Journal of Medicinal Chemistry
Article
(d, J = 13.0 Hz, 1H), 4.45 (d, J = 13.6 Hz, 1H), 3.24−3.16 (m, 2H),
3.05−2.95 (m, 1H), 2.78−2.64 (m, 2H), 2.59−2.47 (m, 1H), 2.18−
2.08 (m, 1H), 2.05−1.97 (m, 1H), 1.92 (d, J = 13.1 Hz, 1H), 1.84 (d, J
= 13.5 Hz, 1H), 1.63 (s, 3H), 1.61−1.44 (m, 2H), 0.93−0.86 (m, 2H),
0.86−0.78 (m, 2H). HRMS calculated for C35H34F3N4O4 (M + H)
631.2532, found 631.2572.
(−)-1-(6-(3-(4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-meth-
ylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoro-
methyl)-1H-pyrazole-4-carboxylic Acid ((−)-19). Method C employ-
ing (−)-ethyl 1-(6-(3-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-
methylphenoxy)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoro-
methyl)-1H-pyrazole-4-carboxylate (tR = 2.19 min) afforded (−)-19
after RP-HPLC-B purification (56 mg, 59%). The analytical data were
substantially identical to (+)-19.
19.7 mmol) and AlCl3 (10.5 g, 79 mmol) was heated at 100 °C for 1 h,
then at 180 °C for 2 h, and subsequently cooled to rt. The excess AlCl3
was carefully quenched with 1 M aq HCI. The resulting mixture was
extracted with DCM. The combined organic layers were washed with
water and passed through an ISOLUTE Phase Separator. The filtrate
was concentrated to afford 7-hydroxy-5-methyl-2,3-dihydro-1H-inden-
1-one, which was used in the next reaction without further purification
1
(946 mg, 30% yield). H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H),
6.80−6.72 (m, 1H), 6.64−6.52 (m, 1H), 3.08−3.03 (m, 2H), 2.71−
2.67 (m, 2H), 2.38 (s, 3H). Step 2. To a solution of 7-hydroxy-5-
methyl-2,3-dihydro-1H-inden-1-one (217 mg, 1.34 mmol) and
pyridine (325 μL, 4.01 mmol) in DCM (13.4 mL) at 0 °C was
added trifluoromethanesulfonic anhydride (316 μL, 1.87 mmol)
dropwise. The resulting suspension was stirred at 0 °C for 1 h. The
reaction was quenched with H2O, and then the mixture was diluted
with 1 N aq HCl. The resulting mixture was passed through an
ISOLUTE Phase Separator. The organic phase was concentrated to
furnish 6-methyl-3-oxo-2,3-dihydro-1H-inden-4-yl trifluoromethane-
sulfonate, which was used in the next step without any further
(+)- and (−)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-
yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-
5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid ((+)- and (−)-20).
Step 1. Following method G, 32 and 42, followed by FCC purification
(0−40% EtOAc/heptane), afforded ethyl 1-(6-(3-oxo-2,3-dihydro-1H-
inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate
(422 mg, 53% yield). 1H NMR (400 MHz, CD3OD) δ 8.19 (d, J = 0.7
Hz, 1H), 8.07 (t, J = 7.9 Hz, 1H), 7.85 (dd, J = 7.8, 0.9 Hz, 1H), 7.77−
7.69 (m, 2H), 7.65 (dq, J = 7.7, 1.0 Hz, 1H), 7.56 (dq, J = 7.4, 0.8 Hz,
1H), 4.36 (q, J = 7.1 Hz, 2H), 3.26−3.18 (m, 2H), 2.77−2.68 (m,
2H), 1.37 (t, J = 7.1 Hz, 3H). Step 2. To a solution of 30 (60 mg,
0.232 mmol) and ethyl 1-(6-(3-oxo-2,3-dihydro-1H-inden-4-yl)-
pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (106 mg,
0.255 mmol) in anhydrous toluene (2.3 mL) was added TsOH (4.42
mg, 0.023 mmol), the reaction flask was fitted with a Dean−Stark trap,
and the reaction mixture was stirred at 130 °C for 22 h. The reaction
mixture was then concentrated. The residue was dissolved in
anhydrous EtOH (2.3 mL) and cooled to 0 °C, and then sodium
borohydride (8.79 mg, 0.232 mmol) was added. The mixture was
stirred at 0 °C for 1.5 h. The reaction was quenched with H2O and
saturated aq NaHCO3, and then the mixture was extracted with
EtOAc. The organic layer was concentrated onto Celite. The residue
was purified by FCC (0−50% EtOAc/heptane) to afford rac-ethyl 1-
(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)-
amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-
1
purification (335 mg, 85% yield). H NMR (400 MHz, CDCl3) δ
7.25−7.21 (m, 1H), 6.90 (s, 1H), 3.11−3.02 (m, 2H), 2.70−2.63 (m,
2H), 2.41 (s, 3H). MS (ESI+) m/z 295.2 (M + H). Step 3. Following
method G, 32 and 6-methyl-3-oxo-2,3-dihydro-1H-inden-4-yl trifluor-
omethanesulfonate afforded ethyl 1-(6-(6-methyl-3-oxo-2,3-dihydro-
1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbox-
ylate after FCC purification (0−50% EtOAc/heptane) (303 mg, 56.2%
yield). 1H NMR (400 MHz, CD3OD) δ 8.19 (d, J = 0.8 Hz, 1H), 8.06
(t, J = 7.9 Hz, 1H), 7.86 (dd, J = 7.8, 0.9 Hz, 1H), 7.71 (dd, J = 8.0, 0.9
Hz, 1H), 7.46 (dq, J = 1.8, 0.9 Hz, 1H), 7.41 (dd, J = 1.7, 0.9 Hz, 1H),
4.37 (q, J = 7.1 Hz, 2H), 3.20−3.15 (m, 2H), 2.73−2.68 (m, 2H), 2.49
(s, 3H), 1.38 (t, J = 7.1 Hz, 3H). MS (ESI+) m/z 430.3 (M + H). Step
4. A mixture of 30 (90 mg, 0.349 mmol), ethyl 1-(6-(6-methyl-3-oxo-
2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyra-
zole-4-carboxylate (150 mg, 0.349 mmol), and TsOH (3.32 mg, 0.017
mmol) in anhydrous toluene (3.5 mL) was charged to a flask equipped
with a condenser and a Dean−Stark trap. The mixture was stirred at
130 °C for 22 h, and then concentrated. The residue was then
dissolved in anhydrous EtOH (3.5 mL). To the solution at 0 °C was
added sodium borohydride (13.2 mg, 0.35 mmol). The mixture was
stirred at rt for 3 h, with the addition of sodium borohydride (13.2 mg,
0.35 mmol) each hour, for a total of 3 additions. The reaction was
quenched with H2O and saturated aq. NH4Cl. The mixture was then
extracted with DCM. The organic layer was passed through an
ISOLUTE Phase Separator and concentrated onto Celite. The residue
was purified by FCC (0−50% EtOAc/heptane) to afford rac-ethyl 1-
(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)-
amino)-6-methyl-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoro-
methyl)-1H-pyrazole-4-carboxylate (130 mg, 55% yield). 1H NMR
(400 MHz, CD3OD) δ 7.97−7.91 (m, 2H), 7.89 (dd, J = 7.9, 1.1 Hz,
1H), 7.49−7.45 (m, 2H), 7.25 (s, 1H), 6.81 (dd, J = 8.2, 2.2 Hz, 1H),
6.71 (d, J = 2.1 Hz, 1H), 6.54 (d, J = 8.3 Hz, 1H), 5.16 (d, J = 6.4 Hz,
1H), 4.64 (d, J = 13.0 Hz, 1H), 4.45 (d, J = 13.7 Hz, 1H), 4.37 (q, J =
7.1 Hz, 2H), 3.25 (s, 1H), 3.17 (dd, J = 16.4, 8.4 Hz, 1H), 2.88 (ddd, J
= 16.1, 8.7, 3.3 Hz, 1H), 2.74 (t, J = 12.3 Hz, 1H), 2.64 (tt, J = 12.1,
3.8 Hz, 1H), 2.44 (s, 3H), 2.40−2.29 (m, 1H), 2.15−2.05 (m, 1H),
2.05−1.97 (m, 1H), 1.92 (d, J = 13.0 Hz, 1H), 1.83 (d, J = 12.9 Hz,
1H), 1.69 (s, 3H), 1.59 (dd, J = 41.5, 16.5 Hz, 2H), 1.40 (t, J = 7.1 Hz,
3H), 0.94−0.86 (m, 2H), 0.85−0.78 (m, 2H). MS (ESI+) m/z 672.4
(M + H). Step 5. Method C employing ethyl 1-(6-(3-((4-(1-
(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-6-
methyl-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-
1H-pyrazole-4-carboxylate afforded rac-21 without any further
purification (63% yield).
