Journal of Medicinal Chemistry
Article
epichlorohydrin (0.08 mL, 1.63 mmol) were added under nitrogen
atmosphere. The reaction mixture was stirred at 60 °C for 14 h, then
cooled to rt and diluted with water and EtOAc. The organic layer was
separated, dried over MgSO4, and filtered over a silica gel pad, and the
solvents were evaporated in vacuo. The crude product 9 (31 mg, 17%)
was used without further purification in the next reaction step. A
solution of 2-methyl-8-(oxiran-2-ylmethoxy)-1,2-dihydrobenzo[e]-
[1,2]azaborinine (9; 0.03 g, 0.14 mmol) and isopropylamine (0.04
mL, 0.432 mmol) in 2-propanol (1 mL) was stirred in a closed vessel
at 50 °C for 20 h. After cooling to rt, the volatiles were evaporated in
vacuo, and the residue thus obtained was purified by flash column
chromatography (silica; DCM/MeOH 100/0 to 90/10). The desired
fractions were collected and concentrated in vacuo to yield a sticky
solid, which was triturated with n-pentane−Et2O to afford 2 (16 mg,
6.80 (d, J = 8.2 Hz, 1H), 6.75 (dd, J = 11.9, 1.5 Hz, 1H), 6.58 (d, J =
8.0 Hz, 1H), 3.94 (s, 3H), 0.73 (s, 3H). LC/MS (m/z): 99% pure, Rt =
3.884 min, [M + H]+ 174.
2-Methyl-1,2-dihydro-benzo[e][1,2]azaborinin-5-ol (14). To a
solution of 5-methoxy-2-methyl-1,2-dihydro-benzo[e][1,2]azaborinine
13 (0.50 g, 2.89 mmol) in dry DCM (10 mL) cooled with acetone/ice
bath was added dropwise boron tribromide (0.54 mL, 5.78 mmol)
under nitrogen. The reaction solution was stirred at 0 °C for 1 h. The
mixture was poured into a mixture of ice and a saturated NaHCO3
solution, and the product was extracted with EtOAc (2×). The
combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The residue thus obtained was purified by
flash column chromatography (silica; EtOAc in heptane 0/100 to 60/
40). The desired fractions were collected and concentrated in vacuo to
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afford 14 (0.27 mg, 58% yield) as a white solid. Mp: 101.2 °C. H
4% yield over three steps) as a beige solid. Mp: 99.5 °C. H NMR
NMR (300 MHz, CDCl3) δ 8.29 (d, J = 11.7 Hz, 1H), 7.61 (br s, 1H),
7.19 (t, J = 8.0 Hz, 1H), 6.85−6.72 (m, 2H), 6.51 (d, J = 7.8 Hz, 1H),
5.06 (s, 1H), 0.74 (s, 3H). LC/MS (m/z): 99% pure, Rt = 3.070 min,
[M + H]+ 160.
(300 MHz, CDCl3) δ 8.48 (s, 1H), 7.89 (d, J = 11.5 Hz, 1H), 7.21 (d,
J = 7.8 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.82
(d, J = 11.5 Hz, 1H), 4.36−4.23 (m, 1H), 4.18−4.05 (m, 2H), 3.11−
2.84 (m, 3H), 1.25−1.15 (m, 6H), 0.78 (s, 3H). LC/MS (m/z): 99%
pure, Rt = 2.320 min, [M + H]+ 275. HRMS: calcd for C16H24BN2O2
[M + H]+ 275.1925, found 275.1935.
2-Methyl-5-oxiran-2-ylmethoxy-1,2-dihydro-benzo[e][1,2]-
azaborinine (15). To a solution of 2-methyl-1,2-dihydro-benzo[e]-
[1,2]azaborinin-5-ol (14, 0.27 g, 1.69 mmol) in acetonitrile (15 mL),
Cs2CO3 (1.10 g, 3.39 mmol) and epichlorohydrin (0.16 mL, 1.86
mmol) were added under nitrogen atmosphere. The reaction mixture
was stirred at 60 °C for 14 h. After cooling to rt, NaHCO3 and EtOAc
were added. The organic layer was separated, dried (MgSO4), and
filtered, and the solvents were evaporated in vacuo. The crude product
was purified by flash column chromatography (silica; EtOAc in
heptane 0/100 to 30/70). The desired fractions were collected and
concentrated in vacuo to yield 15 (0.20 g, 54% yield) as a sticky solid.
1H NMR (300 MHz, CDCl3) δ 8.41 (d, J = 11.8 Hz, 1H), 7.64 (br s,
1H), 7.33−7.19 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 11.8
Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.32 (dd, J = 11.0, 3.1 Hz, 1H), 4.10
(dd, J = 11.0, 5.5 Hz, 1H), 3.51−3.37 (m, 1H), 2.95 (t, J = 4.5 Hz,
1H), 2.82 (dd, J = 4.7, 2.6 Hz, 1H), 0.73 (s, 3H). LC/MS (m/z): 98%
pure, Rt = 3.563 min, [M + H]+ 216.
