Purines, pyrimidines and imidazoles. Part 67. SomeN-substitutedo-(2-hydroxyethyl)benzyl-purines, -pyrimidines and -imidazoles as aromatic acylonucleoside analogues

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1993 Purines, Pyrimidines and Imidazoles. Part 67.' Some N-Substituted 0-(2-Hydroxyethyl) benzyl -purines, -pyrimidines and -imidazoles as Aromatic Acylonucleoside Analogues Demetrios C. Agathocleous and Gordon Shaw Chemistry and Chemical Technology Department, University of Bradford, Richmond Road, Bradford, West Yorkshire, BD7 IDP, UK Reaction of isochromane with hydrogen bromide in acetic acid and further reaction of the products formed with potassium phthalimide gave a mixture of N-o-(2-bromoethyl)benzylphthalimide and N-o-(2-acetoxyethyl) benzyl phthalimide. The mixture, on reaction with silver acetate, gave the latter compound, which with hydrazine gave 0-(2-hydroxyethyl) benzylamine. The amine, on reaction with 2-cyano-2-(ethoxymethy1enamino)acetamide.gave 5-amino-1 -o-(2- hydroxyethyl) benzyl imidazole- 4-carboxamide, which was cyclised to 9-0-(2-hydroxyethyI)benzyl-guanine, -hypoxanthine and -adenine. With N-ethoxycarbonyl-3- met hoxy-2-methylacrylamide, 3-methoxy-2- methylacryloyl isothiocyanate and ethoxymethylenemalonylurethane, the amine produced 1 -o-(2-hydroxyethyl) -benzyllthymine, -2-thiothymine and -N-ethoxycarbonyluracil-5-carboxamide respectively. The latter, on reaction with alkali, gave 1 -o-(2-hydroxyethyl) benzyl uracil-5-carboxylic acid, which was decarboxylated to 1 -o-(2-hydroxyethyl) benzyl uracil. Structures were confirmed by El, FAB and 'H NMR spectra. We have observed that the efficiency of 5'-0-phosphorylation of some imidazole ribonucleosides using a phosphotransferase from wheat shoots was greatly enhanced by the presence of an aromatic ring in the molecule.This led us to suggest that this might have some relevance to the mechanism of action of the phosphotransferase. These observations, together with the well publicised antiviral activity of various acylonucleosides, led us to investigate in the first instance the preparation of a series of aromatic nucleoside analogues of type 1 in which the carbon skeletal structure of a ribo-or 2-deoxyribo-nucleoside is broadly maintained. Our proposed synthetic (Shaw syntheses) 3-8 routes (which give unambiguously substituted derivatives) to both pyrimidine and purine derivatives, required the preparation of 0-(2-hydroxyethy1)benzylamine 2.This compound has been described as a hydrochloride in the literature by hydrogenolysis of the tetrahydrobenzoxazepine 3 which was prepared in turn in low yield by a multistage series of reactions involving separation of mixtures from 0-(2-bromoethyl)benzaldehyde. We now describe a much simpler practical method for the preparation of compound 2 which does not involve chromatography. The proposed synthesis of compound 2 required preparation of the dibromide4. This compound has been earlier prepared lo by the reaction of isochromane with hydrogen bromide in acetic acid. Preliminary experiments in our hands showed that this reaction results in the formation of a mixture of the dibromide 4 and the bromo acetate 5.Thus when the crude reaction product of isochromane and hydrogen bromide in acetic acid was treated with potassium phthalimide in dimethylformamide (DMF), a mixture of the phthalimido