Journal of Medicinal Chemistry
Article
8.68 (s, 1H), 8.58 (s, 1H), 7.52−7.49 (m, 2H), 7.36 (dd, 1H), 5.03 (s,
2H), 2.82 (d, 3H) ppm. HPLC area: 100.0% at 220 nm and 96.5% at
254 nm. Mass: m/z = 286 (M + H, ESI+) and 308 (M + Na, ESI+).
N-Ethyl-5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
yloxy)pyrazine-2-carboxamide (17). This compound was prepared
4 mmol), 2-amino-2-methylpropan-1-ol (430 mg, 4.8 mmol, 1.2
equiv), HOBT (702 mg, 5.2 mmol, 1.3 equiv), and EDC (1g, 5.2
mmol, 1.3 equiv) in DCM (40 mL, c = 0.1) was added TEA (1.2 g, 12
mmol, 3 equiv). The reaction was stirred at rt for 30 min, and a normal
workup resulted in the desired product 57 (670 mg, 80% yield) as
yellow oil. To SOCl2 (6 mL) was added 57 (400 mg, 1.65 mmol), and
the solution was stirred at rt for 2 h. The reaction solution was
concentrated to dryness, and the residue was dissolved in DCM (30
mL), adjusted to pH 8−9 with saturated NaHCO3, and then
separated. The organic phase was washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified
by column chromatography to the desired product 58 (180 mg, 50%
yield) as a white solid. To a solution of 58 (85 mg, 0.4 mmol) in DMF
(4 mL) were added 36 (60 mg, 0.4 mmol, 1 equiv) and Cs2CO3 (325
mg, 1 mmol, 2.5 equiv) at rt. The reaction mixture was stirred at 60 °C
for 2 h, poured into 2 N HCl (100 mL), and extracted with EA (3 ×
50 mL). The combined organic phase was washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography to the desired product 24 (12 mg,
1
by the similar method described above for the synthesis of 15. H
NMR (500 MHz, DMSO-d6): δ 9.25 (s, 1H), 8.77 (t, 1H), 8.68 (s,
1H), 8.58 (s, 1H), 7.52−7.49 (m, 2H), 7.35 (dd, 1H), 5.03 (s, 2H),
3.37−3.27 (m, 2H), 1.15 (t, 3H) ppm. HPLC area: 99% at 220 nm
and 99.3% at 254 nm. Mass: m/z = 300 (M + H, ESI+).
5-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-
N,N-dimethylpyrazine-2-carboxamide (18). This compound was
prepared by the similar method described above for the synthesis of
1
15. H NMR (300 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.54 (s, 1H),
8.38 (s, 1H), 7.51−7.49 (m, 2H), 7.35 (dd, 1H), 5.02 (s, 2H), 3.02 (s,
6H) ppm. HPLC area: 99.6% at 220 nm and 99.2% at 254 nm. Mass:
m/z = 300 (M + 1).
5-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-
(2-hydroxyethyl)pyrazine-2-carboxamide (19). This compound
was prepared by the similar method described above for the synthesis
1
12% yield) as a white solid. H NMR (300 MHz, DMSO-d6): δ 9.25
1
of 15. H NMR (300 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.69 (s, 1H),
(s, 1H), 8.65 (s, 1H), 8.62 (s, 1H), 7.48−7.51 (m, 2H), 7.35 (dd, 1H),
5.02 (s, 2H), 4.14 (s, 2H), 1.30 (s, 6H) ppm. HPLC area: 95.3% at
220 nm and 94.9% at 254 nm. Mass: m/z = 326 (M + H, ESI+).
6-(5-(5-Methyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yloxy)benzo-
[c][1,2]oxaborol-1(3H)-ol (25). To a solution of 48 (172 mg, 1
mmol) in MeOH (7 mL) was added a solution of hydrazine hydrate
(0.11 mL, 2 mmol, 2 equiv) in MeOH dropwise at 0 °C. The reaction
mixture was stirred for 16 h, filtered, and concentrated to the desired
product 59 (100 mg, 58% yield). To a solution of 59 (100 mg, 0.58
mmol) and NMM (203 mg, 1.74 mmol, 3 equiv) in DCM (5 mL) was
added AcCl (46 mg, 0.58 mmol, 1 equiv) dropwise. The mixture was
stirred at rt for 1 h, diluted with H2O (10 mL), and extracted with
DCM (20 mL). The organic phase was washed with 1 N HCl (10
mL), 1N NaHCO3 (15 mL), and brine (15 mL), dried over anhydrous
Na2SO4, and filtered. The residue after rotary evaporation was purified
by column chromatography to the desired product 60 (95 mg, 76%
yield). The solution of 60 (90 mg, 0.42 mmol, 1 equiv) in POCl3 (1.8
mL) was stirred at 110 °C for 0.5 h. After completion, the reaction was
diluted with ice water (10 mL), washed with 1N NaHCO3 (10 mL),
and extracted with EA (15 mL). The organic phase was washed with
brine (10 mL), dried over anhydrous Na2SO4, and filtered. The
residue after rotary evaporation was purified by column chromatog-
raphy to the desired product 61 (62 mg, 76% yield). To a solution of
61 (60 mg, 0.306 mmol) in DMF (1 mL) were added Cs2CO3 (251
mg, 0.765 mmol, 2.5 equiv) and 36 (46 mg, 0.306 mmol, 1 equiv).
The reaction mixture was stirred at 80 °C for 45 min, diluted with
H2O (10 mL), and extracted with EA (10 mL). The organic phase was
washed with brine (10 mL), dried over anhydrous Na2SO4, and
filtered. The residue after rotary evaporation was purified by column
8.66−8.61 (m, 2H), 7.51−7.49 (m, 2H), 7.36 (dd, 1H), 5.03 (s, 2H),
4.82 (t, 1H), 3.55−3.49 (m, 2H), 3.40−3.35 (m, 2H) ppm. HPLC
area: 97.8% at 220 nm and 99.0% at 254 nm. Mass: 316 (M + 1, ESI
+).
N-(2-(Dimethylamino)ethyl)-5-(1-hydroxy-1, 3-
dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxa-
mide hydrochloride (20). This compound was prepared by the
similar method described above for the synthesis of 15 and was
converted to HCl salt. 1H NMR (300 MHz, DMSO-d6): δ 9.63 (br s,
1H), 9.27 (s, 1H), 9.05 (t, 1H), 8.73 (s, 1H), 8.65 (s, 1H), 7.53−7.50
(m, 2H), 7.35 (d, 1H), 5.03 (s, 2H), 3.62−3.68 (m, 2H), 3.28−3.32
(m, 2H), 2.82 (s, 6H) ppm. HPLC area: 99.5% at 220 nm and 99.6%
at 254 nm. Mass: m/z = 343 (M + 1, ESI+).
5-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-
(isopropylsulfonyl)pyrazine-2-carboxamide (21). This com-
pound was prepared by the similar method described above for the
1
synthesis of 15. H NMR (300 MHz, DMSO-d6): δ 11.87 (br s, 1H),
9.25 (s, 1H), 8.76 (s, 1H), 8.65 (s, 1H), 7.54−7.50 (m, 2H), 7.37 (dd,
1H), 5.03 (s, 2H), 3.78 (septet, 1H), 1.33 (d, 6H) ppm. HPLC area:
96.7% at 220 nm and 97.9% at 254 nm. Mass: m/z = 378 (M + 1, ESI
+).
