References
- Pandit , U. K. , Grose , W. F. A. and Eggelte , T. A. 1972 . Synth. Commun. , 2 : 345
- Harnden , M. R. , Jarvest , R. L. , Bacon , T. M. and Boyd , M. R. 1987 . J. Med. Chem. , 30 : 1636 See for instance:, M. R. Harnden, A. Parkin and P.G. Wyatt. J. Chem. Soc. Perkin I 1988, 2757. S. Bailey and M.R. Harnden. J. Chem. Soc. Perkin I 1988, 2767. M.R. Harnden and R.L. Jarvest. J. Chem. Soc. Perkin I 1988, 2777.
- Jarvest , R. L. , Barnes , R. D. , Earnshaw , D. L. , O'Toole , K. J. , Sime , J. T. and Vere Hodge , R. A. 1990 . J. Chem. Soc. Chem. Commun. , : 555
- Chu , C. K. and Cutler , S. J. 1986 . J. Heterocyclic Chem. , 23 : 289
- Abushanab , G. and Sarma , M. S. P. 1989 . J. Med. Chem. , 32 : 76
- Ashton , W. T. 1988 . J. Med. Chem. , 31 : 2304 c. s.
- Lambert , R. W. 1989 . J. Med. Chem. , 32 : 367 c. s.
- van Maarschalkerwaart , D. A. H. , Willard , N. P. and Koomen , G. J. 1990 . Nucleo sides Nucleotides , 9 : 787
- Shaw , G. and Warrener , R. N. 1958 . J. Chem. Soc. , : 153
- Shaw , G. and Warrener , R. N. 1958 . J. Chem. Soc. , : 158
- Shealy , Y. F. and O'Dell , C. A. 1976 . J. Heterocyclic Chem. , 13 : 1041
- 4-benzyloxy-3-benzyloxymethyl-1 -bromobutane 4b To a solution of 6. 5 g CBr4 (20 mmol) and 2. 5 g 4-benzyloxy-3-benzyloxy methylbutanol 4a (8. 4 mmol) in dry diethyl ether under a nitrogen atmos phere is added dropwise a solution of 5. 31 g triphenylphosphine in 20 mL dry diethyl ether. After refluxing the solution during 20 hrs the reaction was quenched with 5 mL methanol. The reaction mixture was stirred at rt for 1 hr, the suspension filtered and the residue washed twice with diethyl ether. After evaporation under reduced pressure the residue is kept for 25 hrs in vacuo to remove the last traces of bromoform. The residue is chromato graphed yielding 2. 3 g 4b as a colourless oil. 4b: 1H NMR (CDCl3 60 mHz): δ 7. 3(m, 10 H, arom.), 4. 5 (s, 4H, CH2Ar.), 3. 7–3. 3 (m. 6H, CH2Br+ CH2OBn), 2. 3–1. 9 (m, 3H, CH-CH2).
- 1-(4′-benzyloxy-3′-benzyloxymethylbutyl)-5-methyl-2, 4-(1H, 3H)-pyrimidine dione 5a To a suspension of 0. 78 g thymine (6. 6 mmol) in 50 mL water/DMF 1: 1 is added a solution of 0. 47 g 4b (1. 3 mmol) and 0. 86 g K2CO3 (6. 2 mmol) in 25 mL DMF. This mixture is stirred during 5 days at rt (mechanical stir rer). Concentration in vacuo of the reaction mixture and extraction with dichloromethane and water gave after drying (MgSO4) the crude product. This was chromatographed (PE/EtOAc, 1/1, v/v), yielding 0. 19 g 5a (0. 47 mmol, 36%), 0. 048 g 5b (0. 12 mmol, 9%), 0. 053 g 5c (0. 078 mmol, 12%), 0. 029 g 5d (0. 14 mmol, 11%), 0. 003 g 5e (0. 013 mmol, 1%). The regioisomerism of compounds 5a 5b was established via the dif ferences in the chemical shifts of protons H-1′. In the N-3 alkylated product 5b the H-1′ protons absorb at lower field than in the N-1 alkylated product 5a due to the elctronwithdrawing properties of the two adjacent carbonyl functionalities. Furthermore is via synthetic evidence established that the observed NMR properties of the N-1 alkylated derivative 5a are in accord with those reported in the doctorate thesis of W. F. A. Grose, University of Amsterdam, 1971, who constructed the thymine moiety on a suitable amine via a Shaw synthesis with the appropriate acyl isocyanate. 5a: oil, 1H NMR (CDCI3, 200 mHz): δ 8. 85 (s, 1H, NH), 7. 3 (m, 10H, ar om.), 6. 95 (s, 1H, H-6), 4. 49 (s, 4H, CH2Ar.), 3. 78 (t, 2H, J=7. 4, H-1′), 3. 5 (m, 4H, CH2O), 1. 99 - 1. 73 (m, 3H, H-3′ + H-2′), 1. 83 (s, 3H, Me). 5b: oil, 1H NMR (CDCI3 200 mHz): δ 9. 69 (d, 1H, J=4. 6, NH), 7. 3 (m, 10H, arom.), 6. 95 (s, 1H, H-6), 4. 50 (s, 4H, CH2Ar.), 4. 00 (t, 2H, J=7. 4, H-1′), 3. 5 (m, 4H, CH2O), 1. 99 - 1. 73 (m, 3H, H-3′+ H-2′), 1. 89 (s, 3H, Me). 5c: oil, 1H NMR (CDCl3 250 mHz): δ 7. 3 (m, 20H, arom.), 6. 88 (s, 1H, H-6), 4. 49 (s, 8H, CH2Ar.), 4. 04 (t. J=7. 4, 2H, CH2N-3), 3. 77 (t, 2H, J=7. 4, CH2N-1), 3, 5 (m, 8H, CH2O), 1. 99–1. 70 (m, 6H, CH2CH), 1. 84 (s, 3H, Me). 5d: oil, 1H NMR (CDCl3 200 mHz): δ 9. 4 (bs, 1H, NH), 6. 95 (s, 1H, H-6), 4. 89 (s, 2H, CH2Ar.), 1. 83 (d, 3H, J=1. 0, Me). 5e: oil, 1H NMR (CDCl3 200 mHz): δ 9. 97 (bs, 1H, NH), 6. 95 (s, 1H, H-6), 5. 13 (s, 2H, CH2Ar.), 1. 90 (d, 3H, J=0. 9, Me).
- Ogilvie , K. K. , Nguyen-Ba , N. , Gillen , M. F. , Radatus , B. K. , Cheriyan , U. O. and Hannah , H. R. 1984 . Can. J. Chem. , 62 : 241
- 1-(4′-hydroxy-3′-hydroxymethylbutyl)-5-methyl-2, 4-(1 H, 3H)-pyrimidinedione 3a A suspension of 0. 219 g dibenzylderivative 5a (0. 54 mmol) and 0. 129 g 10% Pd/C and 4 mL cyclohexene (59 mmol) in 8 mL EtOH is refluxed during 25 hrs. The reaction mixture is filtered over hi-flo. The residue is washed twice with EtOH (60%). The filtrates are combined and concentrat ed in vacuo. The crude product is chromatographed (10% MeOH in EtOAc and 20% MeOH in EtOAc), yielding 0. 102 g diol 3a (0. 46 mmol, 86%) as a colourless oil. 3a: oil, IR (KBr): 3400 (OH, NH), 1700, 1675 (C[dbnd]O). 1H NMR (d-6 DMSO 250 mHz): δ 11. 16 (bs, 1H, NH), 7. 53 (s, 1H, H-6), 4. 44 (t, 2H, J=5. 0, OH), 3. 69 (m, 2H, H-1′), 3. 60 (m, CH2O + DMSO), 1. 77 (s, 3H, CH3), 1. 60–1. 45 (m, 3H, H-2′ + H-3′). (OH and NH exchangeable for D).
- 1-(4′-azido-3′-hydrxymethylbutyl)-2, 4-(1H, 3H)-pyrimidinedione 3b To a mixture of 0. 127 g diol 3a (0. 58 mmol), 0. 316 g PPh3 (1, 2 mmol) and 0. 298 g LiN3 (6. 1 mmol) in 3 mL DMF is added 3. 9 g CBr4 (12 mmol). Af ter stirring the mixture at rt for 4 hrs the reaction mixture is concentrated in vacuo. The residue was chromatographed (5% EtOH in CH2Cl2), yielding 0. 016 g azidoderivative 3b (0. 065 mmol, 12%) as a colorless oil. 3b: oil, IR (CHCl3): 3400 (OH), 3200 (NH), 2100 (N3). 1H NMR (CHCl3, 250 mHz): δ 9. 95 (bs, 1H, NH), 7. 05 (d, 1H, J=1. 1, H-6), 3. 78 (t, 2H, J=7. 4 H-1′), 3. 65 (m, 2H, CH2OH), 3. 38 (m, 2H, CH2N-3), 3. 13 (bs, 1H, OH), 1. 89, (d, J=0. 9, 13H, CH3), 1. 68 (m, 3H, H-2′ + H-3′).