Unsaturated hydantoin derivatives XI. Synthesis and rearrangement of some ethyl esters of ?-substituted hydantoest-?5,?-acetic acids

Ivin, B. A.; Rutkovskii, G. V.; Rusavskaya, T. N.; Smorygo, N. A.; Sochilin, E. G.

doi:10.1007/bf01175095

Cited by 3 publications

(4 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2,6-Dichloro-5-methoxypyrimidine-4-carboxylate (59). N,N-dimethylaniline (0.856 mL, 6.76 mmol) was added to a stirred solution of methyl 2,6-dihydroxy-5-methoxypyrimidine-4-carboxylate 70 (1.0 g, 5 mmol) in POCl 3 (34.5 mL). After refluxing overnight POCl 3 was evaporated and the residue was poured on ice water and extracted into diethyl ether.…”

Section: 6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic Acid (3)mentioning

confidence: 99%

2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase: Discovery, SAR, Modeling, and Mutagenesis

et al. 2006

View full text Add to dashboard Cite

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 microM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.

show abstract

Section: 6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic Acid (3)mentioning

confidence: 99%

2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase: Discovery, SAR, Modeling, and Mutagenesis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…La distinction des compos~s 3 et 3' est difficile vu la similitude de leurs points de fusion (7-9) et de leurs caracteristiques physicochimiques. D'autre part, I'hydrolyse basique de la carbomethoxymethylene-5 hydantolne conduit a l'ester orotique (10)(11)(12). Seule la comparaison de plusieurs composes diversement substitues avec les derives cites dans la litterature nous a permis de prouver la structure hydantolne de ces produits de rearrangement.…”

Section: S C H~m a I M P O~c -C H = C H -C 0 2 M P + R -N H -C O -N Runclassified

Action des hydroxyurées sur les maléate et fumarate de méthyle. Obtention des carbométhoxy-5 oxa-6 dihydrouraciles; transposition en carbométhoxyméthylène-5 hydantoïnes

Bennouna¹,

Petrus²,

Verducci³

et al. 1981

Can. J. Chem.

View full text Add to dashboard Cite

R e p le 3 decembre 1980 CHAKIB BENNOUNA, FRANCOISE PETRUS, JEAN VERDUCCI, CHRISTIAN HAUW et JACQUES GAULTIER. Can. J. Chem. 59, 2891 (1981.Ce travail decrit I'addition de type Michael des hydroxyurees sur les maleate et fumarate de mkthyle. La cyclisation des ureidoxydiesters ainsi obtenus conduit aux carbomCthoxymCthyl-5 oxa-6 dihydrouraciles dont la structure est prouvee par analyse au rayons X. Ces derniers, relativement instables, se transposent en carbomethoxymCthyltne-5 hydantoines par traitement en milieu basique.CHAKIB BENNOUNA, FRANCOISE PETRUS, JEAN VERDUCCI, CHRISTIAN HAUW, and JACQUES GAULTIER. Can. J. Chem. 59,2891Chem. 59, (1981.We describe in this paper the Michael-type addition of hydroxyureas with methyl maleate and fumarate. The cyclization of the ureidoxyester intermediates obtained leads to the isolation of 5-carbomethoxy &oxadihydrouracils; their structure is proved by X-ray analysis. These relatively unstable compounds undergo transposition under basic conditions and give S-carbomethoxyhydantoins.Les travaux precedents realises dans notre laboratoire ont permis de mettre en evidence le caractbre "hydroxylamine N-protegee" des hydroxyurees: une attaque par l'atome d'oxygbne est observee dans les reactions d'addition sur les nitriles a-ethyleniques (I), les esters a-kthyleniques (2), les cetones a-ethyleniques (3,4) ainsi que dans les reactions de substitution sur les a-bromoesters (5) Ces resultats permettent de prevoir ii priori une addition-1,4 des hydroxyurees sur les maleate et fumarate de mkthyle.

