Journal of Medicinal Chemistry
Article
was performed using a medium pressure Biotage or ISCO system, and
columns were prepackaged by various commercial vendors including
Biotage and ISCO. All tested compounds were determined to be >95%
pure by HPLC with UV peak detection at 215 nm. The terms
“concentrated” and “evaporated” refer to the removal of solvent at
reduced pressure on a rotary evaporator with a water bath temperature
not exceeding 60 °C. The configuration of compounds 7b, 4a, and 4b
was assigned based on the X-ray crystal structure analysis of 7a,
supporting that the R enantiomers are active, which is in agreement with
previously published work.10 Optical rotations are reported with
concentration in g/mL with solvent used in parentheses.
General Procedure A (Parallel Format). Step 1. Lindlar’s catalyst
(20 mg, 0.075 mmol) was added to a solution of diethyl 2-ethynyl-2-
hydroxysuccinate (A) (300 mg, 1.4 mmol) and quinoline (50 μL, 0.42
mmol) in toluene (5 mL), and the mixture was stirred at 30 °C under H2
atmosphere (15 psi) for 16 h. The reaction mixture was filtered and the
filtrate concentrated to give diethyl 2-hydroxy-2-vinylsuccinate (B) (160
mg, 0.74 mmol, 53%). The resulting material was dissolved in toluene (6
mL, 0.125 M) and used without further purification.
combined organic layer was dried over magnesium sulfate, filtered, and
concentrated to give an off-white solid. The material was stirred in a 1:5
mixture of ethyl acetate/hexanes (6 mL) for 48 h during which the
material crystallized and 2-hydroxy-2-(2-(2-methoxy-5-methylpyridin-
3-yl)ethyl)succinic acid (4, 4a or 4b) was isolated as a white solid (233−
320 mg, 51−70%) after filtration. Enantiomeric excess of 4a and 4b was
determined by SFC using a 4.6 mm × 250 mm × 5 μm Tech OJ-H
column using a gradient of 5−60% isopropanol containing 0.2%
trifluoroacetic acid/CO2 over 10 min at 3.0 mL/min with monitoring at
210 nm. The configurations of 4a and 4b were assigned by analogy to 1a
and 7a, whose configurations were assigned by X-ray crystal analysis
2-Hydroxy-2-(2-(2-methoxy-5-methylpyridin-3-yl)ethyl)-
succinic Acid (4). 1H NMR (400 MHz, DMSO-d6) δ 12.43 (br s, 2H),
7.98 (dd, J = 5.1, 2.0 Hz, 1H), 7.46 (dd, J = 7.2, 1.8 Hz, 1H), 6.88 (dd, J =
7.2, 4.9 Hz, 1H), 4.93 (br s, 1H), 4.31 (q, J = 7.0 Hz, 2H), 2.78 (d, J =
15.6 Hz, 1H), 2.58−2.71 (m, 1H), 2.54 (d, J = 16.0 Hz, 1H), 2.39 (td, J =
13.1, 4.7 Hz, 1H) 1.74−1.96 (m, 2H), 1.31 (t, J = 7.0 Hz, 3H); m/z =
282.3 [M − 1]−.
(R)-2-Hydroxy-2-(2-(2-methoxy-5-methylpyridin-3-yl)ethyl)-
succinic Acid (4a). Enantiomer 4a eluted at 4.13 min with 99.7% ee. 1H
NMR (500 MHz, DMSO-d6) δ 12.65 (br s, 1H), 12.20 (br s, 1H), 7.80
(d, J = 1.5 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 4.93 (br s, 1H), 3.81 (s, 3H),
2.77 (d, J = 15.7 Hz, 1H), 2.58−2.66 (m, 1H), 2.51−2.55 (m, 1H),
2.30−2.39 (m, 1H), 2.17 (s, 3H), 1.86 (dt, J = 4.8, 12.7 Hz, 1H), 1.79
(dt, J = 4.9, 12.7 Hz, 1H); m/z = 282.3 [M − 1]−. [α]D −0.5° (c 0.0733,
MeOH).
(S)-2-Hydroxy-2-(2-(2-methoxy-5-methylpyridin-3-yl)ethyl)-
succinic Acid (4b). Enantiomer 4b eluted at 3.89 min with 98.9% ee.
