6-Amino-4(3H)-pyrimidinone

White Solid

Step two, the above 2-mercapto-4-amino-6-hydroxypyridine was added to aqueous ammonia, 2-mercapto-4-amino-6-hydroxypyridine and the mass ratio of 1:15 ammonia, the ammonia concentration was 25 percent, and then adding the active nickel and titanium oxide, 2-mercapto-4-amino-6-hydroxypyridine, activated nickel, titanium dioxide molar ratio of these three is 1: 4: 1.5, was heated to 90 deg.] C, refluxed for 5 hours, then take advantage of The active nickel and titanium dioxide were removed by hot filtration, cooled to room temperature, and a solid precipitated. The solid was washed with 30 ml of water and dried at 40 ° C to give 4-amino-6-hydroxypyrimidine in a yield of 98.4percent4-Amino-6-hydroxy-2-sulfanylpyrimidine (20 g) in boiling ethanol (300 mL) was treated under stirring with Raney-Ni until the starting material disappeared. The supension was filtered while hot, the precipitate washed with hot ethanol(300 mL) and the filtrate evaporated to dryness. The residue afforded on crystallization from ethanol (ether added toturbidity) 4-amino-6-hydroxypyrimidine, m.p. 272°C. Yield, 10.0 g (64.4percent). For C4H5N3O (111.10) calculated 43.24percentC, 4.54percentH, 37.82percentN; found 43.40percentC, 4.65percentH, 38.01percentN. Mass spectrum: 112 (MH+). 1H-NMR (CD3SOCD3): 4.97 s, 1H(H-5); 6.42 brs, 2H (NH2); 7.77 s, 1H (H-2); 11.41 brs, 1H (OH).Step two, the above 2-mercapto-4-amino-6-hydroxypyridine was added to aqueous ammonia, 2-mercapto-4-amino-6-hydroxypyridine and the mass ratio of 1:15 ammonia, the ammonia concentration was 25 percent, and then adding the active nickel and titanium oxide, 2-mercapto-4-amino-6-hydroxypyridine, activated nickel, titanium dioxide molar ratio of these three is 1: 4: 1.5, was heated to 90 deg.] C, refluxed for 5 hours, then take advantage of The active nickel and titanium dioxide were removed by hot filtration, cooled to room temperature, and a solid precipitated. The solid was washed with 30 ml of water and dried at 40 ° C to give 4-amino-6-hydroxypyrimidine in a yield of 98.4percent4-Amino-6-hydroxy-2-sulfanylpyrimidine (20 g) in boiling ethanol (300 mL) was treated under stirring with Raney-Ni until the starting material disappeared. The supension was filtered while hot, the precipitate washed with hot ethanol(300 mL) and the filtrate evaporated to dryness. The residue afforded on crystallization from ethanol (ether added toturbidity) 4-amino-6-hydroxypyrimidine, m.p. 272°C. Yield, 10.0 g (64.4percent). For C4H5N3O (111.10) calculated 43.24percentC, 4.54percentH, 37.82percentN; found 43.40percentC, 4.65percentH, 38.01percentN. Mass spectrum: 112 (MH+). 1H-NMR (CD3SOCD3): 4.97 s, 1H(H-5); 6.42 brs, 2H (NH2); 7.77 s, 1H (H-2); 11.41 brs, 1H (OH).This compound (3.6 g, 33.6 mmol) in DMF (70 mL) was treated with NaH (1.36 g, 34 mmol, 60percent dispersion in paraffin oil) 0.5 h under stirring, and diisopropyl 2-chloroethoxymethylphosphonate (9.4 mL, 40.5 mmol) was added. The mixture was stirred 8 h at 80°C, filtered through celite pad and evaporated in vacuo. The residue in chloroform was purified on silica gel; elution with chloroform-ethanol (97.5:2.5) afforded 4-amino-6-[2-(diisopropylphosphonylmethoxy)ethoxy]pyrimidine which was crystallized from ethyl acetate - petroleum ether. Yield, 3.0 g (26.8percent), m.p. 112°C. For C13H24N3O5P (333.32) calculated 46.84percentC, 7.26percentH, 12.61percentN, 9.29percentP; found 46.69percentC, 7.38percentH, 12.45percentN, 9.40percentP. 