4-Chloro-1H-pyrazolo[3,4-d]pyrimidine

Pale Yellow Solid

Synthesis of Compound 4.1. Hydrazine hydrate (11.5 mL, 23.7 mmol) was slowly added to a solution of 4, 6-dichloro-pyrimidine-5-carbaldehyde (40.0 g, 22.6 mmol), and triethylamine (30 mL, 22 mmol) in 1, 4-dioxane (600 mL), while cooling to maintain an internal temperature below 20° C. After the addition was complete, the reaction was warmed to RT. After 1 hr, the reaction was filtered. The solvent was removed in vacuo to afford compound 4.1 (29 g, 83percent) as a light yellow solid. Hydrazine hydrate (2.0 ml, 41 mmol) was slowly added to a solution of 4, 6- dichloropyrimidine-5-carbaldehyde (7.2 g, 41 mmol) in MeOH (150 ml) -60 To the solution of 4, 6-dichloropyrimidine-5-carbaldehyde(1.0 g, 0.006 mol) in methanol (20 mL) at -65 °C, triethylamine (0.97 mL, 1.2 equivalents (eq.)) wasadded. A solution of hydrazine monohydrate (0.274 mL 1.0 eq.) in methanol (10 mL) was slowlydripped into above stirred solution by using a constant-pressure dropping funnel. The mixture wasallowed to warm to room temperature and stirred for 2–3 h. The reaction mixture was concentratedin vacuo and crude product was diluted with water (20 mL), and extracted with EtOAc (60 mL x 3).The combined organic layer was washed with saturated solution of NaCl (60 mL x 3), dried overMgSO4 and concentrated to give compound 2. Yield: 68.9percent. 1H-NMR (400 MHz, deuteriated dimethylsulfoxide (DMSO-d6)) δ 14.51 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H). ESI-MS m/z: 153.00 [M - H]-.In a 100 mL three-necked flask, 1.0 g of 4, 6-dichloro-5-pyrimidinecarboxaldehyde and 20 mL of methanol were added and dissolved with stirring. The temperature was lowered to -65 ° C and 0.97 mL (1.2 eq) of triethylamine was added dropwise. 0.274 mL (1.0 eq) of hydrazine monohydrate was diluted with 10 mL of methanol and dropped slowly using a dropping funnel. Recovery was completed to room temperature, the reaction 2 ~ 3h, TLC monitoring. After the reaction was completed, the solvent was evaporated to dryness. The solid was dissolved with ethyl acetate (30 mL x 3), filtered, and combined, washed with saturated NaCl solution (60 mL x 3). Dried over anhydrous MgSO4, the solvent was removed by rotary evaporation and dried to give a pale yellow solid in a yield of 68.9percent.In a 100 mL three-necked flask, 4, 6-dichloro-5-pyrimidine formaldehyde (1.0 g, 5.68 mmol) was added.Methanol (20 mL) was dissolved by stirring, cooled to -65[deg.] C., and triethylamine (0.97 mL, 6.81 mmol) was added dropwise. Hydrazine monohydrate (0.274 mL, 5.68 mmol) was diluted with methanol (10 mL) and slowly dropped using a dropping funnel. After the completion of the addition, the reaction was allowed to return to room temperature for 2 to 3 h and monitored by TLC. The reaction is over, The solvent was evaporated and dried. The solid was dissolved in ethyl acetate (30 mL x 3), filtered and combined and washed with saturated NaCl solution (60 mL)×3). Dry over anhydrous MgSO4, evaporate the solvent, and dry to give a pale yellow solid (0.60 g, 68.9percent yield)General procedure: To the solution of 4, 6-dichloropyrimidine-5-carbaldehyde 2 (1.0g, 5.6mmol) in methanol (20mL) at−65°C, triethylamine (0.97mL) was added. A solution of hydrazine monohydrate (0.274mL 1.0 eq.) in methanol (10mL) was slowly dripped into above stirred solution by using a constant-pressure dropping funnel. The mixture was allowed to warm to room temperature and stirred for 2–3h. The reaction mixture was concentrated in vacuo and crude product was diluted with water (20mL), and extracted with EtOAc (60mL×3). The combined organic layer was washed with saturated solution of NaCl (60mL×3), dried over MgSOA suspension of 4, 6-dichloropyrimidine-5-carbaldehyde (500 mg, 2.825 mmol) in THF (lOmL) was allowed to stir at RT and treated with 3A sieves and hydrazine (3.461 g, 3.390 mL of 1M in THF, 3.390 mmol) followed by triethylamine (571.7 mg, 787.5 μ, 5.650 mmol). The reaction was allowed to stir at RT for 10 minutes before being heated to 160°C for 20 minutes in the microwave. The mixture was diluted with EtOAc/water and the organic layer washed with saturated NaCl, dried (MgSC ), and concentrated in vacuo. This was purified by column chromatography (ISCO Companion.