1H NMR (500 MHz, DMSO-d6) δ 12.65 (br s, 1H), 12.20 (br s, 1H),
7.79 (d, J = 1.5 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 4.92 (br s, 1H), 3.80 (s,
3H), 2.76 (d, J = 15.7 Hz, 1H), 2.56−2.65 (m, 1H), 2.50−2.55 (m, 1H),
2.28−2.37 (m, 1H), 2.16 (s, 3H), 1.85 (dt, J = 4.9, 12.7 Hz, 1H), 1.78
(dt, J = 4.9, 12.7 Hz, 1H); m/z = 282.3 [M − 1]−. [α]D 9.0° (c 0.0777,
MeOH).
2-Hydroxy-2-(2-(2-methoxypyridin-3-yl)ethyl)succinic Acid
(5). Diethyl 2-hydroxy-2-(2-(2-methoxypyridin-3-yl)ethyl)succinate
(15) (190 mg, 0.58 mmol) was dissolved in THF (3 mL). 1 M sodium
hydroxide (11.7 mL, 11.7 mmol) was added at room temperature. The
mixture was stirred at room temperature for 32 h. The reaction mixture
was extracted with ethyl acetate (3 × 10 mL) and the aqueous layer
concentrated. The residue was extracted with a 10:1 dichloromethane/
methanol mixture (40 mL), and the organic layer was concentrated
under reduced pressure. The residue was purified by prep-HPLC to
provide 2-hydroxy-2-(2-(2-methoxypyridin-3-yl)ethyl)succinic acid (5)
(7.2 mg, 4.6%) as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 7.96
(d, J = 4.8 Hz, 1H), 7.49 (d, J = 6.4 Hz, 1H), 6.88 (dd, J = 7.2, 5.2 Hz,
1H), 3.93 (br s, 3H), 2.96 (d, J = 16.0 Hz, 1H), 2.76 (td, J = 12.7, 4.8 Hz,
1H), 2.67 (d, J = 16.0 Hz, 1H), 2.52 (td, J = 12.7, 4.8 Hz, 1H), 2.01 (td, J
= 12.2, 4.4 Hz, 1H), 1.92 (dt, J = 12.2, 4.4 Hz, 1H); m/z = 270.8 [M +
1]+.
Step 2. Selected aryl halide (0.20 mmol) and triethylamine (0.18 mL,
1.4 mmol) were added to the toluene solution of diethyl 2-hydroxy-2-
vinylsuccinate (B) (1.6 mL, 0.20 mmol). Nitrogen was bubbled in the
reaction mixture for 1 min. Palladium(II) acetate (4.5 mg, 20 μmol) and
tricyclohexylphosphine (5.6 mg, 20 μmol) were added to the reaction
mixture, and bubbling with nitrogen was continued for 1 min. The
reaction vial was sealed and shaken at 130 °C for 16 h. The reaction
mixture was concentrated under reduced pressure, and the resulting
alkyne was purified by TLC.
Step 3. The alkene intermediate obtained in step 2 was dissolved in
methanol (5 mL). Triethylsilane (0.12 mL, 0.75 mmol) and palladium
on carbon (40 mg) were added to the solution, the reaction vial was
sealed, and the mixture was shaken under nitrogen atmosphere at 30 °C
for 16 h. The reaction mixture was filtered and the filtrate concentrated
under reduced pressure.
Step 4. The material was dissolved in ethanol (0.80 mL), and 1 M
solution sodium hydroxide (0.80 mL, 0.80 mmol) was added. The
reaction mixture was stirred at 80 °C for 1 h. Ethanol was removed under
reduced pressure, and 1 N hydrochloric acid was added to adjust the pH
to ∼1. The mixture was extracted with dichloromethane (3 × 2 mL), and
the combined organic layer was concentrated. The residue was purified
by HPLC on a 21.2 mm × 250 mm × 8 μm Phenomenex Gemini C18
column using a gradient of 26−46% acetonitrile in water containing
0.225% trifluoroacetic acid over 8 min at 30 mL/min with UV
monitoring.
