Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 24 8565
13C NMR (100 MHz, CDCl3) δ 162.48, 160.40, 158.33, 148.27,
138.66, 138.29, 129.47, 127.96, 117.77, 113.02, 111.12, 48.19, 45.31.
HRMS calcd for C18H19N4 291.16097, [M þ H]þ found 291.1033.
Anal. (C18H18N4) C, H, N.
DMSO-d6) δ 162.27, 158.00, 157.26, 145.46, 138.81, 138.29,
136.48, 127.12, 126.97, 117.43, 110.18, 109.61, 44.08, 43.63.
HRMS calcd for C17H17ClN5 326.11725 [M þ H]þ, found
326.11638. Anal. (C17H16ClN5) C, H, N.
N-(4-((6-Chloropyridin-2-ylamino)methyl)benzyl)pyrimidin-
2-amine (10g). Starting from aldehyde 9 (0.21 g, 1.0 mmol) and
6-chloro-2-aminopyridine (0.14 g, 1.1 mmol) by treatment with
sodium triacetoxyborohydride (0.32 g, 1.5 mmol) and HOAc
(0.064 mL, 1.1 mmol), general procedure A gave 10g (0.22 g,
N-(4-((2-Fluorophenylamino)methyl)benzyl)pyrimidin-2-amine
(10b). Starting from aldehyde 9 (53.4 mg, 0.25 mmol) and
2-fluoroaniline (29.2 mg, 0.26 mmol), general procedure A
gave 10b (44.2 mg, 57%) as a white solid: mp 126-128 ꢀC
(dec). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 4.8 Hz, 2H),
7.35 (s, 4H), 7.01-6.94 (m, 2H), 6.69-6.61 (m, 2H), 6.57 (t,
J = 4.8, 4.8 Hz, 1H), 5.52 (bs, 1H), 4.65 (d, J = 6.0 Hz, 2H),
4.36 (s, 2H), 4.32 (bs, 1H). 13C NMR (100 MHz, CDCl3) δ
162.47, 158.26, 151.68 (d, J = 237.5 Hz), 138.58 (d, J = 32.6 Hz),
136.75, 136.64, 128.02, 127.81, 124.76, 116.98, 114.55, 112.44,
110.98, 47.70, 45.29. HRMS calcd for C18H18FN4 309.15155
[M þ H]þ, found 309.15050. Anal. (C18H17FN4) C, H, N.
N-(4-((Pyridin-2-ylamino)methyl)benzyl)pyrimidin-2-amine
(10c). Starting from aldehyde 9 (0.43 g, 2.0 mmol) and 2-ami-
nopyridine (0.23 g, 2.4 mmol) by treatment with sodium triace-
toxyborohydride (0.64 g, 3.0 mmol) and HOAc (0.13 mL,
2.2 mmol), general procedure A gave white solid, which was
washed by methanol to afford 10c (0.35 g, 61%) as a white solid:
mp 172 -174 ꢀC (dec). 1H NMR (400 MHz, CDCl3) δ 8.30 (d,
J = 4.8 Hz, 2H), 8.11 (d, J = 4.8 Hz, 1H), 7.43-7.39 (m, 1H),
7.34 (s, 4H), 6.62-6.58 (m, 1H), 6.57 (t, J = 4.8, 4.8 Hz, 1H),
6.37 (d, J = 8.4 Hz, 1H), 5.41 (bs, 1H), 4.88 (bs, 1H), 4.64 (d, J =
6.0 Hz, 2H), 4.50 (d, J = 6.0 Hz, 2H). 13C NMR (150 MHz,
CDCl3) δ 162.48, 158.65, 158.33, 148.05, 138.36, 138.29, 137.90,
127.96, 127.86, 113.37, 111.14, 107.11, 46.24, 45.30. HRMS
calcd for C17H18N5 292.15622 [M þ H]þ, found 292.15518.
Anal. (C17H17N5) C, H, N.
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67%) as a white solid: mp 148-150 ꢀC (dec). H NMR (400
MHz, DMSO-d6) δ 8.24 (d, J = 4.8 Hz, 2H), 7.67 (t, J = 6.0 Hz,
1H), 7.43 (t, J = 6.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.25 (s,
4H), 6.55 (t, J = 4.8 Hz, 1H), 6.49 (d, J = 7.2 Hz, 1H), 6.42 (d,
J = 8.0 Hz, 1H), 4.46 (d, J = 6.4 Hz, 2H), 4.37 (d, J = 6.0 Hz,
2H). 13C NMR (100 MHz, DMSO-d6) δ 162.26, 158.89, 157.97,
148.39, 139.59, 138.93, 137.89, 127.24, 126.99, 110.20, 110.17,
106.42, 43.99, 43.62. HRMS Calcd for C17H17ClN5 326.11725
[M þ H]þ, found 326.11640. Anal. (C17H16ClN5) C, H, N.
N-(4-((2-(Pyrrolidin-1-yl)phenylamino)methyl)benzyl)pyrimidin-
2-amine (10h). A solution of boc-protected 2-(pyrrolidin-1-yl)ani-
line (0.26 g, 1.0 mmol) in CH2Cl2 (5 mL) was treated with HCl
solution in dioxane (5 mL, 4 M in dioxane). After being stirred for
6 h at room temperature, the solvent was removed under reduced
pressure to afford a yellow solid (0.27 g). The yellow solid prepared
above was dissolved in 1,2-dichloroethane (20 mL), to which was
added aldehyde 9 (0.20 g, 0.9 mmol) and HOAc (0.06 mL, 1.0
mmol). The resulting light-brown solution was treated with triace-
toxyborohydride (0.32 mg, 1.5 mmol), and general procedure A
gave the title product 10h (0.31 g, 85%, 2 steps) as a pale-white solid:
mp 124-126 ꢀC (dec). 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J =
4.8 Hz, 2H), 7.33-7.39 (m, 4H), 7.05 (dd, J = 7.6, 1.6 Hz, 1H), 6.95
(td, J = 7.6, 1.6 Hz, 1H), 6.70 (td, J = 7.6, 1.6 Hz, 1H), 6.59 (dd,
J = 7.6, 1.6 Hz, 1H), 6.55 (t, J = 4.8 Hz, 1H), 5.68 (bs, 1H), 4.91
(bs, 1H), 4.65 (d, J = 6.0 Hz, 2H), 4.36 (d, J = 5.2 Hz, 2H),
3.04-3.07 (m, 4H), 1.88-1.95 (m, 4H). 13C NMR (100 MHz,
CDCl3) δ 162.48, 158.22, 143.51, 139.23, 137.97, 137.42, 127.93,
127.69, 124.22, 118.56, 117.10, 110.86, 110.47, 51.42, 48.22, 45.34,
24.23. HRMS calcd for C22H26N5 360.21882 [M þ H]þ, found
360.21805. Anal. (C22H25N5) C, H, N.
N-(4-((5-Fluoropyridin-2-ylamino)methyl)benzyl)pyrimidin-2-
amine (10d). Starting from aldehyde 9 (0.22 mg, 1.0 mmol) and
5-fluoro-2-aminopyridin (0.12 g, 1.0 mmol) by treatment with
sodium triacetoxyborohydride (0.32 g, 1.5 mmol) and HOAc
(0.06 mL, 1.0 mmol), general procedure A gave 10d (0.28 mg,
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90%) as a white solid: mp 167-169 ꢀC (dec). H NMR (400
MHz, CDCl3) δ 8.29 (d, J = 4.8 Hz, 2H), 7.96 (d, J = 2.8 Hz,
1H), 7.33 (s, 4H), 7.21-7.16 (m, 1H), 6.57 (t, J = 4.8, 4.8 Hz,
1H), 6.32 (dd, J = 9.2, 3.2 Hz, 1H), 5.49 (bs, 1H), 4.85 (bs, 1H),
4.63 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 6.0 Hz, 2H). 13C NMR
(150 MHz, CDCl3) δ 162.43, 158.35, 155.44, 153.72, 138.38,
138.26, 134.80, 127.96, 127.88, 125.61, 111.19, 107.40, 46.73,
45.30. HRMS calcd for C17H17FN5 310.14680 [M þ H]þ, found
310.14588. Anal. (C17H16FN5) C, H, N.
N-(4-((3-(Pyrrolidin-1-yl)phenylamino)methyl)benzyl)pyrimidin-
2-amine (10i). The boc-protected 3-(pyrrolidin-1-yl)aniline (0.29 mg,
1.1 mmol) was converted to 10i (0.19 g, 58%, 2 steps) according to
the procedure described above for 10h as a pale-white solid: mp
136-138 ꢀC (dec). 1H NMR (400 MHz, CDCl3) δ 8.19 (bs, 2H),
7.38-7.33 (m, 4H), 7.06 (t, J = 8.0 Hz, 1H), 6.50 (t, J = 4.8, 4.8 Hz,
1H), 6.28 (t, J = 5.6, 5.6 Hz, 1H), 6.03 (dd, J = 6.0, 2.0 Hz, 2H),
5.88 (t, J = 2.0, 2.0 Hz, 1H), 4.64 (d, J = 5.6, 5.6 Hz, 2H), 4.34 (s,
2H), 4.01 (bs, 1H), 3.30-3.24 (m, 4H), 2.01-1.95 (m, 4H). 13C
NMR (100 MHz,CDCl3) δ 162.41, 158.14, 149.36, 149.15, 139.10,
138.04, 129.97, 127.90, 110.77, 102.24, 101.17, 96.34, 48.23, 47.65,
45.29, 25.54. HRMS calcd for C22H26N5 360.21882 [M þ H]þ,
found 360.21805. Anal. (C22H25N5) C, H, N.
N-(4-((4-(Pyrrolidin-1-yl)phenylamino)methyl)benzyl)pyrimidin-
2-amine (10j). The boc-protected4-(pyrrolidin-1-yl)aniline(0.26g,
1.0 mmol) was converted to 10j (0.30 g, 92%, 2 steps) according to
the procedure described above for 10h as a pale-white solid: mp
149-153 ꢀC (dec). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 4.8
Hz, 2H), 7.31-7.37 (m, 4H), 6.65 (bs, 2H), 6.57 (t, J = 4.8 Hz,
1H), 6.55 (bs, 2H), 5.41 (bs,1H), 4.63 (d, J = 5.6 Hz, 2H), 4.27 (bs,
2H), 3.63 (bs, 1H), 3.20 (bs, 4H), 1.95-1.99 (m, 4H). 13C NMR
(100 MHz, CDCl3) δ 162.48, 158.26, 142.07, 139.21, 138.00,
128.04, 127.87, 115.19, 113.31, 110.97, 49.63, 48.51, 25.44. HRMS
calcd for C22H26N5 360.21882 [M þ H]þ, found 360.21829. Anal.
(C22H25N5) C, H, N.
N-(4-((6-Fluoropyridin-2-ylamino)methyl)benzyl)pyrimidin-2-
amine (10e). Starting from aldehyde 9 (0.43 g, 2.0 mmol) and
6-fluoro-2-aminopyridine (0.25 g, 2.4 mmol) by treatment with
sodium triacetoxyborohydride (0.64 g, 3.0 mmol) and HOAc
(0.12 mL, 2.2 mmol), general procedure A gave 10e (0.46 g,
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73%) as a white solid: mp 170-171 ꢀC (dec). H NMR (400
MHz, CDCl3) δ 8.24 (d, J = 4.4 Hz, 2H), 7.66 (t, J = 6.2 Hz,
1H), 7.51-7.40 (m, 2H), 7.24 (s, 4H), 6.55 (t, J = 4.8 Hz, 1H),
6.34 (dd, J = 8.0, 2.4 Hz, 1H), 6.08 (dd, J = 8.0, 2.8 Hz, 1H),
4.45 (d, J = 6.4 Hz, 2H), 4.35 (d, J = 6.0 Hz, 2H). 13C NMR
(150 MHz, CDCl3) δ 162.77, 162.26, 158.22, 157.96, 141.42,
138.88, 137.99, 127.14, 126.99, 110.17, 104.46, 93.52, 43.96,
43.62. HRMS calcd for C17H18FN5 310.14680 [M þ H]þ, found
310.14954. Anal. (C17H16FN5) C, H, N.
N-(4-((5-Chloropyridin-2-ylamino)methyl)benzyl)pyrimidin-2-
amine (10f). Starting from aldehyde 9 (0.22 g, 1.0 mmol) and
5-chloro-2-aminopyridine (0.14 g, 1.1 mmol) by treatment
with sodium triacetoxyborohydride (0.32 g, 1.5 mmol) and
HOAc (0.06 mL, 1.1 mmol), general procedure A gave 10f
(0.20 g, 60%) as a white solid: mp 163-165 ꢀC (dec). 1H
NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 4.8 Hz, 2H), 7.93
(d, J = 2.8 Hz, 1H), 7.66 (t, J = 6.4 Hz, 1H), 7.41 (dd, J =
8.8, 2.4 Hz, 1H), 7.25 (d, J = 6.0 Hz, 1H), 7.23 (s, 4H), 6.55 (t,
J = 4.8, 4.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 4.44 (d, J = 6.4
Hz, 2H), 4.39 (d, J = 6.4 Hz, 2H). 13C NMR (150 MHz,
N,N0-(1,4-Phenylenebis(methylene))bis(5-fluoropyrimidin-2-
amine) (13). A mixture of 2-chloro-5-fluoropyrimidine (0.92 g,
6.9 mmol), 1,4-phenylenedimethanamine (0.45 g, 3.3 mmol),
and cesium carbonate (2.58 g, 7.9 mmol) in DMF (25 mL) was
stirred at 100 ꢀC overnight. After removing the solvent under
reduced pressure, the yellow residue was washed with H2O and