(E)-5-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
yloxy)pyrazine-2-carbaldehyde oxime (22). To a solution of 50
(100 mg, 0.39 mmol) and hydroxylamine hydrochloride (31 mg, 0.45
mmol, 1.14 equiv) in EtOH (1.36 mL) was added sodium hydroxide
solution (3N, 0.26 mL). The reaction mixture was stirred at rt for 2 h,
poured into water (5 mL), and extracted with EA (2 × 10 mL). The
organic phases were combined, washed with brine, dried over MgSO4,
filtered, and concentrated. The residue was purified by column
chromatography on silica gel (MeOH:DCM = 1%) to 22 (38 mg, 36%
yield). 1H NMR (300 MHz, DMSO-d6): δ 11.77 (s, 1H), 9.25 (s, 1H),
8.56 (s, 1H), 8.52 (s, 1H), 8.14 (s, 1H), 7.50−7.47(m, 2H), 7.35 (d,
1H), 5.02 (s, 2H) ppm. HPLC area: 94.6% at 220 nm and 98.8% at
254 nm.
1
chromatography to the desired product 25 (35 mg, 50% yield). H
NMR (300 MHz, DMSO-d6): δ 9.25 (s, 1H), 8.84 (s, 1H), 8.73 (s,
1H), 7.54−7.49 (m, 2H), 7.36 (dd, 1H), 5.01 (s, 2H), 2.60 (s, 3H)
ppm. HPLC area: 96.8% at 220 nm and 95.5% at 254 nm. Mass: m/z =
311 (M + H, ESI+) and 333 (M + Na).
(Z)-N′-Hydroxy-5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]-
oxaborole-6-yloxy)pyrazine-2-carboximidamide (23). To a
solution of 11 (250 mg, 0.99 mmol) and hydroxylamine hydrochloride
(137 mg, 1.98 mmol, 2.0 equiv) in H2O (3 mL) was added a solution
of Na2CO3 (209 mg, 19.8 mmol, 2.0 equiv) in H2O (0.9 mL). The
reaction mixture was stirred at 40 °C for 3 h, poured into water (20
mL), and extracted with EA (4 × 15 mL). The organic phases were
combined, washed with brine, dried over MgSO4, filtered, and
concentrated. The residue was purified by column chromatography on
silica gel (MeOH:DCM = 1%) to the product 23 (34 mg, 12% yield).
1H NMR (300 MHz, DMSO-d6): δ 9.99 (s, 1H), 9.23 (s, 1H), 8.59 (s,
6-(5-(1H-Tetrazol-5-yl)pyrazin-2-yloxy)benzo[c][1,2]-
oxaborol-1(3H)-ol (26). To a solution of 11 (200 mg, 0.75 mmol) in
DMF (2 mL) were added NH4Cl (68 mg, 1.27 mmol, 1.7 equiv) and
NaN3 (82 mg, 1.27 mmol, 1.7 equiv). The reaction mixture was stirred
at 95 °C overnight, diluted with H2O (40 mL), and extracted with EA
(2 × 20 mL). The aqueous phase was adjusted to pH < 7 with 0.5 N
HCl and extracted with EA (2 × 30 mL). The combined organic
phases were washed with brine (2 × 30 mL), dried over anhydrous
Na2SO4, and filtered. The residue after rotary evaporation was purified
by column chromatography to the desired product 26 (40 mg, 18%
yield). 1H NMR (300 MHz, DMSO-d6): δ 9.32 (s, 1H), 9.06 (s, 1H),
7.18 (d, 1H), 7.09 (s, 1H), 6.87 (dd, 1H), 4.86 (s, 2H) ppm. HPLC
area: 99.8% at 220 nm and 93.9% at 254 nm. Mass: m/z = 319 (M +
Na, ESI+).
1H), 8.52 (s, 1H), 7.52−7.43 (m, 2H), 7.34 (dd, 1H), 5.88 (s, 2H),
5.02 (s, 2H) ppm. HPLC area: 100% at 220 nm and 98.2% at 254 nm.
Mass: m/z = 287 (M + H, ESI+).
6-(5-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)pyrazin-2-yloxy)-
benzo[c][1,2]oxaborol-1(3H)-ol (24). To a solution of 45 (632 mg,
Ethyl 5-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
yloxy)pyrazine-2-carboxylate (27). A solution of 45 (2g, 12.62
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J. Med. Chem. XXXX, XXX, XXX−XXX