6.2. Experimental Procedure
4-(7-chloro-1
H-[
1,
2,
3]triazolo[4,5-
c]quinolin-1-yl)-
N,
N-diethylpentan-1-amine diphosphate (
4)
7-chloro-N4-(5-(diethylamino)pentan-2-yl)quinoline-3,4-diamine (50 mg, 0.14 mmol) was dissolved in a solution of 3.2 M sulfuric acid (pH 0–1). This solution was cooled to 0 °C, and to it was added a 1 mL solution of 2.5 M sodium nitrite dropwise. The reaction mixture was stirred at this temperature for 15 min. After 15 min 1 mL 4.5 M sodium azide was added dropwise to the reaction mixture at 0 °C. Addition of azide resulted in visible N2 gas evolution. The reaction mixture was left to stir for a further 1 h and the mixture was allowed to warm from 0 °C to room temperature. Once complete, the reaction mixture was treated with saturated Na2CO3 solution and the compound was extracted with DCM (3 × 10 mL). The combined organic layers were rinsed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced vacuum to reveal a bright orange oil. The oil was purified by flash chromatography on silica gel with the solvent system: 55/40/5 hexanes/dichloromethane/triethylamine. Bright orange oil, 49% yield. The free base was then converted to a phosphate salt with phosphoric acid.
Yield: 49%. 1H NMR (400 MHz, deuterium oxide-d2) δ 9.26 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.69 (dd, J = 8.9, 2.2 Hz, 1H), 5.43 (p, J = 6.6 Hz, 1H), 3.19–3.09 (m, 6H), 2.47–2.34 (m, 1H), 2.28–2.15 (m, 1H), 1.81 (d, J = 6.6 Hz, 3H), 1.79–1.63 (m, 2H), 1.22–1.18 (m, 6H). 13C NMR (126 MHz, deuterium oxide-d2) δ 144.70, 142.82, 139.06, 135.94, 133.40, 129.23, 126.81, 123.73, 113.20, 57.99, 50.95, 47.23, 32.16, 19.96, 19.89, 8.07 (d, J = 4.6 Hz). 31P NMR (162 MHz, deuterium oxide-d2) δ 0.03. HRMS (ESI) calcd. for C18H25ClN5 [M + H]: 346.1798, found: 346.1793.
N-(5-(diethylamino)pentan-2-yl)formamide (
9)
A mixture of 2-Amino-5-diethylaminopentane (5 g, 31.6 mmol) and ethyl formate (7.7 mL, 3 equiv.) was heated at 70 °C for 18 h in a round-bottom flask with molecular sieves. After completion, the mixture was cooled to room temperature and ethyl acetate was added. The resulting solution was washed with 1 M HCl and extracted with ethyl acetate (3 × 150 mL). The organic layer was then basified with 1 M NaOH and extracted with ethyl acetate (3 × 200 mL), and then rinsed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the N-(5-(diethylamino)pentan-2-yl)formamide product. Used without further purification. Orange oil, 5.689 g, 97% yield.
Yield: 97%. Major trans rotamer: 1H NMR (500 MHz, chloroform-d) δ 8.10 (s, 1H), 6.55 (s, 1H), 4.08–3.97 (m, 1H), 2.53 (dd, J = 7.2, 4.7 Hz, 4H), 2.45–2.35 (m, 2H), 1.50 (dd, J = 6.2, 3.8 Hz, 4H), 1.15 (d, J = 6.6 Hz, 3H), 1.04–1.00 (m, 6H). 13C NMR (126 MHz, chloroform-d) δ 160.68, 53.02, 46.77, 44.01, 34.80, 23.14, 20.84, 11.42. Minor cis rotamer: 1H NMR (500 MHz, chloroform-d) δ 8.07 (d, J = 12.0 Hz, 1H), 5.93 (s, 1H), 3.49 (s, 1H), 2.53 (dd, J = 7.2, 4.7 Hz, 4H), 2.45–2.35 (m, 2H), 1.50 (dd, J = 6.2, 3.8 Hz, 4H), 1.21 (d, J = 6.6 Hz, 3H), 0.99 (s, 6H). 13C NMR (126 MHz, chloroform-d) δ 163.78, 52.65, 48.37, 46.86, 36.00, 23.58, 22.79, 11.62. HRMS (APCI) calcd. for C10H23ON2 [M + H]: 187.1804, found: 187.1803.
