| 99.01% |
With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 8h; |
Add 2,6-dichloropurine (4.62g, 24.03mmol) to a 250ml round bottom flask,3,4-dihydropyran (4.38g, 48.06mmol),P-toluenesulfonic acid (0.27g, 1.44mmol),Dichloromethane was used as the solvent and reacted at room temperature for 8 hours.After the reaction was completed, it was washed with water and the organic phase was collected.The product was purified by column chromatography conditions where the mobile phase was petroleum ether: ethyl acetate = 5: 1, and the product was obtained as 6.50 g of white solid with a yield of 99.01%. |
| 99.01% |
With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 8h; |
2,6-dichloro-9H-purine (4.62 g, 24.03 mmol), 3,4-dihydropyran (4.38 g, 48.06 mmol) and p-toluenesulfonic acid (0.27 g, 1.44 mmol) were added to a 250 mL round bottom flask. DCM was used as the solvent, and the solution was reacted at room temperature for 8 h. After the reaction was completed, the reaction solution was washed with water. The organic phase was collected and dried under a vacuum to give crude the product. The crude product was then purified by silica gel column chromatography to afford 6.5 g of the target compounds as white solid with yield 99.01%. 1 H NMR (400 MHz, DMSO-d6) delta 8.95 (s, 1H), 5.74 (dd, J = 10.8, 2.3 Hz, 1H), 4.10-3.93 (m, 1H), 3.78-3.66 (m, 1H), 2.31-2.19 (m, 1H), 2.07-1.88 (m, 2H), 1.82-1.71 (m, 1H), 1.60 (p, J = 5.9, 4.9 Hz, 2H). |
| 95% |
With toluene-4-sulfonic acid; In ethyl acetate; at 50℃; for 2h; |
A mixture of 2,6-dichloropurine (3.9g, 20mmol, leq), TsOH H2O (117mg, O.lmmol) and 2H-3,4-dihydropyran (4.6mL, 50mmol, 2.5eq) in ethyl acetate was heated to 5O0C for 2h. The mixture was concentrated and purified by column chromatography to give 69a (5.Og, yield: 95%) as a white solid. ES-MS m/z: 273(M+H+). |
| 95% |
With toluene-4-sulfonic acid; In ethyl acetate; at 50℃; for 2h; |
Step 1 : A mixture of 2,6-dichloropurine (3.9g, 20mmol, leq), TsOH.H20 (117mg, 0.61mmol) and 2H-3,4-dihydropyran (4.6mL, 50mmol, 2.5eq) in ethyl acetate was heated to 50C for 2h. The mixture was concentrated and purified by column chromatography to give 5a (5.0g, yield: 95%) as a white solid. ES-MS m/z:273(M+H+). |
| 94% |
With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 6h; |
[00201] A mixture of 2,6-dichloropurine 7 (2.4 g, 12.7 mmol), PTSA (222 mg, 1.17 mmol) and 2H-3,4-dihydropyran (1.26 g, 15 mmol) in DCM (30 mL) was stirred at room temperature for 6h. The mixture was concentrated and purified by column chromatography to give 8 (3.2 g, yield, 94%, M+H+ = 273) as a pale yellow solid |
| 90% |
With toluene-4-sulfonic acid; In ethyl acetate; at 20 - 50℃; for 3.5h; |
To a solution of 2,6-dichloropurine 1a (2 g, 10.58 mmol) and PTSA (200 mg, 0.11 mmol) in EtOAc (35 mL) at RT was added 3,4-DHP (2.4 mL, 26.45 mmol). The mixture was stirred at 50 C for 3.5 h. After cooling to RT, saturated aqueous NaHCO3 (35 mL) was added and layers were separated. The aqueous layer was extracted with EtOAc (2 30 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The oily residue was triturated with Et2O (20 mL) and subsequent filtration gave compound 1b (2.60 g, 90%) as a white solid. 1H NMR (500 MHz, CDCl3)d 8.33 (s, 1H), 5.76 (dd, J 2.4, 10.8 Hz, 1H), 4.19 (dt, J 2.1, 11.9 Hz,1H), 3.78 (td, J 2.6, 11.7 Hz, 1H), 2.22e2.14 (m, 1H), 2.13e2.06 (m,1H), 1.97 (qd, J 3.9, 12.4 Hz, 1H), 1.87e1.71 (m, 2H), 1.71e1.65 (m,1H). 13C NMR (126 MHz, CDCl3) d 153.08, 152.29, 151.87, 143.81,130.91, 82.62, 69.07, 32.17, 24.84, 22.64. |
| 90% |
With toluene-4-sulfonic acid; In ethyl acetate; for 2h;Reflux; |
Example 1 Step 1: 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine To a stirred solution of 2,6-dichlor-9H-purine (50 g, 264.5 mmol) in ethyl acetate (500 mL), was added p-toluenesulfonic acid (1.36 g, 7.935 mmol) and slow addition of 3,4-dihydro-2H-pyran (55.6 g, 661.2 mmol). The reaction mixture was heated at reflux for 2 h, cooled to RT and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 50% ethyl acetate in hexane) affording 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine as a cream solid (65 g, 90%): H NMR (400 MHz, Chloroform-d) delta 8.33 (s, 1H), 5.77 (1H, dd, J=10.5, 2.6), 4.24 - 4.14 (1H, m), 3.86 - 3.71 (m, 1H), 2.21 - 1.65 (m, 6H). |
| 88% |
toluene-4-sulfonic acid; In dichloromethane; water; at 20℃; for 4h; |
To a solution of piperidine (18.0 g, 211.8 mmol) in dichloromethane (360 mL) at 0 C. is added 4-nitrobenzoyl chloride (18.6 g, 100 mmol) cautiously in several portions. The reaction mixture is stirred at room temperature for 10 minutes before it is washed with HCl (1%, 2×200 mL) solution and water (300 mL) and dried with Na2SO4. After evaporation of the solvent, (4-nitro-phenyl)-piperidin-1-yl-methanone (23.2 g, 99%) is obtained and used directly in hydrogenation (1.0 g of 10% Pd/C in 400 mL of ethanol). After filtration of the catalyst and evaporation of ethanol, (4-amino-phenyl)-piperidin-1-yl-methanone (19.6 g, 96%) is obtained. A mixture of 2,6-dichloropurine (18.80 g, 100 mmol), 3,4-dihydro-2H-pyran (12.62 g, 150 mmol), p-toluenesulfonic acid monohydrate (1.90 g, 10 mmol) and anhydrous dichloromethane (200 mL) is stirred at room temperature for 4 hours. After filtration, it is washed with Na2CO3 (10% aqueous, 100 mL), water (100 mL) and dried with Na2SO4. Evaporation of the solvent followed by titration with ethyl acetate (5 mL) and hexanes (60 mL) induces precipitate which upon filtration yields 2,6-dichloro-9-(tetrahydro-pyran-2-yl)-9H-purine (24.01 g, 88%). The mixture of 2,6-dichloro-9-(tetrahydro-pyran-2-yl)-9H-purine (5.44 g, 20 mmol), (4-amino-phenyl)-piperidin-1-yl-methanone (4.08 g, 20 mmol), diisopropylethylamine (24 mmol) and ethanol (100 mL) are refluxed for 24 hours. Then trans-1,4-cyclohexanediamine (6.84 g, 60 mmol) and diisopropylethylamine (24 mmol) are added and the mixture is refluxed for another 24 hours. The oily residue obtained after evaporation of ethanol is treated with ethyl acetate (250 mL) and water (200 mL). The aqueous phase is extracted with ethyl acetate (2×100 mL) and the combined organic phase dried with Na2SO4. After evaporation, the oily residue obtained is treated with p-toluenesulfonic acid monohydrate (3.80 g, 20 mmol) in methanol (100 mL) at 55 C. for 4 hours and the reaction monitored until deprotection is completed. Diisopropylethylamine is added to neutralize the mixture. The oily residue obtained is subjected to column chromatography (EtOAc: MeOH=9:1, then CH2Cl2:MeOH (containing 7N ammonia)=9:1) to give 