bromo and related acetate derivatives 6 and 7 respectively was obtained. On a small scale these were separated by column chromatography and identified by elemental analysis, and mass and 'H NMR spectroscopy. In particular, in the 'H NMR spectra of compounds 6 and 7 the signals for the benzylic hydrogen atoms were identical (6 4.96) and compared well with that of the CH, group in N- benzylphthalimide (S4.84). These observations have enabled us to produce a good synthesis of the phthalimido acetate 7 by reaction of the mixture of bromides 4 and 5 with potassium phthalimide followed by reaction of the crude mixture of phthalimides so produced with silver acetate in acetic acid.This produced an overall yield of at least 50 of pure 1 X = base 3 4 X=Y=Br 2 X=NH2 5 X=OAc,Y=Br 6 X = Br, Y = phthalimido 7 X = OAc, Y = phthalimido recrystallised acetate 7without the need for chromatography. The phthalimido acetate 7reacted with hydrazine hydrate in ethanol solution when heated on a steam-bath for a few minutes to give a 90 yield of the amine 2, which was readily converted into a crystalline hydrochloride by treatment with hydrochloric acid. The amine 2 was converted into a series of purine, pyrimidine and imidazole acylonucleoside analogues by using methods developed earlier by one of In particular, reaction of amine 2 with the ethoxymethylenimino derivative 8 (prepared from aminocyanoacetamide and triethyl orthoformate) gave the aminoimidazole derivative 9 a 5-amino- l-ribofuranosyl- imidazole-4-carboxamide 5'-phosphate (AICAR) analogue which, with benzoyl isothiocyanate in DMF at room temperature gave, after 1.5 h, the thiourea 10.This, on reaction with aq. sodium hydroxide or triethylamine and methyl iodide, produced the S-methyl isothiourea derivative 11 which, when heated with aq. ammonia, gave the guanine analogue 12 in 51 yield (Scheme 1). The hypoxanthine derivative 13 was prepared from com- pound 9 in 96 yield by reaction with formic acetic anhydride followed by aq. sodium hydrogen carbonate. Treatment of the hypoxanthine 13 with acetic anhydride in pyridine produced the 0-acetate 14 which, with tetraethylammonium chloride, N,N- dimethylaniline and phosphoryl trichloride, gave presumably the corresponding 6-chloropurine (not isolated) which, with hot aq.ammonia, readily gave the adenine 15 in 50 yield (Scheme 2). The thymine derivative 16was prepared by reaction of the amine 2 with N-et hox ycarbon y 1-3-me t hoxy -2-methyl-acrylamide4 17 followed by sodium hydroxide, and the corre- sponding 2-thiothymine derivative 18 by a similar reaction of EtOCH=NCH(CN)CONH2 i(!-JCONH2 8 R NH2 9 I ii t iii R NZyNHCOPh SMe 11P R NHCSNHCOPh 10 0 CHpCHpOH R= R 12 Scheme 1 Reagents: i, RNH,; ii, PhCONCS; iii, MeI, base; iv, NH, 0 0 9-13 14 iv*v/ y2 15 Scheme 2 Reagents: i, HCO,H, Ac,O; ii, aq.NaHCO,; iii, Ac,O, Py; iv, NEt,Cl, PhNMe,, POCI,; v, NH,. R (see Scheme 1). Me o +YO J. CHEM. SOC. PERKIN TRANS. 1 1993 RNH2 + EtOCH=C(CONHC02Et)2 20 21 22 23 Scheme 4 Reagents and conditions: i, 2 rnol dm-, NaOH; ii, N-ethylmorpholine, reflux, 1 h. R (see Scheme 1). Experimental Reactions were monitored by TLC on silica gel sheets 60 F254 (0.2 mm thick) (Merck); m.p.s were measured on a Gallenkamp m.p. apparatus and are uncorrected, 'H NMR spectra (6; J-values in Hz) were recorded with a JEOL JNM-GX270 spectrometer (tetramethylsilane as internal standard) for solutions in (CD,),SO or CDCl,, FAB mass spectra (3- nitrobenzyl alcohol) were determined by the SERC MS Service Centre, Swansea and EI mass spectra were measured using an AE1 MS 903 spectrometer. Evaporations were carried out under reduced pressure (water-pump) with a flask temperature of below 40 "C.N-o-(2-Acetoxyethyl)benzylphthalirnide7.-Isochromane (25 g, 0.19 mol) and hydrogen bromide in acetic acid (45, w/v; 145 cm3) were heated on a steam-bath for 4 h. The solution was cooled, water (500 cm3) was added, and the mixture was extracted with chloroform. The extract was washed successively with aq. sodium hydrogen carbonate and water, then was dried (anhyd. MgSO,) and evaporated to give a pale brown oil (45 g). This, in DMF (200 cm3), was treated with potassium phthalimide (30 g, 0.16 mol) and the suspension was heated on a steam-bath for 2 h.The mixture was diluted with both chloroform (200 cm3) and water (1 50 cm3). The organic layer was separated and the aqueous phase was extracted with chloroform (150 cm3). The combined organic phases were washed successively with 0.2 mol dm-3 sodium hydroxide (100 an3) and water (100 an3), dried (anhyd. MgSO,), then evaporated to give a thick syrup which solidified on cooling. TLC examination revealed that this consisted of two products (see later). A solution of the crude solid (33 g) and silver acetate (33 g, 0.2 mol) in acetic acid (330 an3)was boiled under reflux for 5 h, then was filtered, and the filtrate was diluted with water (200 cm3). The resulting precipitate was extracted into chloroform.The extract was washed successively with aq. sodium hydrogen carbonate (2 x 150 cm') and water (100 cm3), dried (anhyd. MgSO,), and evaporated to leave a solid. Crystallisation of this from ethanol gave the title compound (30 g, 50), m.p. 109-1 10 "C; G(CDC1,) 2.05 (3 H, s, Me), 3.23 (2 H, t, J7.33 and 6.96, CH2CH,0), 4.33 (2 H, t, J7.33 and 6.96, CH,O), 4.96 (2 H, s, CH,N) and 7.15-7.9 (8 H, m, ArH) (Found: C, 70.5; H, 5.4; N, 4.25; MH', 323,325. C19H17N04 requires C, 70.59; H, 5.3; N, 4.33; MH, 323, 325). N-o-(2-Brornoethyl)benzylphthaZimide 6.-The mixture of solids obtained in a small-scale repetition of the latter experiment was separated by chromatography on silica gel (chloroform as eluting solvent) to give the title compound, m.p.131-132 "C; G(CDC1,) 3.44 (2 H, t, J 7.33, CH2CH,Br), 3.63 (2 H, t, J 7.33, CH,CH,Br) 4.96 (2 H, s, CH2N) and 7.2-7.88 (8 H, m, ArH) (Found: C, 59.25; H, 4.2; N, 4.1; MH', 344,346. C,,H,,BrNO, requires C, 59.3; H, 4.09; N, 4.07; MH, 344, 346). Compound 7 was also isolated and the ratio 6 :7 formed was approximately 1 :3. R-NKNH R-NKNH 0 S 16 18 MeOCH=C(Me)CONHC02Et MeOCH=C(Me)CONCS 17 19 Scheme 3 Reagent: i, 2 mol dm-, NaOH. R (see Scheme 1). the amine 2 with the acyl isothiocyanate 19 and sodium hydroxide (Scheme 3). Reaction of the amine 2 with ethoxymethylenemalonyl- urethane' 20 readily produced the uracil derivative 21, hydrolysis of which with 2 mol dmP3 sodium hydroxide gave the uracil-5-carboxylic acid 22.When the latter compound was refluxed in N-ethylmorpholine solution for 1 h, the uracil derivative23 was obtained in good yield (62) (Scheme 4). The compounds were tested for antiviral activity against Herpes Simplex 1 (HSV 1) in Veros cells. They were essentially inactive except at high concentrations, when the guanine derivative 12 was the most active (ECSo 150 pg crn-,) (Table 1). J. CHEM. soc. PERKIN TRANS. 