(E)-pent-2-enoic acid

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of trans-2-pentenoic acid (7.62 g, 76.2 mmol) in tetrahydrofuran (350 mL) was stirred at −15° C. and treated with N-methylmorpholine (8.37 mL, 76.2 mmol). After 10 minutes, isobutyl chloroformate (9.87 mL, 76.2 mmol) was added. After 10 minutes, a precipitate had formed. A solution of 2-(4-fluorophenyl)ethylamine (10.6 g, 76.2 mmol) in tetrahydrofuran (50 mL) was added slowly, and the mixture was stirred at room temperature, and the residue was dissolved in ethyl acetate. The then with saturated aqueous sodium bicarbonate, then was dried over sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate/hexane to provide white crystals (11.69 g, 69%). 1H NMR (300 MHz, CDCl3) δ7.17 (m, 2H), 7.01 (t, J=9 Hz, 2H), 6.88 (dt, J=15, 7 Hz, 1H), 5.72 (dt, J=15, 2 Hz, 1H), 5.61 (bs, 1H), 3.56 (m, 2H), 2.83 (t, J=7 Hz, 2H), 2.20 (m, 2H), 1.05 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 221.9 (M+H+, 100%). After 10 minutes a precipitate had formed The then with saturated aqueous sodium bicarbonate, then was dried over sodium sulfate concentrated The residue was recrystallized from ethyl acetate/hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of trans-2-pentenoic acid (7.62 g, 76.2 mmol) in tetrahydrofuran (350 mL) was stirred at −15° C. and treated with N-methylmorpholine (8.37 mL, 76.2 mmol). After 10 minutes, isobutyl chloroformate (9.87 mL, 76.2 mmol) was added. After 10 minutes, a precipitate had formed. A solution of 2-(4-fluorophenyl)ethylamine (10.6 g, 76.2 mmol) in tetrahydrofuran (50 mL) was added slowly, and the mixture was stirred at room temperature, and the residue was dissolved in ethyl acetate. The then with saturated aqueous sodium bicarbonate, then was dried over sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate/hexane to provide white crystals (11.69 g, 69%). 1H NMR (300 MHz, CDCl3) δ7.17 (m, 2H), 7.01 (t, J=9 Hz, 2H), 6.88 (dt, J=15, 7 Hz, 1H), 5.72 (dt, J=15, 2 Hz, 1H), 5.61 (bs, 1H), 3.56 (m, 2H), 2.83 (t, J=7 Hz, 2H), 2.20 (m, 2H), 1.05 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 221.9 (M+H+, 100%). After 10 minutes a precipitate had formed The then with saturated aqueous sodium bicarbonate, then was dried over sodium sulfate concentrated The residue was recrystallized from ethyl acetate/hexane

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: S,S-dimethyl carbonodithioate (1.467 g, 12.00 mmol) was added with vigorous stirring to a solution of (E)-pent-2-enoic acid (2.002 g, 20 mmol) in 30% KOH solution (prepared from potassium hydroxide (3.87 g, 69 mmol) and Water (10 mL)). The reaction mixture was slowly heated to 90° C. over a period of 20-30 min Heating was continued for 3 hours before the reaction was cooled down to 25° C. and quenched slowly with HCl. The mixture was then extracted with DCM (3×30 mL), combined organic layer dried and concentrated to give 3-(methylthio)pentanoic acid (2.7 g, 18.22 mmol, 91% yield) as light orange oil: IR (Thin film) 2975, 1701 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.92 (qd, J=7.3, 5.6 Hz, 1H), 2.63 (d, J=7.2 Hz, 2H), 2.08 (s, 3H), 1.75-1.51 (m, 2H), 1.03 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.14, 43.95, 39.78, 27.04, 12.95, 11.29; EIMS m/z 148. Heating was cooled down to 25° C. quenched slowly with HCl The mixture was then extracted with DCM (3×30 mL) dried concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5-(azetidin-3-ylamino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one di-hydrobromide (Example 14, Step 4, 80 mg, 0.19 mmol), in DMF (1 mL) was added (E)-pent-2-enoic acid (28 mg 0.28 mmol), HATU (105 mg, 0.277 mmol), and DIPEA (120 mg, 0.923 mmol). The reaction mixture was stirred at RT under nitrogen for 16 h. The residue was purified by Prep. HPLC to afford (E)-2′-(methylamino)-5-((1-(pent-2-enoyl)azetidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one (34 mg, 42%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 6.97 (dt, J=15.3, 6.4 Hz, 1H), 6.62 (dd, J=5.3, 1.6 Hz, 1H), 6.38 (d, J=1.8 Hz, 2H), 5.85 (dt, J=15.3, 1.7 Hz, 1H), 5.48 (d, J=6.6 Hz, 1H), 4.80 (d, J=5.5 Hz, 1H), 4.60 (t, J=7.9 Hz, 1H), 4.55-4.46 (m, 1H), 4.33 (dt, J=12.5, 6.3 Hz, 1H), 4.07 (m, 2H), 2.97 (d, J=4.9 Hz, 3H), 2.22 (m, 2H), 1.06 (t, J=7.4 Hz, 3H); MS (ES) m/z 354 (M+H). The residue was purified by Prep

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5-(azetidin-3-ylamino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one di-hydrobromide (Example 14, Step 4, 80 mg, 0.19 mmol), in DMF (1 mL) was added (E)-pent-2-enoic acid (28 mg 0.28 mmol), HATU (105 mg, 0.277 mmol), and DIPEA (120 mg, 0.923 mmol). The reaction mixture was stirred at RT under nitrogen for 16 h. The residue was purified by Prep. HPLC to afford (E)-2′-(methylamino)-5-((1-(pent-2-enoyl)azetidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one (34 mg, 42%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 6.97 (dt, J=15.3, 6.4 Hz, 1H), 6.62 (dd, J=5.3, 1.6 Hz, 1H), 6.38 (d, J=1.8 Hz, 2H), 5.85 (dt, J=15.3, 1.7 Hz, 1H), 5.48 (d, J=6.6 Hz, 1H), 4.80 (d, J=5.5 Hz, 1H), 4.60 (t, J=7.9 Hz, 1H), 4.55-4.46 (m, 1H), 4.33 (dt, J=12.5, 6.3 Hz, 1H), 4.07 (m, 2H), 2.97 (d, J=4.9 Hz, 3H), 2.22 (m, 2H), 1.06 (t, J=7.4 Hz, 3H); MS (ES) m/z 354 (M+H). The residue was purified by Prep

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 24 (50 mg, 0.2242 mmol) and trans-2-pentenoic acid 25 (24.6 mg, 0.246 eq) in DMF was added EDC.HCl (33 mg, 0.2706 mmol) and HOBt (36.5 mg, 0.2706 mmol). DIPEA (57.9 mg, 0.448 eq) was added to the reaction, stirred 12 h at RT and check the TLC for completion of the reaction and quench the reaction mixture with dilute water. The organic layer was treated with ethyl acetate (25 mL) and was washed with brine solution (25 mL) and dried over sodium sulphate, filtered and concentrated to get the crude product. The resulting oil was purified through silica gel chromatography using a gradient of 4% Ethyl acetate:hexane to afford 8 mg of Compound 26. MS-ES+305.1 1H NMR (400 MHz, DMSO-D6-d6): 11.45 (s, 1H), 10.08 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.85 (d, 1H), 7.61 (m, 1H), 7.36 (m, 2H), 7.30 (d, 1H), 5.62 (m, 1H), 2.35 (s, 3H). for completion of the reaction quench the reaction mixture with dilute water The organic layer was treated with ethyl acetate (25 mL) was washed with brine solution (25 mL) dried over sodium sulphate filtered concentrated to get the crude product The resulting oil was purified through silica gel chromatography

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: S,S-dimethyl carbonodithioate (1.467 g, 12.00 mmol) was added with vigorous stirring to a solution of (E)-pent-2-enoic acid (2.002 g, 20 mmol) in 30% KOH solution (prepared from potassium hydroxide (3.87 g, 69 mmol) and Water (10 mL)). The reaction mixture was slowly heated to 90° C. over a period of 20-30 min. Heating was continued for 3 hours before the reaction was cooled down to 25° C. and quenched slowly with HCl. The mixture was then extracted with DCM (3×30 mL), combined organic layer dried and concentrated to give 3-(methylthio)pentanoic acid (2.7 g, 18.22 mmol, 91% yield) as light orange oil: IR (Thin film) 2975, 1701 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.92 (qd, J=7.3, 5.6 Hz, 1H), 2.63 (d, J=7.2 Hz, 2H), 2.08 (s, 3H), 1.75-1.51 (m, 2H), 1.03 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.14, 43.95, 39.78, 27.04, 12.95, 11.29; EIMS m/z 148. Heating was cooled down to 25° C. quenched slowly with HCl The mixture was then extracted with DCM (3×30 mL) dried concentrated

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: S,S-dimethyl carbonodithioate (1.467 g, 12.00 mmol) was added with vigorous stirring to a solution of (E)-pent-2-enoic acid (2.002 g, 20 mmol) in 30% KOH solution (prepared from potassium hydroxide (3.87 g, 69 mmol) and Water (10 mL)). The reaction mixture was slowly heated to 90° C. over a period of 20-30 min Heating was continued for 3 hours before the reaction was cooled down to 25° C. and quenched slowly with HCl. The mixture was then extracted with DCM (3×30 mL), combined organic layer dried and concentrated to give 3-(methylthio)pentanoic acid (2.7 g, 18.22 mmol, 91% yield) as light orange oil: IR (Thin film) 2975, 1701 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.92 (qd, J=7.3, 5.6 Hz, 1H), 2.63 (d, J=7.2 Hz, 2H), 2.08 (s, 3H), 1.75-1.51 (m, 2H), 1.03 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.14, 43.95, 39.78, 27.04, 12.95, 11.29; EIMS m/z 148. Heating was cooled down to 25° C. quenched slowly with HCl The mixture was then extracted with DCM (3×30 mL) dried concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of trans-2-pentenoic acid (7.62 g, 76.2 mmol) in tetrahydrofuran (350 mL) was stirred at −15° C. and treated with N-methylmorpholine (8.37 mL, 76.2 mmol). After 10 minutes, isobutyl chloroformate (9.87 mL, 76.2 mmol) was added. After 10 minutes, a precipitate had formed. A solution of 2-(4-fluorophenyl)ethylamine (10.6 g, 76.2 mmol) in tetrahydrofuran (50 mL) was added slowly, and the mixture was stirred at room temperature, and the residue was dissolved in ethyl acetate. The then with saturated aqueous sodium bicarbonate, then was dried over sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate/hexane to provide white crystals (11.69 g, 69%). 1H NMR (300 MHz, CDCl3) δ7.17 (m, 2H), 7.01 (t, J=9 Hz, 2H), 6.88 (dt, J=15, 7 Hz, 1H), 5.72 (dt, J=15, 2 Hz, 1H), 5.61 (bs, 1H), 3.56 (m, 2H), 2.83 (t, J=7 Hz, 2H), 2.20 (m, 2H), 1.05 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 221.9 (M+H+, 100%). After 10 minutes a precipitate had formed The then with saturated aqueous sodium bicarbonate, then was dried over sodium sulfate concentrated The residue was recrystallized from ethyl acetate/hexane