1
1H-pyrazole-4-carboxylate (32 mg, 21% yield). H NMR (400 MHz,
CD3OD) δ 7.97−7.92 (m, 2H), 7.90 (dd, J = 7.9, 1.1 Hz, 1H), 7.63
(dd, J = 5.6, 3.3 Hz, 1H), 7.49 (dd, J = 7.6, 1.0 Hz, 1H), 7.43 (d, J =
5.6 Hz, 2H), 6.80 (dd, J = 8.3, 2.2 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H),
6.54 (d, J = 8.3 Hz, 1H), 5.24 (d, J = 6.5 Hz, 1H), 4.64 (d, J = 13.0 Hz,
1H), 4.45 (d, J = 13.3 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.21 (dt, J =
16.3, 8.2 Hz, 2H), 2.94 (ddd, J = 16.1, 8.7, 3.5 Hz, 1H), 2.73 (t, J =
12.7 Hz, 1H), 2.65 (tt, J = 12.0, 3.6 Hz, 1H), 2.37 (dtd, J = 12.8, 8.5,
6.7 Hz, 1H), 2.15−2.06 (m, 1H), 2.04−1.97 (m, 1H), 1.95−1.88 (m,
1H), 1.87−1.79 (m, 1H), 1.69 (s, 3H), 1.66−1.45 (m, 2H), 1.40 (t, J =
7.1 Hz, 3H), 0.94−0.85 (m, 2H), 0.85−0.78 (m, 2H). MS (ESI+) m/z
658.5 (M + H). Step 3. Method A employing rac-ethyl 1-(6-(3-((4-(1-
(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-di-
hydro-1H-inden-4-yl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-
carboxylate afforded ( )-20 after RP-HPLC-B purification. Step 4.
Resolution of the racemate was achieved by chiral SFC using Daicel
CHIRALCEL OJ-H column with 20% (5 mM NH4OH in MeOH) in
CO2 to afford (+)-20 (tR = 3.10 min, > 97% ee) and (−)-20 (tR = 4.40
min, > 97% ee). 1H NMR (400 MHz, CD3OD) δ 7.98−7.91 (m, 2H),
7.91−7.87 (m, 1H), 7.67−7.61 (m, 1H), 7.51−7.47 (m, 1H), 7.43 (d, J
= 5.9 Hz, 2H), 6.85−6.80 (m, 1H), 6.74−6.71 (m, 1H), 6.55 (d, J =
8.2 Hz, 1H), 5.24 (s, 1H), 4.63 (d, J = 13.0 Hz, 1H), 4.45 (d, J = 13.3
Hz, 1H), 3.26−3.16 (m, 2H), 2.98−2.89 (m, 1H), 2.79−2.61 (m, 2H),
2.42−2.31 (m, 1H), 2.16−2.07 (m, 1H), 2.05−1.97 (m, 1H), 1.93 (d, J
= 13.2 Hz, 1H), 1.84 (d, J = 12.9 Hz, 1H), 1.70 (s, 3H), 1.67−1.45 (m,
2H), 0.93−0.78 (m, 4H). HRMS calculated for C35H35F3N5O3 (M +
H)+ 630.2692, found 630.2451.
Resolution of the racemate was achieved by chiral SFC using Daicel
CHIRALCEL OJ-H column with isocratic 20% MeOH in CO2 to
afford (+)-21 (tR = 3.23 min, 99% ee) and (−)-21 (tR = 4.73 min,
>99% ee). 1H NMR (400 MHz, CD3OD) δ 7.94−7.89 (m, 2H),
7.89−7.85 (m, 1H), 7.49−7.45 (m, 2H), 7.25−7.23 (m, 1H), 6.84−
6.81 (m, 1H), 6.75−6.71 (m, 1H), 6.55 (d, J = 8.2 Hz, 1H), 5.20−5.16
(m, 1H), 4.63 (d, J = 13.1 Hz, 1H), 4.43 (d, J = 13.1 Hz, 1H), 3.28−
(+)- and (−)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-
yl)-2-methylphenyl)amino)-6-methyl-2,3-dihydro-1H-inden-4-yl)-
pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid ((+)-
and (−)-21). Step 1. A mixture of m-tolyl 3-chloropropanoate (3.92 g,
N
J. Med. Chem. XXXX, XXX, XXX−XXX