N1,
N1-diethyl-
N4-methylpentane-1,4-diamine (
10)
To a suspension of 2 M LiAlH4 in THF, N-(5-(diethylamino)pentan-2-yl)formamide (4.5 g, 24.2 mmol) which was dissolved and degassed in anhydrous THF, was added portion-wise under stirring and cooling in an ice bath. The mixture was stirred at 0 °C for 30 min then the reaction mixture was refluxed for 24 h under nitrogen. After completion 1 M NaOH was added dropwise to hydrolyze any remaining LiAlH4. All precipitates were filtered off and washed with THF. The filtrate was then placed in a separatory funnel and the organic layer was separated. The organic layer was then acidified with 1 M HCl and extracted with dichloromethane (3 × 200 mL). The combined organic layers were then basified with sat. NaOH and extracted with dichloromethane (3 × 300 mL). The organic layers were then rinsed with brine and dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to reveal pure N1,N1-diethyl-N4-methylpentane-1,4-diamine, which was used without further purification. Orange oil, 2.685 g, 65% yield.
Yield: 65% yield. 1H NMR (500 MHz, chloroform-d) δ 2.52 (q, J = 7.2 Hz, 4H), 2.40 (d, J = 6.5 Hz, 5H), 1.51–1.42 (m, 3H), 1.34–1.23 (m, 1H), 1.05 (d, J = 6.3 Hz, 3H), 1.01 (t, J = 7.2 Hz, 6H). 13C NMR (126 MHz, chloroform-d) δ 55.07, 53.32, 46.87, 34.91, 33.79, 23.68, 19.79, 11. HRMS (APCI) calcd. for C10H25N2 [M + H]: 173.2012, found: 173.2009.
N4-(7-chloroquinolin-4-yl)-
N1,
N1-diethyl-
N4-methylpentane-1,4-diamine (
6)
The mixture of 4,7-dichloroquinoline (500 mg, 2.5 mmol) and N1,N1-diethyl-N4-methylpentane-1,4-diamine (652.6 mg, 3.8 mmol, 1.5 equiv.) were placed in a microwave flask with p-toluenesulfonic acid (816 mg, 4.3 mmol, 1.7 equiv.). This mixture was heated at 120 °C for 1.5 h. Once complete, the reaction was cooled to room temperature. The mixture was poured into ice water, and then 1 M NaOH was added. This was extracted with ethyl acetate (3 × 100 mL), washed with brine, and the organic layers were then dried over anhydrous MgSO4. The solvent was removed under reduced vacuum to reveal an orange oil. The oil was purified by flash chromatography on silica gel with solvent system: 50% hexanes, 50% ethyl acetate to 100% ethyl acetate and 5–10% triethylamine to give an orange oil 534.5 mg, 63% yield.
Yield: 63%. 1H NMR (500 MHz, chloroform-d) δ 8.60 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.35 (dd, J = 9.0, 2.2 Hz, 1H), 6.75 (d, J = 5.2 Hz, 1H), 3.85 (h, J = 6.8 Hz, 1H), 2.85 (s, 3H), 2.43 (qd, J = 7.1, 1.6 Hz, 4H), 2.34–2.29 (m, 2H), 1.76–1.65 (m, 1H), 1.56–1.47 (m, 1H), 1.46–1.31 (m, 0H), 1.25 (d, J = 6.5 Hz, 3H), 0.94 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, chloroform-d) δ 157.55, 151.53, 150.78, 134.64, 128.90, 125.98, 125.22, 121.86, 109.02, 58.80, 52.87, 46.91, 32.49, 32.35, 24.64, 17.10, 11.70. HRMS (APCI) calcd. for C19H29ClN3 [M + H+]: 334.2045, found: 334.2046.