2-Bromo-3-methoxyaniline (11). A mixture of 2-bromo-3-nitro-
anisole (5 g, 24.54 mmol), ammonium chloride (4.61 g, 86.19 mmol),
and powdered iron (4.81 g, 86.19 mmol) in toluene (85 mL) and
water (50 mL) was vigorously stirred at 100 °C for 6 h. TLC (EtOAc
in heptane 10:90 v/v) showed complete conversion. The reaction
mixture was cooled to rt and filtered over a Celite pad. The filtrate was
diluted with EtOAc (100 mL) and water. The organic layer was dried
over MgSO4, filtered, and concentrated to dryness under reduced
pressure. The crude product was purified by flash column
chromatography (silica, 80 g; EtOAc in heptane 0/1 to 1/9). The
desired fractions were collected and concentrated in vacuo to give 11
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(4.3 g, 98% yield) as an orange oil. H NMR (300 MHz, CDCl3) δ
7.05 (t, J = 8.1 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 6.31 (d, J = 8.1 Hz,
1H), 4.15 (s, 2H), 3.87 (s, 3H). LC/MS (m/z): 99% pure, Rt = 2.463
min, [M + H]+ 201, 203.
1-Isopropylamino-3-((2-methyl-1,2-dihydro-benzo[e][1,2]-
azaborinin-5-yl)oxy)-propan-2-ol (3). A solution of 2-methyl-5-
oxiranylmethoxy-1,2-dihydro-benzo[e][1,2]azaborinine (15; 0.20 g,
0.93 mmol) and isopropylamine (0.15 mL, 1.86 mmol) in 2-propanol
(3 mL) was stirred in a closed vessel at 50 °C for 20 h. The solvent
was evaporated under reduced pressure. The crude product was
purified by flash column chromatography (silica; DCM/MeOH 100/0
to 90/10). The desired fractions were collected and concentrated in
vacuo to yield a sticky solid, which was triturated with n-pentane−Et2O
3-Methoxy-2-vinylaniline (12). A vessel equipped with a magnetic
stirring bar was charged with potassium vinyltrifluoroborate (3.71 g,
27.76 mmol), 2-bromo-3-methoxyaniline (11; 2.8 g, 13.85 mmol),
Pd(OAc)2 (0.093 g, 0.415 mmol, 3 mol %), SPhos (0.34 g, 0.83 mmol,
6 mol %), acetonitrile (30 mL), and water (20 mL). The mixture was
purged with nitrogen for 5 min, and the vessel was sealed, after which
it was heated at 95 °C for 10 h. The mixture was diluted with water
and extracted with EtOAc. The organic layer was separated, dried
(MgSO4) and filtered, and the solvents were evaporated in vacuo. The
crude product was purified by flash column chromatography (silica;
EtOAc in heptane 0/100 to 10/90). The desired fractions were
collected and concentrated in vacuo to afford 12 (0.8 g, 39% yield). 1H
NMR (300 MHz, CDCl3) δ 7.01 (t, J = 8.1 Hz, 1H), 6.76 (dd, J =
18.2, 11.7 Hz, 1H), 6.36 (d, J = 8.1 Hz, 1H), 6.31 (d, J = 8.2 Hz, 1H),
5.63 (dd, J = 18.2, 2.0 Hz, 1H), 5.55 (dd, J = 11.8, 2.0 Hz, 1H), 3.97
(br s, 2H), 3.80 (s, 3H). LC/MS (m/z): 95% pure, Rt = 1.693 min, [M
+ H]+ 150.
5-Methoxy-2-methyl-1,2-dihydro-benzo[e][1,2]azaborinine (13).
To an oven-dried closed vial equipped with a stirring bar was added
potassium methyltrifluoroborate (0.98 g, 8.04 mmol). The vial was
sealed with a Teflon septum, evacuated under vacuum, and purged
with nitrogen three times. Dry CPME (20 mL) and dry toluene (20
mL) were added, followed by 3-methoxy-2-vinyl-phenylamine (12;
1.20 g, 8.04 mmol). This mixture was degassed with nitrogen for 5
min. Then, silicon tetrachloride (0.92 mL, 8.04 mmol) and
triethylamine (1.67 mL, 12.06 mmol) were added at rt. The resulting
mixture was heated at 60 °C for 1.5 h and then cooled to rt. Saturated
NaHCO3 solution was added, and the mixture was extracted with
EtOAc. The combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The crude product was purified by flash
column chromatography (silica; EtOAc in heptane 0/100 to 10/90).
The desired fractions were collected and concentrated in vacuo to give
13 (1.10 g, 79% yield) as colorless oil. 1H NMR (300 MHz, CDCl3) δ
8.38 (d, J = 11.8 Hz, 1H), 7.63 (br s, 1H), 7.30 (d, J = 8.1 Hz, 1H),
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to afford 3 (187 mg, 73% yield) as a white solid. Mp: 131.3 °C. H
NMR (300 MHz, CDCl3) δ 8.36 (d, J = 11.8 Hz, 1H), 7.64 (br s, 1H),
7.31−7.21 (m, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 11.8 Hz,
1H), 6.59 (d, J = 8.0 Hz, 1H), 4.22−3.97 (m, 3H), 3.06−2.92 (m,
1H), 2.93−2.73 (m, 2H), 1.11 (d, J = 6.2 Hz, 6H), 0.73 (s, 3H). LC/
MS (m/z): 99% pure, Rt = 1.972 min, [M + H]+ 275. HRMS: calcd for
C16H24BN2O2 [M + H]+ 275.1925, found 275.1933.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
Modeling of the binding mode of propranolol, 2, and 3 at
the β2 adrenergic receptor, detailed PK data, 26 receptor
panel screening data, and cytotoxicity data for 1−3
Molecular strings for compounds (XLS)
AUTHOR INFORMATION
Corresponding Author
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J. Med. Chem. XXXX, XXX, XXX−XXX