| 81.5% |
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 70℃; for 12h; |
Step 2: (2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol Tetrabutylammonium fluoride trihydrate (18.8 g, 59.6 mmol) was added to a solution of 3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)prop-2-yn-1-ol (6.0 g, 23.8 mmol) in tetrahydrofuran (150 mL). The mixed solution was kept at 70 C to react for 12 h. The reaction mixture was cooled, water (150 mL) was added thereto, and the resulting mixture was extracted with ethyl acetate (150 mL*2). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to obtain (2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d] pyrimidin-6-yl)methanol (4.89 g, yield: 81.5 %). 1H NMR (400 MHz, CDCl3): 8.65 (1H, s), 6.43 (1H, s), 4.87-4.95 (1H, m), 4.82 (2H, s), 2.35-2.43 (2H, m), 1.99-2.19 (6H, m). |
| 68% |
With trifluoroacetic acid; In tetrahydrofuran; at 29 - 60℃; for 12h;Inert atmosphere; |
A solution of compound (3).(5g, 19.9 mmol) in THF (50 mL) was stirred at 29 C undernitrogen atmosphere, tetrabutylammonium fluoride solution1.0M in THF (45 mL) was added to the mixture and heatedat 60 C for 12 hours. Progress of the reaction was monitoredby TLC. After completion of the reaction, the resultingmixture was concentrated under vacuum and residue wasdissolved in 2-propanol (10 mL) at 50C. The clear solutionwas cooled to 29C, with slowly charged water (75 mL) andstirred for 4 hours. Precipitate was filtered and washed withwater, followed by being dried at 50C under vacuum toobtain compound (4). Brown solid, Yield: 68%, mp. 173-175 C. 1H NMR (400 MHz, DMSO-d6): 1.64-1.65 (m, 2H, -CH2), 1.98-2.03 (m, 4H, CH2), 2.22-2.29 (m, 2H, CH2), 4.67(d, 2H, J=5.12 Hz, CH2OH), 4.87-4.89 (m, 1H, -NH-CH-),5.52 (s, 1H, CH2OH), 6.55 (s, 1H, Ar-H), 8.82 (s, 1H, Ar-H).13C NMR (75.46 MHz, DMSO-d6): 152.3, 151.5, 150.9,144.7, 118.21, 98.5, 56.4, 52.3, 30.7, 24.9. ESI-HRMS (m/z):Calcd. for C12H14ClN3O: 251.7129. Found: m/z 251.8001[M+]. |
|
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 25 - 60℃; for 1.66667h;Inert atmosphere; |
A dry nitrogen-flushed 5 L 4-neck round bottom flask is charged with 100 g (Purity: 98%, 0.389 mol 1.0 eq.) of 3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)prop-2-yn-1-01, (A1d), 880 g (1000 mL) of peroxide free tetrahydrofuran and 753 g, (856 mL) of tetrabutylammonium fluoride, 1.0M solution in THF. The content is stirred at 25 C. for 10 min, and then the solution is warmed to 60 C. This temperature is maintained for 1.5 h until the starting material, A1d, is ?2.5±0.5% as determined by HPLC analysis. The resulting solution is cooled to below 30±3 C. , and distilled under reduced pressure to remove THF. 79 g (100 mL) of 2-propanol is added. The sample is stirred for 15 min and 1000 g (1000 mL) of water then add slowly over 30 min The sample is stirred at 20±3 C. for 30 min and then filtered. The cake is washed twice with 200 g (2*100 mL) of water. The solids are dried at 50 C. for 16 h to afford Compound A1c as a tan, crystalline solid, mp=174-176 C. |
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