A general procedure for the synthesis of dimethoxypyrimidines and uracils with highly functionalised C-5 substituents

摘要

J. CHEM. SOC. PERKIN TRANS. I 1989 1165 A General Procedure for the Synthesis of Dimethoxypyrimidines and Uracils with Highly Functionalised C-5 Substituentsl Nitya G. Kundu," Lakshmi N. Choudhuri. and Biswaiit Das Department of Organic Chemistry, Indian Association for he Cultivation of Science, Jada vpur, Calcutta-700 032, India A versatile method for the synthesis of 5-(3-alkyl or, 3-aryl-3- hydroxy)propynyl -2,4-dimethoxy- pyrimidines (5)-( 13), 5-(2-acyl -et hyny I)2,4-di met hoxypyri midines (14)-( 22), 5-(2 -acyl -c h loro -viny1)uracils (23)-(27) and 5-(2-acylethynyl)uracils (28)-(30) is described. Whilst the importance of 5-substituted uracils as anticancer and antiviral agents is well e~tablished,~,~ such compounds have acquired increased importance because of the effectiveness of some of them against AIDS.4 Inherent in the choice of these compounds as anticancer and antiviral agents is their role as inhibitors of thymidylate synthetase and other enzymes essential for cellular multiplication processes.' We have a long term interest in the development of inhibitors of thymidylate synthetase and dihydro-orotate dehydrogenase, essential enzymes required for the growth of cells and have developed methods for the synthesis of various 5-and 6-substituted derivatives of uracil and dihydr~uracil.~ Recently we became interested in novel 5-substituted uracils where the 5-substituent contains an ethynyl or vinyl group conjugated with an acyl or other functional groups.We felt such molecules (after being converted into the corresponding 2'- deoxyribonocleotides) could act as potent inhibitors of thymidylate synthetase or other enzymes, and hence could be of use as anticancer and antiviral agents.With that objective, we have reported' a method for the synthesis of a few 5-(2- acylethynyl-uracils. In view of the promising biological properties of these compound^,^ and lack of methods for the synthesis of uracil derivatives with highly functionalised C-5- substituents, it became imperative to develop alternative methods for the synthesis of uracil derivatives with an activated 5-ethynyl or 5-vinyl substituent. Here, we report a versatile method for the synthesis of such compounds. Copper(1) 3-tetrahydropyranyloxyprop-1-ynidehas been a useful reagent for the synthesis of aromatic and heterocyclic ethynyl substituted compounds." We have utilised this unique reagent for the introduction of a protected ethynyl side-chain on the pyrimidine ring.5-Iodo-2,4-dimethoxypyrimidine (1) when refluxed with copper(1) 3-tetrahydropyranyloxyprop-1-ynide in pyridine for 2.5 h gave 2,4-dimethoxy-5-(3-tetra-hydropyranyloxypropyn-1-yl)pyrimidine (2) as a gum (87). This when deblocked with toluene-p-sulphonic acid in methanol (reflux, 1 h) yielded 5-(2-hydroxymethylethynyl)-2,4-dimethoxypyrimidine (3) as a crystalline solid (m.p. 122 "C; Sl), which on oxidation with Swern reagent l2 gave 5-(2- formylethynyl)-2,4-dimethoxypyrimidine(4) (m.p. 130 "C, 76"). Compound (4) has proved to be a very crucial compound in our synthetic strategy.On treatment of (4) with various Grignard reagents a number of 5-(3-alkyl or aryl-3-hydroxy)- propyn- 1 -yl-2,4-dimethoxypyrimidineswere obtained in excel- lent to satisfactory yields: (5; R' = Me), m.p. 110 "C (90); (6; R' = Et), m.p. 75 "C (83); (7; R' = Pri), gum (20); (8; R' = Bu), m.p. 66 "C (46); (9 R' = CH=CH,), m.p. 78 "C (55); (10; R' = Ph), gum (74); (11; R' = C,H,Me-p), m.p. 110 "C (70); (12; R' = C6H40Me-p), m.p. 116-117 "C (80);and * For details of the Supplementary publication see 'Introduction for Authors (1989)', J. Chem. Soc., Perkin Trans. I, 1989, Issue 1. OMe H R (23)-(271 C(CI)=CHC(O) R'vii I,(281 -(30) C CC (0)R' 1Scheme.Reagents and conditions: i, CU'-C=C-CH,OCH(CH,)~O (1.3 mol equiv.)