, and obtaining the infrared absorption spectrum of the residue. When reaction is complete, the spectrum exhibited typical infrared imide bands at 1701 and 1710 cm-1 whereas if incomplete, the infrared spectrum contains amide and carboxyl absorption bands at 1680, 1760 and 3300 cm 1. 

Two synthetic routes for 3-[4-[4-(2-methoxyphenyl)piperazin-l-yl]butyl]-thieno[3,4-d]pyrimidine-2,4-dione 316 were described by Russell et al. (90JHC1761). Carbamate 310a, prepared by treating a mixture of amine hydrochloride 309 and ethyl chloroformate with dilute sodium hydroxide, was reacted with 4-[(2-methoxyphenyl)piperazin-l-yl]butanamine 313 in the presence of trimethylaluminum/toluene. The yield of 316 was a modest 20%. However, when bromobutyl urea 314 was heated with l-(2-methoxyphenyl)piperazine hydrochloride 315 in the presence of sodium bicarbonate and sodium iodide in propan-2-ol, compound 316 was obtained in 84% yield. The first route was also used to synthesize thieno[3,4-d]py-rimidine-2,4-dione 312 in 36% yield from 310a and 4-(2-methoxyphenyl)-1-piperazinethanamine 311. 

Symmetrical piperazine-2,5-diones may be prepared in very good yields by subjecting a-halocarboxamides to PTC using the novel Duolite A-109 as catalyst (equation 176)931. 

Pyridyl quinolone carboxylic acids, (V), and 7-piperazine quinazolin-2,4-dione derivatives, (VI), prepared by Park (5) and Domagala (6), respectively, exhibited broad-spectrum antibacterial activity with reduced cytotoxicity. 

Synthesis of Enantiomerically Pure C2-symmetric Vicinal Diamines via Chirality Transfer from DPEN. Several C2-sym-metric vicinal diamines and their derivatives are prepared in optically pure form by chirality transfer from DPEN. For example, condensation of (5, 5)-DPEN with butane-2,3-dione in benzene at the reflux temperature is followed by stereoselective reduction with NaBHsCN and PPTS at -20 °C to afford the (25,35,5R,6R)-piperazine 4 and its diastereomer in a 15 1 ratio (eq 12). The crude product is purified by silica gel column chromatography. Formation of the biscarbamate followed by reductive cleavage of benzylic C-N bonds with lithium in liquid ammonia, and then removal of isobutyloxycarbonyl with HBr in acetic acid results in (/ ,/ )-2,3-diaminobutane dihydrobromide 5 in 99% ee. 

Examples of photorearrangement in nitrones and heteroaromatic N-oxides have again been described, and the subject has been critically reviewed. The hydroxyoxaziridines (81) have been prepared by irradiation of the corresponding 1-pyrroline 1-oxides (82), ° whereas photorearrangement of the dinitrone (83) gave the oxaziridines (84) and (85) and the lactam (86) oxaziridines (84), (85), and (86) were converted into the piperazine-2,5-dione (87) by further irradiation. ... 

Some unusual zwitterionic pyrazines have been prepared by dehydrogenation of 1,4-disubstituted piperazine-2,6-diones. Honzl et al. (476a) prepared theanhydro-2,6-dihydroxy-l, 4-diphenyl-3,5-bis(phenylthio)pyrazinium dihydroxide [s/c] (92) (which yields adducts by dipolar cycloaddition of maleic anhydride or formaldehyde) by the reaction of 1,4-diphenylpiperazine-2,6-dione with benzenesulfonyl chloride in pyridine. Tanaka et al. (476b), from I,4-diphenylpiperazine-2,6-dione with benzoyl chloride, and tosyl chloride in pyridine at reflux, obtained the anhydro - 3 - benzoyl - 2,6 -dihydroxy -1,4 -diphenyl - 5 - (p - toly lthio)pyrazinium dihydroxide [src] (93), together with some of the S-p-tolyl analogue of (92). 

The preparations of hydroxypyrazines by primary syntheses have been described in Chapter II, and are summarized briefly, together with further data, as follows Section II.IG, from the reaction of a, 3-dicarbonyl compounds with ammonia [282 (cf. 281, 280), 283, 285] with additional information (1042, 1043) Section II.IM, from 1,2-dicarbonyl compounds with a-amino acids (311) Section II.IN, from a-amino acids through piperazine-2,5-diones (93,95,101,282,312,313)with additional data (843) Section 11.10, from aldehyde cyanohydrins ( ) [317-319 (cf. 282)1 and Section II.IP, from o-nitromandelonitrile and ethereal hydrogen cyanide (325). The preparations from a,iJ-dicarbonyl compounds with a,/ -diamino compounds are described in Section 11.2 (60, 80, 358, 359, 361-365b, 365d, 366-375) additional data have also been reported (824, 825, 827,845,846,971, 1044, 1045) and some reaction products have been isolated as the dihydro-pyrazines (340,341,357). 

Honzl (853) has described the preparation of alkyl(or aryl)-2-oxo-l, 2-dihydropyrazines by reaction of A,A -dialkyl(or aryl)piperazine-2,5-diones with phosphorus pentachloride. For example, 1,4-dicyclohexyl(or diethyl)piperazine-2,5-dione (85, R = cyclohexyl, Et) with phosphorus pentachloride in 1,2-dichloroethane gave... 

Dihydropyrazines may be prepared by the self-condensation of o -(primary amino)carbonyl compounds and some of these syntheses have been described in Sections II.lA (169, 172, 178, 186, 190), Il.lJ (294-298), and II.IL (306). The conversion of a-amino acids through piperazine-2,5-diones (2,5-dihydroxy-3,6-dihydropyrazines) to pyrazines has been described in Section II.IN (93, 95, 101, 282, 312-314a) and Section II.6 (314, 314a) and ring transformations to 2,5-dihydropyrazines in Section II.9 (302, 505a, cf. 1541). 3-Phenylazirine dimerizes on standing to 2,5-diphenyl-3,6-dihydropyrazine (1577). 

The preparation and reactions of piperazine-2,S-diones has been much discussed in the reviews mentioned above and in papers by Sammes and co-workers (314, 314a, 1066-1068, 1078,1127,1128, 1616). 

Some preparations are described in Section 1C(1) and additional preparative data are as follows. Aminoacetonitrile with hydroxylamine gave 2,5-bishydroxy-iminopiperazine (92) (465), which was hydrolyzed with dilute hydrochloric acid to the monoxime in contrast, nitrous acid converted the dioxime (92) into piperazine-2,5-dione (465). fV-(Aminoacyl)aminoacetonitrile with hydroxylamine formed 5-hydroxyiminopiperazin-2-one (1619). Reduction of diethyl hydroxy-iminomalonate in ethanol with hydrogen over palladium-charcoal gave diethyl aminomalonate and 3,6-diethoxycarbonylpiperazine-2,5-dione (821) and heating of diethyl A -methylaminomalonate formed 3,6-diethoxycarbonyl-l,4-dimethyl-piperazine-2,5-dione (1620), which with sodium hydride in dioxane followed by treatment with sulfur monochloride gave 3,6-epidithio- (93) and 3,6-epitetrathio-... 

Sterically pure piperazinediones have been prepared from formate salts of dipeptide methyl esters (1622). The conformation of piperazine-2,5-diones has been reviewed (1623). 

Piperazine-2,6-diones have been prepared as follows. A group of 3,3-dialkyl-piperazine-2,6-diones were obtained by treating 7V-(l-cyanoalkyl)glycine esters... 

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