Journal of Medicinal Chemistry
Article
1-(Isopropyl(methyl)amino)-3-(naphthalen-1-yloxy)propan-2-ol
(26). 2-((Naphthalen-1-yloxy)methyl)oxirane (34a, 100 mg, 0.499
mmol, 1.00 equiv) was dissolved in N-isopropylmethylamine (35, 1.0
mL, 9.6 mmol, 19 equiv) under an inert atmosphere. The reaction
mixture was stirred under microwave irradiation at 100 °C for 45 min.
After cooling to rt, EtOAc (20 mL) was added, and the mixture was
extracted with aqueous HCl solution (1 M, 2 × 15 mL). To the
combined aqueous layers, a sodium hydroxide solution (1 M, 35 mL)
was added, and the aqueous mixture was extracted with EtOAc (2 ×
15 mL). The combined organic layers were washed twice with brine
and dried over MgSO4, and the solvent was removed in vacuo. The
crude product was purified by silica gel column chromatography (1:1
n-hexane/EtOAc + 2% triethylamine) to obtain the title compound as
a colorless oil (40 mg, 0.15 mmol, 29%). Rf = 0.5 (1:1 n-hexane/
The combined organic layers were dried over Na2SO4, and the solvent
was evaporated in vacuo. The crude product was purified by silica gel
column chromatography (4:1 n-hexane/EtOAc + 2% triethylamine)
to obtain the title compound as a brown solid (25 mg, 0.091 mmol,
1
90%). Rf = 0.3 (4:1 n-hexane/EtOAc + 2% triethylamine). H NMR
(500 MHz, CDCl3): δ 8.29−8.18 (m, 1H), 7.81−7.78 (m, 1H),
7.55−7.41 (m, 3H), 7.40−7.32 (m, 1H), 6.82 (d, J = 7.4 Hz, 1H),
4.27−4.21 (m, 2H), 3.97−3.90 (m, 1H), 3.59 (s, 3H), 3.04 (dd, J =
12.1, 3.8 Hz, 1H), 2.96−2.88 (m, 2H), 1.15 (d, J = 3.1 Hz, 3H), 1.14
(d, J = 3.1 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 154.54,
134.66, 127.64, 126.60, 125.94, 125.75, 125.43, 122.08, 120.75,
104.89, 78.90, 68.66, 58.47, 49.25, 48.67, 22.71, 22.44 ppm. MS (ESI
+) m/z: calcd for C17H24NO2 ([M + H]+), 274.18; found, 274.25.
HR-MS (MALDI) m/z: calcd for C17H24NO2 ([M + H]+),
274.18016; found, 274.18114.
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EtOAc + 2% triethylamine). H NMR (500 MHz, CDCl3): δ 8.30−
8.20 (m, 1H), 7.82−7.78 (m, 1H), 7.51−7.43 (m, 3H), 7.39−7.35
(m, 1H), 6.84 (d, J = 7.2 Hz, 1H), 4.27−4.22 (m, 2H), 4.15−4.11 (m,
1H), 3.02 (sept, J = 6.6 Hz, 1H), 2.73 (d, J = 6.3 Hz, 2H), 2.38 (s,
3H), 1.11 (t, J = 7.1 Hz, 6H) ppm. 13C NMR (126 MHz, CDCl3): δ
154.22, 134.65, 127.74, 126.59, 126.01, 125.61, 125.44, 121.79,
120.93, 105.14, 70.17, 65.26, 57.12, 56.28, 37.37, 17.87, 17.14 ppm.
MS (ESI+) m/z: calcd for C17H24NO2 ([M + H]+), 274.18; found,
274.19. HR-MS (MALDI) m/z: calcd for C17H24NO2 ([M + H]+),
274.18016; found, 274.17971.
N-Isopropyl-3-(naphthalen-1-yloxy)propan-1-amine Hydro-
chloride (30). 3-(Naphthalen-1-yloxy)propan-1-amine hydrochloride
(41, 88 mg, 0.37 mmol, 1.0 equiv) was suspended in 1,2-
dichloroethane (2 mL) under an inert atmosphere. Triethylamine
(100 μL, 0.743 mmol, 2.00 equiv), acetone (42, 36 μL, 0.48 mmol,
1.3 equiv), and acetic acid (28 μL, 0.48 mmol, 1.3 equiv) were added,
and the suspension was stirred for 30 min at rt. Sodium
triacetoxyborohydride (236 mg, 1.11 mmol, 3.00 equiv) was added,
and the resulting mixture was stirred at rt for 17 h. Aqueous NaOH
solution (2 M, 20 mL) was added, and the mixture was extracted with
methylene chloride (1 × 30 mL). The organic layer was washed with
water (3 × 10 mL), dried over Na2SO4, and concentrated in vacuo.