1 1993 Table 1 Anti-Herpes simplex activity" Mean number of plaques per well Conc. As percentage of EC~O TCso Compound (pg (pfub/well) control value (CLg a-3)(CLg a-3) 0 500 30 40 200 34 45 100 40 53 40 51 68 150 lo00 20 55 73 8 72 96 4 74 99 12 1000 20 27 Me 500 30 40 200 39 52 100 55 73 40 56 75 20 61 81 8 66 88 4 79 105 16 Control 75 100 a The compounds were tested in Veros cells infected with HSV-1 17-1 by using a plaque-reduction assay.Plaque forming units. 0-(2-HydroxyethyZ)benzyZamine(2-o-(Amin0methyZ)phen-yllethanol) 2.-A mixture of the phthalimido acetate 7 (30 g, 0.09 mol), hydrazine hydrate (7 cm3, 0.14 mol) and ethanol (60 cm3) was heated on a steam-bath for 10 min. A clear solution formed, which rapidly became a thick paste. Hydrochloric acid (100 cm3, 10 mol drn-,) was added slowly to the cooled mixture and the resulting mixture was heated on a steam-bath for 15 min. The cooled mixture was filtered and the filtrate was evaporated to -30 cm'. Solid potassium hydroxide was added (to pH 11 using test papers) and the solution was extracted with chloro- form (4 x 50 cm').The combined extracts were dried (anhyd.MgSOJ and evaporated to afford the title compound as an oil (12.7 g, 90.7). A portion (0.5 g) of the amine was treated with hydrochloric acid (5 cm3; 10 mol drn-,) and the solution was evaporated to leave a gum which rapidly crystallised. Recrystal- lisation from propan-2-01 gave the title compound hydrochlo- ride (0.4 g), m.p. 161 "c(lit.," 168-169 "c);6(2H6Me2SO) 2.82 (2 H, t, J 6.23, ArCH,), 3.62 (2 H, t, J 6.23, CH,O), 4.05 (2 H, s, CH,N), 5.5 (1 H, br s, OH, exch. with D,O), 6.84-7.22 (4 H, m, Ar) and 8.4 (3 H, br s, NH, +,exch. with D20) Found: C, 57.7; H, 7.75; N, 7.25; Cl, 19.0; MH+ (-Cl), 152. Calc. for C9- H,.ClNO:C,57.6;H,7.52;N,7.46;Cl,18.88;MH(-Cl), 1521.5-Amino- 1 -0-(2-hydroxjvthy l)benzyl imidazole-4-carbox- amide 9.-A solution of 2-amino-2-cyanoacetamide (1.5 g, 15 mmol), and triethyl orthoformate in acetonitrile (30 cm3)was boiled under reflux for 45 min. A solution of the foregoing amino alcohol 2 (1.8 g, 10 mmol) in acetonitrile (5 cm3) was added and the solution was boiled under reflux for 15 min. The title compound(2.2 g, 76) precipitated from the cooled solution and was recrystallised from ethanol; m.p. 183-1 84 "C (decomp.); G(C2H,Me,SO) 2.81 (2 H, t, J 6.96, CH,CH,OH), 3.64 (2 H, t, J 6.96, CH,CH,OH), 4.79 (1 H, br s, OH, exch. with D,O), 5.13 (2 H, s, CH,N), 5.8 (2 H, br s, NH,, exch. with D,O), 6.63 (2 H, br s, CONH,, exch. with D20) and 6.79-7.2 (5 H, m, Ar and CH=) (Found: C, 60.1; H, 6.25; N, 21.4; MH', 261.Calc. for Cl3Hl6N4O2 requires C, 60.0; H, 6.19; N, 21.54; MH, 261). The compound gave a strong Bratton-Marshall test for a primary aromatic amine. 5-~'-Benzoyl( thioureido)- 1-o-(2-hydroxyethy1)benzyZl-imidazole-4carboxamide 10.-A mixture of the foregoing aminoimidazole9 (3 g, 11.5 mmol) and benzoyl isothiocyanate (1.8 cm3, 13 mmol) in dry DMF (60 cm3) was stirred at room temperature for 1.5 h. The solvent was evaporated off and the residue was triturated with water, when it readily solidified. The title compound (4.5 g, 92) was crystallised from ethanol; m.p. 157-158 "C; d(2H6Me,SO) 2.75 (2 H, t, J 6.96, CH,CH,OH), 3.5 (2 H, t, J6.96, CH,OH), 4.69 (1 H, br s, OH, exch.with D,O), 5.25 (2 H, s, CH,N), 6.95-8.0 (12 H, CONH,, Ar and CH=N, former exch. with D,O), 11.96 (1 H, s, NHCOPh, exch. with D,O) and 12.0 (1 H, s, CSNH, exch. with D,O) (Found: C, 59.35; H, 4.8; N, 16.2; MH+, 424. C21H21N503Srequires C, 59.57; H, 5.0; N, 16.55; MH, 424). 