2-(4-amino-cyclohexylamino)-6-[4-(piperidine-1-carbonyl)-phenylamino]-9H-purine (6.50 g, 75%). A reaction vial containing a mixture of 2-(4-amino-cyclohexylamino)-6-[4-(piperidine-1-carbonyl)-phenylamino]-9H-purine (86.8 mg, 0.2 mmol) prepared as above, copper(I) iodide (38.2 mg, 0.2 mmol) and potassium phosphate (170 mg, 0.8 mmol) is degassed and refilled with dry nitrogen. N,N'-Dimethylethylenediamine (35.3 mg, 43 muL, 0.4 mmol) and iodobenzene (40.8 mg, 0.2 mmol) in DMF (700 muL) are added and the mixture is stirred at 88 C. overnight. AcOH-MeOH (1:10, 1.5 mL) is added to neutralize the mixture followed by filtration through a syringe filter. Column chromatography (EtOAc: MeOH=9:1, then CH2Cl2:MeOH (containing 7N ammonia)=9:1) yields {4-[2-(4-amino-cyclohexylamino)-9-phenyl-9H-purin-6-ylamino]-phenyl}-piperidin-1-yl-methanone as a solid; 1H NMR 400 MHz (CD3OD) d 8.03 (s, 1H), 7.90-7.95 (m, 2H), 7.75-7.65 (m, 2H), 7.50-7.42 (m, 2H), 7.38-7.30 (m, 3H), 3.80-3.50 (m, 5H), 2.83-2.73 (m, 1H), 2.15-2.05 (m, 2H), 1.95-1.90 (m, 2H), 1.70-1.40 (m, 6H), 1.40-1.20 (m, 4H); MS m/z 511.3 (M+1). |
| 88% |
With trifluoroacetic acid; In ethyl acetate; at 20℃; for 2h;Inert atmosphere; |
To a suspension of 2,6- dichloro-9H-purine ( 1 eq., 5 g) and 3,4-dihydro-2H-pyran (2 eq.) under Ar atmosphere in dry ethyl acetate (50 ml) was trifluoroacetic acid (1.8 eq.) dropwise added and resulting solution was stirred at room temperature for 2 hours. After cooling in ice bath pH of the reaction mixture was adjusted to 7-8 by cone. NH3/water (2:3, v/v). Resulting solid was filtered, washed with cold water and dried at room temperature. Second portion of product was obtained by extraction of filtrate ans washings by ethyl acetate (3x 25 ml). The combined organic layers were washed with brine (2x 15 ml) dried (NaaSO/i) and concentrated under reduced pressure to give a yellow gel. The solid material was obtained after crystallization from diethyl ether. White solid, chemical formula: C10H10CI2N4O, yield (%): 88. HPLC-UV/VIS retention time, purity (min., %): 22.87, 98.4. ESI+-MS m/z (tel. int. %, ion): 273.0 (10, [35C1-M+H]+), 275.0 (8, [37C1- M+H]+), 189.0 ( 100, [35C1-M-THP+H]+), 191.0 (74, [37C1-M-THP+H]+). lH NMR (500 MHz, DMSO- ) delta (ppm): 1.56-1.61 (m, 2H), 1.73-1.77 (m, 1H), 1.94-2.01 (m, 2H), 2.21-2.29 (m, 1H), 3.70-3.75 (m, 1H), 4.00-4.03 (m, 1H), 5.73 (dd, / = 10.9, 2.3 Hz, 1H), 8.95 (s, 1H). 13C NMR (126 MHz, DMSO- ) delta (ppm): 22.0, 24.3, 29.6, 67.7, 81.6, 130.5, 146.4, 149.9, 151.2, 152.7. |
| 82% |
With toluene-4-sulfonic acid; In acetonitrile; at 60℃; for 3h; |
Synthesized from 2,6-dichloropurine (0.568 g, 3.0 mmol), 3,4-dihydropyran (0.9 mL, 4.5 mmol), p-TSA (0.010 g, 0.06 mmol) in 9 mL of anhydrous CH3CN at 60 C. After 3 h, TLC analysis showed complete consumption of 2,6-dichloropurine. Column chromatography was performed using 5%-20% EtOAc in hexanes to give 1a as off white solid in 82% yield. |
| 80% |
With toluene-4-sulfonic acid; In ethyl acetate; at 57℃; for 4h; |
REFERENCE EXAMPLE 1 2,6-Dichloro-9-(tetrahydropyran-2-yl)-9H-purineTo a suspension of 2,6-dichloropurine (2.00 g, 10.58 mmol) in EtOAc (36 mL) under Ar-atmosphere, 3,4-dihydro-2H-pyrane (2.40 mL, 26.40 mmol) and p- toluensulfonic acid (0.30 g, 1.59 mmol) were added. The resulting mixture was stirred at 57 0C for 4 h. It was allowed to reach room temperature. EtOAc was evaporated. The crude product obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 2.30 g of the title compound (80% yield). LC-MS (method 1 ): tR = 6.79 min; m/z = 271 (MH"). |
| 75% |
With toluene-4-sulfonic acid; In tetrahydrofuran; at 100℃; for 18h; |
Step 1 : 2,6-Dichloro-9-(tetrahydro-pyran-2-yl)-9H-purineA mixture of 2,6-dichloro-9H-purine (10.0 g, 53 mmol), 3,4-dihydro-2H-pyran (9.5 mL,93 mmol) and p-toluenesulfonic acid monohydrate (1.0 g, 5.0 mmol) in THF (100 mL) was heated at 100 C for 18 h, then cooled to RT and concentrated in vacuo. The resulting residue was purified by column chromatography (Si02, 0 to 10% ethyl acetate in cyclohexane) affording 2,6-Dichloro-9-(tetrahydro-pyran-2-yl)-9H-purine as a cream solid (10.9 g, 75%). 1H NMR (400 MHz, CDCI3): delta 8.33 (1H, s), 5.77 (1H, dd, J = 10.4, 2.4 Hz), 4.19 (1H, m), 3.78 (1H, dt, J = 11.6, 2.9 Hz), 2.17 (1H, m), 2.09 (1H, m), 1.98 (1H, m), 1.87-1.69 (3H, m). |
| 54% |
With toluene-4-sulfonic acid; In ethyl acetate; at 50℃; for 2h; |
2,6-Dichloro-9H-purine (300 mg, 1.59 mol) Ethyl acetate (5 mL)To the solution was added 3,4-dihydro-2H-pyran (360 mg, 4.3 mol)And p-toluenesulfonic acid (8 mg, 0.05 mmol)And the mixture was stirred at 50 C for 2 hours.The reaction mixture was distilled under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain the target compound (301 mg, 70%, 1.1 mmol) as a white solid. |
|
With toluene-4-sulfonic acid; In tetrahydrofuran; at 60℃; for 4h; |
Reference Example 382,6-Dichloro-9-(tetrahydro-pyran-2-yl)-9J-purine A solution of 2,6-dichloropurine (3.1 g), 3,4-dihydro-2H-pyran (2.76 g) andp- toluenesulfonic acid (0.31 g) in THF (35 mL) was heated at 60 C for 4 h. The solvent was evaporated in vacuo and the residue purified by column chromatography (50% ethyl acetate petrol) to give the title compound as a white solid (3.62 g). deltaH (400 MHz, CDCl3) 1.69 - 2.21 (m, 6H), 3.80 (m, IH), 4.21 (m, IH), 5.78 (dd, J = 2.5, 10.6, IH), 8.34 (s, IH). |
|
|
Preparation 8 2.6-Dichloro-(9-tetrahydro-2H-pyran-2-yl)-9H-purine 2,6-Dichloro-9H-purine (20 g, 0.11 mol) and 4-toluenesulphonic acid monohydrate (0.2 g) were dissolved in ethyl acetate (300 ml), the mixture heated to 50 C. and a solution of 2,3-dihydropyran (12.6 ml, 0.14 mol) in ethyl acetate (50 ml) added slowly over 30 minutes. The reaction mixture was cooled to room temperature, water (100 ml) added and the pH of the solution adjusted to 7 by addition of a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was azeotroped twice with pentane to afford the slightly impure title compound as a white solid (30.9 g). 1H-NMR (400 MHz, CDCl3) delta: 8.30 (1H, s), 5.75 (1H, dd), 4.25-4.15 (1H, m), 3.85-3.70 (1H, m), 2.20-1.60 (6H, m). |
|
With toluene-4-sulfonic acid; In ethyl acetate; at 50℃; for 4h;Product distribution / selectivity; |
Intermediate 1 : 2,6-Dichloro-9-(tetrahvdro-2/-/-pyran-2-yl)-9H-purine; To 2,6-dichloropurine (25.0 g) (available from, for example, Aldrich, UK) was added ethyl acetate (260 ml_), followed by p-toluenesulfonic acid (0.253 g). The mixture was heated to 500C and then 3,4-dihydro-2H-pyran (16.8 g) was added. The reaction mixture was then heated at 500C for 4 hours. The reaction mixture was evaporated in vacuo to give the title compound as a yellow solid (36.9g). 1 H NMR (CDCI3): 8.35 (1 H, s), 5.77 (1 H, dd), 4.20 (1 H, m), 3.79 (1 H, m), 2.20-1.65 (6H, m). |
