SelectiVe NMDA NR2B Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4 815
2 H), 7.30 (m, 5 H), 6.52 (t, J ) 4.8 Hz, 1 H), 5.81 (q, J ) 6.3 Hz,
1 H), 5.17 (br s, 1 H), 4.20 (br d, J ) 13.3 Hz, 2 H), 3.33 (br s, 2
H), 2.77 (m, 2 H), 1.81 (m, 3 H), 1.53 (d, 3 H, J ) 6.6 Hz), 1.20
(m, 2 H) ppm; HRMS (ESI) m/z 341.1990 [(M + H)+; calcd for
C19H25N4O2: 341.1972]. Anal. (C19H24N4O2) C, H, N.
2,3-Dihydro-1H-inden-2-yl 4-[(Pyrimidin-2-ylamino)methyl]-
piperidine-1-carboxylate (20d). Using the above procedure for
20b, with 2-indanol provided 20d (46%): mp 104-105 °C
(triturated from ether/hexane); 1H NMR (400 MHz, CDCl3) δ 8.26
(d, J ) 4.8 Hz, 2 H), 7.16-7.36 (m, 4 H), 6.52 (t, J ) 4.8 Hz, 1
H), 5.47 (m, 1 H), 5.14 (br m, 1 H), 4.21 (br s, 1 H), 4.01 (br s, 1
H), 3.31 (m, 4 H), 3.02 (dd, J ) 3.2, 16.9 Hz, 2 H), 2.72 (dt, J )
13.2, 2.7 Hz, 2 H), 1.60-1.90 (m, 3 H), 1.00-1.20 (m, 2 H) ppm;
HRMS (ESI) m/z 352.1975 [(M + H)+; calcd for C20H25N4O2:
353.1972]. Anal. (C20H24N4O2‚C2H2O4) C, H, N.
2-Fluorobenzyl 4-[(2-Pyrimidinylamino)methyl]-1-piperidi-
necarboxylate (20e). 2-Fluorobenzyl alcohol (83 mg, 0.66 mmol)
was added to a solution of N,N′-carbonyldiimidazole in DMF (4
mL), the mixture was stirred at room temperature for 1 h, and amine
24 dihydrochloride (175 mg, 0.66 mmol) was added, followed by
triethylamine (202 µL, 1.452 mmol), and the reaction mixture was
heated to 55 °C for 18 h. The cooled mixture was partitioned
between aqueous NH4Cl solution and EtOAc, the organic layer was
washed with water and brine and dried over anhydrous Na2SO4,
and solvent was evaporated in vacuo. The crude product was
purified by chromatography on silica (30-100% EtOAc/hexane)
to afford 20e (147 mg): mp 46-47 °C (triturated from ether/
hexane); 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J ) 4.8 Hz, 2 H),
7.00-7.40 (m, 4 H), 6.52 (t, J ) 4.8 Hz, 1 H), 5.19 (s, 2 H), 5.15
(m, 1 H), 4.10-4.30 (m, 2 H), 3.33 (t, J ) 6.4 Hz, 2 H), 2.70-
2.90 (m, 2 H), 1.70-1.90 (m, 3 H), 1.10-1.30 (m, 2 H) ppm;
HRMS (ESI) m/z 345.1723 [(M + H)+; calcd for C18H22FN4O2:
345.1722]. Anal. (C18H21FN4O2) C, H, N.
3-Fluorobenzyl 4-[(2-Pyrimidinylamino)methyl]-1-piperidi-
necarboxylate (20f). Using the above procedure for 20e, with
3-fluorobenzyl alcohol provided 20f (67%): mp 70-71 °C
(triturated from ether/hexane); 1H NMR (400 MHz, CDCl3) δ 8.26
(d, J ) 4.8 Hz, 2 H), 7.31 (q, J ) 7.9 Hz, 1 H), 7.11 (d, J ) 7.6
Hz, 1 H), 7.05 (d, J ) 9.6 Hz, 1 H), 6.99 (dt, J ) 2.4, 8.5 Hz, 1
H), 6.53 (t, J ) 4.8 Hz, 1 H), 5.17 (m, 1 H), 5.11 (s, 2 H), 4.10-
4.30 (m, 2 H), 3.33 (t, J ) 6.5 Hz, 2 H), 2.70-2.90 (m, 2 H),
1.70-1.90 (m, 3 H), 1.10-1.30 (m, 2 H) ppm; HRMS (ESI) m/z
345.1722 [(M + H)+; calcd for C18H22FN4O2: 345.1722]. Anal.
(C18H21FN4O2) C, H, N.
4-Methylbenzyl 4-[(2-Pyrimidinylamino)methyl]-1-piperidi-
necarboxylate (20j). 4-Aminomethylpiperidine (56 g, 495 mmol)
and benzaldehyde (52 g, 495 mmol) in toluene (1,100 mL) were
heated to reflux under Dean-Stark conditions for 2 h, until the
accumulation of water ceased. The reaction mixture was cooled,
and the toluene was removed under reduced pressure. To the
resulting oil was added CH2Cl2 (1,100 mL), and the solution was
cooled to 5 °C and treated with 4-methyl-N-(benzyloxycarbonyl-
oxy)succinimide30 (130 g, 495 mmol). After 10 min, the cooling bath
was removed and the resulting reaction mixture stirred for 1 h.
The solvents were evaporated, and the residue was stirred with THF
(550 mL) and 2 M HCl (550 mL) for 1 h. The mixture was
concentrated to remove organics and extracted with ether (3 × 300
mL). The cooled (0 °C) aqueous phase was adjusted to pH 14 with
50% NaOH and extracted with EtOAc. The organic layer was
washed with water and brine and dried over anhydrous Na2SO4,
and the solvent was evaporated to give 42 as an oil. Compound 42
(138 g crude weight) was dissolved in n-butanol/ diisopropylethyl-
amine (1:1 mixture, 380 mL) and treated with 2-chloropyrimidine
(66.0 g, 576 mmol). The reaction mixture was heated to reflux for
3 h, cooled to room temperature, and concentrated to an oil which
was chromatographed on silica (EtOAc to 1% MeOH/EtOAc). This
material was dissolved in 2-propanol (556 mL) with gentle warming
and allowed to cool and crystallize. Upon stirring 3 h at room
temperature, hexane (556 mL) was added dropwise, and the mixture
was stirred for 18 h. The solids were filtered, washed with
2-propanol/hexane (1:1, 50 mL), and dried to give 20j (127 g, 75%
1
overall yield): mp 99-100 °C; H NMR (400 MHz, CDCl3) δ
8.25 (d, J ) 4.8 Hz, 2 H), 7.25 (d, J ) 7.8 Hz, 2 H), 7.16 (d, J )
7.8 Hz, 2 H), 6.51 (t, J ) 4.8 Hz, 1 H), 5.32 (br t, J ) 5.6 Hz, 1
H), 5.07 (s, 2 H), 4.19 (br s, 2 H), 3.32 (t, J ) 6.4 Hz, 2 H), 2.76
(br t, J ) 12.1 Hz, 2 H), 2.35 (s, 3 H), 1.77 (m, 3 H), 1.19 (m, 2
H) ppm; HRMS (ESI) m/z 341.1968 [(M + H)+; calcd for
C19H25N4O2: 341.1972]. Anal. (C19H24N4O2) C, H, N.
4-Ethylbenzyl 4-[(2-Pyrimidinylamino)methyl]-1-piperidin-
ecarboxylate (20k). Using the above procedure for 20b, with
4-ethylbenzyl alcohol provided 20k (42%): mp 132-134 °C
1
(triturated from iPrOH/hexane); H NMR (500 MHz, CD3OD) δ
8.60 (br s, 2 H), 7.28 (d, J ) 8.1 Hz, 2 H), 7.22 (d, J ) 7.8 Hz, 2
H), 7.00 (t, J ) 5.4 Hz, 1 H), 5.09 (s, 2 H), 4.19 (br d, J ) 13.4
Hz, 2 H), 3.43 (d, J ) 6.8 Hz, 2 H), 2.86 (br s, 2 H), 2.66 (q, J )
7.6 Hz, 2 H), 1.93 (m, 1 H), 1.81 (br d, J ) 12.2 Hz, 2 H), 1.15-
1.30 (m, 5 H) ppm; HRMS (ESI) m/z 355.2131 [(M + H)+; calcd
for C20H27N4O2: 355.2129]. Anal. (C20H26N4O2‚HCl) C, H, N.
4-Isopropylbenzyl 4-[(2-Pyrimidinylamino)methyl]-1-pipe-
ridinecarboxylate (20l). Using the above procedure for 20b, with
4-isopropylbenzyl alcohol provided 20l (48%): mp 74-75 °C
(triturated from ether/hexane); 1H NMR (400 MHz, CDCl3) δ 8.25
(d, J ) 4.8 Hz, 2 H), 7.28 (d, J ) 8.1 Hz, 2 H), 7.21 (d, J ) 8.1
Hz, 2 H), 6.52 (t, J ) 4.8 Hz, 1 H), 5.20 (m, 1 H), 5.09 (s, 2 H),
4.20 (br s, 2 H), 3.33 (t, J ) 6.4 Hz, 2 H), 2.91 (sept, J ) 6.9 Hz,
1 H), 2.77 (m, 2 H), 1.78 (m, 3 H), 1.24 (d, J ) 6.9 Hz, 6 H), 1.20
(m, 2 H) ppm; HRMS (ESI) m/z 369.2311 [(M + H)+; calcd for
C21H29N4O2: 369.2285]. Anal. (C21H28N4O2) C, H, N.
4-Fluorobenzyl 4-[(2-Pyrimidinylamino)methyl]-1-piperidi-
necarboxylate (20g). Using the above procedure for 20b, with
4-fluorobenzyl alcohol provided 20g, characterized as the HCl salt
1
(43%): mp 125-127 °C; H NMR (400 MHz, CDCl3) δ 8.25 (d,
J ) 4.8 Hz, 2 H), 7.33 (m, 2 H), 7.03 (m, 2 H), 6.51 (t, J ) 4.8
Hz, 1 H), 5.72 (br t, J ) 5.9 Hz, 1 H), 5.08 (s, 2 H), 4.10-4.30
(m, 2 H), 3.32 (t, J ) 6.2 Hz, 2 H), 2.70-2.90 (m, 2 H), 1.70-
1.90 (m, 3 H), 1.10-1.30 (m, 2 H) ppm; HRMS (ESI) m/z 345.1726
[(M + H)+; calcd for C18H22FN4O2: 345.1722]. Anal. (C18H21-
FN4O2‚HCl) C, H, N.
4-tert-Butylbenzyl 4-[(2-Pyrimidinylamino)methyl]-1-piperidi-
necarboxylate (20m). Using the above procedure for 20e, with
4-tert-butylbenzyl alcohol provided 20m (61%): mp 107-109 °C
(triturated from ether/hexane); 1H NMR (400 MHz, CDCl3) δ 8.26
(d, J ) 4.8 Hz, 2 H), 7.38 (d, J ) 8.2 Hz, 2 H), 7.29 (d, J ) 8.2
Hz, 2 H), 6.52 (t, J ) 4.8 Hz, 1 H), 5.16 (m, 1 H), 5.09 (s, 2 H),
4.10-4.30 (m, 2 H), 3.33 (t, J ) 6.4 Hz, 2 H), 2.70-2.90 (m, 2
H), 1.70-1.90 (m, 3 H), 1.10-1.30 (m, 2 H) ppm; HRMS (ESI)
m/z 383.2439 [(M + H)+; calcd for C22H31N4O2: 383.2442]. Anal.
(C22H30N4O2) C, H, N.
4-Methoxybenzyl 4-[(2-Pyrimidinylamino)methyl]-1-piperidi-
necarboxylate (20n). Using the above procedure for 20e, with
4-methoxybenzyl alcohol provided 20n (55%): mp 95-96 °C
(triturated from ether/hexane); 1H NMR (500 MHz, CDCl3) δ 8.26
(d, J ) 4.9 Hz, 2 H), 7.29 (d, J ) 8.6 Hz, 2 H), 6.88 (d, J ) 8.6
Hz, 2 H), 6.52 (t, J ) 4.9 Hz, 1 H), 5.19 (m, 1 H), 5.05 (s, 2 H),
4.10-4.30 (m, 2 H), 3.81 (s, 2 H), 3.32 (t, J ) 6.4 Hz, 2 H), 2.70-
2-Methylbenzyl 4-[(2-Pyrimidinylamino)methyl]-1-piperidi-
necarboxylate (20h). Using the above procedure for 20e, with
2-methylbenzyl alcohol provided 20h (60%) as an oil: 1H NMR
(400 MHz, CDCl3) δ 8.25 (d, J ) 4.8 Hz, 2 H), 7.32 (d, J ) 7.1
Hz, 1 H), 7.15-7.30 (m, 3 H), 6.51 (t, J ) 4.8 Hz, 1 H), 5.42 (m,
1 H), 5.13 (s, 2 H), 4.10-4.30 (m, 2 H), 3.33 (t, J ) 6.4 Hz, 2 H),
2.70-2.90 (m, 2 H), 2.34 (s, 3 H), 1.70-1.90 (m, 3 H), 1.10-
1.30 (m, 2 H) ppm; HRMS (ESI) m/z 341.1980 [(M + H)+; calcd
for C19H25N4O2: 341.1972].
3-Methylbenzyl 4-[(2-Pyrimidinylamino)methyl]-1-piperidi-
necarboxylate (20i). Using the above procedure for 20e, with
3-methylbenzyl alcohol provided 20i (53%) as an oil: 1H NMR
(400 MHz, CDCl3) δ 8.26 (d, J ) 4.8 Hz, 2 H), 7.10-7.30 (m, 4
H), 6.51 (t, J ) 4.8 Hz, 1 H), 5.27 (m, 1 H), 5.08 (s, 2 H), 4.10-
4.30 (m, 2 H), 3.33 (t, J ) 6.4 Hz, 2 H), 2.70-2.90 (m, 2 H), 2.35
(s, 3 H), 1.70-1.90 (m, 3 H), 1.10-1.30 (m, 2 H) ppm; HRMS
(ESI) m/z 341.1981 [(M + H)+; calcd for C19H25N4O2: 341.1972].