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With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; lithium chloride; In ethanol; water; toluene; at 100.0℃; for 5h;Inert atmosphere; |
General procedure: Ethyl cyanoacetate (5.3mL, 50mmol) was added to a suspension of sodium (1.15g, 50mmol) in 150mL of anhydrous EtOH at 0C. After 20min at room temperature, the reaction mixture was concentrated and the resultant solid was added to a solution of 1-(2-aminopyrimidin-4-yl)-2-bromoethanone hydrobromide (35, 14.85g, 50mmol) and N,N-diisopropylethylamine (8.8mL, 50mmol) in anhydrous THF (300mL). The reaction mixture was stirred overnight at room temperature, concentrated and the residue was suspended in water and extracted with DCM. The organic extracts were dried over sodium sulfate and concentrated. The crude was purified by flash chromatography (DCM/MeOH 95:5) to give ethyl 4-(2-aminopyrimidin-4-yl)-2-cyano-4-oxobutanoate (36, 5.16 g, 41%). 1H NMR (400MHz, DMSO-d6) δ 8.52 (d, J=4.9Hz, 1H), 6.97 (d, J=4.9Hz, 1H), 4.56 (t, J=5.6Hz, 1H), 4.19 (q, J=7.1Hz, 2H), 3.74 (d, J=5.6Hz, 2H), 1.21 (t, J=7.1Hz, 3H); LC-MS (ESI): m/z 249 [M+H]+; HRMS (ESI): m/z calcd for C11H12N4O3+H+ 249.0982, found 249.0975. A suspension of 36 (5.0g, 20.14mmol) in DCM (40mL) was added dropwise to 33% HBr in AcOH (40mL) at 0C. The mixture was left at 0C for 30min and then at room temperature until disappearance of the starting material. The solid was filtered, washed with DCM, neutralized with 7N NH3 in MeOH to afford ethyl 5-(2-aminopyrimidin-4-yl)-2-bromo-1H-pyrrole-3-carboxylate (37, 5.5g, 88%). 1H NMR (400MHz, DMSO-d6) δ 12.84 (br s, 1H), 8.22 (d, J=5.4Hz, 1H), 7.23 (s, 1H), 6.99 (d, J=5.1Hz, 1H), 6.42 (br s, 2H), 4.21 (q, J=7.1Hz, 2H), 1.29 (t, J=7.1Hz, 3H); LC-MS (ESI): m/z 312 [M+H]+; HRMS (ESI): m/z calcd for C11H11BrN4O2+H+ 311.0138, found 311.0139. To a solution of 37 (2.0g, 6.43mmol) dissolved in EtOH (20mL) and toluene (20mL), LiCl (408mg, 9.64mmol), 1M aq Na2CO3 (17mmol), 5-chloro-2-methylphenylboronic acid (1.423g, 8.35mmol) were added. The resulting reaction mixture was degassed three times back filling with argon each time before being charged with Pd(Ph3P)2Cl2 (470mg, 0.67mmol), degassed four times back filling with argon each time and then heated at 100C for 5h. After cooling to room temperature, the precipitate was filtered and the filtrate was evaporated under reduced pressure, dissolved in DCM and washed with water. The organic layer was then dried over sodium sulfate and concentrated. The crude material was chromatographed on silica gel (DCM/EtOAc 50:50) to afford ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxylate (38e, 1.99g, 87%). 1H NMR (400MHz, DMSO-d6) δ 12.18 (br s, 1H), 8.21 (d, J=5.2Hz, 1H), 7.40 (dd, J=8.2, 2.2Hz, 1H), 7.27-7.34 (m, 3H), 7.01 (d, J=5.2Hz, 1H), 6.41 (s, 2H), 4.04 (q, J=7.1Hz, 2H), 2.11 (s, 3H), 1.09 (t, J=7.1Hz, 3H); LC-MS (ESI): m/z 357 [M+H]+; HRMS (ESI): m/z calcd for C18H17ClN4O2+H+ 357.1113, found 357.1115. The intermediate 38e (1.0g, 2.80mmol) was treated with 1.5M KOH in 95% EtOH (37.3mL, 20equiv) under reflux for 20h. After cooling, the residue was concentrated, dissolved in water and washed with DCM. A solution of 2N HCl was added, under agitation, to the aqueous phase cooled to 5C. The resultant precipitate was collected by filtration to give 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxylic acid (39e, 0.92g, 95%). 1H NMR (400MHz, DMSO-d6) δ 12.54 (br s, 1H), 12.06 (s, 1H), 8.28 (d, J=6.5Hz, 1H), 7.77 (br s, 1H), 7.59 (d, J=2.6Hz, 1H), 7.40-7.45 (m, 1H), 7.28-7.37 (m, 3H), 2.12 (s, 3H); LC-MS (ESI): m/z 329 [M+H]+; HRMS (ESI): m/z calcd for C16H13ClN4O2+H+ 329.0800, found 329.0799. A solution of 39e (470mg, 1.43mmol) in DMF/ THF (1/1, 5mL) and N,N-diisopropylethylamine (1.02mL, 5.86mmol) was stirred at 0C. EDCI (594mg, 3.1mmol) and HOBT·NH3 (430mg, 2.79mmol) were added and the reaction mixture was stirred for 3h at room temperature. The mixture was dropped into a saturated solution of NaHCO3 and ice and the resulting precipitate was collected by filtration to afford 6 (384mg, 82%). 1H NMR (400MHz, DMSO-d6) δ 11.84 (br s, 1H), 8.19 (d, J=5.2Hz, 1H), 7.32-7.40 (m, 2H), 7.26-7.30 (m, 2H), 7.22 (br s, 1H), 6.93 (d, J=5.2Hz, 1H), 6.73 (br s, 1H), 6.32 (br s, 2H), 2.12 (s, 3H); LC-MS (ESI): m/z 328 [M+H]+; HRMS (ESI): m/z calcd for C16H14ClN5O+H+ 328.0960, found 328.0959. The following compounds 2-5, and 25-34 were prepared according to the method described above using the suitable aryl boronic acid. |
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