| 90.1% |
Stage #1: 4-chloro-1H-pyrrolo[2,3-d]pyrimidine With sodium hydroxide In tetrahydrofuran at -5 - 0℃; for 1h;
Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at 20℃; for 2h; |
4.a Step a: Synthesis of tert-butyl 4-chloropyrrolo[2,3-d]pyrimidine-7-carboxylate
Weigh 18.8g sodium hydrogen and dissolve itIn 240mL tetrahydrofuran,Cool the reaction solution to -5-0°C,Add 60g 4-chloro-7H-pyrrole-[2.3-d]-pyrimidine in batches, keep stirring for 1 hour, add 93.8g di-tert-butyl dicarbonate, after the addition, stir at room temperature and react for 2 hours, TLC (DCM: MeOH = 10:1) Monitoring. After the reaction is over, lower the temperature and control the temperature to <15°C. Add 150 mL of water dropwise to quench, stir for 30 minutes, add 100 mL EA for extraction once, combine the organic phases, and wash once with 200 mL saturated sodium chloride aqueous solution. Drying with sodium sulfate, filtering and evaporating to dryness give tert-butyl 4-chloropyrrolo[2,3-d]pyrimidine-7-carboxylate (89.3g, 90.1%). |
| 75.9% |
With dmap; 1,8-diazabicyclo[5.4.0]undec-7-ene In 1,4-dioxane at 20℃; for 24h; Inert atmosphere; |
tert-Butyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (3c).; To a 250 mL round bottom flask equipped with a stir bar and nitrogen inlet was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 5.00 g, 0.0326 mol), 1,4-dioxane (40 ml, 0.500 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 24.3 mL, 0.163 mol, 5.0 equiv) and 4-(N,N-dimethyl)aminopyridine (DMAP, 0.80 g, 0.0065 mol, 0.2 equiv). To this solution was added di-tert-butyldicarbonate (BOC2O, 21.2 g, 0.0976 mol, 3.0 equv) in one portion at room temperature. The resulting reaction solution becomes yellow/orange in color with the evolution of carbon dioxide. The reaction was monitored by TLC (80% hexane/ethyl acetate) and was complete after stirring at room temperature for about 24 hours. The reaction mixture was then diluted with 20% aqueous brine solution (40 mL) and ethyl acetate (40 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield the crude, desired product (3c) as a red to orange oil. Flash column chromatography purification (SiO2, 0 to 15% ethyl acetate/hexane gradient elution) afforded pure tent-butyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (3c, 6.28 g, 8.27 g theoretical, 75.9% yield) as off-white solids. For 3c: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.79 (s, 1H), 7.94 (d, 1H, J=4.0 Hz), 6.80 (d, 1H, J=4.2 Hz), 1.60 (s, 9H); C11H12ClN3O2 (MW, 253.68), LCMS (EI) m/e 276/278 (M++Na). |
| 73% |
With dmap; triethylamine In 1,4-dioxane at 20℃; for 16h; |
75 Synthesis of tert-butyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (2)
Synthesis of tert-butyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (2) A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.5 g, 3.26 mmol), triethylamine (0.99 g, 9.80 mmol), di-tert-butyl dicarbonate (0.71 g, 3.26 mmol) and 4-dimethylaminopyridine (0.08 g, 0.65 mmol) in dioxane (15 mL) was stirred at room temperature for 16 h. After TLC showed completion, the reaction mixture was extracted with ethyl acetate (2*50 mL). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was then purified by flash column chromatography eluting with 30-40% ethyl acetate in hexane. The desired fractions were concentrated to dryness under vacuum to afford tert-butyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (2) as an off-white solid. Yield: 0.6 g, 73%; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.96-7.95 (d, J=4.0 Hz, 1H), 6.83-6.82 (d, J=4.0 Hz, 1H), 1.62 (s, 9H). |
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