541-Benzoyl-2-methyZ-3-isothioureido)-1 -0-(2-hydroxy- ethyl)benzyZimidazole-4-carboxamide11.-A solution of the foregoing thiourea 10(2 g, 4.72 mmol) in 0.5 mol dm-, sodium hydroxide (25 cm3) was stirred with methyl iodide (0.6 cm3,9.6 mmol) for 1 h. The solution was adjusted to pH 6-7 using test papers with 2 mol dm-3 hydrochloric acid. The title compound (1.6 g, 77) precipitated, was collected by filtration, and was washed with water.A similar yield was obtained when using methyl iodide and triethylamine in DMF. Compound 11 was crystallised from ethanol; m.p. 13 1-1 32 "C; G(CDC1,) 2.48 (3 H, s, Me), 2.78 (2 H, t, J 6.96, CH,CH,OH), 3.77 (2 H, t, J 6.96, CH,OH), 5.15 (2 H, s, CH,N), 5.62 (1 H, br s, OH, exch. with D,O), 6.94-7.93 (12 H, ArH, CH=N, CONH,, latter exch. with D,O) and 11.59 (1 H, s, NH, exch. with D,O) (Found: C, 60.1; H, 5.0; N, 15.9; MH+, 438. C,,H,,N,O,S requires C, 60.27; H, 5.29; N, 15.98; MH, 438). 9-0-(2-Hydroxyethyl)benzylguanine 12.-The foregoing methylthio derivative 11(0.6 g, 1.37 mmol) and aq. ammonia (30 cm3; 33) was heated at 100"C in a sealed tube for 2 h. The solvent was evaporated off to give a solid. Crystallisation from methanol gave the title compound (0.2 g, 51), m.p.275 "C (decomp.); 6(2H6Me2So) 2.87 (2 H, t, J 6.96, CH2CH,0H), 3.59 (2 H, t, J 6.96, CH,OH), 4.78 (1 H, br s, OH, exch. with D20),5.20 (2 H, s, CH,N), 6.82-7.24 (4 H, m, ArH), 7.72 (3 H, br s, CH=N, NH,, latter exch. with D20)and 10.64 (1 H, br s, NH, exch. with D,O) (Found: C, 58.8; H, 5.2; N, 24.4; MH+, 286. C,,H,,N,O, requires C, 58.95; H, 5.3; N, 24.56; MH, 286). 9-o-(2-Hydroxyethyl)benzylhypoxanthine13.-A solution of the aminoimidazole 9 (1 g, 3.8 mmol) in a pre-mixed solution of formic acid (30 cm3) and acetic anhydride (100 cm3) was set aside overnight at room temperature. The solution was evaporated to leave a solid. This was heated on a steam-bath with saturated aq. sodium hydrogen carbonate (50 cm3) for 15 min.The resulting solution was adjusted to pH 6-7 using test papers with 2 mol dm-, hydrochloric acid to precipitate the title compound (1 g, 96), m.p. 225-226 "c;d(2H6Me2so) 2.89 (2 H, t, J6.96, CH,CH,OH), 3.6 (2 H, t, J6.96, CH,OH), 4.75 (1 H, br s, OH, exch. with D,O), 5.45 (2 H, s, CH,N), 6.84-7.22 (4 H, m, ArH), 8.05 (1 H, s, 8-H), 8.08 (1 H, s, 2-H) and 12.34 (1 H, br s, NH, exch. with D,O) (Found: C, 62.1; H, 5.7; N, 20.55; M', 270) C,,H,,N,02 requires C, 62.2; H, 5.2; N, 20.74; M, 270). 9-0-(2-Acetoxyethyl)benzylhypoxanthine14.-A solution of compound 13 (1 g, 3.7 mmol) in pyridine (30 cm3)-acetic anhydride (2.5 cm3) was left at 5 "C overnight. The solution was evaporated and a solution of the residue in chloroform was washed successively with water (20 cm3), saturated aq.sodium hydrogen carbonate (20 cm3) and water (20 cm3). The dried extract (anhyd. MgSO,) was evaporated to leave a solid. The title compound (1 g, 87) was crystallised from ethanol; m.p. 193-194°C; G(CDC1,) 2.2 (3 H, s, Me), 2.87 (2 H, t, J 6.96, CH,CH,OAc), 4.16 (2 H, t, J 6.96, CH,OAc), 5.2 (2 H, s, CH,N), 6.92-7.35 (6 H, ArH, 2- and 8-H) and 8.89 (1 H, br s, NH, exch. with D20)(Found: C, 61.3; H, 5.1; N, 18.05; M', 312. Cl6Hl6NO3 requires C, 61.53; H, 5.16; N, 17.95; M, 3 12). 9-0-(2-Hydroxyethyl)benzyl)adenine15.-A solution of the acetate 14 (0.7 g, 2.24 mmol) in acetonitrile (1 5 cm3) was treated with tetraethylammonium chloride (0.9 g, 5.44 mmol, previously dried over P,O,) and N,N-dimethylaniline (0.4 cm3, 3.15 mmol) followed by phosphoryl trichloride (1.6 cm3, 17.12 mmol).The mixture was heated on a steam-bath for 30 min and the solvents were evaporated off. The residue was dissolved in chloroform (50 cm3) and the solution was added to ice-water (30 cm3). The organic layer was separated and the aqueous layer was extracted with chloroform (2 x 50 cm3) and the combined organic phases were washed successively with 10 aq. sodium hydrogen carbonate (3 x 25 an3) and water (2 x 25 cm3). The dried (anhyd. MgSO,) solution was evaporated to give an oil (1 g). This was heated in a sealed tube with saturated methanolic ammonia (50 cm3) at 120 "C for 4h. The solvent was evaporated off and the residue was triturated with water.The title compound (0.3 g, 49) was crystallised from ethanol; m.p. 214-215 "C; G(C2H,Me,SO) 2.92 (2 H, t, J 6.96,CH2CH,OH),3.56(2H,q,J6.96and5.13,CH20H),4.76 (1 H, t, J 6.96 and 5.13, OH, exch. with D,O), 5.44 (2 H, s, CH,N), 6.85-7.27 (6 H, ArH, NH,, the latter exch. with D,O), 8.13(1H,s,8-H)and8.14(1H,s,2-H)(Found:C,62.1;H,5.5; N, 25.75; M', 269. C,,H,,N,O requires C, 62.45; H, 5.62; N, 26.02; M, 269). 1-0-(2-Hydroxyethyl)benzylthymine16.-A solution of N-ethoxycarbonyl-3-methoxy-2-methylacrylamide17 (1 g, 5.35 mmol) and the amine 2 (1 g, 6.62 mmol) in butan-1-01 (5 cm3) was boiled under reflux for 1 h. The solution was evaporated to dryness and the residue was treated with 2 mol dm-, sodium hydroxide then was heated on a steam-bath for 5 min.The J. CHEM. SOC. PERKIN TRANS. 1 1993 cooled solution was acidified with hydrochloric acid to precipitate a gummy solid. The aqueous phase was decanted and the gum was triturated with ethanol to give a solid. The title compound(0.7 g, 41) was crystallised from ethanol; m.p. 179- 180 "C; d(2H6Me2SO) 1.75 (3 H, s, Me), 2.80 (2 H, t, J 6.96, CH2CH,0H),3.54(2H,q,J6.96and5.13,CH20H),4.72(1H, s, OH, exch., with D,O), 5.42 (2 H, s, CH,N), 6.97-7.24 (4 H, m, ArH), 7.49 (1 H, s, 6-H) and 11.37 (1 H, s, 3-NH, exch. with D20) (Found: 64.4; H, 6.1; N, 10.6; M+, 260. Cl4HI6N2O3 requires C, 64.61; H, 6.2; N, 10.77; M, 260). 1--(2-Hydroxyethyl)benzyZ-2-thiothymine18.-A solution of 3-methoxy-2-methylacryloylisothiocyanate 19 (1 g, 6.32 mmol) and the amine 2 (0.96 g, 6.36 mmol) in diethyl ether (5 cm3) was warmed on a steam-bath for 5 min, then 2 mol dmP3 sodium hydroxide (4 cm3) was added and the mixture was heated on a steam-bath for 5 min.Any excess of diethyl ether was removed by evaporation and the resulting aqueous solution was acidified with hydrochloric acid to precipitate a gum which rapidly solidified. It was collected, and washed with water. The title compound(0.8 g, 46) was crystallised from methanol; m.p. 197-198 "C; d('H6Me2SO) 1.73 (3 H, s, Me), 2.81 (2 H, t, J 6.96, CH,CH,OH), 3.62 (2 H, t, J6.96, CHZOH), 4.75 (1 H, S, OH, exch. with D,O), 5.47 (2 H, s, CH,N), 6.83-7.24 (4 H, m, ArH), 7.7 (1 H, s, 6-H) and 12.7 (1 H, s, 3-NH, exch.with D,O) (Found: C, 59.7; H, 5.7; N, 10.0; M+, 276. C,,H16N,S~HH,0 requires C, 59.89; H, 5.93; N, 9.98; M, 276). 