(TM)., 40g column, MeOH / DCM) to give the required product (117mg, 27percent Yield).A suspension of 4, 6-dichloropyrimidine-5-carbaldehyde (500 mg, 2.825 mmol) in THF (10 mL) was allowed to stir at RT and treated with 3A sieves and hydrazine (3.461 g, 3.390 mL of 1M in THF, 3.390 mmol) followed by triethylamine (571.7 mg, 787.5 μL, 5.650 mmol).Preparation 95; 4-Chloro-lH -pyrazolo[3, 4-t/1pyrimidine; To a solution of allopurinol (20 g, 146.94 mmoles) in toluene (205.71 mL), add phosphoryl chloride (68.27 mL, 734.68 mmoles) and diisopropylethylamine (56.38 mL, 323.26 mmoles) and heat the mixture at 8OExample I.A.I. Intermediate 1 : 4-chloro-lH-pyrazolo[3, 4-d]pyrimidine [0185] To a suspension of allopurinol (2.0 g, 15 mmol) in toluene (20 mL) was added POCITo a solution of 1 , 5-dihydro-4/-/-pyrazolo[3, 4-c/]pyrimidin-4-one (2.0 g, 14.8 mmol) in POCIIntermediate 30: 4-Chloro-1H-pyrazolo[3, 4-d]pyrimidine; Phosphorus oxychloride (300 mL, 3.2 mol) was added to allopurinol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 20 g, 0.15 mol) and then N, N-dimethylaniline (30 mL, 0.24 mol) was added at room temperature. The resulting mixture was heated at reflux for 90 min and then cooled. The solvent was removed under vacuum. The residue was co-evaporated twice with toluene, and the resulting dark colored syrup was poured into a mixture of ice and water (500 mL). The mixture was stirred for 15 min, then transferred to a separatory funnel and extracted with ether (4.x.500 mL) and ethyl acetate (2.x.500 mL). The combined organic layers were washed twice with ice-water, dried (sodium sulfate), and concentrated to approximately 1.5 L. Charcoal was added to the slightly purple solution and the mixture was filtered through Celite. The Celite was washed with ethyl acetate and the combined filtrates were evaporated to dryness to give 4-chloro-1H-pyrazolo[3, 4-d]pyrimidine (13 g, 56percent) as a pale green solid. A mixture of allopurinol (2.00 g, 14.69 mmol) and N, N-dimethylaniline (2.00 g, 16.52 mmol) wasstirred in POCl3 (25 mL) at 80 °C for 2 h. The reaction mixture was diluted with water (35 mL), andextracted with ethyl acetate. The organic layer was washed with water and the organic phase wasconcentrated to dryness, and the residue was purified by column chromatography on silica gel using4:1.5 petroleum ether/ethyl acetate as eluent to give 2 [22]: white flake solid, 70 percent yield.Compound 79; 4-Chloro-1H-pyrazolo[3, 4-d]pyrimidine; To a mixture of commercially available 4-hydroxypyrazolo[3, 4-d]pyrimidine (78) (Acros, 14.5 g, 106.5 mmol) stirred in POClThe 4-hydroxypyrazolopyrimidine (2.5 g, 18 mmol) was dissolved in POC13 (34 mL, 0. 37mol) and N, N-dimethyl aniline (4.7 mL, 37 mmol.) This mixture was heated to reflux (120 °C) for 1.5 hours to afford a dark red solution. The mixture was concentrated to a viscous oil and cooled to 0 °C in an ice bath. The oil was poured into a mixture of ice-water and was stirred for 5 minutes. The acidic melt was extracted with ether (4 x 100mL), and the organics were combined. The organic was washed with cold water, then cold half saturated NaHC03 solution, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 4-Chloro-lH-pyrazolo [3, 4-d] pyrimidine (l. lg, 39percent) as a light yellow powder. lH NMR (DMSO-d6, 400 MHz) 8 8.79 (1H, s), 8.41 (1H, s. )The 1H-Pyrazolo [3, 4-d] pyrimidin-4-ol (5.00 g, 36.73 mmol) was dissolved in 68.5 mL of phosphorous oxychloride and 9.31 mL of N, N-dimethyl aniline (73.47 mmol). This mixture was heated to reflux (120C) for 90 minutes to completion affording a dark red solution. The mixture was concentrated in vacuo and cooled to 0 °C in an ice bath. The residue was poured into ice water and stirred for three minutes. The acidic melt was extracted with ether, and the organics were combined. The organic was washed with cold water, cold half saturated NaHC03 solution, brine, separated, dried over MgS04, filtered, and concentrated in vacuo to afford the 4-chloro-lH-pyrazolo [3, 4-d] pyrimidine as a light yellow powder (2.30 g, 41percent). IH NMR (DMSO-d6, 400 MHz) 8 8.84 (s, 1H), 8.46 (s, 1H), NH not observed.[0149] To a suspension of allopurinol (2.0 g, 15 mmol) in toluene (20 mL) was added POCI3 (7 mL, 74 mmol) and DIPEA (6 mL, 32 mmol). The mixture was heated to 85°C with stirring for 2hrs. The mixture was allowed to cool, concentrated to half of the volume and poured into 2M K2HPO4 (200 mL). The mixture was stirred overnight at room temperature and filtered. The filter mass was washed with EtOAc, and the filtrate was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to afford the title compound as pale orange powder (1.6 g, 70percent). MS (ESl) calcd for C5H3CIN4: 154.0; found: 155 [M+H]. 1H NMR (400 MHz, dG-DMSO) 6 14.47 (brs, 1H), 8.82 (s, 1H), 8.43 (s, 1H).General procedure: To a 20 mL vial was added 1 (97percent, 88 mg, 0.5 mmol), Et

Has a SK channel blocker effect

Molecular Weight:154.56
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:154.0046238
Monoisotopic Mass:154.0046238
Topological Polar Surface Area:54.5
Heavy Atom Count:10
Complexity:131
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes