Journal of Medicinal Chemistry
Article
3-(2(S)-Azetidinylmethoxy)-5-[3-(2-methoxyethyl)-5-isoxazolyl]-
pyridine (24). To a solution of compound 14 (150 mg, 0.4 mmol) in
anhydrous DMF (3 mL) were added NaH (32 mg, 0.8 mmol, 60% in
oil) under argon with ice cooling. After stirring at rt for 30 min, CH3I
was added. The reaction mixture was quenched with satd NH4Cl and
extracted with EtOAc (20 mL). The organic phase was washed with
water (2 × 15 mL), dried over Na2SO4, and concentrated. The residue
was purified by CC on SiO2 (hexane/EtOAc) to obtain 2-[[5-[3-(2-
methoxyethyl)isoxazol-5-yl]pyridin-3-yloxy]methyl]azetidine-1-car-
boxylic acid tert-butyl ester (130 mg, 84%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) δ 8.56 (s, 1H), 8.33 (s, 1H), 7.56 (s, 1H), 6.54 (s,
1H), 4.50 (m, 1H), 4.35 (m, 1H), 4.15 (dd, 1H, J = 2.4, 10.0 Hz), 3.85
(t, 2H, J = 7.6 Hz), 3.66 (t, 2H, J = 6.2 Hz), 3.34 (s, 3H), 2.95 (t, 2H, J
= 6.4 Hz), 2.35−2.22 (m, 2H), 1.36 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 166.7, 152.5, 156.3, 155.2, 139.7, 139.5, 124.3, 117.6, 101.3,
79.9, 70.5, 58.8, 47.4, 28.5, 26.8, 19.2.
mg, 0.05 mmol), and Et3N (0.17 mL, 1.25 mmol) in 10 mL of
anhydrous CH2Cl2 was added under argon with ice cooling p-TsCl
(130 mg, 0.65 mmol). The reaction mixture was stirred overnight at rt.
Purification by CC on SiO2 (hexane/EtOAc) afforded the
1
intermediate p-toluenesulfonate (240 mg, 86%) as a colorless oil. H
NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.28 (s, 1H), 7.66 (d, 2H, J
= 8.0 Hz), 7.49 (s, 1H), 7.21 (d, 2H, J = 7.6 Hz), 6.37 (s, 1H), 4.44
(m, 1H), 4.31 (m, 1H), 4.09 (dd, 1H, J = 1.2, 10.0 Hz), 4.02 (t, 2H, J
= 6.0 Hz), 3.79 (t, 2H, J = 7.4 Hz), 2.67 (t, 2H, J = 7.4 Hz), 2.30 (s,
3H), 2.26−2.21 (m, 2H), 1.99 (m, 2H), 1.30 (s, 9H). 13C NMR (100
MHz, CDCl3) δ 166.7, 163.0, 156.1, 155.1, 144.8, 139.6, 139.2, 132.7,
129.8, 127.7, 117.3, 100.6, 79.6, 69.2, 68.8, 60.0, 53.5, 47.1, 43.9, 28.3,
27.1, 22.1, 21.5, 19.0. To a solution of the above p-toluenesulfonate
(240 mg, 0.44 mmol) in 2 mL of anhydrous THF was added at rt 1 M
TBAF in THF (3 mL, 3 mmol). After stirring for 3 h, the reaction
mixture was quenched with satd NH4Cl and extracted with EtOAc (2
× 15 mL). The combined organic phases were washed with brine,
dried over Na2SO4, and evaporated. The residue was purified by CC
on SiO2 (CH2Cl2/MeOH 98:2) to afford the desired product (110
The title compound was obtained from the preceding intermediate
employing method B and gradient I; colorless oil; yield 45%; purity
20
1
99.7%; [α]D −3.5 (c = 0.97, MeOH). H NMR (400 MHz, D2O) δ
8.91 (s, 1H), 8.67 (d, 1H, J = 1.6 Hz), 8.56 (s, 1H), 7.09 (s, 1H), 5.01
(m, 1H), 4.64 (d, 2H, J = 3.6 Hz), 4.12 (m, 2H), 3.79 (t, 2H, J = 6.0
Hz), 3.34 (s, 3H), 3.02 (t, 2H, J = 6.0 Hz), 2.71 (q, 2H, J = 8.4 Hz).
13C NMR (100 MHz, D2O) δ 163.3, 162.6, 161.7 (TFA), 156.3, 131.7,
1
mg, 64%) as a colorless oil. H NMR (400 MHz, CDCl3) δ 8.51 (s,
1H), 8.30 (s, 1H), 7.54 (s, 1H), 6.45 (s, 1H), 4.45 (dt, 1H, JH−F = 46.8
Hz, JH−H = 5.8 Hz), 4.46 (m, 1H), 4.33 (m, 1H), 4.12 (dd, 1H, J = 2.8,
10.0 Hz), 3.81 (t, 2H, J = 7.6 Hz), 2.79 (t, 2H, J = 7.6 Hz), 2.30 (m,
2H), 2.04 (m, 2H), 1.32 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
166.8, 163.6, 156.2, 155.2, 139.7, 139.3, 124.1, 117.5, 100.7, 82.7 (d,
JC−F = 164.8 Hz), 79.7, 68.9, 60.2, 53.6, 43.9, 28.8 (d, JC−F = 20.1 Hz),
28.4, 22.1 (d, JC−F = 5.5 Hz), 19.0.
130.1, 127.4, 127.3, 115.9 (TFA), 104.1, 69.1, 67.7, 58.2, 57.4, 43.3,
40.5, 25.3, 19.8. Anal. Calcd for C15H19N3O3·2.05TFA·1H2O (FW
541): C, 42.40; H, 4.29; F, 21.59; N, 7.77. Found: C, 42.21; H, 4.09; F,
21.41; N, 7.82.
The title compound was obtained from the preceding intermediate
3-(2(S)-Azetidinylmethoxy)-5-[3-(3,3-difluoropropyl)-5-
isoxazolyl]pyridine (25). To a solution of oxalyl chloride (54 μL, 0.61
mmol) in anhydrous CH2Cl2 (5 mL) was added dropwise at −78 °C, a
solution of anhydrous DMSO (54 μL, 0.72 mmol) in anhydrous
CH2Cl2 (2 mL). This Swern reagent solution was stirred for another
15 min at the same temperature. A solution of alcohol 16 (140 mg,
0.36 mmol) in anhydrous CH2Cl2 (2 mL) was added in 10 min. After
stirring for 20 min, Et3N (310 μL, 2.2 mmol) was added within 5 min.
After maintaining the temperature for another 20 min, the reaction
mixture was warmed slowly to rt. The mixture was washed with water
(2 × 5 mL), dried over Na2SO4, and concentrated to obtain the
aldehyde, which was carried on without further purification.
employing method B and gradient II; colorless oil; yield 97%; purity
20
1
99.4%; [α]D −3.2 (c = 1.99, MeOH). H NMR (400 MHz, D2O) δ
8.89 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 7.07 (s, 1H), 5.03 (m, 1H),
4.66−4.60 (m, 3H), 4.50 (t, 1H, J = 5.4 Hz), 4.15 (m, 2H), 2.87 (t,
2H, J = 7.4 Hz), 2.74 (t, 2H, J = 8.4 Hz), 2.17−2.04 (m, 2H). 13C
NMR (100 MHz, D2O) δ 165.4, 163.0, 162.3 (TFA), 156.5, 132.4,
130.9, 127.6, 127.1, 115.5 (TFA), 104.3, 83.9 (d, JC−F = 158.4 Hz),
68.0, 58.5, 43.7, 27.9 (d, JC−F = 19.5 Hz), 21.4 (d, JC−F = 5.6 Hz), 20.2.
19F NMR (376 MHz, D2O) δ −74.2 (TFA), −217.8. Anal. Calcd for
C15H18FN3O2·1.65TFA·1.5H2O (FW 506): C, 43.40; H, 4.51; F,
22.32; N, 8.30. Found: C, 43.36; H, 4.13; F, 22.05; N, 7.91.
To a solution of triethylamine trihydrofluoride (120 μL, 0.72 mmol)
in CH2Cl2 (2 mL) was successively added XtalFluor-E (125 mg, 0.54
mmol). A solution of the crude aldehyde in anhydrous CH2Cl2 (2 mL)
was slowly added, and the resulting mixture was stirred at rt for 2 h
under argon. The reaction mixture was quenched with 5% aqueous
Na2CO3 solution and extracted with CH2Cl2 (20 mL). The combined
organic layers were washed with H2O, brine, dried over Na2SO4, and
evaporated. The residue was purified by CC on SiO2 (hexane/acetone
4:1) to afford the desired product (105 mg, 71%, two steps) as a
4-[2-[5-[5-(2(S)-Azetidinylmethoxy)-3-pyridinyl]-3-isoxazolyl]-
ethyl]morpholine (27). This compound was obtained from 14
employing methods D, E, and B and gradient II; colorless oil; yield
20
63% over three steps; purity 99.4%; [α]D −4.5 (c = 0.62, MeOH).
1H NMR (400 MHz, D2O) δ 8.95 (s, 1H), 8.70 (s, 1H), 8.58 (s, 1H),
7.16 (s, 1H), 5.04−5.02 (m, 1H), 4.65 (d, 2H, J = 2.0 Hz), 4.18−4.10
(m, 1H), 3.85 (t, 2H, J = 12.4 Hz), 3.68−3.62 (m, 4H), 3.37−3.26 (m,
4H), 2.73 (q, 2H, J = 12.4 Hz). 13C NMR (100 MHz, D2O) δ 163.4,
162.2 (TFA), 160.8, 156.3, 131.9, 130.4, 127.3, 127.1, 115.8 (TFA),
103.9, 63.2, 58.1, 53.9, 51.4, 43.3, 20.2, 19.8. Anal. Calcd for
C18H24N4O3·2.95TFA·0.65H2O (FW 692): C, 41.45; H, 4.11; F,
24.28; N, 8.09. Found: C, 41.07; H, 3.73; F, 23.91; N, 7.90.