1-(3-((7-chloroquinolin-4-yl)amino)propyl)azepan-2-one
4,7-dichloroquinoline (126 mg, 0.64 mmol), N1,N1-diethyl-N4-methylpentane-1,4-diamine (100 mg, 0.58 mmol) and DBU (0.43 mL, 2.9 mmol) were placed in a round-bottom flask and heated to 125 °C. The mixture was stirred for 18 h. The brown mixture was then cooled to room temperature and washed with sat. NaOH and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were then rinsed with water and dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. The oil was purified by flash chromatography on silica gel with the solvent system: 85% ethyl acetate, 10% methanol, and 5% triethylamine to give a white solid, 82% yield.
Yield: 82%. 1H NMR (500 MHz, chloroform-d) δ 8.46 (d, J = 5.5 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.39 (dd, J = 9.0, 2.2 Hz, 1H), 7.02 (s, 1H), 6.39 (d, J = 5.6 Hz, 1H), 3.53–3.47 (m, 2H), 3.41–3.33 (m, 4H), 2.64–2.58 (m, 2H), 1.85–1.70 (m, 6H), 1.67 (p, J = 5.6 Hz, 2H). 13C NMR (126 MHz, chloroform-d) δ 177.42, 151.23, 150.33, 148.73, 135.16, 127.91, 125.47, 122.25, 117.65, 98.09, 49.88, 45.11, 38.47, 37.17, 29.93, 28.44, 25.63, 23.46. HRMS (ESI) calcd. for C18H23ClN3O [M + H]: 332.1524, found: 332.1520.
N4-(7-chloro-3-nitroquinolin-4-yl)-
N1,
N1-diethyl-
N4-methylpentane-1,4-diamine (
16)
To a solution of 4,7-dichloro-3-nitroquinoline (500 mg, 2.1 mmol) in acetonitrile was added N1,N1-diethyl-N4-methylpentane-1,4-diamine (709 mg, 4.1 mmol, 2 equiv.) and N,N-diisopropylethylamine (0.54 mL, 1.5 equiv.), which was stirred until it formed a homogenous solution. This mixture was stirred at room temperature for up to 10 min. The reaction mixture was then transferred to an 85 °C oil bath and stirred for 30 min. Once complete, the reaction mixture was evaporated to dryness under reduced pressure. The residue was diluted with ethyl acetate and water and basified with 1 M NaOH. The resulting solution was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were then rinsed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was purified by flash silica column chromatography with 85/10/5 hexanes/ethyl acetate/triethylamine to reveal a bright orange solid, 719.7 mg, 92%.
Yield: 92%. 1H NMR (500 MHz, chloroform-d) δ 8.93 (s, 1H), 8.06 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.50 (dd, J = 9.1, 2.2 Hz, 1H), 4.03–3.95 (m, 1H), 2.85 (s, 3H), 2.51 (d, J = 7.3 Hz, 4H), 2.42 (d, J = 7.7 Hz, 2H), 1.89–1.81 (m, 1H), 1.65 (dq, J = 13.5, 8.0 Hz, 1H), 1.47 (q, J = 7.8 Hz, 2H), 1.43 (d, J = 6.6 Hz, 3H), 1.00 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, chloroform-d) δ 151.13, 150.70, 147.90, 137.63, 137.04, 129.68, 127.55, 127.18, 123.82, 60.99, 52.76, 46.94, 33.91, 32.73, 24.46, 18.19, 11.42. HRMS (APCI) calcd. for C19H27ClN4O2 [M − H+]: 378.1828, found: 378.1822.