The crude product in methylene chloride was treated with a HCl
solution in 1,4-dioxane (4 M, 371 μL, 1.49 mmol, 4.00 equiv), and the
suspension was stirred for 72 h at rt. The resulting colorless
precipitate was filtered off and washed with methylene chloride to
obtain the title compound as a colorless solid (48 mg, 0.17 mmol,
1-(Naphthalen-1-yloxy)-3-(piperidin-1-yl)propan-2-ol (27). 2-
((Naphthalen-1-yloxy)methyl)oxirane (34a, 0.10 g, 0.50 mmol, 1.0
equiv) was dissolved in piperidine (36, 1.0 mL, 9.6 mmol, 19 equiv)
under an inert atmosphere. The reaction mixture was stirred under
microwave irradiation at 100 °C for 30 min. After cooling to rt,
EtOAc (15 mL) was added, and the mixture was washed with water
(3 × 10 mL). The organic layer was dried over MgSO4, and the
solvent was removed in vacuo to obtain the title compound as a brown
1
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oil (127 mg, 0.445 mmol, 89%). Rf = 0.1 (1:1 n-hexane/EtOAc). H
46%). Rf = 0.5 (9:1 methylene chloride/methanol). H NMR (500
NMR (500 MHz, CDCl3): δ 8.28−8.24 (m, 1H), 7.81−7.77 (m, 1H),
7.51−7.45 (m, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.39−7.34 (m, 1H),
6.84 (dd, J = 7.5, 0.5 Hz, 1H), 4.33−4.25 (m, 1H), 4.22 (dd, J = 9.5,
5.1 Hz, 1H), 4.12 (dd, J = 9.5, 5.3 Hz, 1H), 2.77−2.64 (m, 4H), 2.49
(s, 2H), 1.73−1.60 (m, 4H), 1.53−1.45 (m, 2H) ppm. 13C NMR
(126 MHz, CDCl3): δ 154.57, 134.64, 127.62, 126.54, 125.97, 125.75,
125.34, 122.08, 120.69, 105.02, 70.73, 65.45, 61.83, 55.00, 25.97,
24.18 ppm. MS (ESI+) m/z: calcd for C18H24NO2 ([M + H]+),
286.18; found, 286.19. HR-MS (MALDI) m/z: calcd for C18H24NO2
([M + H]+), 286.18016; found, 286.17968.
1-Isopropyloxy-3-(naphthalen-1-yloxy)propan-2-ol (28). A so-
dium hydride suspension in paraffin oil (60% w/w, 23 mg, 0.32 mmol,
1.3 equiv) was added to 2-propanol (37, 5 mL), and the mixture was
stirred for 15 min at rt. 2-((Naphthalen-1-yloxy)methyl)oxirane (34a,
50 mg, 0.25 mmol, 1.0 equiv) dissolved in 2-propanol (37, 2 mL) was
added, and the mixture was stirred for 12 h at rt. Aqueous HCl
solution (5% v/v, 20 mL) was added, and the mixture was extracted
with EtOAc (3 × 15 mL). The combined organic layers were dried
over MgSO4, and the solvent was removed in vacuo to obtain the title
compound as a yellow oil (59 mg, 0.22 mmol, 90%). Rf = 0.2 (4:1 n-
hexane/EtOAc). 1H NMR (500 MHz, CDCl3): δ 8.26−8.23 (m, 1H),
7.83−7.78 (m, 1H), 7.52−7.42 (m, 3H), 7.40−7.33 (m, 1H), 6.85 (d,
J = 7.1 Hz, 1H), 4.32−4.26 (m, 1H), 4.22 (dd, J = 5.5, 2.0 Hz, 2H),
3.75 (dd, J = 9.5, 4.4 Hz, 1H), 3.70−3.64 (m, 2H), 1.20 (d, J = 2.1
Hz, 3H), 1.19 (d, J = 2.1 Hz, 3H) ppm. 13C NMR (126 MHz,
CDCl3): δ 154.43, 134.64, 127.68, 126.58, 125.98, 125.70, 125.40,
121.96, 120.78, 105.09, 72.55, 69.49, 69.29, 69.16, 22.23, 22.19 ppm.
MS (ESI+) m/z: calcd for C16H20O3Na ([M + Na]+), 283.13; found,
283.15. HR-MS (MALDI) m/z: calcd for C16H20O3 ([M]•),
260.14070; found, 260.14100.
MHz, DMSO-d6): δ 9.04 (s, 2H), 8.23−8.17 (m, 1H), 7.87 (dd, J =
7.3, 1.9 Hz, 1H), 7.56−7.46 (m, 3H), 7.45−7.39 (m, 1H), 7.01−6.95
(m, 1H), 4.27 (t, J = 6.0 Hz, 2H), 3.38−3.27 (m, 1H), 3.18−3.12 (m,
2H), 2.30−2.24 (m, 2H), 1.28 (d, J = 6.5 Hz, 6H) ppm. 13C NMR
(126 MHz, DMSO-d6): δ 153.74, 134.00, 127.47, 126.45, 126.18,
125.28, 124.84, 121.48, 120.07, 105.23, 65.04, 49.42, 41.36, 25.80,
18.57 ppm. MS (ESI+) m/z: calcd for C16H22NO ([M + H]+),
244.17; found, 244.05. HR-MS (MALDI) m/z: calcd for C16H21NO
([M + H]+), 244.16959; found, 244.17072.
1-(Isopropyl(methyl)amino)-3-(quinolin-4-yloxy)propan-2-ol Hy-
drochloride (31). 4-(Oxiran-2-ylmethoxy)quinoline (34b, 571 mg,
2.84 mmol, 1.00 equiv) was dissolved in isopropylamine (38, 9.73
mL, 114 mmol, 40.0 equiv). The solution was stirred at 60 °C for 10 h
and afterward for 24 h at rt. The excess of isopropylamine was
removed in vacuo, and the crude product was dissolved in methylene
chloride (5 mL). A total of 2.5 mL of this homogenous solution was
treated with a HCl solution in 1,4-dioxane (4 M, 2.84 mL, 11.4 mmol,
8.00 equiv). The mixture was stirred at rt for 72 h. The resulting
colorless precipitate was filtered off and washed with methanol to
obtain the title compound as a colorless solid (366 mg, 1.23 mmol,
1
87%). Rf = 0.5 (9:1 methylene chloride/methanol). H NMR (500
MHz, DMSO-d6): δ 9.26 (s, 1H), 8.86 (s, 1H), 8.56 (d, J = 7.3 Hz,
1H), 8.36 (dd, J = 8.2, 1.4 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.98
(ddd, J = 8.7, 7.0, 1.5 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 6.96 (d, J =
7.3 Hz, 1H), 4.94 (dd, J = 14.1, 2.6 Hz, 1H), 4.40 (dd, J = 14.2, 9.5
Hz, 1H), 4.36−4.28 (m, 1H), 3.37−3.26 (m, 2H), 3.06−2.96 (m,
1H), 1.29 (d, J = 4.1 Hz, 3H), 1.28 (d, J = 4.1 Hz, 3H) ppm. 13C
NMR (126 MHz, DMSO-d6): δ 172.49, 148.74, 139.65, 133.70,
126.05, 124.94, 123.37, 118.09, 106.46, 64.77, 56.93, 49.93, 46.76,
18.59, 18.24 ppm. MS (ESI+) m/z: calcd for C15H21N2O2 ([M +
H]+), 261.16; found, 261.14. HR-MS (MALDI) m/z: calcd for
C15H21N2O2 ([M + H]+), 261.15975; found, 261.16004.
2-((Naphthalen-1-yloxy)methyl)oxirane (34a). rac-Epichlorohy-
drin (33, 1.8 mL, 23 mmol, 1.1 equiv) was dissolved in DMF (10
mL). 1-Naphthol (32a, 3.00 g, 20.8 mmol, 1.00 equiv) and NaOH
(990 mg, 25.1 mmol, 1.20 equiv) were dissolved in a DMF/H2O (2:1
v/v, 9 mL) mixture and stirred for 50 min at rt. Subsequently, the
N-Isopropyl-2-methoxy-3-(naphthalen-1-yloxy)propan-1-amine
(29). tert-Butylisopropyl(2-methoxy-3-(naphthalen-1-yloxy)propyl)-
carbamate (46, 38 mg, 0.10 mmol, 1.0 equiv) was dissolved in
methylene chloride (5 mL), and a HCl solution in 1,4-dioxane (4 M,
0.44 mL, 1.8 mmol, 18 equiv) was added. The mixture was stirred at
rt for 120 h. Aqueous NaOH solution (1 M, 15 mL) was then added,
and the mixture was extracted with methylene chloride (3 × 15 mL).
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J. Med. Chem. 2021, 64, 8727−8738