Journal of Medicinal Chemistry
Article
(m, 2H), 4.41 (s, 2H), 4.09 (m, 1H), 4.02−3.95 (m, 1H), 3.45 (t, 2H,
J = 6.8 Hz), 2.64−2.52 (m, 2H), 1.53−1.48 (m, 2H), 1.28−1.23 (m,
6H), 0.83−0.80 (m, 3H); 13C NMR (100 MHz, D2O) δ 170.8, 170.4,
161.8 (TFA), 120.2, 115.8 (TFA), 94.1, 70.7, 67.5, 62.8, 58.2, 43.1,
30.9, 28.6, 24.9, 21.8, 19.9, 13.0. Anal. Calcd for
C14H24N2O3·1.0TFA·0.05H2O (FW 385): C, 50.14; H, 6.60; N,
7.31; F, 14.87. Found: C, 49.93; H, 6.26; N, 7.18; F, 14.56.
19.8. Anal. Calcd for C8H12N2O3·1.4TFA (FW 344): C, 37.73; H,
3.93; N, 8.15; F, 23.21. Found: C, 37.82; H, 4.10; N, 8.47; F, 23.26.
5-[(2(S)-Azetidinyl)methoxy]-3-(phenoxymethyl)isoxazole
(32). The title compound was obtained from 29 employing Method A
and Gradient II. Colorless solid; yield 38%; purity 98.9%. [α]D20 −1.0
1
(c = 1.1, MeOH); H NMR (400 MHz, CD3OD) δ 7.30−7.26 (m,
2H), 7.00−6.94 (m, 3H), 5.69 (s, 2H), 4.90 (m, 1H), 4.59 (m, 1H),
4.52 (m, 1H), 4.09 (m, 1H), 4.00 (m, 1H), 2.62 (m, 1H); 13C NMR
(100 MHz, CD3OD) δ 172.6, 163.0, 160.1 (TFA), 157.7, 128.8, 120.8,
115.9 (TFA), 114.1, 77.4, 69.9, 61.3, 58.0, 42.8, 19.9. Anal. Calcd for
C14H16N2O3·1.55TFA·0.45H2O (FW 445): C, 46.14; H, 4.18; N, 6.29;
F, 19.85. Found: C, 45.98; H, 4.04; N, 6.39; F, 20.03.
3-[(2(S)-Azetidinyl)methoxy]-5-[(cyclopropylmethoxy)-
methyl]isoxazole (21). This compound was obtained from 17 and
(bromomethyl)cyclopropane employing Methods F and A and
Gradient II. Colorless oil; yields of the individual steps 77% and
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59%; purity 99.8%. [α]D −0.1 (c = 2.8, MeOH); H NMR (400
MHz, D2O) δ 6.25 (s, 1H), 4.93 (m, 1H), 4.60 (s, 2H), 4.57−4.51 (m,
2H), 4.12 (m, 1H), 4.05 (m, 1H), 3.40 (d, 2H, J = 7.2 Hz), 2.69−2.62
(m, 2H), 1.04 (m, 1H), 0.56−0.52 (m, 2H), 0.22−0.18 (m, 2H); 13C
NMR (100 MHz, D2O) δ 170.9, 170.2, 162.2 (TFA), 115.9 (TFA),
94.6, 75.7, 67.6, 62.2, 58.4, 43.2, 19.9, 9.2, 2.1. Anal. Calcd for
C12H18N2O3·1.1TFA·0.65H2O (FW 378): C, 45.43; H, 5.48; N, 7.46;
F, 16.70. Found: C, 45.20; H, 5.19; N, 7.31; F, 16.84.
3-(Phenoxymethyl)-5-[(2(S)-pyrrolidinyl)methoxy]isoxazole
(33). This compound was obtained employing Method A and
20
Gradient II. Colorless solid; yield 75%; purity 100%. [α]D −1.7 (c
= 1.5, MeOH); 1H NMR (400 MHz, CD3OD) δ 7.30−7.26 (m, 2H),
7.00−6.94 (m, 3H), 5.69 (s, 2H), 5.04 (s, 2H), 4.62 (m, 1H), 4.40 (m,
1H), 4.06 (m, 1H), 3.36 (t, 2H, J = 7.2 Hz), 2.26 (m, 1H), 2.13−2.05
(m, 2H), 1.87 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 172.3,
162.8, 160.0 (TFA), 157.5, 128.6, 120.6, 115.7 (TFA), 113.8, 77.1,
69.8, 61.1, 57.7, 45.0, 25.1, 22.7. Anal. Calcd for
C15H18N2O3·1.2TFA·0.35H2O (FW 417): C, 50.06; H, 4.80; N,
6.71; F, 16.38. Found: C, 50.22; H, 4.73; N, 6.67; F, 16.14.