7-chloro-
N4-(5-(diethylamino)pentan-2-yl)-
N4-methylquinoline-3,4-diamine (
17)
N4-(7-chloro-3-nitroquinolin-4-yl)-N1,N1-diethyl-N4-methylpentane-1,4-diamine (500 mg, 1.3 mmol) and stannous chloride (1.49 g, 5 equiv.) were placed in a round-bottom flask. Ethanol was added and the mixture was stirred at 80 °C for 2 h. Once complete, the mixture was cooled to room temperature. Once cool, the solvent was removed by reduced pressure. The residue was diluted with ethyl acetate and basified with sat NaOH and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to reveal a dark orange oil. This was purified by column chromatography with the solvent system: ethyl acetate (100–90%)/MeOH (0–10%)/NEt3 (5%) to give an orange oil, 313 mg, 68% yield.
Yield: 68%. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 8.53 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.40 (dd, J = 9.0, 2.3 Hz, 1H), 5.34 (s, 2H), 3.36 (q, J = 6.5, 5.5 Hz, 1H), 2.81 (s, 3H), 2.35 (q, J = 7.1 Hz, 4H), 2.25 (q, J = 5.9 Hz, 2H), 1.54 (d, J = 12.7 Hz, 1H), 1.44–1.29 (m, 2H), 1.03 (d, J = 6.4 Hz, 3H), 0.85 (t, J = 7.1 Hz, 7H). HRMS (ESI) calcd. for C19H30ClN4O2 [M + H−]: 349.2153, found: 349.2143.
N4-(3-azido-7-chloroquinolin-4-yl)-
N1,
N1-diethyl-
N4-methylpentane-1,4-diamine (
18)
7-chloro-N4-(5-(diethylamino)pentan-2-yl)-N4-methylquinoline-3,4-diamine (330 mg, 0.95 mmol) was dissolved in a solution of concentrated sulfuric acid 98% and water (3.2 M). The resultant solution was cooled to 0 °C, and to this a solution of sodium nitrite in water (2.5 M) was added dropwise with stirring. The solution was stirred at this temperature for 5 min. Then, a solution of sodium azide in water (4.5 M) was added to it with vigorous stirring. The mixture was stirred for 5 min at 0 °C. The reaction mixture was then quenched with sat. NaCO3 and extracted with ethyl acetate (3 × 25 mL). The combined extracts were rinsed with brine and dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to reveal a dark orange oil. This oil was purified by column chromatography with the solvent system: 65/35/5 ethyl acetate/hexanes/triethylamine to reveal a dark orange oil, 101 mg, 28%.
Yield: 28%. 1H NMR (500 MHz, chloroform-d) δ 8.67 (s, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 9.0, 2.2 Hz, 1H), 3.49 (q, J = 6.4 Hz, 1H), 2.49 (q, J = 7.2 Hz, 4H), 2.38 (t, J = 7.3 Hz, 2H), 1.69–1.61 (m, 1H), 1.53–1.43 (m, 3H), 1.21 (d, J = 6.5 Hz, 3H), 0.98 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, chloroform-d) δ 147.93, 146.13, 145.08, 134.30, 128.91, 128.14, 127.48, 125.96, 125.91, 58.61, 53.02, 46.94, 35.52, 32.74, 24.11, 17.90, 11.54. IR (cm−1) 2966.6, 2933.2, 2110.6, 1559.3, 1451.4, 1381.8, 1319.9, 1073.4, 915.8. HRMS (ESI) calcd. for C19H28ClN6 [M + H+]: 375.2072, found: 375.2074.
3-azido-7-chloroquinolin-4-ol (
19)
See procedure for 17.
Yield: 46%. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 12.23 (d, J = 6.2 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.7, 2.0 Hz, 1H). 13C NMR (126 MHz, dimethyl sulfoxide-d6) δ 171.72, 139.35, 136.45, 130.19, 127.04, 124.10, 122.37, 120.30, 117.71. IR (cm−1) 3075.6, 2124.7, 1627.9, 1558.2, 1512.3, 1460.4, 1350.8, 1188.7, 1075.2, 812.8. HRMS (ESI) calcd for C9H5ClN4O [M + Na+]: 243.0044, found: 243.0043.