8-Bromo-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1H-purine-2,6-dione

White powder

1 g (0.0041 mol) of 8-bromo-3-methyl-1H-purine-2, 6(3H, 7H)-dione (Compound VI, prepared according to the process disclosed in Journal of Medicinal Chemistry, 2009, vol 52, No. 20, 6433-6445), tetrahydrofuran (50 mL), diisopropylethylamine (DIPEA, base 1, 0.68 g, 0.0053 mol), 1-bromo-2-butyne (Compound II, 0.54 g, 0.0041 mol) and potassium iodide (cocatalyst MXRoom temperature, to a 5L three bottles, 1000 mL of DMF was added, 100 g (0.408 mol) of 8-bromo-3-methylxanthine (a), 62 g (0.4797 mol) of N, N-diisopropylethylamine (DIEA)Stirring heated to 40 ° C, To dissolve completely.81.5 g (0.6128 mol) of 1-bromo-2-butyne (b) was slowly added dropwise, Incubation reaction 7h (HPLC detection).After completion of the reaction, The reaction mixture was slowly added with 2000 mL of water, And stirred at room temperature for 2 h, filter.The filter cake was washed with 100 mL of water.The resulting cake was added with 700 mL of methanol, At 60 stirred for 1h.Cooling to room temperature, stirring 1h.Filtered and washed with 100 mL of methanol, After drying, 89.3 g of product was obtained, Purity 98.3percentYield 83.7percent.1000 ml of DMF, 62 g of N, N-Diisopropyl ethylamine ( 0.6128 moles) and 100 g of 8-bromo-3-Methyl-xanthine (0.4081 moles, prepared as per Example- 1) were added to a 5 lit. R. B. flask equipped with overhead stirrer, thermo pocket and dropping funnel at 20-30°C and stirred for 5-10 minutes to get clear solution. To the reaction mixture was slowly added 81.45 g of 1 -Bromo-2-butyne (0.6128 moles) at 25-30°C and maintained the reaction mixture at same temperature for 3-4 hrs. After completion of the reaction, slowly added 2000 ml of chilled DM water to the reaction mixture and stirred for 1-2 hrs at 25-30°C. The solid was filtered and washed with 100 ml of DM water. The wet material was charged into RB flask and charged 700 ml of methanol and the temperature was raised to 60-65 °C and maintained for 60 min. The reaction mixture was cooled to 40-45 °C and maintained for 60 minutes. The solid was filtered and washed with 100 ml of methanol; Dried at 40-45 °C for 5-8 hours to get title compound (106 g, 87.6percent, purity > 99 percent).Using a known method, the 3-methyl-8-bromoxanthine (10g, 40.8mmol) was dissolved in N, N- dimethylformamide (60ml) was added N, N-diisopropylethylamine (5.27g, 40.8mmol), 1-bromo-2-butyne (5.43g, 40.8mmol), to obtain a reaction mixture, said reaction mixture at room temperature overnight and reaction progress was followed by thin layer chromatography, the reaction after completion, the reaction solution was poured into water, suction filtered, the resulting solid was suction filtered washed with water three times, and dried to give 3- Methyl-7-(2-butyn-1-yl) -8-bromo-xanthine 1a (10.5g, pale yellow solid), yield: 87percent. MS m / z (ES): 297, 299 [M + 1].General procedure: To a mixture of 8-bromo-3-methyl-1H-purine-2, 6(3H, 7H)-dione (244 mg, 1 mmol) and DIPEA (277 μL, 1.3 mmol) in DMF (4 mL) was added 3-bromo-1-butyne (93 μL, 1.2 mmol). The reaction mixture was stirred overnight at r.t. The precipitate was collected by filtration, washed with water and EtOH, and dried to give 3b as a white solid (212 mg, 75percent).Step 1: By utilizing the well known method, 8-bromo-3-methyl-xanthine (5 g, 20.4 mmol) was dissolved in N, N-dimethylformamide (30 ml). N, N-diisopropylethylamine (2.633 g, 20.4 mmol) and 1-bromo-2-butyne (2.714 g, 20.4 mmol) were added to obtain a reaction mixture. Using known method, the 8-bromo-3-methyl xanthine (20g, 81.6mmol) dissolved in DMF (120 ml) in, adding N, N-diisopropyl ethylamine (15.8g, 122 . 4mmol), 1-bromo-2-butyne (10.9g, 81 . 