反应详情

A heavy-walled Pyrex tube was charged with a suspension of N-(3-bromopropyl)phthalimide (1.00 g, 3.72 mmol) and sodium azide (0.32 g, 4.84 mmol) in H2O (2 mL). The tube containing the resulting mixture was sealed with an aluminum crimp cap fitted with a silicon septum and then it was exposed to microwave irradiation for 30 min at a temperature of 120° C. After the irradiation, the reaction tube was cooled with high-pressure air until the temperature had fallen below 40° C. The product was extracted with ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude material (0.62 g, 72% yield) was used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ 7.86-7.83 (m, 2H), 7.73-7.70 (m, 2H), 3.77 (t, J=6.4 Hz, 2H), 3.36 (t, J=8.0 Hz, 2H), 1.94 (m, 2H). Step b: Preparation of 2-(3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl)-isoindoline-1,3-dione (21). A solution of 2-(3-azidopropyl)isoindoline-1,3-dione, 20, (0.62 g, 2.69 mmol) in propargyl alcohol (4 mL) was warmed to 90° C. and stirred for 18 h. The reaction mixture was concentrated under reduced pressure. The crude product containing both regioisomers (˜1:1 ratio) was used in the next step without further purification. ESI+ MS: m/z (rel intensity) 301.1 (100, [M+H]+). Step c: Preparation of 1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1H-1,2,3-triazole-4-carbaldehyde (22). A solution of the regioisomers 21 (0.77 g, 2.69 mmol) in dichloromethane (10 mL) was treated with manganese dioxide (0.94 g, 10.77 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through Celite and concentrated. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.24 g (31% yield) of 22 as a single regioisomer: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.34 (s, 1H), 7.85-7.65 (m, 4H), 4.45 (t, J=12.0 Hz, 2H), 3.77-3.71 (m, 2H), 2.42-2.34 (m, 2H); ESI+ MS: m/z (rel intensity) 285.0 (100, [M+H]+). Step d: Preparation of 2-(3-(4-((methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino)-methyl)-1H-1,2,3-triazol-1-yl)propyl)isoindoline-1,3-dione (AH). A solution of 1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1H-1,2,3-triazole-4-carbaldehyde, 22, (0.24 g, 0.84 mmol), N-methyl-N-(prop-2-ynyl)-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.17 g, 1.01 mmol), sodium triacetoxyborohydride (0.27 g, 1.26 mmol) and a catalytic amount of acetic acid (2 drops) in 1,2-dichloroethane (10 mL) was warmed to 65° C. and stirred at this temperature for 24 h. The reaction mixture was cooled to room temperature. A saturated aqueous solution of sodium bicarbonate was added. The product was extracted with dichloromethane. The combined organic layers were dried over potassium carbonate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.19 g (80% yield) of the desired product, AH: 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=4.4 Hz, 1H), 7.79-7.76 (m, 2H), 7.71 (s, 1H), 7.68-7.65 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.00 (dd, J=4.8, 8.0 Hz, 1H), 4.32 (dt, J=3.2, 7.2 Hz, 2H), 3.91 (dd, J=6.0, 9.2 Hz, 1H), 3.77-3.66 (m, 4H), 2.82-2.70 (m, 1H), 2.70-2.60 (m, 1H), 2.29 (s, 3H), 2.29-2.23 (m, 2H), 2.12-2.02 (m, 1H), 2.02-1.92 (m, 1H), 1.92-1.80 (m, 1H), 1.70-1.56 (m, 1H); ESI+ MS: m/z (rel intensity) 431.2 (100, [M+H]+). Step e: Preparation of N-((1-(3-aminopropyl)-1H-1,2,3-triazol-4-yl)methyl)-N-methyl-5,6,7,8-tetrahydroquinolin-8-amine tetrahydrochloride (W). A solution of 2-(3-(4-((methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino)-methyl)-1H-1,2,3-triazol-1-yl)propyl)isoindoline-1,3-dione, AH, (0.16 g, 0.37 mmol) in ethanol (5 mL) was treated with hydrazine (23 μL, 0.74 mmol). The resulting mixture was warmed to 80° C. and stirred for 20 h. The reaction mixture was cooled to room temperature. The white precipitate that formed was filtered and the filtrate was concentrated in vacuo. Chloroform was added. More of the precipitate crashed out and was filtered off. The solution was concentrated and dried under reduced pressure to afford 0.08 g (72% yield) of product W: 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=3.6 Hz, 1H), 7.65 (s, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.02 (d, J=4.8, 8.0 Hz, 1H), 4.39 (t, J=7.2 Hz, 1H), 3.95 (dd, J=5.6, 9.2 Hz, 1H), 3.75 (q, J=13.6 Hz, 2H), 2.85-2.60 (m, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.31 (s, 3H), 2.25-2.05 (m, 2H), 2.05-1.95 (m, 2H), 1.95-1.80 (m, 1H), 1.75-1.58 (m, 1H); ESI+ MS: m/z (rel intensity) 301.2 (95, [M+H]+).

1. additionThe tube containing the resulting mixture
2. customcap
3. customfitted with a silicon septum
4. customirradiation for 30 min at a temperature of 120° C
5. customAfter the irradiation
6. temperaturethe reaction tube was cooled with high-pressure air until the temperature
7. customhad fallen below 40° C
8. extractionThe product was extracted with ethyl acetate
9. dry with materialThe combined organic layers were dried with magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customThe crude material (0.62 g, 72% yield) was used without further purification in the next step
13. concentrationThe reaction mixture was concentrated under reduced pressure
14. additionThe crude product containing both regioisomers (˜1:1 ratio)
15. customwas used in the next step without further purification
16. customStep c: Preparation of 1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1H-1,2,3-triazole-4-carbaldehyde (22)
17. stirringThe resulting mixture was stirred at room temperature for 2 h
18. filtrationThe reaction mixture was filtered through Celite
19. concentrationconcentrated
20. customThe crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2)