-Py, 2.5 h, reflux; ii, p-TSA, MeOH, 1 h, reflux; 111, oxalyl chloride (1.3 mmol equiv.), DMSO (1 ml), Et,N (5 ml) dropwise addition at -78OC, then brought to room temp.; iv, RMgX (2 equiv. in ether or THF); v, CrO, (3 mol equiv.) in pyridine; vi, 6111 HCI, heat at 90 "C for 4 h; vii, KOH (2M)in dioxane, stirring at room temp. for 24 h. (13; R' = 3,4-dimethoxyphenyl), gum (47). The acetylenic alcohols were readily oxidised with Collins' reagent l3 or with manganese dioxide in dichloromethane. The following acetylenic ketones were obtained: (14; R' = Me), m.p. 96deg;C (61); (15; R' = Et), m.p. 76deg;C (64); (16; R' = Pri), m.p. 92 "C (50): (17; R' = Bu), gum (71); (18 R' = CH=CH,), m.p.110-112 "C (61); (19; R' = Ph), m.p. 124-125 "C (54); (20; R' = C,H,Me-p), m.p. 140-141 "C (91); (21;R' = C,amp;OMe-p), m.p. 136 "C (50);(22; R' = C6H3(OMe),-3,4), m.p. 142-144 "C (39). Although iodotrimethylsilane or chlorotrimethylsilane and sodium iodide have been utilised by us 'to deblock 5-(2-acylethynyl-2,4-dimethoxyprimidines,we found 6~ hydrochloric acid conveniently converted compounds (14), (15), (19)-(21) into the corresponding 5-(2-acyl-1-chloroviny1)uracils: (23;R' = Me), m.p. 236deg;C (67); (24; R' = Et), m.p. 236 "C (75); (25; R' = Ph), m.p. 240-242 "C (84); (26; R' =C,H,Me-p), m.p. 246-250 "C (87), and (27; R' = C,H40Me-p), m.p. 234-235 "C (86). The 5-(2-acyl-1- chloroviny1)uracils which were found to be stable and easier to handle than the corresponding 1-iodo analogues, were easily converted into 5-(2-acylethynyl)uracils on treatment with potassium hydroxide in dioxane: (28; R' = Ph), m.p.290 "C (69); (29; R' =C,H,Me-p), m.p. 290 "C (70); and (30; R' = C,H,OMe-p, m.p. 290 "C(57). Preliminary biological studies on some of the synthesised Ssubstituted uracils have been extremely encouraging: compounds (25) and (26) led to 57 and 74 inhibition respectively whereas compounds (28) and (29) led to 100 inhibition of growth of Ehrlich ascites carcinoma cells in Swiss Albino mice. Acknowledgements We are grateful to Dr. (Mrs.) A. Majumdar for the biological data and one of us (L.N.C.)thanks the U.G.C., Government of India, for a U.G.C.fellowship. References 1 Part 1 1 of the series on Studies on Uracil Derivatives and Analogues: for Part 10, see ref. 8 and part 9, ref. 11. 2 C. Heidelberger, 'Pyrimidine and Pyrimidine Nucleoside Antimeta- bolites, in Cancer Medicine', eds. J. F. Holland and E. Frei, Lea and Febiger, Philadelphia, 1984, 801-824. 3 E. DeClercq, J. DesCamps, P. DeSomer, P. J. Barr, A. S. Jones, and R. T. Walker, Proc. Natl. Acud. Sci. (USA), 1979,76, 2947; J. J. Fox, C. Lopez, and K. A. Watanabe in 'Medicinal Chemistry Advances', eds. F. G. DeLas Heras and S. Vega, Pergamon Press, Oxford and New York, 1981, 2740; M. E. Perlman, K. A. Watanabe, R. F. Schinazi, and J. J. Fox, J, Med. Chem., 1985, 28, 741. J. CHEM. SOC. PERKIN TRANS.I 1989 4 E. DeClercq, J. Med. Chem., 1986, 29, 1561; P. Herdewijn, J. Balzarini, E. DeClercq, R. Pauwels, M. Baba, S. Broder, and H. Vanderhaeghe, J. Med. Chem., 1987, 30, 1270; T-S. Lin, J-Y. Guo, R. F. Schinazi, C. K. Chu, J-N. Xiang, and W. H. Prusoff, J. Med. Chern., 1988, 31, 336. 5 D. V. Santi and T. T. Sakai, Biochem. Binphys. Res. Commun., 1971, 42,s 13; J. S. Park, C. T.-C.Chang, and M. P. Mertes, J. Med. Chem., 1979, 22, 1134; E. DeClercq, J. Balzarini, P. F. Torrence, M. P. Mertes, C. L. Schmidt, D. Shugar, P. J. Barr, A. S. Jones, G. Verhelst, and R. T. Walker, MoL Pharmucol., 1981, 19, 321; P. V. Danenberg, R. S. Bhatt, N. G. Kundu, K. Danenberg, and C. Heidelberger, J. Med. Chem., 1981, 24, 1537; P. J. Barr, M. J. Robins, and D. V. Santi, Biochemistry, 1983,22, 1696. 6 R. S. Bhatt, N. G. Kundu, T. L. Chwang, and C. Heidelberger, J. Heterocycl. Clzem., 1981, 18, 771; N. G. Kundu and S. A. Schmitz, J. Heterocycl. Chem., 1982, 19,463. 7 N. G. Kundu, S. Sikdar, R. P. Hertzberg, S. A. Schmitz, and S. G. Khatri, J. Chem. Soc., Perkin Trans. I, 1985, 1293. 8 N. G. Kundu, B. Das, A. Majumdar, and L. N. Choudhuri, Tetrahedron Lett., 1987,28, 5543. 9 Unpublished observations from our laboratory. 10 R. E. Atkinson, R. F. Curtis, D. M. Jones, and J. A. Taylor, J. Chem. Soc. C, 1969,2173; M. M. Kwatra, D. 2. Simon, R. L. Salvador, and P. D. Cooper, J. Med. Chem., 1978,21,253. 11 B. Das and N. G. Kundu, Synth. Commun., 1988,18,855. 12 A. J. Mancuso, S. L. Huang, and D. Swern, J.Org. Chem., 1978,43, 2480. 13 J. C. Collins, W. W. Hess, and F. J. Frank, Tetrahedron Lert., 1973, 2875. Received 30th August 1988 (Accepted 12th January 1989); Paper 9/00223E