6mmol), overnight reaction at room temperature, thin layer chromatographic tracking of the reaction process, after the reaction is complete, the reaction solution is poured into the water, filtered, the solid washing 3 times, dried to get the product compound 1a (20.8g, strawcoloured solid), yield: 85.5percent.8-bromo-3-methyl-xanthine (5 g, 20.4 mmol) was dissolved in N, N-dimethylformamide (35 ml) by a known method, N, N-diisopropylethylamine (2.714 g, 36.2 mmol) at room temperature overnight. The reaction was complete by thin layer chromatography. The reaction was poured into 400 ml of water, solidified, filtered, washed with water Solid and dried to give 8-bromo-7- (2-butyn-1-yl) -3-methyl-xanthine 1a (5.2 g, yellow solid) in 85percentAt room temperature, suspending 8-bromo-3-methylxanthine (2.5 g, 10.2 mmol) in 15mL N, N-dimethylformamide (abbreviated to DMF), adding diisopropylethylamine (1.326 g, 10.2 mmol) and 1-bromo-2-butyne (1.357 g, 10.2 mmol) dropwise, and stirring at room temperature for 12 hours after the dripping was finished. 17.06 g 1-bromo-2-butyn are added to 30.17 g of 3-methyl-8-bromo-xanthine and 27.00 ml Huenig base in 370 ml N, N-dimethylformamide. EXAMPLE III At room temperature, the 8-bromo-3, 7-dihydro-3-methyl - purine-2, 6-dione (24.5g, 100mmol) were suspended in 150mL N, N- dimethylformamide (abbreviation is: DMF) was added diisopropylethylamine (27mL, 150mmol), mechanically stirred 10 minutes, then added dropwise a solution of 1-bromo-2-butyne (15g, 110mmol) in N, N- dimethyl formamide solution (50 mL), after the addition, stirred at room temperature for 10-12 hours.Completion of the reaction, the reaction solution was poured into ice water, stirring the precipitated solid was suction filtered, and dried in vacuo give a pale yellow solid 25g, yield 84.1percentAt room temperature, to a 5 L three-necked flask, 1000 mL of DMF, 100 g (0.408 mol) of 8-bromo-3-methylxanthine (a), 62g (0.4797 mol) N, N-diisopropylethylamine (DIEA) was added, and the mixture was heated to 40 ° C with stirring to dissolve all. 81.5 g (0.6128 mol) of 1-bromo-2-butyne (b) was slowly added dropwise, insulation reaction 7h (HPLC detection). After the reaction was complete, 2000 mL of water was slowly added to the reaction mixture and stirred at room temperature for 2 h and filtered. The filter cake was washed with 100 mL of water. The resulting cake was added with 700 mL of methanol and stirred at 60 deg. C for 1 h. Cooling to room temperature, stirring 1h. Filtered, washed with 100 mL of methanol and dried to give 89.3 g of product, 98.3percent pure with a yield of 83.7percent.8-Bromo-3-methyl-1H-2, 6-dicarbonylindole 5a (11.00 g, 44.7 mmol) and N, N-diisopropylethylamine(5.78 g, 44.7 mmol) was dissolved in N, N-dimethylformamide (65 mL), and stirred at room temperature 25 ° C for 30 min, then 1-bromo-2-butyne (5.95 g, 44.7 mmol) was added dropwise. Stir at 80 ° C for 5 h. After the reaction is completed, it is cooled to 0 ° C and passed to the reaction system.Add 200mL of ice water and stir for 30min, precipitate a white solid, filter, wash the filter cake with ice water (200mL), dry in vacuumIntermediate a, an off-white solid 10.26 g, yield 77.5percent.3-Methyl-8-bromo-xanthine (30 gm) and N, N-dimethylformamide (170 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Diisopropylethylamine (DIPEA, 15.9 gm) and 1-bromo-2-butyne (16.2 gm) were added at 30°C. The reaction mixture was heated to 85°C and maintained the temperature for 4 hours. The reaction mixture was cooled to 30°C and pre cooled water (300 mL) was added. The solid formed was collected by filtration and washed with pre cooled water (150 mL) and diethyl ether (30 mL). The solid was dried in oven under vacuum at 50°C to get 30.9 gm of the title compound.8-bromo-3-methylxanthine (5 g, 20.4 mmol) was dissolved in N, N-dimethylformamide (30 ml) by a known method, N, N-diisopropylethylamine (2.633 G, 20.4 mmol), 1-bromo-2-butyne (2.714 g, 20.4 mmol) at room temperature overnight. The reaction was carried out by thin layer chromatography. After completion of the reaction, the reaction solution was poured into water, And dried to give 1a (5.15 g, pale yellow solid) in 85percent yield.

Molecular Weight:297.11
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:295.99089
Monoisotopic Mass:295.99089
Topological Polar Surface Area:67.2
Heavy Atom Count:17
Complexity:427
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes