Journal of Medicinal Chemistry
Article
1
isotopic pattern]. HRMS (method I): found, 182.0125; calculated for
the product as a white solid (210 mg, 99%). H NMR (500 MHz,
+
C H N ClO (M + H) , 182.0121.
CDCl ) δ 0.01 (s, 9H), 0.96−1.00 (m, 2H), 2.86 (t, J = 6.3 Hz, 2H),
7
4
3
3
8
-Chloro-3-((2-(trimethylsilyl)ethoxy)methyl)pyrido[3,4-d]-
3.67−3.72 (m, 2H), 3.88 (t, J = 6.3 Hz, 2H), 5.46 (s, 2H), 7.81 (s, 1H),
pyrimidin-4(3H)-one (35). 8-Chloropyrido[3,4-d]pyrimidin-4(3H)-
8.07 (d, J = 5.1 Hz, 1H), 8.30 (s, 1H), 8.60 (s, 1H), 8.62 (d, J = 5.1 Hz,
one (1.87 g, 10.3 mmol, 1 equiv) was dissolved in dry DMF (15 mL,
1H), OH signal not observed. LC-MS (method H; ESI, m/z) t =
1.34 min −388 [(M + H) ]. HRMS (method I): found, 388.1798;
calculated for C H N O Si (M + H) , 388.1805.
8-(4-(2-((4-Fluorobenzyl) (methyl)amino)ethyl)-1H-pyrazol-
1-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)pyrido[3,4-d]-
pyrimidin-4(3H)-one (49d). Methanesulfonic anhydride (94 mg,
0.542 mmol, 1.5 equiv) was added in one portion to a solution of alcohol
47 (140 mg, 0.361 mmol, 1 equiv) and triethylamine (0.1 mL,
R
+
0
.7 M). The solution was heated to 60 °C, and potassium carbonate
+
(
2.85 g, 20.6 mmol, 2 equiv) was added. After 5 min of stirring,
18
26
5
3
(
2-(chloromethoxy)ethyl)trimethylsilane (2.06 g, 12.36 mmol,
1.2 equiv) was slowly added. Stirring was continued at 60 °C for 4 h,
the reaction cooled to room temperature, and EtOAc (60 mL) was
added. The heterogeneous mixture was washed with water (2 × 60 mL),
dried (Na SO ), and concentrated in vacuo. The crude product was
2
4
purified by silica gel column chromatography eluting with 3% EtOAc in
0.717 mmol, 2 equiv) in anhydrous CH
under N . The reaction mixture was stirred for 15 min at 0 °C and
monitored by LCMS. When the reaction was complete, the reaction
mixture was quenched with saturated NaHCO (10 mL) solution and
extracted with CH Cl (3 × 15 mL). The combined organic layers were
washed with saturated brine solution (30 mL), dried over MgSO , and
2 2
Cl (4 mL, 0.09 M) at 0 °C
CH Cl to provide the title compound as a white powder (2.7 g, 84%).
2
2
2
1
H NMR (500 MHz, CDCl ) δ 0.01 (s, 9H), 0.97−1.00 (m, 2H), 3.67−
3
3.71 (m, 2H), 5.46 (s, 2H), 8.06 (d, J = 5.1 Hz, 1H), 8.34 (s, 1H), 8.49
3
(
d, J = 5.1 Hz, 1 H). LC-MS (method H; ESI, m/z) t = 1.4 min (100%
2
2
R
+
purity) −254, 256 [(M − SEM + TMS) , Cl isotopic pattern)]. This
compound was also prepared in lower yield (55 to 65%) by performing
the reaction at room temperature.
4
concentrated in vacuo to give 2-(1-(4-oxo-3-((2-(trimethylsilyl)-
ethoxy)methyl)-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-1H-pyrazol-
4-yl)ethylmethanesulfonate as a pale-yellow oil. This was used in the
next step without further purification. H NMR (500 MHz, CDCl
4
-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-pyrazole (45).
1
tert-Butylchlorodimethylsilane (7.09 g, 47.0 mmol, 1.05 equiv) was
added to a solution of 1H-imidazole (3.35 g, 49.2 mmol, 1.1 equiv) and
3
) δ
0.01 (s, 9H), 0.96−1.01 (m, 2H), 2.99 (s, 3H), 3.07 (t, J = 6.7 Hz, 2H),
2-(1H-pyrazol-4-yl)ethanol (5.02 g, 44.8 mmol, 1 equiv) in DMF
3.68−3.72 (m, 2H), 4.44 (t, J = 6.7 Hz, 2H), 5.47 (s, 2H), 7.81 (s, 1H),
(50 mL, 0.9 M) at room temperature. The resultant solution was stirred
8.09 (d, J = 5.1 Hz, 1H), 8.31 (s, 1H), 8.64 (d, J = 5.1 Hz, 1H), 8.68 (s,
+
for 30 min at room temperature and monitored by LCMS. On
completion, the reaction mixture was diluted with water (100 mL) and
extracted three times with EtOAc (3 × 100 mL). The combined organic
layers were washed with saturated lithium chloride solution (150 mL)
1H). LC-MS (method H; ESI, m/z) t
R
= 1.34 min −466 [(M + H) ].
According to general procedure 1, cesium carbonate (340 mg,
1.044 mmol), 2-(1-(4-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-3,4-
dihydropyrido[3,4-d]pyrimidin-8-yl)-1H-pyrazol-4-yl)-
ethylmethanesulfonate (162 mg, 0.348 mmol), and 1-(4-fluorophenyl)-
N-methylmethanamine (0.1 mL, 0.759 mmol) were reacted together in
anhydrous DMF (2 mL). Purification on a KP-Sil snap cartridge (2%
and saturated brine solution (150 mL) and dried over MgSO . The
4
filtrate was concentrated in vacuo to give the product as a clear, pale-
1
yellow oil (9.63 g, 95%). H NMR (500 MHz, CDCl ) δ 0.04 (s, 6H),
3
0
2
1
.91 (s, 9H), 2.73 (t, J = 6.8 Hz, 2H), 3.76 (t, J = 6.8 Hz, 2H), 7.47 (s,
EtOH in CH
29%). H NMR (500 MHz, CDCl
2
Cl
2
) gave the title product as a pale-yellow oil (27.7 mg,
) δ 0.01 (s, 9H), 0.95−1.01 (m, 2H),
2.28 (s, 3H), 2.69 (t, J = 7.4 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 3.54 (s,
2H), 3.68−3.72 (m, 2H), 5.47 (s, 2H), 6.96−7.01 (m, 2H), 7.28−7.31
(m, 2H), 7.78 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 8.30 (s, 1H), 8.54 (s,
1H), 8.63 (d, J = 5.1 Hz, 1H). LC-MS (method C; ESI, m/z) t =
1.19 min −509 [(M + H) ]. HRMS (method B): found, 509.2514;
calculated for C H FN O Si (M + H) , 509.2496.
8-(4-(2-((4-Fluorobenzyl) (methyl)amino)ethyl)-1H-pyrazol-
1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (52d). According to general
procedure 4, 8-(4-(2-((4-fluorobenzyl) (methyl)amino)ethyl)-1H-
pyrazol-1-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-pyrido[3,4-d]-
pyrimidin-4(3H)-one (42.46 mg, 0.083 mmol) and hydrochloric acid
(6 M, 1 mL) were reacted together in THF (1 mL). Purification on a
KP-NH snap cartridge (25% EtOH in CH Cl ) gave the product as a
1
H), NH signal not observed. LC-MS (method C; ESI, m/z) t =
3
R
+
.46 min −227 [(M + H) ]. HRMS (method B): found, 227.1580;
+
calculated for C H N OSi (M + H) , 227.1574.
11
23
2
8
-(4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-1-yl)-
3
4
-((2-(trimethylsilyl)ethoxy)methyl)pyrido[3,4-d]pyrimidin-
R
+
(3H)-one (46). Note: when attempted at scale, these reactions were
+
carried out in batches, generally using ∼150 mg portions of 8-chloro-3-
26
34
6
2
(
(2-(trimethylsilyl)ethoxy)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
per microwave vial. Cesium carbonate (1.33 g, 4.09 mmol, 2 equiv)
and 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole (920 mg,
4.06 mmol, 2 equiv) were added to a microwave vial equipped with a
stirrer bar. This was sealed and evacuated and flushed with N2.
Anhydrous MeCN (14 mL, 0.15 M) was added to the vial and the
reaction mixture stirred for 20 min under N at room temperature. The
2
2
2
1
cap was then removed, 8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-
white solid (23.6 mg, 75%). H NMR (500 MHz, MeOH-d ) δ 2.35 (s,
4
pyrido[3,4-d]pyrimidin-4(3H)-one (637 mg, 2.04 mmol, 1 equiv) was
3H), 2.73−2.78 (m, 2H), 2.83−2.88 (m, 2H), 3.66 (s, 2H), 7.02−7.08 (m,
added, the vial resealed, and evacuated and flushed with N . The reaction
2H), 7.34−7.39 (m, 2H), 7.75 (s, 1H), 8.04 (d, J = 5.2 Hz, 1H), 8.23 (s,
2
mixture was then stirred at reflux for 18 h. Solids were removed by
filtration and rinsed with CH Cl (3 × 15 mL). The filtrate was
1H), 8.55 (d, J = 5.2 Hz, 1H), 8.70 (s, 1H), NH signalnot observed. LC-MS
+
2
2
(method C; ESI, m/z) t = 0.68 min −379 [(M + H) ]. HRMS (method
R
+
concentrated in vacuo and purified by Biotage column chromatography
B): found, 379.1665; calculated for C H FN O (M + H) , 379.1677.
20
20
6
on a KP-Sil snap cartridge (30% EtOAc in cyclohexane) to give the title
product as a pale-yellow solid (724 mg, 71%). H NMR (500 MHz,
8-(4-(2-(4-(4-Chlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-
1-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)pyrido[3,4-d]-
pyrimidin-4(3H)-one (51a). According to general procedure 2,
2-(1-(4-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydropyrido-
[3,4-d]pyrimidin-8-yl)-1H-pyrazol-4-yl)ethylmethanesulfonate (96 mg,
0.206 mmol), 4-(4-chlorophenyl)piperidine (48 mg, 0.247 mmol), and
triethylamine (0.057 mL, 0.409 mmol) in DMF were reacted at 50 °C
overnight. After workup, the resulting oil was passed through a plug of
1
CDCl ) δ 0.01 (s, 9H), 0.06 (s, 6H), 0.91 (s, 9H), 0.95−1.00 (m, 2H),
3
2
.80 (t, J = 6.7 Hz, 2H), 3.67−3.71 (m, 2H), 3.84 (t, J = 6.7 Hz, 2H), 5.47
(
8
s, 2H), 7.79 (s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 8.29 (s, 1H), 8.61 (s, 1H),
.63 (d, J = 5.1 Hz, 1H). LC-MS (method C; ESI, m/z) t = 1.79 min
R
+
−
502 [(M + H) ]. HRMS (method B): found, 502.2672; calculated for
+
C H N O Si (M + H) , 502.2670.
24
40
5
3
2
8
-(4-(2-Hydroxyethyl)-1H-pyrazol-1-yl)-3-((2-(trimethylsilyl)-
silica eluting with 30% MeOH/DCM to afford a yellow oil which was
1
ethoxy)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one (47). Hydro-
used without further purification. H NMR (500 MHz, CDCl ) δ 0.01
3
chloric acid (1 M, 5.5 mL, 10 equiv) was added to a solution of
(s, 9H), 0.96−1.02 (m, 2H), 1.75−1.90 (m, 4H), 2.12−2.19 (m, 2H),
2.48−2.57 (m, 1H), 2.67−2.73 (m, 2H), 2.81−2.86 (m, 2H), 3.14 (br s,
1H), 3.16 (br s, 1H), 3.68−3.73 (m, 2H), 5.47 (s, 2H), 7.11 (d, J =
8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 8.08 (d, J = 5.1 Hz,
1H), 8.30 (s, 1H), 8.57 (s, 1H), 8.64 (d, J = 5.1 Hz, 1H). LC-HRMS
(method C) tR = 1.28 min, m/z −565.2515 Cl isotopic pattern
8
-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-1-yl)-3-((2-
(
(
trimethylsilyl)ethoxy)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one
274 mg, 0.546 mmol, 1 equiv) in MeOH (5.5 mL, 0.1 M) at 0 °C. The
reaction was stirred at 0 °C for 5 min, then diluted with EtOAc (20 mL),
washed with saturated NaHCO solution (20 mL) and saturated brine
3
+
solution (20 mL), dried over MgSO , and concentrated in vacuo to give
[(M + H) ].
4
S
J. Med. Chem. XXXX, XXX, XXX−XXX