|
With toluene-4-sulfonic acid; In ethyl acetate; at 50℃; for 4h;Product distribution / selectivity; |
Intermediate 1 : 2,6-Dichloro-9-(tetrahvdro-2/-/-pyran-2-yl)-9/-/-purine; To 2,6-dichloropurine (25.Og) (available from, for example Aldrich, UK) was added ethyl acetate (260ml), followed by p-toluenesulfonic acid (0.253g). The mixture was heated to 500C and then 3,4-dihydro-2/-/-pyran (16.8g) was added. The reaction mixture was then heated at 500C for 4 hours. The reaction mixture was evaporated in vacuo to give the title compound as a yellow solid (36.9g).1 H NMR (CDCI3): 8.35 (1 H, s), 5.77 (1 H, dd), 4.20 (1 H, m), 3.79 (1 H, m), 2.20-1.65 (6H, m). |
|
With toluene-4-sulfonic acid; In ethyl acetate; at 50℃;Product distribution / selectivity; |
Intermediate 2 (alternative method): 2-Chloro-9-(tetrahvdro-2/-/-pyran-2-yl)-9H-purin- 6-amine To a solution of 2,6-dichloropurine (25 g) (available from, for example, Aldrich, UK) in dry ethyl acetate (200 ml) was added p-toluenesulfonic acid monohydrate (235 mg).The reaction was heated to 50C and 3,4-dihydro-2H-pyran (18.1 ml) was added in one go. The reaction was allowed to stir at 5O C for 1 hour and the solvent was removed under reduced pressure. This afforded a yellow solid. A suspension of this solid (-36 g) in 2.0M ammonia in isopropanol (460 ml) was heated under nitrogen at60C for 4 hours with an attached condenser. The reaction was poured into water(50 ml) and left to cool overnight. The precipitate was filtered and dried on a rotary evaporator (60C) for 30 minutes to afford the title compound as an off-white solid,31g (93%, 2 steps).MS calcd for (CI0H12CIN5O)+ = 254, 256MS found (electrospray): (M)+ = 254, 256 (3:1 )1H NMR ((CDs)2SO): delta 8.43 (1 H, s), 7.82 (2H, s), 5.55 (1 H, dd), 4.00 (1 H, m), 3.69(1 H, m), 2.21 (1 H, m), 1.95 (2H, m), 1.74 (1 H, m), 1.56 (2H, m). |
|
toluene-4-sulfonic acid; In tetrahydrofuran;Reflux; |
[00551] 2,6-Dichloro-9-(tetrahydro-pyran-2-yl)-purine (83): To a solution of2,6-dichloropurine (1 g, 5 mmol) in THF (50 mL) was added /?-TSA (0.2 g, 1 mmol) and 3,4 dihydro-2H-pyran (1.4 mL, 16 mmol). The reaction was heated to reflux and allowed to stir for 18 hours. The reaction was concentrated and partitioned between ethyl acetate (100 mL) and a solution of saturated citric acid (100 mL). The organic layer was collected, washed with a saturated solution of NaHCO3 (100 mL) then brine (100 mL). The organic layer was dried (Na2SO4), concentrated in vacuo, and purified via silica gel column chromatography (Hexane : Ethyl acetate) to afford the desired product 83 (1.1 g) as a white solid. |
|
|
Step 4: Synthesis of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineTo a solution of 2,6-dichloropurine(2.0g) in CH2Cl2 (3OmL) was added para-toluenesulfonic acid (0.22g) and 3,4-dihydro-2H-pyran. The reaction was stirred for 4h. The solution was washed with an aqueous sodium carbonate solution and water, dried and concentrated to afford to afford 2.7 g white solid. 1H NMR 600 MHz (DMSO-d6) delta 8.98 (s, IH), 5.72 (m, IH), 4.00 (m, IH), 3.72 (m, IH), 2.24 (m, IH), 1.96 (m, 2H), 1.74 (m, IH). 1.56 (m, 3H). MS m/z: 274.12 (M+1). |
|
toluene-4-sulfonic acid; In ethyl acetate; at 50℃; for 4h; |
To 2,6-dichloropurine (25.0 g) (commercially available from, for example, Aldrich) was added ethyl acetate (260 mL), followed by p-toluenesulfonic acid (0.253 g). The mixture was heated to 50 C and then 3,4-dihydro-2H-pyran (16.8g) (commercially available from, for example, Aldrich) was added. The reaction mixture was then heated at 50 C for 4 hours. The reaction mixture was evaporated in vacuo to give the title compound as a yellow solid (36.9 g).1H NMR (CDCI3): 8.35 (1 H, s), 5.77 (1 H, dd), 4.20 (1 H, m), 3.79 (1 H, m), 2.20-1.65 (6H, m). |
|
With toluene-4-sulfonic acid; In ethyl acetate; at 50℃; for 7h; |
p-Toluenesulfonic acid (0.01 equiv) was added to a suspension of 2,6-dichloropurine in ethyl acetate (0.5 M). The mixture was heated to 50C and 3,4-dihydro-2H-pyran (1.5 equiv) was added. The reaction mixture was stirred at 50C for 2 h then concentrated and dried under vacuum. The resulting yellow solid was heated with 2 M ammonia in isopropanol (7.0 equiv) at 50C for 7 h and the reaction mixture poured into water. After standing at rt overnight, the yellow solid was filtered off, washed with isopropanol, dried under vacuum and purified by chromatography on silica gel (0-2% CHCl3 in CH3OH) to give 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine31 in 86% yield. Sodium t-butoxide (4.0 equiv) was added portionwise to n-butanol (20 equiv) (Note: exothermic reaction). The suspension was stirred until homogeneous (?20 min) and 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.0 equiv) was added. The reaction mixture was then stirred at 100C overnight and concentrated under vacuum. After aqueous work-up (CH2Cl2/H2O) and purification by chromatography on silica gel (0-1.2% CH3OH in CHCl3), compound 520 was isolated in 85% yield. 1H NMR (CDCl3): delta 7.86 (1H, s), 6.10 (broad s, 2H), 5.63 (d, J=10.0Hz, 1H), 4.36 (m, 2H), 4.14 (d, J=9.6Hz, 1H), 3.75 (t, J=11.2Hz, 1H), 2.06 (m, 3H), 1.37-1.81 (m, 7H), 0.92 (t, J=7.2Hz, 3H). N-Bromosuccinimide (1.05equiv) was slowly added to a solution of 5 in CHCl3 (0.65M) at 0C. The reaction mixture was stirred at 0C for 20 min then at rt for 4 h. After aqueous work-up (CH2Cl2/H2O) and purification by chromatography on silica gel (0-1.5% CH3OH in CHCl3) 8-bromo-2-butoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine20 was obtained in 88% yield. A solution of 8-bromo-2-butoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine in CH3OH (0.35 M) was heated to reflux with a solution of sodium methoxide in CH3OH (2.7 equiv) for 4 h. The reaction mixture was concentrated and after aqueous work-up (ethyl acetate and saturated NH4Cl solution) the crude was purified by chromatography on silica gel (0-1.5% CH3OH in CHCl3) to give 2-butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine.20 TFA (10% v/v TFA/CH3OH) was added to a solution of 2-butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine in CH3OH (0.23 M) and stirred at rt for 3 days. The reaction mixture was concentrated, diluted with ethyl acetate and filtered. The yellow solid was washed with a small volume of ethyl acetate and dried under vacuum to give 620 as an off-white solid in 87% yield (2 steps). 1H NMR (CD3OD/CDCl3) delta 4.50 (t, J=6.8Hz, 2H), 4.15 (s, 3H), 1.80 (m, 2H), 1.48 (m, 2H), 0.99 (t, J=7.2Hz, 3H). |
| 2.34 g |
With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 5h; |
Intermediate-1: 2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineTo a solution of 2,6-dichloro-9H-purine (1.7 g, 8.99 mmol) in dry DCM (20.0 ml), was added 3,4-dihydro-2H-pyran (1.23 ml, 13.49 mmol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.89 mmol) at room temperature. The reaction was stirred for 5 hour at room temperature. Quenched the reaction mixture with 10% aq. NaHCO3 (15 ml). The combined organic phase was washed with water and brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound 2.34g as brown solid MS (M+) m/z. 273.08. 1H NMR (CHCl3-d) 8.35 (s, 1H), 5.78 (dd, J = 10.7, 2.5 Hz, 1H), 4.21 (ddt, J = 11.8, 4.0, 1.8 Hz, 1H), 3.80 (td, J = 11.6, 2.9 Hz, 1H), 2.22 - 2.15 (m, 1H), 2.10 (dddd, J = 13.3, 10.0, 6.5, 3.1 Hz, 1H), 1.98 (tdd, J = 12.4, 10.6, 3.9 Hz, 1H), 1.88 - 1.80 (m, 1H), 1.79 - 1.74 (m, 1H), 1.73 - 1.67 (m, 1H). |
|
With toluene-4-sulfonic acid; In ethyl acetate; at 65℃;Inert atmosphere; |
Step 1.2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine 2,6-Dichloropurine i-D (1 equiv), dihydropyran (1.05 equiv), and para- toluenesulfonic acid (0.11 equiv) in EtOAc (~0.5 M) were stirred at 65 C overnight. After this time, the reaction was cooled to room temperature and washed with saturated NaHCO3 solution followed by brine. The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to afford a clear residue. The resulting residue was triturated with MeOH and the resulting white solid was collected by suction filtration to afford ii-D as a white solid; ESI MS (M+H) 273. |
| 36.9 g |
With toluene-4-sulfonic acid; In ethyl acetate; at 50℃; |
To 2,6-dichloropurine (25.0 g) (available from, for example, Aldrich, UK) was added ethyl acetate (260 mL), followed by p-toluenesulfonic acid (0.253 g). The mixturewas heated to 50C and then 3,4-dihydro-2H-pyran (16.8 g) was added. The reaction mixture was then heated at 50C for 4 hours. The reaction mixture was evaporated in vacuo to give 2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine as a yellow solid (36.9g).?H NIVIR (CDC13): 8.35 (1H, s), 5.77 (1H, dd), 4.20 (1H, m), 3.79 (1H, m), 2.20- 1.65 (6H, m). |
| 70 mg |
With ammonia; toluene-4-sulfonic acid; In ethyl acetate; at 70 - 80℃; for 4h; |
To a solution of 2,6-dichloro-9H-purine (50 g, 264.5 mmol) in ethyl acetate (500 ml), p-toluenesulfonic acid monohydrate (1.36 g, 7.92 mmol) was added and subsequently 3,4-dihydro-2H-pyran (55.36 g, 661.4 mmol) was added by use of a dropping funnel. Thereafter, the reaction solution was stirred at 70-80 C. for 4 hours, cooled to room temperature. To this, ammonia (15 ml) was added and the solution was stirred for 15 minutes. Subsequently, water (400 ml) was added to the solution, which was extracted with ethyl acetate (300 ml*3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was put in hexane (500 ml) and stirred. The solid substance precipitated was filtered and dried under reduced pressure to obtain the title compound (70 g). 1H NMR (400 MHz, DMSO-d6) delta ppm: 8.96 (s, 1H), 5.75 (dd, J=2.01, 10.79 Hz, 1H), 3.99-4.12 (m, 1H), 3.69-3.83 (m, 1H), 2.20-2.34 (m, 1H), 1.93-2.07 (m, 2H), 1.69-1.84 (m, 1H), 1.39-1.67 (m, 2H). |
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