| 20% |
With trichlorophosphate; for 3h;Reflux; |
Synthesis of intermediate XI 11-011-07 XIII-01A mixture of Intermediate 1-07 (4.85 g, 24.34 mnmol) and POCI3 (20 mL) was refluxed for 3 h. On cooling, the solvents were removed in vacuo, the residue was suspended in water and the suspension was cooled to 0 C. Aqueous saturated Na2C03 was added dropwise at 0 C up to pH~8. The resulting solid was filtered, washed with water and dried to give Intermediate XIII-01 (1.1 g, 20%) as a white solid. H NMR (300 MHz, DMSO) δ 9.01 (s, 1H), 8.19 (q, J = 1.1 Hz, 1H), 2.39 (d, J = 1.1 Hz, 3H). |
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7-Methylthieno[3,2-d]pyrimidine-4(3H)-one (1.5g) was added to POCl3 (lOmL), and the mixture was stirred at 110C for 2 hours. The reaction mixture was cooled to room temperature, concentrated and dilluted with DCM, and sat. NaHC03 solution was added thereto. The aqueous layer was extracted with DCM to combine organic layers. The organic layer was dried with MgS04 and filtered to obtain the title compound as a white solid.1H NMR (400MHz, DMSO-d6) δ 9.06 (s, 1H), 8.24 (s, 1H), 2.43 (s, 3H). |
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7-Methylthieno[3,2-d]pyrimidine-4(3H)-one(1.5g) was dissolved in phosphorous oxychloride(lOmL) and stirred at 110 C for 2 hrs. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. The resulting concentrate was added to a mixture of dichloromethane and a saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane four times. The combined organic layers were dried over magnesium sulfate and concentrated under a reduced pressure to obtain the title compound as a cream and white solid.1H NMR (400MHz, DMSO-d6) δ 9.06(s, 1H), 8.24 (s, 1H), 2.43(s, 3H). |
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With trichlorophosphate; at 100℃; for 1h; |
A suspension of 7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (2.1 g) in phosphorus oxychloride (10 mL) was heated at 100 C. for 1 hour. The reaction mixture was then cooled and poured into a mixture of ice-water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM) to afford 2.0 g of 4-chloro-7-methyl-thieno[3,2-d]pyrimidine. |
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With trichlorophosphate; at 110℃; for 2h; |
b. 4-Chloro-7-methylthieno[3,2-d]pyrimidine 7-Methylthieno[3,2-d]pyrimidine-4(3H)-one (1.5 g) was dissolved in phosphorous oxychloride (10 mL) and stirred at 110 C. for 2 hrs. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. The resulting concentrate was added to a mixture of dichloromethane and a saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane four times. The combined organic layers were dried over magnesium sulfate and concentrated under a reduced pressure to obtain the title compound as a cream and white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.24 (s, 1H), 2.43 (s, 3H). |
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With trichlorophosphate; at 110℃; for 2h; |
Step 2: 4-Chloro-7-methylthieno[3,2-d]pyrimidine 7-Methylthieno[3,2-d]pyrimidine-4(3H)-one (1.5 g) was added to POCl3 (10 mL), and the mixture was stirred at 110 C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated and diluted with DCM, and sat. NaHCO3 solution was added thereto. The aqueous layer was extracted with DCM to combine organic layers. The organic layer was dried with MgSO4 and filtered to obtain the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.24 (s, 1H), 2.43 (s, 3H). |
| 1.9 g |
With trichlorophosphate; at 100℃; for 6h; |
Commercially available methyl 3-amino-4-methylthiophene-2-carboxylate 13 (16.5 g, 96.0 mmol) was dissolved in formamide (100 mL) and stirred at 150 C under nitrogen atmosphere. After the starting material consumption had been confirmed by LC-MS, the reaction mixture was cooled to room temperature and then H2O (500 mL) was added to the mixture. The suspension was filtered to collect a white solid that was dried by an oil pump to give 7-methylthieno[3,2-d]pyrimidin-4(3H)-one (12.2 g). The solid was used for the next reaction without further purification. The aforementioned 7-methylthieno[3,2-d]pyrimidin-4(3H)-one (1.85 g) was treated with POCl3 (8.80 mL) and stirred at 100 C for 6 h. The reaction mixture was cooled to 0 C, poured into ice-water/ethyl acetate, and extracted with ethyl acetate twice. The organic layer was washed with brine, dried over Na2SO4, and filtered. The organic solvent was concentrated under reduced pressure to give a crude residue. Water (200 mL) was added to the residue and the mixture cooled at 5 C in the refrigerator for a day. The suspension was filtered to afford 14 (1.90 g, 2 steps 72%) as a white solid. 1H NMR (400 MHz, DMSO-D6) δ: 9.07 (1H, s), 8.25 (1H, d, J = 1.2 Hz), 2.45 (3H, d, J = 1.2 Hz). 13C NMR (100 MHz, DMSO-D6) δ: 160.7, 153.9, 153.6, 133.9, 133.2, 130.0, 12.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C7H6ClN2S 184.9940; Found 184.9937. |
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