93% |
With trifluoroacetic acid; In isopropyl alcohol; at 80℃; for 0.5h; |
To a mixture of <strong>[175358-02-8]4,6-dichloropyrido[3,2-d]pyrimidine</strong> (1.00 g, 5.00 mmol, 1.00 eq) and 3,4-dichloro-2-fluoro-aniline (899 mg, 5.00 mmol, 1.00 eq) in propan-2-ol (10.0 mL) was added trifluoroacetic acid (114 mg, 999 umol, 74.0 uL, 0.200 eq) in one portion at 25 C. The mixture was stirred at 80 C for 0.5 h. Petroleum ether (20.0 mL) was added with stirring and the mixture was filtered. The solid was washed with petroleum ether (3.00 mL), dried to give 6-chloro-N-(3,4-dichloro -2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (1.60 g, 4.66 mmol, 93% yield) as a yellow solid. To a mixture of 6-chloro-N-(3,4-dichloro -2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (1.00 g, 2.91 mmol, 1.00 eq) and methyl 3- mercaptopropanoate (524 mg, 4.37 mmol, 472 uL, 1.50 eq) in dioxane (10.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (106 mg, 116 umol, 0.0400 eq), Xantphos (101 mg, 174 umol, 0.0600 eq), diisopropylethylamine (752 mg, 5.82 mmol, 1.01 mL, 2.00 eq) in one portion at 25 C under nitrogen. The mixture was stirred at 110 C for 18 h. The mixture was concentrated to give residue. The crude product was purified by re-crystallization from acetonitrile (30.0 mL) at 25 C to give methyl 3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)thio)propanoate (1.14 g, 2.67 mmol, 91% yield) as an off-white solid. To a mixture of methyl 3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)thio) propanoate (0.300 g, 702 umol, 1.00 eq) in ethanol (18.0 mL) was added dropwise sodium ethoxide (1.00 M, 1.40 mL, 2.00 eq) at 0 C under nitrogen,then heated to 80 C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give sodium 4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d] pyrimidine-6-thiolate (0.254 g, crude) as a brown solid. To a mixture of sodium 4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-6-thiolate (0.254 g, 699 umol, 1.00 eq) and (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (556 mg, 2.10 mmol, 3.00 eq) in ethanol (12.0 mL) was added potassium carbonate (144 mg, 1.05 mmol, 1.50 eq) in one portion at 20 C under nitrogen. Then the mixture was heated to 60 C and stirred for 12 h. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated to give (S)-tert-butyl3-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)thio)pyrrolidine-1-carboxylate (0.626 g, crude) as a yellow solid. A mixture of (S)-tert-butyl3-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)thio) pyrrolidine-1-carboxylate (0.736 g, 1.44 mmol, 1.00 eq) in hydrochloric acid/ ethyl acetate (50.0 mL) was stirred at 20 C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um;mobile phase: [water(0.225%FA)-ACN];B%: 20%-50%,10min) to give (S)-N-(3,4-dichloro-2-fluorophenyl)-6- (pyrrolidin -3-ylthio)pyrido[3,2-d]pyrimidin-4-amine (0.184 g, 448 umol, 31% yield) as a white solid. To a mixture of (S)-N-(3,4-dichloro-2-fluorophenyl)-6-(pyrrolidin -3-ylthio)pyrido[3,2- d]pyrimidin-4-amine (0.130 g, 316 umol, 1.00 eq) and triethylamine (96.1 mg, 950 umol, 132 uL, 3.00 eq) in dimethyl formamide (0.600 mL) was added dropwise acryloyl chloride (57.3 mg, 633 umol, 51.6 uL, 2.00 eq) at 0 C under nitrogen,then stirred at 0 C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep- HPLC (column: Phenomenex Luna C18 200*40mm*10um;mobile phase: [water(0.2%FA)- ACN];B%: 50%-80%,10min) to give (S)-1-(3-((4-((3,4- dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)thio)pyrrolidin-1-yl)prop-2-en-1-one 59 (58.92 mg, 126 umol, 40% yield, 100% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 8.60 (s, 1H), 8.13 (t, J = 8.3 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.81 (dd, J = 2.9, 8.8 Hz, 1H), 7.63 (br d, J = 8.7 Hz, 1H), 6.68 - 6.52 (m, 1H), 6.15 (ddd, J = 2.1, 8.2, 16.7 Hz, 1H), 5.74 - 5.60 (m, 1H), 4.87 - 4.78 (m, 1H), 4.28 -4.01 (m, 1H), 3.76 (br t, J = 6.9 Hz, 1H), 3.68 - 3.50 (m, 2H), 2.65 - 2.56 (m, 1H), 2.16 - 1.97 (m, 1H). MS (ESI) m/z 464.1 [M+H]+. |