2-Hydroxy-2-phenethylsuccinic Acid (2). Diethyl 2-hydroxy-2-
phenethylsuccinate (11) (150 mg, 0.51 mmol) was dissolved in THF (2
mL). 1 N sodium hydroxide (2.0 mL, 2.0 mmol) was added at room
temperature. The mixture was stirred at room temperature for 16 h.
Water (10 mL) was added to the reaction mixture which was extracted
with ethyl acetate (2 × 15 mL). The aqueous layer was acidified to a pH
of 3 with 1 N HCl. The aqueous layer was extracted with ethyl acetate (2
× 25 mL). The organic layer was dried over magnesium sulfate, filtered,
and concentrated to give 2-hydroxy-2-phenethylsuccinic acid (2) (90
mg, 74%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.29−
7.25 (m, 2H), 7.18−7.15 (m, 3H), 5.05 (s, 1H), 2.77 (d, J = 15.6 Hz,
1H), 2.70 (td, J = 12.5, 5.6 Hz, 1H), 2.53 (d, J = 15.6 Hz, 1H), 2.41 (td, J
= 12.5, 5.6 Hz, 1H), 1.92−1.83 (m, 2H); m/z = 236.8 [M − 1]−.
2-Hydroxy-2-(2-methoxy-5-methylphenethyl)succinic Acid
(3). 2-Hydroxy-2-(2-methoxy-5-methylphenethyl)succinic acid (3)
was prepared according to general procedure A in parallel format
using 2-bromo-1-methoxy-4-methylbenzene (40 mg, 0.20 mmol). m/z
= 281 [M − H]−.
2-(2-(2-Ethoxy-5-methylpyridin-3-yl)ethyl)-2-hydroxysuc-
cinic Acid (6). Diethyl 2-(2-(2-ethoxy-5-methylpyridin-3-yl)ethyl)-2-
hydroxysuccinate (17) (55 mg, 0.16 mmol) was dissolved in ethanol (4
mL). 1 M potassium hydroxide (0.78 mL) was added at room
temperature. The mixture was stirred at room temperature for 12 h.
Water (20 mL) was added to the reaction mixture, and ethanol was
removed under reduced pressure. 1 M HCl was added to the resulting
aqueous solution to adjust the pH to ∼5. The mixture was extracted with
ethyl acetate (3 × 50 mL), and the combined organic layer was
concentrated. The residue was purified by prep-HPLC to provide 2-(2-
(2-ethoxy-5-methylpyridin-3-yl)ethyl)-2-hydroxysuccinic acid (6) as a
1
white solid (10 mg, 22%). H NMR (400 MHz, MeOD-d4) δ 7.75 (s,
2-Hydroxy-2-(2-(2-methoxy-5-methylpyridin-3-yl)ethyl)-
succinic Acid (4). Diethyl ester 13, 13a or 13b (550 mg, 1.6 mmol),
was dissolved in tetrahydrofuran (3 mL) and MeOH (1 mL). 3 M
sodium hydroxide (2.2 mL, 6.6 mmol) was added and the mixture
stirred at room temperature for 16 h. Water (20 mL) was added and the
mixture extracted with a 1:2 mixture of ethyl acetate/heptane (24 mL).
The aqueous layer was adjusted to pH of ∼3 with 1 N HCl (3 mL) and
washed with 20% isopropanol in dichloromethane (3 × 60 mL). The
1H), 7.35 (s, 1H), 4.30 (q, J = 7.2 Hz, 2H), 2.97 (d, J = 16.8 Hz, 1H),
2.77−2.67 (m, 2H), 2.55−2.47 (m, 1H), 2.23 (s, 3H), 2.04 (td, J = 4.8,
12.8 Hz, 1H), 1.91 (td, J = 12.4, 4.4 Hz, 1H), 1.39 (t, J = 7.2 Hz, 3H); m/
z = 298.4 [M + 1]+.
2-(2-(2-Ethoxypyridin-3-yl)ethyl)-2-hydroxysuccinic Acid (7).
Diethyl ester 19, 19a or 19b (245 mg, 0.722 mmol), was dissolved in
tetrahydrofuran (3 mL) and methanol (1 mL) at room temperature. 2 M
H
J. Med. Chem. XXXX, XXX, XXX−XXX