3-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-
methylisoxazole (23). This compound was obtained from 1-(tert-
butoxycarbonyl)-2(S)-azetidinylmethanol and 3-hydroxy-5-methylisox-
1
azole as a pale-yellow solid in 67% yield employing Method B. H
NMR (400 MHz, CDCl3) δ 5.63 (s, 1H), 4.48−4.42 (m, 2H), 4.29−
4.26 (m, 2H), 3.83 (t, 2H, J = 9.4 Hz), 2.31−2.16 (m, 5H), 1.39 (s,
9H); 13C NMR (100 MHz, D2O) δ 172.3, 170.6, 156.3, 93.1, 79.8,
69.9, 60.2, 47.0, 28.5, 21.9, 19.0, 13.0.
3-[(2(S)-Azetidinyl)methoxy]-5-methylisoxazole (24). This
compound was obtained employing Method A and Gradient III.
Colorless oil; yield 58%; purity 99.7%. [α]D20 −0.2 (c = 2.4, MeOH);
1H NMR (400 MHz, D2O) δ 5.90 (s, 1H), 4.98 (m, 1H), 4.46 (m,
1H), 4.12 (m, 1H), 4.00 (m, 1H), 2.66−2.58 (m, 2H), 2.30 (s, 3H);
13C NMR (100 MHz, D2O) δ 172.3, 171.2, 162.1 (TFA), 115.9
3-(Anilinomethyl)-5-[(2(S)-azetidinyl)methoxy]isoxazole
(34). The title compound was obtained from 29 employing Methods
D, G, and A and Gradient III. Pale-yellow oil; yields of the individual
steps 76%, quantitative and 35%; purity 99.9%. [α]D20 −2.7 (c = 0.79,
1
MeOH); H NMR (400 MHz, D2O) δ 7.52 (t, 2H, J = 7.6 Hz), 7.44
(t, 1H, J = 7.4 Hz), 7.35 (d, 2H), 5.61 (s, 1H), 4.94−4.92 (m, 1H),
4.63 (s, 1H), 4.58−4.53 (m, 2H), 4.17−4.10 (m, 1H), 4.06−3.99 (m,
1H), 2.70−2.60 (m, 2H); 13C NMR (100 MHz, D2O) δ 172.8, 162.5
(TFA), 159.0, 135.7, 129.8, 127.8, 120.7, 115.9 (TFA), 78.8, 69.9,
58.0, 44.6, 43.2, 19.7. Anal. Calcd for C14H17N3O2·1.8TFA·1.25 H2O
(FW 487): C, 43.40; H, 4.41; N, 8.63; F, 21.06. Found: C, 43.34; H,
4.27; N, 8.76; F, 21.09.
(TFA), 92.4, 67.3, 58.5, 43.2, 19.8, 11.6. Anal. Calcd for
C8H12N2O2·1.15TFA·0.55H2O (FW 312): C, 40.01; H, 4.64; N,
9.06; F, 21.20. Found: C, 39.88; H, 4.43; N, 9.11; F, 21.41.
5-[(2(S)-Azetidinyl)methoxy]-3-[(4-fluoroanilino)methyl]-
isoxazole (35). This compound was obtained from 29 employing
Methods D, G, and A and Gradient III. Pale-yellow oil; yields of the
individual steps 76%, quantitative, and 74%; purity 99.5%. [α]D20 −2.0
5-[(1-(tert-Butoxycarbonyl)-2(S)-azetidinyl)methoxy]-
isoxazole-3-carboxylic Acid Ethyl Ester (27). This compound was
obtained from 1-(tert-butoxycarbonyl)-2(S)-azetidinylmethanol and 5-
hydroxyisoxazole-3-carboxylic acid ethyl ester (Princeton Bio) as a
1
(c = 1.4, MeOH); H NMR (400 MHz, D2O) δ 7.13−7.08 (m, 4H),
1
5.58 (s, 1H), 4.92 (m, 1H), 4.63 (s, 1H), 4.58−4.54 (m, 2H), 4.44 (s,
2H), 4.13 (m, 1H), 4.02 (m, 1H), 2.68−2.59 (m, 2H); 13C NMR (100
MHz, D2O) δ 172.5, 162.2, 162.2 (TFA), 158.7 (d, JC−F = 20.3 Hz),
137.5, 119.1 (d, JC−F = 8.3 Hz), 115.9 (TFA), 115.9 (d, JC−F = 238.4
Hz), 78.3, 69.8, 58.0, 43.2, 42.5, 19.7. Anal. Calcd for
C14H16FN3O2·1.4TFA·0.55H2O (FW 447): C, 45.16; H, 4.17; N,
9.40; F, 22.11. Found: C, 45.17; H, 4.13; N, 9.35; F, 22.09.
pale-yellow solid in 55% yield employing Method B. H NMR (400
MHz, CDCl3) δ 5.71 (s, 1H), 4.52 (m, 2H), 4.41 (q, 2H, J = 7.2 Hz),
4.31 (dd, 1H, J = 2.4, 10.0 Hz), 3.89−3.84 (m, 2H), 1.41 (s, 9H), 1.25
(t, 3H, J = 7.2 Hz).
5-[(1-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl)methoxy]-
isoxazole-3-carboxylic Acid Ethyl Ester (28). This compound was
obtained from 1-(tert-butoxycarbonyl)-2(S)-pyrrolidinylmethanol and
5-hydroxyisoxazole-3-carboxylic acid ethyl ester as a pale-yellow solid
5-[(2(S)-Azetidinyl)methoxy]-3-[(N-phenylcarbamoyloxy)-
methyl]isoxazole (36). This compound was obtained from 29 and
phenyl isocyanate employing Methods H and A and Gradient II.
Colorless oil; yields of the individual steps 93% and 40%; purity 99.8%.
1
in 65% yield employing Method B. H NMR (400 MHz, CDCl3; two
rotamers about the N-Boc bond in an approximate ratio of 1:1) δ 5.66
(br, 1H), 4.35 (q, 2H, J = 7.2 Hz), 4.28 (br, 1.5H), 4.07 (br, 1.5H),
3.29 (br, 2H), 2.01−1.83 (m, 4H), 1.41 (s, 9H), 1.34 (t, 3H, J = 7.2
Hz).
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[α]D −3.7 (c = 3.4, MeOH); H NMR (400 MHz, D2O) δ 7.22 (d,
2H, J = 8.0 Hz), 7.09 (t, 2H, J = 8.0 Hz), 6.87 (t, 2H, J = 7.4 Hz), 5.39
(s, 1H), 4.93 (s, 2H), 4.74 (m, 1H), 4.31−4.25 (m, 2H), 4.01 (m, 1H),
3.90−3.85 (m, 1H), 2.55−2.36 (m, 2H); 13C NMR (100 MHz, D2O)
δ 172.2, 162.2, 162.0 (TFA), 153.8, 137.0, 128.5, 123.4, 118.8, 115.9
(TFA), 77.7, 69.7, 58.0, 57.8, 43.1, 20.0. Anal. Calcd for
C15H17N3O4·1.55TFA·2.35 H2O (FW 552): C, 41.62; H, 4.49; N,
8.04; F, 16.91. Found: C, 41.51; H, 4.46; N, 8.19; F, 16.94.
5-[(1-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl)methoxy]-3-
isoxazolylmethanol (30). This compound was obtained from 5-[[1-
(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]isoxazole-3-carbox-
ylic acid ethyl ester as a pale-yellow solid in 94% yield employing
1
Method C. H NMR (400 MHz, CDCl3; two rotamers about the N-
Boc bond in an approximate ratio of 1:1) δ 5.28 (br, 0.5H), 5.22 (br,
0.5H), 4.43 (d, 2H, J = 5.6 Hz), 4.25−3.97 (m, 4H), 3.22 (br, 2H),
1.90−1.75 (m, 4H), 1.32 (s, 9H).
5-[(2(S)-Azetidinyl)methoxy]-3-[(N-ethylcarbamoyloxy)-
methyl]isoxazole (37). This compound was obtained from 29 and
ethyl isocyanate employing Methods H and A and Gradient III.
Colorless oil; yields of the individual steps 99% and 50%; purity 99.6%.
5-[(2(S)-Azetidinyl)methoxy]-3-isoxazolylmethanol (31). 5-
[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-isoxazolylme-
thanol (29) was obtained from 27 as a pale-yellow solid in quantitative
yield employing Method C. The title compound 31 was obtained from
29 employing Method A and Gradient III. Colorless oil; yield 67%;
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1
[α]D −3.0 (c = 2.8, MeOH); H NMR (400 MHz, D2O) δ 5.62 (s,
1H), 5.04 (s, 2H), 4.96 (m, 1H), 4.63−4.55 (m, 2H), 4.15 (m, 1H),
4.04 (m, 1H), 3.13 (q, J = 7.2 Hz, 2H), 2.72−2.62 (m, 2H), 1.08 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, D2O) δ 172.4, 163.1, 162.2 (TFA),
157.0, 115.9 (TFA), 77.7, 69.9, 58.1, 58.0, 43.2, 35.2, 19.8, 13.6. Anal.
Calcd for C11H17N3O4·1.4TFA·0.95H2O (FW 432): C, 38.37; H, 4.74;
N, 9.73; F, 18.47. Found: C, 38.13; H, 4.86; N, 9.97; F, 18.63.
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purity 100%. [α]D −3.0 (c = 1.2, MeOH); H NMR (400 MHz,
D2O) δ 5.52 (s, 1H), 4.85 (m, 1H), 4.53−4.45 (m, 4H), 4.06 (m, 1H),
3.95 (m, 1H), 2.60−2.53 (m, 2H); 13C NMR (100 MHz, D2O) δ
172.3, 166.1, 162.3 (TFA), 115.9 (TFA), 77.4, 69.8, 58.1, 55.5, 43.2,
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dx.doi.org/10.1021/jm201301h | J. Med. Chem. 2012, 55, 812−823