1
colorless oil. H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.36 (s,
1H), 7.59 (s, 1H), 6.50 (s, 1H), 5.94 (tt, 1H, JH−H = 4.2 Hz, JH−F
=
56.4 Hz), 4.51 (m, 1H), 4.38 (m, 1H), 4.17 (dd, J = 2.8, 10.0 Hz), 3.87
(t, 2H, J = 7.6 Hz), 2.89 (t, 2H, J = 8.4 Hz), 2.37−2.20 (m, 4H), 1.38
(s, 9H). 13C NMR (100 MHz, CDCl3) δ 167.3, 162.8, 156.4, 155.3,
140.0, 139.5, 124.1, 117.7, 116.2 (t, JC−F = 240.0 Hz), 100.6, 80.0, 69.1,
60.1, 47.3, 32.3 (t, JC−F = 21.8 Hz), 28.5, 19.3 (t, JC−F = 6.4 Hz), 19.2.
19F NMR (376 MHz, CDCl3) δ −117.4 (dt, 2F, JH−F = 56.6, 17.1 Hz).
The title compound was obtained from the preceding intermediate
employing method B and gradient II; colorless oil; yield 65%; purity
4-[2-[5-[5-(2(S)-Pyrrolidinylmethoxy)-3-pyridinyl]-3-isoxazolyl]-
ethyl]morpholine (28). This compound was obtained from 19
employing methods D, E, and B and gradient II; colorless oil; yield
20
57% over three steps; purity 98.8%; [α]D −1.4 (c = 0.36, MeOH).
1H NMR (400 MHz, D2O) δ 8.89 (s, 1H, J = 2.0 Hz), 8.64 (d, 1H, J =
2.0 Hz), 8.54 (s, 1H), 7.14 (s, 1H), 4.68−4.66 (m, 1H), 4.47 (m, 1H),
4.15−4.11 (m, 3H), 3.83 (t, 2H, J = 12.4 Hz), 3.66−3.60 (m, 4H),
3.42 (t, 2H, J = 7.2 Hz), 3.35−3.28 (m, 4H), 2.32−2.30 (m, 1H),
2.17−2.09 (m, 1H), 2.00−1.98 (m, 1H). 13C NMR (100 MHz, D2O)
δ 163.3, 162.2 (TFA), 160.8, 156.2, 131.7, 130.2, 127.3, 127.1, 115.6
(TFA), 103.9, 99.6, 67.8, 63.2, 57.9, 53.9, 51.4, 45.6, 25.3, 23.0, 20.2.
Anal. Calcd for C19H26N4O3·3TFA·0.5H2O: H, 42.32; C, 4.26; F, 24.1;
N, 7.90. Found: C, 42.34; H, 4.15; F, 24.07; N, 7.79.
20
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99.7%; [α]D −2.8 (c = 1.2, MeOH). H NMR (400 MHz, D2O) δ
8.90 (s, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 6.05 (t, 1H, JH−F = 56.2 Hz),
5.04 (m, 1H), 4.65 (d, 2H, J = 3.2 Hz), 4.15 (m, 2H), 2.95 (t, 2H, J =
5.8 Hz), 2.74 (q, 2H, J = 8.4 Hz), 2.30 (m, 2H). 13C NMR (100 MHz,
D2O) δ 164.3, 162.8, 162.3 (TFA), 132.2, 130.6, 127.1, 126.7, 116.6 (t,
JC−F = 240.0 Hz), 115.8 (TFA), 103.8, 67.6, 58.1, 43.3, 30.8 (t, JC−F
=
21.4 Hz), 19.9, 18.0 (t, JC−F = 6.6 Hz). 19F NMR (376 MHz, D2O) δ
−75.6 (TFA), −117.3 (dt, 2F, JH−F = 56.4, 18.8 Hz). Anal. Calcd for
C15H17F2N3O2·1.9TFA·0.75H2O (FW 539): C, 41.86; H, 3.81; F,
27.12; N, 7.79. Found: C, 42.01; H, 3.84; F, 27.23; N, 7.61.
Ethylcarbamic Acid 2-[5-[5-(2(S)-Azetidinylmethoxy)-3-pyridinyl]-
3-isoxazolyl]ethyl Ester (29). This compound was obtained from 14
and ethyl isocyanate employing methods F and B and gradient I;
cfolorless oil; yield 77% over two steps; purity 99.5%; [α]D20 −3.6 (c =
1
0.39, MeOH). H NMR (400 MHz, D2O) δ 8.87 (s, 1H), 8.70 (s,
3-(2(S)-Azetidinylmethoxy)-5-[3-(3-fluoropropyl)-5-isoxazolyl]-
pyridine (26). To the solution of 16 (200 mg, 0.5 mmol), DMAP (6
1H), 8.50 (s, 1H), 7.11 (s, 1H), 5.03−4.99 (m, 1H), 4.63 (d, 2H, J =
10005
dx.doi.org/10.1021/jm301177j | J. Med. Chem. 2012, 55, 9998−10009