5-(Ethoxycarbonylcarbamoy1)-1-0-(2-hydroxyethyl)benzyl-uracil21 .-A solution of ethoxymethylenemalonylurethane 20 (3 g, 10 mmol) and the amine 2 (1.5 g, 10 mmol) in methanol (5 cm3) was heated on a steam-bath for 10 min. The title compoundwasprecipitated as a crystalline solid (2.8 g, 78) and was recrystallised from ethanol; m.p. 270 OC; 6(2H6Me2so) 1.22(3 H, t, J 6.96, Me), 2.79 (2 H, t, J 6.95, CH2CH,0H), 3.6 (2H, t, J6.96,CH20H),4.14(2H,q, J6.96,CH2Me),4.71 (1 H, br s, OH, exch. with D,O), 5.15 (2 H, s, CH,N), 7.06-7.28 (4 H, m, ArH), 8.57 (1 H, s, 6-H), 11.15 (1 H, s, 3-NH, exch.with D,O) and 12.27 (1 H, s, CONH, exch. with D,O) (Found: C, 56.2; H, 5.25; N, 11.6; MH', 362. Cl,Hl9N3o6 requires C, 56.51; H, 5.31; N, 11.63; MH, 362). 1-o-(2-Hydroxyethyl)benzyluracil-5-carboxylicAcid 22.-A solution of the uracil 21 (2 g, 5.54 mmol) in 2 mol dm-3 sodium hydroxide (25 cm3) was boiled under reflux for 3 h. The solution was acidified with hydrochloric acid to give a solid precipitate. The titleproduct(1.3 g, 81) was collected, and was crystallised from ethanol; m.p. 197-198 "c; 6(2H6Me,SO) 2.83 (2 H, t, J 6.23, CH2CH,0H), 3.75 (2 H, t, J6.23, CH,OH), 4.72 (1 H, br s, OH, exch. with D,O), 5.16 (2 H, s, CH,N), 7.08-7.22 (4 H, m, ArH), 8.59 (1 H, s, 6-H) and 12.5 (2 H, br s, NH, CO,H, both exch. with D,O) (Found: C, 57.9; H, 4.7; N, 9.7; M', 290. Cl4HI4N2O5requires C, 57.9; H, 4.86; N, 9.65; M, 290).l-o-(2-Hydroxyethyl)benzyluracil23.-A solution of the acid 22 (0.5 g, 1.72 mmol) in N-ethylmorpholine (8 cm3) was boiled under reflux for 1 h. The solution was evaporated and the residue was treated with water to produce a solution, which was acidified with hydrochloric acid to give a solid precipitate. The title compound (0.26 g, 62) was collected and was crystallised from ethanol; m.p. 145-146 "C; 6(2H6Me,SO) 2.8 (2 H, t, J 6.96, CH,CH,OH), 3.6 (2 H, t, J 6.96, CH,OH), 4.73 (1 H, br s, OH, exch. with D,O), 4.95 (2 H, s, CH,N), 6.98-7.61 (6 H, m, ArH, 5- and 6-H) and 1 1.37 (1 H, br s, 3-NH, exch. with D20) (Found: C, 63.3; H, 5.4; N, 11.3; M+, 246.C1,H14N203 requires C, 63.41; H, 5.73; N, 11.38; M, 246). J. CHEM. SOC. PERKIN TRANS. 1 1993 Acknowledgements We thank the Yorkshire Cancer Research Campaign for a research grant (to D. C. A.), and the M.R.C. Collaborative Centre, Mill Hill, London for antiviral tests. References 1 Part 66. D. C. Agathocleous and G. Shaw, J. Chem. Soc., Perkin Trans. 1, 199 1,23 17. 2 R. W. Humble, G. Mackenzie and G. Shaw, Nucleosides, Nucleotides, 1984,3, 363. 3 G. Shaw and R. N. Warrener, J. Chem. SOC.,1958,153. 4 G. Shaw and R. N. Warrener, J. Chem. Soc., 1958,157. 5 G. Shaw, R. N. Warrener, R. K. Ralph and D. Butler, J. Chem. Soc., 1959,1648. 6 G. Shaw and D. Butler, J. Chem. Soc., 1959,4040. 7 N. J. Cusack, B. J. Hildick, D. H. Robinson, P. W. Rugg and G. Shaw, J. Chem. SOC.,Perkin Trans. 1, 1973, 1720. 8 N. J. Cusack, D. H. Robinson, P. W. Rugg, R. Lofthouse and G. Shaw, J, Chem. SOC.,Perkin Trans. I, 1974,73. 9 G. Pifferi, P. Consonni, R. Monguzzi and A. Omodei-Sale, J. Heterocycl. Chem., 1971,8,911. 10 J. Colonge and P. Boisde, Bull. Soc. Chim. Fr., 1956, 1337. 11 C. Bratton, D. Babbitt, A. R. Hendrickson and E. K. Marshall, J. Biol. Chem., 1939,128,537. Paper 3/03342B Received 10th June 1993 Accepted 13th July 1993