6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

Pale Yellow Solid

A suspension of 6-chloro-9H-purine (25.36 g, 164 mmol) and 4-methylbenzenesulfonic acid (0.565 g, 3.28 mmol) in EtOAc (250 mL) was treated with 3, 4-dihydro-2H-pyran (44.9 mL, 492 mmol). The mixture was heated at 90 6-chloro-9H-purine (500 mg, 3.2 mmol), 4-methyl benzene sulfonic acid (12 mg, 0.07 mmol), and 3, 4-dehydro-2H-pyran (0.9 mL, 9.7 mmol) were added into ethylacetate solvent and stirred. The reactant was stirred at 90°C for approximately 1 hour until the solid is dissolved completely. After concentrating the solvent, the residuals were refined by means of column chromatography, so that 749 mg of the target compound, 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (percentage yield: 97percent), was obtained.p-TSA (0.01 g) was added to a solution of 6-chloropurine(0.15 g, 1 mmol) in dry THF at reflux. After 3, 4-dihydro-2H-pyran (0.098 g, 1.18 mmol) was added andthe mixture refluxed for 15 h. After cooling to ambienttemparature the reaction mixture was treated with 1 mL25percent NH4OH and sitirred for 5 min. The solution was evaporatedin vacuo and treated with 25 mL EtOAc, washedwith brine and water. The organic phase was dried overNa2SO4, the solvent was evaporated in vacuo, and recrystallizedfrom hexane petroleum ether to yield 2 (220 mg;95percent): mp 69–71 °C (67–69 °C30). 1H NMR (CDCl3) δ1.64–1.88 (m, 3H, H-pyran), 2.02–2.21 (m, 3H, H-pyran), 3.80 (td, J1 = 2.8 Hz, J2 = 12 Hz, 1H, H-5’a in pyran), 4.20(d, 1H, H-5’b in pyran), 5.80 (dd, J1 = 10.8 Hz, J2 = 2.4Hz, 1H, H-1’ in pyran), 8.35 (s, 1H, H-8 in purine), 8.76(s, 1H, H-2 in purine). MS (ESI+) m/z: 239.70 (10percent)(M+H).Ethyl acetate (300 ml) was added to 6-chloropurine (25 g, 162 mmol) and tosylic acid monohydrate (460 mg, 2.43 mmol)and the resulting mixture was heated at 60° C. Dihydropyrane (16 ml, 178 mmol) was added and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was cooled to room temperature followed by the addition of 28percent aqueous ammonia solution (15 ml) and the organic layer was fractionated, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (35 g, 91percent) as a pale yellow solid.General procedure: A suspension of 6-chloro-9H-purine (or 4-iodo-1H-pyrazole) (13mmol) and 4-methylbenzenesulfonic acid (0.12g, 0.65mmol) in EtOAc (25ml) was treated with 3, 4-dihydro-2H-pyran (3.54ml, 39mmol). The mixture was heated at 90°C and the solid slowly dissolved over 1h. The flask was removed from the oil bath and the cloudy yellow solution was filtered and concentrated under vacuum. The pale yellow residue was purified by flash chromatography to give title compound.A mixture of 6-chloro-9H-purine 17 (2.01 g, 13 mmol), 3, 4-dihydro-2H-pyran (3.30 g, 39 mmol) and TsOH (516 mg, 0.3 mmol) dissolved in anhydrous ethyl acetate (30 mL) was refluxed for 3 h. Then cooled to the room temperature and washed with water and brine. The organic layer was dried (anhydrous Na6-Chloropurine (15.5 g) and p-toluenesulfonic acid (0.26 g) were dissolved in ethyl acetate (180 ml)Heated to 50 ° C, 2, 3 dihydropyran (10.5ml) was slowly dropped to the reaction solution, the dropwise addition, stirring was continued for 1 hour at this temperature, slowly cooled to room temperature, stirred under saturated ammonium chloride solution (10ml ), Then washed twice with water, once with brine, dried and concentrated to give an oily crude which was recrystallized from n-hexane (150 ml)Chloro-9- (tetrahydro-2-pyranyl) -purine 19.6 g, yield 82.1percent.Example 1BStep 1 : 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineTo a solution of 6-chloro-9H-purine (61.8 g, 0.4 mol) in EtOAc (300 mL) was added 3, 4-dihydro-2H-pyran (101 g, 1.2 mol), followed by 4-methylbenzenesulfonic acid (1percent) and the resulting reaction mixture was heated to refluxing for 2 hrs. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Naa, 6-Chloropurine (1, 7.7 g, 50 mmol)And p-toluenesulfonic acid (172 mg, 1 mmol) in EtOAc was stirred at room temperature, 3, 4-dihydro-2H-pyran (8.4 g, 100 mmol) was added dropwise, The reaction was heated to reflux for about 2 h;When the reaction solution is near the clear state, Hot filter to remove part of the raw materials 1, The filtrate was washed with water, Saturated salt water were washed, Collecting oil layer, Anhydrous Na2SO4 drying oil layer, Removal of the solvent gave 6-chloro-9- (tetrahydro-2H-2-pyran-2-yl) -9H-purine (Intermediate 2, 11.3 g);To a solution of 6-chloropurine (61.8 g, 0.4 mol) in ethyl acetate (300 mL) was added 3, 4-dihydropyran (101 g, 1.2 mol) and the catalytic amount of p-toluenesulfonic acid (1percent). The reaction solution was heated under reflux for 2 hours. Water was added thereto, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting viscous material was recrystallized from diethyl ether to give the title compound (65.8 g, 69percent)Synthesis of compound 7 (0183) R-3 To a 1 L flask, 6-chloropurine (30 g, 194.1 mmole, 1 equiv), 3, 4-dihydropyran (24.5 g, 291.1 mmol, 1.5 equiv) and PTSA monohydrate (2.95 g, 15.5 mmol, 8percent equiv) were added, followed by EtOAc (240 mL). The mixture was refluxed for 2 hours. After the mixture cooled down, it was washed with NaHCCh (250 mL) to adjust pH = 7-8 and brine 150 mL x 3. The EtOAc layer was dried over Na2SC>4 and concentrated to dryness. The residue was purified by silica gel plug with hexane : EtOAc (2: 1, 1 : 1 and 1 :2 ) to get 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine as an off-white solid (31.6 g, 67percent).The compound was prepared from 6-chloropurine according to the literature (Taddei et al., Org. Biomol. Chem. 2004, 2, 665). A mixture of 6-chloropurine (20.0 g, 129 mmol), p-toluenesulfonic acid (0.23 g, 1.85 mmol), 3, 4-dihydro-2H-pyran (14.5 ml, 159 mmol) in tetrahydrofuran (175 ml) was refluxed under argon at 84°C for 22 h. After cooling, concentrated ammonia (5 ml) was added, undissolved particles were filtered off and the filtrate evaporated to dryness. The yellowish oil was dissolved in ethyl acetate (250 ml) and extracted with brine (75 ml), water (2 x 75 ml) and then dried over sodium sulfate. The organic extracts were concentrated in vacuo into an yellow oil that was extracted with boiling cyclohexane (cca 250 ml). Light yellow cyclohexane extract was separated from the undissolved orange rest by decantation. The extraction procedure was repeated twice with 150 ml cyclohexane. The cyclohexane extracts were cooled in a fridge overnight to precipitate colourless crystals. Yield: 19.1 g, 62 percent. M.p.: 68°C. *H NMR (300 MHz, DMSO-6-Chloropurine (19. 9 g, leq) was dissolved in dichloromethane (199 mL)A solution of 2-hydropyran (16. 3 g, L 5 eq)30 ° C for 2 hours, The reaction solution was added to water, Layered, The organic layer was washed with saturated sodium chloride solution, Dried over anhydrous sodium sulfate, Concentrated to dryness under reduced pressure. 27 g of solid, Scrape aside.Yield:90percent, purity:96percent (area normalization).

Molecular Weight:238.67
XLogP3:0.8
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:238.0621387
Monoisotopic Mass:238.0621387
Topological Polar Surface Area:52.8
Heavy Atom Count:16
Complexity:255
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes