Efficient Syntheses of Ethyl 2-Methylthio- and Ethyl 2-Benzylthio-6-methyl(aryl)pyrimidine-4-carboxylates and Their Carboxylic Acid Derivatives

Abstract

A simple and efficient procedure for the synthesis of ethyl 2-methylthio- and ethyl 2-benzylthio-6-methyl(aryl)-pyrimidine-4-carboxylates and their corresponding acid derivatives is reported. The products are obtained in good yields via the cyclocondensation reaction of ethyl 4-alkoxy-2-oxo-4-methyl(aryl)-but-3-enoates with 2-meth­ylisothiourea sulfate or 2-benzylisothiourea hydrochloride, under mild, basic, aqueous conditions.

Key words

2,4,6-trisubstituted pyrimidines - 2-thiopyrimidines - ethyl pyrimidine-4-carboxylates - pyrimidine-4-carboxylic acids - cyclocondensation

• References

• 1 Agarwal A, Srivastava K, Puri SK, Chauhana PM. S. Bioorg. Med. Chem. 2005; 13: 4645
• 2 Bailey JP, Giles MB, Pass M. WO 2006005914 A1, 2006 ; Chem. Abstr. 2006, 144, 150379.
• 3 Rotili D, Tarantino D, Artico M, Nawrozkij MB, Ortega EG, Clotet B, Samuele A, Esté JA, Maga G, Mail A. J. Med. Chem. 2011; 54: 3091
• 4 Agarwal A, Srivastava K, Puri SK, Sinha S, Chauhana PM. S. Bioorg. Med. Chem. Lett. 2005; 15: 5218
• 5a Skulnik HI, Ludens JH, Wendling MG, Glenn EM, Rohloff NA, Smith RJ, Wierenga W. J. Med. Chem. 1986; 29: 1499
• 5b Kawauchi K, Fukazawa N, Ishibashi D, Yano O, Iwata D, Etatsugu H, Sobashima T. JP 06172377, 1994 ; Chem. Abstr. 1995, 123, 33585f
• 5c Magnus A, Confalone PN, Storace L. Tetrahedron Lett. 2000; 41: 3015
• 6a Pees K, Liers P, Karla C. EP 834513, 1998 ; Chem. Abstr. 1998, 128, 257444a.
• 6b Drewes MW, Andree R, Dollinger M. WO 9854155, 1999 ; Chem. Abstr. 1999, 130, 38393w.
• 6c Ishii S, Akimoto K, Nakayama K, Yagi K, Ooya E, Umehara T, Kudo M, Inoe Y. JP 0543555, 1993 ; Chem. Abstr. 1993, 119, 180804x.
• 6d Inoue Y, Kobayashi T, Masu A, Asahina K. JP 03197467, 1991 ; Chem. Abstr. 1991, 115, 280054p.
• 6e Djuric SW, BaMaung NY, Basha A, Liu H, Luly JR, Madar DJ, Sciotti RJ, Tu NP, Wagenaar FL, Wiedeman PE, Zhou X, Ballaron S, Bauch J, Chen Y, Chiou XG, Fey T, Gauvin D, Gubbins E, Hsieh GC, Marsh KC, Mollison KW, Pong M, Shaughnessy TK, Sheets MP, Smith M, Trevillyan JM, Warrior U, Wegner CD, Carter GW. J. Med. Chem. 2000; 43: 2975
• 7 Xu X, Xu J, Xiau L, Peng X, Shi Y, Ma R, Chen S, Li G. CN 101255137 A, 2008 ; Chem. Abstr. 2008, 149, 378750.
• 8 Matsushita A, Yoshii K, Oue M, Nakamura T, Yamada S. US 20030055252 A1, 2003 ; Chem. Abstr. 2003, 138, 238198.
• 9a Kim C.-H, Marquez VE, Mao DT, Haines DR, McCormack JJ. J. Med. Chem. 1986; 29: 1374
• 9b Liverton NJ, Butcher JW, McIntyre CJ, Claiborne CF, Claremon DA, McCauley JA, Romano JJ, Thompson W, Munson PM. US 2003119811 A1, 2003 ; Chem. Abstr. 2002, 137, 310932.
• 10 Grima PP. M, Karstens WF. J, Timmers CM. WO 2006117368 A1, 2006 ; Chem. Abstr. 2006, 145, 489143.
• 11 Haddida Ruah SS, Hazlewood AR, Grooten-Huis PD. J, Sing AK, Cleveland T, van Goor F. WO 2006127588 A2, 2006 ; Chem. Abstr. 2006, 146, 27856.
• 12 Bolli M, Lescop C, Mathys B, Mueller C, Nayler O, Steiner B. WO 2009057079 A2, 2009 ; Chem. Abstr. 2009, 150, 515194.
• 13 Piotrowski DW, Futatsugi K, Warmus JS, Orr ST. M, Freeman-Cook KD, Londregan AT, Wei L, Jennings SM, Herr M, Coffey SB, Jiao W, Storer G, Hepworth D, Wang J, Lavergne SY, Chin JE, Hadcock JR, Brenner MB, Wolford AC, Janssen AM, Roush NS, Buxton J, Hinchey T, Kalgutkar AS, Sharma R, Flynn DA. ACS Med. Chem. Lett. 2013; 4: 63
• 14 Leprêtre A, Turck A, Plé A, Knochel P, Quéguiner G. Tetrahedron 2000; 56: 265
• 15 Obrecht D, Ermert P, Luther A, Eberle M, Bachmann F. WO 200487679 A1, 2004 ; Chem. Abstr. 2004, 141, 350188.
• 16 Clark MP, Laughlin SK, Laufersweiler MJ, Bookland RG, Brugel TA, Golebiowski A, Sabat MP, Townes JA, van Rens JC, Djung JF, Natchus MG, De B, Hsieh LC, Xu SC, Walter RL, Mekel MJ, Heitmeyer SA, Brown KK, Juergens K, Taiwo YO, Janusz MJ. J. Med. Chem. 2004; 47: 2724
• 17 Kim JY, Kim D, Kang SY, Park W.-K, Kim HJ, Jung ME, Son E.-J, Pae AN, Kim J, Lee J. Bioorg. Med. Chem. Lett. 2010; 20: 6439
• 18a Druzhinin SV, Balenkova ES, Nenajdenko VG. Tetrahedron 2007; 63: 7753
• 18b Martins MA. P, Cunico W, Pereira CM. P, Sinhorin AP, Flores AF. C, Bonacorso HG, Zanatta N. Curr. Org. Synth. 2004; 1: 391
• 19a Machado P, Rosa FA, Rossatto M, Sant’Anna GS, Sauzem PD, Silva RM. S, Rubin MA, Ferreira J, Bonacorso HG, Zanatta N, Martins MA. P. ARKIVOC 2007; (xvi): 281
• 19b Machado P, Lima GR, Rotta M, Bonacorso HG, Zanatta N, Martins MA. P. Ultrason. Sonochem. 2011; 18: 293
• 19c Stepaniuk OO, Matviienko O, Kondratov IS, Vitruk IV, Tolmachev AO. Synthesis 2013; 45: 925
• 20a Boyer J, Arnoult E, Médebielle M, Guillemont J, Unge J, Jochmans D. J. Med. Chem. 2011; 54: 7974
• 20b Summa V, Petrocchi A, Matassa VG, Taliani M, Laufer R, De Francesco R, Altamura S, Pacel P. J. Med. Chem. 2004; 47: 5336
• 20c Crescenzi B, Poma M, Ontoria JM, Marchetti A, Nizi E, Matassa VG, Gardelli C. Lett. Drug Des. Discovery 2005; 2: 451
• 20d Ponzi S, Giuliano C, Donghi M, Poma M, Matassa VG, Stansfield I. Lett. Drug Des. Discovery 2005; 2: 456
• 20e Stansfield I, Avolio S, Colarusso S, Gennari N, Narjes F, Pacini B, Ponzi S, Harper S. Bioorg. Med. Chem. Lett. 2004; 14: 5085
• 20f Radi M, Dreassi E, Brullo C, Crespan E, Tintori C, Bernardo V, Valoti M, Zamperini C, Daigl H, Musumeci F, Carraro F, Naldini A, Filippi I, Maga G, Schenone S, Botta M. J. Med. Chem. 2011; 54: 2610
• 20g Hieke M, Greiner C, Dittrich M, Reisen F, Schneider G, Zsilavecz MS, Werz O. J. Med. Chem. 2011; 54: 4490
• 20h Chang LC. W, Spanjersberg RF, von Frijtag Drabbe Künzel JK, Mulder-Krieger T, van den Hout G, Beukers MW, Brussee J, IJzerman AP. J. Med. Chem. 2004; 47: 6529
• 20i Nugent RA, Schlachter ST, Murphy MJ, Cleek GJ, Poel TJ, Wishka DG, Graber DR, Yagi Y, Keiser BJ, Olmsted RA, Kopta LA, Swaney SM, Poppe SM, Morris J, Tarpley WG, Thomas RC. J. Med. Chem. 1998; 41: 3793
• 20j Jonak JP, Mead LH, Ho YK, Zakrzewski SF. J. Med. Chem. 1873; 16: 724
• 21 Petricci E, Mugnaini C, Radi M, Togninelli A, Bernardi C, Manetti F, Parlato MC, Renzulli ML, Alongi M, Falciani C, Corelli F, Botta M. ARKIVOC 2006; (vii): 452
• 22 Zanatta N, Flores DC, Madruga CC, Faoro D, Flores AF. C, Bonacorso HG, Martins MA. P. Synthesis 2003; 894
• 23 Nilsson LI, Ertan A, Eeigelt D, Nolsöe JM. J. J. Heterocycl. Chem. 2010; 47: 887
• 24a Khan S, Tyagi V, Mahar R, Kumar B, Chauhan PM. S. Synthesis 2013; 45: 2405
• 24b Badawey E.-SA. M. J. Heterocycl. Chem. 1996; 33: 229
• 25 Bossahard HH, Mary R, Schmid M, Zollinger H. Helv. Chim. Acta 1959; 42: 1659
• 26 Zanatta N, Cortelini MF. M, Carpes MJ. S, Bonacorso HG, Martins MA. P. J. Heterocycl. Chem. 1997; 34: 509