show abstract

“…For an easy access to the desired target structures, it is mandatory that the N1-substituted pyrimidones are readily accessible. Sochilin 6 and co-workers had described the synthesis of pyrimidone 5a. We applied their methodology to access 2-chloropyrimidone 3a, as well as the benzyl and phenyl analogues 3b and 3c, which we needed to explore the scope and limitations of the methodology.…”

mentioning

confidence: 99%

“…All three compounds were accessible in multigram quantities by the four-step route shown in Scheme 2. Condensation of commercially available N-substituted ureas with diethyl 2-ethoxy-3-oxosuccinate 6,7 afforded hydantoins 4a-c which underwent a base-promoted ring expansion to the corresponding 2-hydroxypyrimidones 5a-c. Esterification and reaction with phosphorous oxychloride afforded the chlorides 3a-c which were obtained pure with only one column chromatographic purification after the last step.…”

mentioning

confidence: 99%

Suzuki Coupling at the 2-Position of Densely Functionalized Pyrimidones

Colarusso¹,

Girardin²,

Conte³

et al. 2006

Synthesis

View full text Add to dashboard Cite

A variety of ethyl 1-substituted 2-aryl-5-ethoxy-6-oxo-1,6-dihydropyrimidine-4-carboxylates were synthesized by efficient thermal or microwave-promoted Suzuki coupling of 2-chloro-N1-substituted precursors.A recent research project revealed 1-substituted 2-aryl-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylic acids (pyrimidones, 1) as a novel class of Hepatitis C virus (HCV) RNA-dependent RNA polymerase inhibitors 1,2 (Figure 1). Figure 1 1-Substituted 2-aryl-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylic acids 1For a rapid exploration of the SAR (structure-activity relationship) in the series, we were targeting an efficient methodology to insert aryl groups in position 2 of the pyrimidone in the presence of different groups on the N1 nitrogen. The remaining substitution pattern of the pyrimidone scaffold, which has been shown to be essential for biological activity, 1,2 was kept fixed. The route typically used 1 for the synthesis of the pyrimidone scaffold was not very efficient for a combined SAR in positions 1 and 2, since the aryl group was introduced early in the synthesis from the amidoxime 2 (Scheme 1) and the alkylation of N1 nitrogen proceeded with low selectivity for the desired N-alkylated product, being furthermore limited to the more reactive electrophiles, and hence to a small number of substituents.Carbon-carbon bond formation in position 2 of the pyrimidone scaffold having the appropriate N1 substituent already in place was an attractive route for our purposes. From a survey of the literature it was found that carboncarbon bond formation on 2-halopyrimidines via transition-metal-catalyzed 3 cross-coupling reactions is well documented. The analogous reaction on N1-substituted pyrimidones has very little precedent 4 despite the interest in this class of compounds related to their wide range of biological activities 5 .Herein we report the Suzuki cross-coupling of densely functionalized ethyl 1-substituted 2-chloro-5-ethoxy-6-oxo-1,6-dihydropyrimidine-4-carboxylates with a variety of boronic acids. For an easy access to the desired target structures, it is mandatory that the N1-substituted pyrimidones are readily accessible. Sochilin 6 and co-workers had described the synthesis of pyrimidone 5a. We applied their methodology to access 2-chloropyrimidone 3a, as well as the benzyl and phenyl analogues 3b and 3c, which we needed to explore the scope and limitations of the methodology.All three compounds were accessible in multigram quantities by the four-step route shown in Scheme 2. Condensation of commercially available N-substituted ureas with diethyl 2-ethoxy-3-oxosuccinate 6,7 afforded hydantoins 4a-c which underwent a base-promoted ring expansion to the corresponding 2-hydroxypyrimidones 5a-c. Esterification and reaction with phosphorous oxychloride afforded the chlorides 3a-c which were obtained pure with only one column chromatographic purification after the last step.

show abstract

Unsaturated hydantoin derivatives XI. Synthesis and rearrangement of some ethyl esters of ?-substituted hydantoest-?5,?-acetic acids

Cited by 3 publications

References 3 publications

2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase: Discovery, SAR, Modeling, and Mutagenesis

2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase: Discovery, SAR, Modeling, and Mutagenesis

Action des hydroxyurées sur les maléate et fumarate de méthyle. Obtention des carbométhoxy-5 oxa-6 dihydrouraciles; transposition en carbométhoxyméthylène-5 hydantoïnes

Suzuki Coupling at the 2-Position of Densely Functionalized Pyrimidones

Contact Info

Product

Resources

About