2-Amino-4-hydroxypyrrolo[2,3-d]pyrimidine

Pink solid

To a suspension of bromoacetaldehyde diethyl acetal (10.4 mL, 68.98 mmol) in water (35 mL) was added concentrated hydrochloric acid (1.5 mL). The reaction mixture was stirred at 90 °C. After 30 min, the solution was cooled to room temperature, and sodium acetate(6.8 g, 82.75 mmol) was added. The mixture solution was added to a suspension of 2, 6-diamino-4-pyrimidinone (10.0 g, 79.29 mmol) and sodium acetate (3.5 g, 42.82 mmol) in water (75 mL). The reaction mixture was stirred at 80 °C. After 2 h, the mixture was stirred at 0 °Cfor 90 min. The precipitate was filtered off, and washed with a little amount of cold water and acetone to afford the title product (11.9 g, quantitative yield); 1H NMR (300 MHz, DMSO‑d6) δ 10.97 (s, 1H), 10.23 (s, 1H), 6.61–6.60 (m, 1H), 6.18–6.17 (m, 1H), 6.05 (s, 2H).Step one: After adding Sm-1 (27.3 g, 138 mmol) to 70 mL of water, an additional 3.0 mL of concentrated hydrochloric acid was added and stirred at 90 ° C for 0.5 h. After cooling to room temperature, sodium acetate (13.6 g, 165 mmol) (7.0 g, 85.4 mmol) was dissolved in 150 mL of water and stirred for 2 h at 80 ° C. The mixture was stirred at 0 ° C for 1.5 h, filtered, and washed with ice-water (20.0 g, 159 mmol) and sodium acetate And acetone, and dried to give 15.4 g of a yield of 74percent.After Sm-1 (27.3 g, 138 mmol) was added to 70 mL of water, 3.0 mL of concentrated hydrochloric acid was added and the mixture was stirred at 90 ° C. for 0.5 h.After cooling to room temperature, sodium acetate (13.6 g, 165 mmol) was added and stirred, Sm-2 (20.0 g, 159 mmol) and sodium acetate (7.0 g, 85.4 mmol) were dissolved in 150 mL of water and added to the reaction. After stirring for 2 h at 80 ° C the reaction mixture was shifted to zero degrees Celsius for 1.5 h, filtered, Water and acetone, pumping dry 15.4g, yield 74percent.Bromoacetaldehyde diethyl acetal (1.1 mL, 0.91 equiv) was suspended in water (4.0 mL) and cone, hydrochloric acid (0.15 mL) was added. The mixture was stirred at 90 °C until a clear solution was formed (approximately 30 min). The solution was cooled to room temperature and sodium acetate (0.71 g) was added. This mixture was added to a suspension of 2, 6-diamino- 4-pyrimidinone (1.0 g, 7.93 mmol, 1.00 equiv) and sodium acetate (0.35 g) in water (10 mL). The resulting mixture was stirred at 80 °C for 2 h. During this period the suspension first dissolved partially, before a white solid gradually precipitated. The obtained suspension was stirred at 0 °C for 90 min. The precipitate was collected and washed with a small amount of cold water and acetone. Drying in vacuo yielded 2-amino-3H, 4H, 7H-pyrrolo[2, 3-d]pyrimidin-4-one (0.5 g, 42 percent) as white solid.The mixture Sm-2 (12. 6g, 100mmol) was dissolved in 120mL DMF and 20mL of water, stirred at room temperature after 15min, was added Sm-1 (12. 7mL, 100mmol), stirred for 46h at room temperature the solvent was spin-solid was dissolved in 2. 5mL water was filtered and dried in vacuo to give 12. 9g worm 86percent yield.The mixture of 14 2, 4-diamino-6-hydroxypyrimidine (1, 5.14g; 0.04mol) and 15 sodium acetate (3.34g; 0.04mol) was dissolved in the mixture of 16 DMF:17 HExample 1Step Al:2-Amino-3, 7-dihydro-pyrrolo[2, 3-d]pyrimidin-4-one. To a mixture of 2, 4-diamino-6- hydroxypyrimidine (20.0 g, 159 mmol) and NaOAc (26.0 g, 317 mmol) in HStep 1. 2, 4-diamino-6-hydroxypyrimidine (3.02 g, 23.6 mmol) was dissolved in water (60 mL) containing sodium acetate (1.97 g, 24.0 mmol). The solution was heated to 80 °C until a clear solution was obtained. Then 50percent aq. alpha-chloroacetaldehyde (2.52 mL, 39.0 mmol) was introduced and the solution was left stirring at 80°C overnight. A brown precipitate was recovered, dried and purified by flash chromatography using CHClStep 1. Creation of the heterocycle (FIG. 3). To a solution of 2, 4-diamino-6-hydroxypyrimidine (1, 25.2 g) in DMF (480 mL) and water (80 mL) was added sodium acetate (27.2 g). The resulting yellow solution was stirred for 1 h. To the solution was added chloroacetaldehyde (50percent solution, 25.4 mL) and the mixture was stirred at rt for 2 days. The volatiles were removed in vacuo and the residue was mixed with methanol (70 mL) and stored at rt overnight. The resulting solid was filtered. The solid was mixed with methanol (150 mL) and heated at 60° C. for 10 min and cooled to rt overnight. The resulting solid was filtered and dried. The yield of 2 was 15 g to 19 g. (0032) A mixture of 7-deazaguanine (14.2 g) and dimethylaniline (6 mL) in POClAdd bromoacetaldehyde (9.4 mL, 1.0 eq) to water (40 mL) and add hydrochloric acid (2 mL) while stirring.The reaction was heated to 90° C. for 1 hour. After the reaction was completed, the reaction mixture was cooled with ice water, and sodium acetate trihydrate (12 g, 1.1 eq.) was added thereto to give a reaction solution.Then 2, 4-diamino-6-hydroxypyrimidine compound 2302 (10 g, 0.080 mol) was added to water (80 mL) and sodium acetate trihydrate (7.6 g) was added.The aforementioned reaction solution was added, heated to 80C, and reacted overnight. TLC tests showed that the reaction was complete.The reaction solution was stirred under ice for two hours, filtered, and the cake was washed with water. The filter cake was dissolved as much as possible with 95percent ethanol, dissolved three times, the ethanol phases were combined, and the solution was spin-dried to obtain a red-purple solid 2303 (4.7 g, yield: 40percent).Synthesis of Compound (37)Intermediate AA (0.5g, 3.96 mmol) was added to a solution of NaOAc (0.647g, 4.76 mmol, 1.2 eq.) in H