1H NMR (CD3SOCD3): 1.22 d, 6 H and 1.23 d, 6 H, J(CH3, CH)=6.1 (4xCH3); 3.78 brt, 2 H, J(2', 1')=4.5 (H-2'); 3.78 d, J(CH2-P)=8.4 (CH2-P); 4.31 brt, 2H, J(1', 2')=4.5 (H-1'); 4.59 m, 2 H (P-OCH); 5.67 s, 1 H (H-5); 6.62 bs, 2H (NH2); 8.07 s, 1H (H-2). 13C NMR (CD3SOCD3): 64.42 (C-1'). Further elution of the crude reaction mixture on silica gel column with chloroform-ethanol (95:5) gave the oily4-amino-1-[2-(diisopropylphosphonylmethoxy)-ethyl]pyrimidin-6(1H)-one which was dried in vacuo. Yield, 4.6 g (41.1percent). This compound was treated with bromotrimethylsilane (10 mL) in acetonitrile (70 mL) overnight at room temperature.After evaporation in vacuo, the residue was treated with water (100 mL). After 10 min, conc. aqueous ammonia wasadded to alkaline reaction and the mixture was evaporated. The residue was applied on a column (100 mL) of Dowex50 X 8 and eluted with water. The main UV-absorbing fraction was evaporated and the residue was crystallized from70percent aqueous ethanol (ether added to turbidity). Yield, 2.8 g (91percent) 4-amino-1-[2-(phosphonomethoxy)ethyl]pyrimidin-6(1H)-one, m.p. 233°C. For C7H12N3O5P (249.16) calculated 33.74percentC, 4.85percentH, 16.86percentN, 12.43percentP; found 34.02percentC, 4.80percentH, 16.88percentN, 12.58percentP. 1H NMR (CD3SOCD3): 3.56 d, 2H, J(CH2, P)=8.8 (CH2P); 3.64 t, 2H, J(2?, 1?)=4.9 (H-2?);3.90t, 2H, J(1?, 2?)=4.9 (H-1?); 5.06 s, 1 H (H-5); 6.45 brs, 2H (NH2); 6.90 brs, 2H (P-OH); 7.98 s, 1H (H-2). 13C NMR(CD3SOCD3): 44.44 (C-1?).Step three, the above-mentioned 4-amino-6-hydroxypyridine and sodium acetate added to the water quality amino-6-hydroxy-pyrimidine and water ratio of 1: 15, 4- amino-6-hydroxypyridine and sodium acetate in molar ratio of 1: 4, was heated to 70 , 2- chloroacetaldehyde solution was added slowly, the concentration of the aqueous solution of 2-chloro-acetaldehyde was 30percent, 4-amino-6-hydroxypyridine and 2-chloroacetaldehyde the molar ratio of 1: 4, the reaction was stirred for 5 hours, cooled to room temperature, filtered and the solid washed with 30ml of water, 40 dried to give 4-hydroxy-pyrrolopyrimidine in 89percent yield;4-amino-6-hydroxy-2-thiopyrimidine was treated with Raney nickel (RaNi) in water and ammonia and heated to reflux for 2h. Purification afforded the 4-amino-6-hydroxy-2-thiopyrimidine was treated with Raney nickel (RaNi) in water and ammonia and heated to reflux for 2h. Purification afforded the (+-)-3, 4, 5, 8-Tetrahydro-7-methyl-5-(3-nitrophenyl)-4-oxo-pyrido[2, 3-d]pyrimidine-6-carboxylic acid methyl ester (process b) Seventeen and 0.5 g (70 mmol) 3-nitrobenzylidene aceto-acetic methyl ester and 7.8 g (70 mmol) 4-Amino-6-hydroxypyrimidine [(1.] 77 g) was stirred in aqueous sodium hydroxide (1. 5N, 12.7 [ML)] and heated to [60 C] for 30 minutes. After cooling to ambient temperature, iodine (4.04 g) was added and the mixture refluxed for 2 hours. The mixture was cooled in an ice bath, filtered, washed with ice-cold water (10 mL), dried by suction then in a vacuum oven over [PXOG] at [60 C] for 16 hours to afford the title compound as a white solid [(886] mg, 23percent); 1H NMR [(DMSO-D6)] 8 6.65 (b s, 1H), 7.76 (s, 1H), 11.34 (b s, [2H)] ; MS m/e [MT] [238.]