2-Chloro-4-(morpholin-4-yl)thieno[3,2-d]pyrimidine

Reference 2-Chloro-4-morpholin-4-yl-thienof3, 2-dlpyrimidine(65) (65)A mixture of 2, 4-dichloro-thieno[3, 2-d]pyrimidine (64), (8.68g, 42.34mmol), morpholine (8.1 ImL, 2.2eq.) and MeOH (15OmL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield the title compound as a white solid (11.04 g, 100percent). EPO A mixture of 2, 4-dichloro-thieno[3, 2-d]pyrimidine (VIII), (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield the title compound as a white solid (11.04 g, 100percent). A mixture of 2, 4-dichloro-thieno[3, 2-d]pyrimidine (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and methanol (150 mL) was stirred at room temperature for 1 hour. A mixture of 2, 4-dichloro-thieno[3, 2-d]pyrimidine 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (15OmL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 2-chloro-4- moφholin-4-yl-thieno[3, 2-d]pyrimidine 4 as a white solid (11.04 g, 100percent). A mixture of 2, 4-dichloro-thieno[3, 2-d]pyrimidine 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 2-chloro-4- morpholin-4-yl-thieno[3, 2-d]pyrimidine 4 as a white solid (11.04 g, 100percent). A mixture of 2, 4-dichloro-thieno[3, 2-cφyrimidine (8.68 g, 42.34mmol), morpholine (8.11 mL, 2.2 equivalents) and methanol (150 mL) was stirred at room temperature for 1 hour. The reaction mixture was then filtered, washed with water to yield the title compound as a white solid (11.04 g, 100percent).<5H (400 MHz, d-6 DMSO) 8.30 (IH, d, J 5.6), 7.40 (IH, d, J 5.6), 3.90 (4H, t, J 4.9), 3.74(4H. U 4.9).Step If: 4-(2-Chlorothieno[3, 2-d]pyrimidin-4-yl)morpholine (Compound 0111)A mixture of compound 0110 (8.68 g, 42.34 mmol) and morpholine (8.11 mL, 93.15 mmol) in methanol (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water (50 mL x 3) and methanol (50 mL x 1) to give the title compound 0111 (11.04 g, 100percent) as a white solid: LCMS: 256 [M+l]Step 1f: 4-(2-Chlorothieno[3, 2-d]pyrimidin-4-yl)morpholine (Compound 0111)[0176]A mixture of compound 0110 (8.68 g, 42.34 mmol) and morpholine (8.11 mL, 93.15 mmol) in methanol (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water (50 mL×3) and methanol (50 mL×1) to give the title compound 0111 (11.04 g, 100percent) as a white solid: LCMS: 256 [M+1]A mixture of 2, 4-dichloro-thieno[3, 2-d]pyrimidine 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. In methanol (150 mL), compound 0110 (8.68g, 42.34mmol) and morpholine (8.11mL, 93.15mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water (50mL x 3) and methanol (50mL x 1), to give the title compound 0111 (11.04g, 100percent) as a white solid:A mixture of 2, 4-dichloro-thieno[3, 2-d]pyrimidine 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 2-chloro-4-morpholin-4-yl-thieno[3, 2-d]pyrimidine 4 as a white solid (11.04 g, 100percent).Reference 2-Chloro-4-morphoIin-4-yl-thieno f3, 2-d] pyrimidine; 2-Chloro-4-moφholin-4-yl-tbieno[3, 2-d]pyrimidine 4 A mixture of compound 13 (7.42, 1 equiv.) and morpholine (7.11 mL, 2.2 equiv) in methanol (150 mL) was stirred at rt for 1 h. The resulting precipitate was filtered, and then washed with water (3 x 50 ml) and remaining solid was dried in vacuo to furnish compound 14 (9.09 g, 99percent) as white solid. NMR (400 MHz, DMSO-Step m: To a mixture of compound 103 (34.2 g, 167 mmol, 1.0 eq) and methanol (500 mL) was added morpholine (31.2 mL, 367 mmol, 2.2 eq) slowly. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with methanol and dried in vacuo to give the desired product compound 104 as a light- yellow solid (39 g, 91percent). M.p.: 250-255°C. LCMS (m/z): 256.0 [M+1f ‘H NMR (400 MHz, DMSO-d6): ö 3.76 (t, J= 5.2 Hz, 4H), 3.92 (t, J= 5.2 Hz, 4H), 7.42 (d, J 5.2 Hz, 1H), 8.32 (d, J 5.2 Hz, 1H).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.To a stirred solution of compound 3 (16.9g, 83.2mmol) in dry methanol (300mL) and morphine (15.9g, 183.1mmol) was added. After the addition, the reaction mixture was stirred at room temperature for 1h. Separated gray solid was filtered and washed with water and methanol. The gray solid was dried and filtered. The crude product was found to be pure and taken to the next step without purification, yield a solid 4 (15.6g). Yield 73.5percent.

Molecular Weight:255.72
XLogP3:2.4
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:255.0233108
Monoisotopic Mass:255.0233108
Topological Polar Surface Area:66.5
Heavy Atom Count:16
Complexity:252
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes