| 96% |
In water; for 0.25h;Heating / reflux; |
Example 66 Preparation of N2-[2-(3,4-Dimethoxy-phenyl)-ethyl]-6-morpholin-4-yl-N8-p-tolyl-9H-purine-2,8-diamine The title compound was synthesised by the method shown in Scheme 3 As shown in Scheme 3 above, a mixture of 2,6-dichloropurine (1.90 g, 10 mmol) and morpholine (2.34 g, 30 mmol) in water (25 mL) was heated under reflux for 15 min. Solidified reaction mixture was cooled to room temperature. Solid was filtered out and washed with water, methanol and ether. The 2-chloro-6-morpholin-4-yl-9H-purine was obtained in 96% yield (2.30 g). |
| 95% |
In ethanol; at 20℃; for 3h; |
At room temperature 2,6-dichloropurine(10 g, 0.05 mol) was added to ethanol (120 ml), and after lyophilization, morpholine (6.91 g, 0.08 mol) was added dropwise to the reaction mixture, and stirred at room temperature for about 3 h. After the reaction was stopped, it was filtered, and the filter cake was washed three times with diethyl ether to give a pale yellow powder (12.02 g, yield 95%). |
| 90% |
In tetrahydrofuran; at 20℃; for 16h; |
Step 1: Synthesis of 4-(2-chloro-9H-purin-6-yl)morpholine (13a)Morpholine (1.39 mL, 15.87 mmol) was added to a solution of la (1.0 g, 5.29 mmol) in THF (26 mL). The resulting mixture was stirred at room temperature for 16 h. White precipitate was observed immediately upon addition of morpholine. The white precipitate was filtered off and washed with water (x2) and methanol (x2) to afford 13a (1.13 g, 90%). |
| 90% |
at 0 - 22℃; for 2h; |
Put 2,6-dichloropurine (18.900g, 100mmol) in a three-necked flask, add MeOH (500mL), cool the reaction solution to 0-5C, add morpholine (150mmol) dropwise, and increase the temperature to 20- Reacted at 22 for 2h, filtered with suction, the filter cake was washed with water (50mL) and methanol (30mL) successively, and then dried under vacuum at 45 to obtain the product 4-(2-chloro-9H-purin-6-yl)morpholine (21.384g ), the yield is 90%. |
| 84% |
With triethylamine; In ethanol; at 20℃; for 6h; |
General procedure: To an oven dried round-bottomed flask (25 mL) containing EtOH(10 mL) was added compound 5 (1 mmol), respective secondaryamines (1.2 mmol) and triethyl amine (1.5 mmol). The reactionmixture was then allowed to stirred for 6 h at room temperature.The progress of the reaction was monitored by TLC. After completionof the reaction organic solvent was evaporated under reducedpressure, water (50 mL) was added to the reaction mixture andextracted with EtOAc (2 x 25 mL). Organic layer was then collected,washed with water (2 x 100 mL) and brine, dried over Na2SO4 andfinally excess of solvent was evaporated under vacuum. The cruderesidue thus obtained was purfied column using MeOH/CHCl3 aseluent to afford compounds 6a-j. |
| 80.8% |
With triethylamine; In ethanol; for 10h;Reflux; |
General procedure: A suspension of 300 mg of 2,6-dichloro-9H-purine (1), 2,4-dichlorothieno[3,2-d]pyrimidine (6) or 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (9) in 10mL of EtOH was added morpholine or 4-aminotetrahydropyran (1.2 equiv) and 300 mL of triethylamine. The mixtrue was refluxed for 10 h. After the disappearance of compounds 1, 6 or 9 detected by TLC, the solution was evaporated in vacuum to yield a syrup. Then, it was neutralized by concentrated ammonium hydroxide. After filtering off, the residue was washed with cold water and cold acetone successively to remove the triethylammonium hydrochloride. |
| 80% |
With N-ethyl-N,N-diisopropylamine; In 2-methyl-propan-1-ol; at 75℃; for 16h; |
