Journal of Medicinal Chemistry
Article
crude bromide 153a as a waxy solid, which was used directly. A
solution of alcohol 95 (99 mg, 0.53 mmol) and bromide 153a in
anhydrous DMF (4 mL) at 0 °C was treated with excess 60% NaH (66
mg, 1.65 mmol). The mixture was stirred at 20 °C for 15 min and then
quenched with water and extracted with EtOAc. The extracts were
washed with brine, dried, and concentrated under reduced pressure to
give an oil, which was chromatographed on silica gel. Elution with
EtOAc gave 66 (84 mg, 34%) as a light-yellow solid; mp 73−76 °C.
1H NMR [(CD3)2SO] δ 8.01 (s, 1 H), 7.32 (br d, J = 8.1 Hz, 2 H),
(m, 3 H), 4.46 (br d, J = 11.9 Hz, 1 H), 4.29−4.18 (m, 3 H), 3.68 (s, 2
H), 3.67 (s, 2 H), 2.80 (br s, 1 H). Anal. (C22H21F3N4O5) C, H, N.
N-Methyl[4-({[(6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]-
oxazin-6-yl]oxy}methyl)phenyl]-N-[4-(trifluoromethoxy)benzyl]-
methanamine (71). A mixture of the amine 70 (81 mg, 0.169 mmol),
CH3I (0.011 mL, 0.177 mmol), and K2CO3 (47 mg, 0.34 mmol) in
anhydrous acetone (1 mL) was stirred at 20 °C for 5 h. Water was
added, the mixture was extracted with EtOAc, and the extract was
dried and concentrated under reduced pressure to give an oil, which
was chromatographed on silica gel. Elution with EtOAc gave 71 (57
mg, 68%) as a cream solid; mp 109−111 °C. 1H NMR [(CD3)2SO] δ
8.00 (s, 1 H), 7.46 (br d, J = 8.7 Hz, 2 H), 7.34−7.25 (m, 6 H), 4.68−
4.58 (m, 3 H), 4.46 (br d, J = 11.9 Hz, 1 H), 4.29−4.19 (m, 3 H), 3.50
(s, 2 H), 3.49 (s, 2 H), 2.06 (s, 3 H). Anal. (C23H23F3N4O5) C, H, N.
Synthesis of 72 (Scheme 5C). Procedure Y: Methyl 4-{[4-
(Trifluoromethoxy)phenoxy]methyl}benzoate (157a). 4-
(Trifluoromethoxy)phenol (0.120 mL, 0.926 mmol) was added to a
mixture of methyl 4-(bromomethyl)benzoate (91) (200 mg, 0.873
mmol) and K2CO3 (184 mg, 1.33 mmol) in anhydrous acetone (4
mL), and the mixture was stirred at 57 °C for 6 d. After cooling, water
(50 mL) was added and the mixture was extracted with CH2Cl2 (4 ×
50 mL). The combined extracts were evaporated to dryness, and the
residue was chromatographed on silica gel (20 g). Elution with
petroleum ether first gave foreruns, and then further elution with 0−
5% Et2O/petroleum ether gave 157a (284 mg, 100%) as a white solid;
mp (CH2Cl2/pentane) 90−91 °C. 1H NMR (CDCl3) δ 8.06 (br d, J =
8.4 Hz, 2 H), 7.49 (br d, J = 8.6 Hz, 2 H), 7.14 (br d, J = 9.1 Hz, 2 H),
6.95 (br d, J = 9.2 Hz, 2 H), 5.12 (s, 2 H), 3.93 (s, 3 H). HRESIMS
calcd for C16H14F3O4 m/z [M + H]+, 327.0839; found, 327.0828.
Procedure Z: (4-{[4-(Trifluoromethoxy)phenoxy]methyl}phenyl)-
methanol (158a). A solution of ester 157a (276 mg, 0.846 mmol) in
anhydrous THF (2.5 mL, then 3 × 2 mL to rinse) was added carefully
to a stirred suspension of LiAlH4 (39.1 mg, 1.03 mmol) in anhydrous
THF (3 mL) at 0 °C under N2. After being stirred at 20 °C for 24 h,
the reaction was cooled to 0 °C and quenched with water (0.5 mL),
then 2 M NaOH (1.5 mL), and the resulting mixture was diluted with
water (50 mL) and extracted with CH2Cl2 (5 × 50 mL). The
combined extracts were evaporated to dryness, and the residue was
chromatographed on silica gel (20 g). Elution with 50% CH2Cl2/
petroleum ether first gave foreruns, and then further elution with 67−
75% CH2Cl2/petroleum ether gave 158a (245 mg, 97%) as a white
solid; mp (CH2Cl2/pentane) 70−71 °C. 1H NMR (CDCl3) δ 7.43 (br
d, J = 8.5 Hz, 2 H), 7.40 (br d, J = 8.5 Hz, 2 H), 7.14 (br d, J = 9.1 Hz,
2 H), 6.95 (br d, J = 9.2 Hz, 2 H), 5.06 (s, 2 H), 4.72 (d, J = 6.0 Hz, 2
H), 1.66 (t, J = 5.9 Hz, 1 H). HRESIMS calcd for C15H13F3NaO3 m/z
[M + Na]+, 321.0709; found, 321.0704.
7.26 (br d, J = 8.1 Hz, 2 H), 7.01 (br d, J = 8.5 Hz, 2 H), 6.57 (br d, J =
9.0 Hz, 2 H), 6.51 (br t, J = 5.9 Hz, 1 H), 4.68−4.56 (m, 3 H), 4.45
(br d, J = 12.0 Hz, 1 H), 4.29−4.17 (m, 5 H). 13C NMR [(CD3)2SO]
δ 147.8, 147.1, 142.1, 139.3, 138.4, 136.1, 127.8 (2 C), 127.1 (2 C),
122.0 (2 C), 120.3 (q, JC−F = 254.0 Hz), 118.0, 112.5 (2 C), 69.5, 67.9,
66.3, 46.7, 46.2. Anal. (C21H19F3N4O5) C, H, N. HPLC purity: 98.7%.
N-Methyl-N-[4-({[(6S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b]-
[1,3]oxazin-6-yl]oxy}methyl)benzyl]-4-(trifluoromethoxy)aniline
(69). Sodium cyanoborohydride (20 mg, 3.18 mmol) was added to a
stirred solution of amine 66 (92 mg, 0.198 mmol) and aqueous
formaldehyde (0.17 mL of a 37% solution, 2.28 mmol) in EtOH (8
mL). After 5 min, AcOH (0.113 mL, 1.97 mmol) was added and the
solution was stirred at 20 °C for 2 h. The resulting mixture was diluted
with water and extracted with EtOAc. The extracts were washed with
aqueous NaHCO3 and brine, then dried and concentrated under
reduced pressure to give 69 (77 mg, 81%) as a light-yellow solid; mp
1
80−82 °C. H NMR [(CD3)2SO] δ 8.01 (s, 1 H), 7.26 (br d, J = 8.1
Hz, 2 H), 7.17 (br d, J = 8.1 Hz, 2 H), 7.11 (br d, J = 8.5 Hz, 2 H),
6.71 (br d, J = 9.2 Hz, 2 H), 4.67−4.56 (m, 3 H), 4.55 (s, 2 H), 4.45
(br d, J = 12.0 Hz, 1 H), 4.28−4.18 (m, 3 H), 3.02 (s, 3 H). 13C NMR
[(CD3)2SO] δ 148.1, 147.1, 142.1, 138.5 (q, JC−F = 1.6 Hz), 138.2,
136.2, 128.0 (2 C), 126.7 (2 C), 122.0 (2 C), 120.3 (q, JC−F = 254.1
Hz), 118.0, 112.5 (2 C), 69.5, 67.9, 66.3, 55.2, 46.7, 38.7 (NMe;
revealed by HSQC experiment). Anal. (C22H21F3N4O5) C, H, N.
Syntheses of 70 and 71 (Scheme 5B). Methyl 4-({[4-
(trifluoromethoxy)benzyl]amino}methyl)benzoate (154). A stirred
solution of methyl 4-(aminomethyl)benzoate (150) (0.257 g, 1.56
mmol) and 4-(trifluoromethoxy)benzaldehyde (0.22 mL, 1.54 mmol)
in MeOH (15 mL) was refluxed for 4 h. After cooling, NaBH4 (0.11 g,
2.91 mmol) was added and the mixture was stirred at 20 °C for 30
min. The resulting solution was diluted with brine and extracted with
EtOAc, and the extracts were washed with water, dried, and
concentrated under reduced pressure to give 154 (0.513 g, 97%) as
1
a colorless oil. H NMR [(CD3)2SO] δ 7.91 (br d, J = 8.2 Hz, 2 H),
7.49 (br d, J = 8.2 Hz, 2 H), 7.46 (br d, J = 8.7 Hz, 2 H), 7.29 (br d, J =
8.0 Hz, 2 H), 3.84 (s, 3 H), 3.76 (s, 2 H), 3.65 (s, 2 H), 2.83 (br s, 1
H). HREIMS calcd for C17H16F3NO3 m/z (M+), 339.1082; found,
339.1073.
1-(Iodomethyl)-4-{[4-(trifluoromethoxy)phenoxy]methyl}benzene
(159a). Iodination of alcohol 158a with I2, imidazole, and PPh3, using
procedure T for 2.5 h, gave 159a (83%) as a cream waxy solid that was
used directly in the next step. 1H NMR (CDCl3) δ 7.40 (br d, J = 8.2
Hz, 2 H), 7.34 (br d, J = 8.2 Hz, 2 H), 7.14 (br d, J = 9.1 Hz, 2 H),
6.94 (br d, J = 9.2 Hz, 2 H), 5.01 (s, 2 H), 4.46 (s, 2 H). APCI MS m/
z 281 [M + H − HI]+.
(6S)-2-Nitro-6-[(4-{[4-(trifluoromethoxy)phenoxy]methyl}benzyl)-
oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (72). Reaction of
alcohol 95 with iodide 159a and NaH (1.3 equiv), using procedure I
for 70 min, gave 72 (78%) as a cream solid; mp (CH2Cl2/hexane)
140−141 °C. 1H NMR [(CD3)2SO] δ 8.03 (s, 1 H), 7.42 (br d, J = 8.2
Hz, 2 H), 7.34 (br d, J = 8.1 Hz, 2 H), 7.29 (br d, J = 9.0 Hz, 2 H),
7.08 (br d, J = 9.2 Hz, 2 H), 5.11 (s, 2 H), 4.71−4.60 (m, 3 H), 4.47
(br d, J = 11.8 Hz, 1 H), 4.31−4.19 (m, 3 H); 13C NMR [(CD3)2SO]
δ 157.1, 147.1, 142.1, 141.8 (q, JC−F = 1.6 Hz), 137.5, 136.1, 127.8 (4
C), 122.5 (2 C), 120.2 (q, JC−F = 255.1 Hz), 118.0, 116.0 (2 C), 69.4
(2 C), 67.9, 66.4, 46.8. Anal. (C21H18F3N3O6) C, H, N.
[4-({[4-(Trifluoromethoxy)benzyl]amino}methyl)phenyl]-
methanol (155). Reduction of ester 154 with LiAlH4 (2.0 equiv),
using the second half of procedure W, gave 155 (94%) as a colorless
1
oil. H NMR [(CD3)2SO] δ 7.46 (br d, J = 8.7 Hz, 2 H), 7.31−7.23
(m, 6 H), 5.08 (br t, J = 5.3 Hz, 1 H), 4.47 (d, J = 4.5 Hz, 2 H), 3.68
(s, 2 H), 3.66 (s, 2 H), 2.64 (br s, 1 H). HREIMS calcd for
C16H16F3NO2 m/z (M+), 311.1133; found, 311.1129.
[4-({[(6S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl]-
oxy}methyl)phenyl]-N-[4-(trifluoromethoxy)benzyl]methanamine
(70). A solution of alcohol 155 (0.44 g, 1.41 mmol) in 48% HBr (30
mL) was stirred at 80 °C for 16 h. The solvent was then removed
under reduced pressure, and the residue was azeotroped several times
with benzene and dried under high vacuum, to give the crude bromide
156 as a white solid, which was used directly. A solution of alcohol 95
(0.248 g, 1.34 mmol) and bromide 156 in anhydrous DMF (5 mL) at
0 °C was treated with excess 60% NaH (0.17 g, 4.25 mmol). The
mixture was stirred at 20 °C for 15 min and then quenched with water
and extracted with EtOAc. The extracts were washed with brine, dried,
and concentrated under reduced pressure to give an oil, which was
chromatographed on silica gel. Elution with EtOAc first gave foreruns,
and then further elution with 5% MeOH/EtOAc gave 70 (0.36 g,
53%) as a light-yellow solid; mp 91 °C. 1H NMR [(CD3)2SO] δ 8.01
(s, 1 H), 7.45 (br d, J = 8.7 Hz, 2 H), 7.33−7.23 (m, 6 H), 4.68−4.57
Synthesis of 74 (Scheme 5C). 5-{[(tert-Butyldimethylsilyl)oxy]-
methyl}-2-{[4-(trifluoromethoxy)phenoxy]methyl}pyridine (163a).
Diethyl azodicarboxylate (0.420 mL, 2.70 mmol) was added dropwise
to a stirred solution of (5-{[(tert-butyldimethylsilyl)oxy]methyl}-
pyridin-2-yl)methanol55 (162) (529 mg, 2.09 mmol), 4-
(trifluoromethoxy)phenol (0.330 mL, 2.55 mmol), and PPh3 (658
S
J. Med. Chem. XXXX, XXX, XXX−XXX