A solution of 2,6-dichloro-9H-purine (5g, 26mmol), morpholine (2g, 26mmol) and N,N- diisopropylethylamine (6.7g, 52mmol) in isopropanol (200 mL) was stirred at 75 C for 16h. The mixture was filtered to obtain 4-(2-chloro-9H-purin-6-yl)morpholine (5g, 80%) as white solid. 1H NMR (400 MHz, DMSO-de) d 13.24 (s, 1 H), 8.16 (s, 1 H), 4.19 (s, 4H), 3.83 - 3.59 (m, 4H). |
| 80% |
With N-ethyl-N,N-diisopropylamine; In 2-methyl-propan-1-ol; at 75℃; for 16h; |
A solution of 2,6-dichloro-9H-purine (5g, 26mmol), morpholine (2g, 26mmol) and N,N- diisopropylethylamine (6.7g, 52mmol) in isopropanol (200 mL) was stirred at 75 C for 16h. The mixture was filtered to obtain 4-(2-chloro-9H-purin-6-yl)morpholine (5g, 80%) as white solid. 1H NMR (400 MHz, DMSO-de) d 13.24 (s, 1 H), 8.16 (s, 1 H), 4.19 (s, 4H), 3.83 - 3.59 (m, 4H). |
| 80% |
With N-ethyl-N,N-diisopropylamine; In 2-methyl-propan-1-ol; at 75℃; for 16h; |
A solution of 2,6-dichloro-9H-purine (5g, 26mmol), morpholine (2g, 26mmol) and N,N- diisopropylethylamine (6.7g, 52mmol) in isopropanol (200 mL) was stirred at 75 C for 16h. The mixture was filtered to obtain 4-(2-chloro-9H-purin-6-yl)morpholine (5g, 80%) as white solid. 1H NMR (400 MHz, DMSO-de) d 13.24 (s, 1 H), 8.16 (s, 1 H), 4.19 (s, 4H), 3.83 - 3.59 (m, 4H). |
|
In ethanol; |
2,6-dichloropurine (approximately 0.20 g, 1.1 mmol) was taken up in ethanol (50 mL) and treated with morpholine (2 mL). The white precipitate was collected by filtration, washed with ethanol, and dried under house vacuum to provide 4-(2-chloro-9H-purin-6-yl)morpholine. MS (ES+): 240.0, 242.0 (M+H)+ |
|
In ethanol; at 20℃; for 2.5h;Reflux; |
Morpholine (46.9 ml, 538.2 mmol) was added to an ethanol solution (1.2 l) of 2,6-dichloropurine (50.9 g, 269.1 mmol) at room temperature and the resulting mixture was stirred and heated to reflux for 2.5 hours. The reaction mixture was left standing to cool and then concentrated until the solvent was reduced nearly by half in volume and the solid was collected by filtration. The solid was washed with ethanol and dried at 50 C. under reduced pressure to give a mixture (63.3 g, 95%) of the title compound and morpholine hydrochloride (approx. 13:1) as a white solid.1H-NMR (DMSO-d6) δ: 3.67-3.77 (4H, m), 3.84-4.56 (4H, brm), 8.16 (1H, s). |
|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 80℃; for 2h; |
To a n-butanol containing round bottom flask, 2,6-dichloropurine (1) (50 mmol), N,N-diisopropylethylamine (DIPEA) (10 mmol) and morpholine (2) (50 mmol) were added and was refluxed at 80 C for 2 h to generate a reactive intermediate (3). Thin layer chromatography [hexane(7):ethyl acetate(3)] was utilized to identify the complete formation of product. After 12 h stirring at room temperature, it was poured intoice-cold water and stirred for 1 h to isolate free material in powder form. The separated product was filtered and washed with cold water. The isolated product was dried for next 12 h at room temperature.For the purification purpose, hexane stripping was performed using roteva evaporator at 60 C and 500 mm pressure through 100 rpm speed. The step-I crude product was characterized by 1H NMR and IR techniques to carry out further reactions |
|
In butan-1-ol; at 70℃; for 1h;Microwave irradiation; |
General procedure: 15 mL n-BuOH, 2,6-dichloro-9H-purine 1 (1.0 equiv.)and relative amines 2 (3.0 equiv.) were added in a microwave reactiontube. The vessel was heated to 70 C for 1 h. The reaction was cooled to room temperature, the suspension was filtered andwashed with methanol to afford the compound 3 as a yellow solid. |
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