294 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2
Barbachyn et al.
(42), 43 (11), 30 (17); HRMS (FAB) calcd for C19H21N3O4 + H1
N-[[4,5-dihydro-3-[4-[1,2,3,6-tetrahydropyridinyl]phenyl]-5-
isoxazolyl]methyl]acetamide, 105 mg (31%) of the title compound
was recovered as a pale-yellow solid with the following
characteristics: [R]25D ) -54° (c 0.87, DMSO); IR (mull) 3408,
3304, 1653, 1630, 1554, 1445, 1413, 1319, 1286, 1234, 1108,
1052, 910, 816, 601 cm-1; MS (EI) m/z (rel intensity) 357 (M+,
10), 298 (36), 296 (26), 285 (99), 241 (47), 198 (32), 183 (53),
128 (36), 115 (29), 73 (97), 56 (43); HRMS (EI) calcd for
356.1610, found 356.1582. Anal. (C19H21N3O4‚1.40H2O) C, H,
N.
(R)-4,5-Dih yd r o[3-(4-br om op h en yl)-5-(h yd r oxym eth yl-
)]isoxa zole (21) a n d (S)-4,5-Dih yd r o[3-(4-br om op h en yl)-
5-(h yd r oxym eth yl)]isoxa zole (22). The racemate 8 (7 g) was
resolved on a 5 cm × 50 cm Chiralpak AD column (Chiral
Technologies) using the following conditions: 15 mL (300 mg)
injections, 270 nm UV detection, 50 mL/min flow rate, 3/1
heptane/isopropyl alcohol (v/v) mobile phase. Each injection
required a total run time of 120 min with two passes on the
column required to obtain adequate resolution using a closed-
loop recycling HPLC (EM ST140, R&S Technologies Inc.) and
peak shaving for fraction collection. The (R)-isomer 21 was a
C
19H23N3O4 357.1689, found 357.1694. Anal. (C19H23N3O4‚
0.65H2O) C, H, N.
(S)-N-[[4,5-Dih ydr o-3-[4-[1,2,3,6-tetr ah ydr o-1-(h ydr oxy-
a cet yl)-4-p yr id in yl]p h en yl]-5-isoxa zolyl]m et h yl]a cet -
a m id e (26). Following the general procedure for (()-N-[[4,5-
dihydro-3-[4-[1,2,3,6-tetrahydro-1-(hydroxyacetyl)-4-pyridinyl]-
phenyl]-5-isoxazolyl]methyl]acetamide (15) but substituting
(S)-N-[[4,5-dihydro-3-[4-[1,2,3,6-tetrahydropyridinyl]phenyl]-
5-isoxazolyl]methyl]acetamide (140 mg, 0.47 mmol) for (()-
N-[[4,5-dihydro-3-[4-[1,2,3,6-tetrahydropyridinyl]phenyl]-5-
isoxazolyl]methyl]acetamide, 62 mg (37%) of the title compound
white solid: mp 119-120 °C; [R]25 -137° (c 0.92, CHCl3); IR
D
(mull) 3393, 1594, 1442, 1401, 1108, 1076, 1052, 1010, 959,
934, 908, 823, 810, 627, 604 cm-1; MS (EI) m/z (rel intensity)
255 (M+, 73), 257 (71), 255 (73), 226 (95), 224 (99), 198 (87),
196 (89), 157 (65), 155 (66), 76 (57), 75 (56). Anal. (C10H10
-
was recovered as a pale-yellow solid: [R]25 ) +54° (c 0.82,
BrNO2) C, H, N. The (S)-isomer 22 was a white solid: mp 119-
D
121 °C; [R]25 +138° (c 0.75, CHCl3); IR (mull) 3392, 1594,
DMSO); IR (mull) 3402, 3305, 1653, 1631, 1554, 1444, 1413,
1320, 1286, 1234, 1108, 1052, 910, 816, 602 cm-1; MS (EI) m/z
(rel intensity) 357 (M+, 10), 298 (37), 296 (28), 285 (99), 283
(31), 241 (74), 198 (29), 183 (45), 128 (27), 73 (82), 56 (31);
HRMS (EI) calcd for C19H23N3O4 357.1689, found 357.1690.
Anal. (C19H23N3O4‚0.75H2O) C, H, N.
D
1442, 1401, 1108, 1076, 1052, 1010, 959, 933, 908, 824, 810,
627, 602 cm-1; MS (EI) m/z (rel intensity) 255 (M+, 70), 257
(69), 255 (70), 226 (99), 224 (99), 198 (90), 196 (95), 157 (70),
155 (73), 76 (64), 75 (63). Anal. (C10H10BrNO2) C, H, N.
Alter n a tive P r ep a r a tion of (R)-4,5-Dih yd r o[3-(4-br o-
m op h en yl)-5-(h yd r oxym eth yl)]isoxa zole (21). Following
the procedure of Ukaji and co-workers,21 a solution of allyl
alcohol (0.23 g, 0.27 mL, 3.88 mmol) in CHCl3 (7 mL) was
cooled to 0 °C and treated with Et2Zn (0.48 g, 3.92 mL of a 1
M solution in hexane, 3.92 mmol). After the mixture was
stirred for 10 min more, CHCl3 (7 mL) and (+)-diisopropyl
tartrate (0.77 g, 0.69 mL, 3.29 mmol) were added and the
mixture was then stirred at 0 °C. After 1 h, Et2Zn (0.53 g, 4.26
mL of a 1 M solution in hexane, 4.26 mmol), CHCl3 (7 mL),
and 4-bromo-N-hydroxybenzenecarboximidoyl chloride (7, 1.00
g, 4.26 mmol) were added and the mixture was stirred at 0
°C. After 3 h, the reaction was quenched with saturated NH4-
Cl, the mixture was transferred to a separatory funnel, and
the mixture was extracted with CHCl3 (2 × 25 mL). The
combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated in under reduced pressure
to give a crude product. Chromatography over silica gel, eluting
with 99/1 CHCl3/MeOH, afforded, after concentration of ap-
propriate fractions, 0.567 g of the title compound as a white
solid with the following specific rotation: [R]25D -119° (c 0.98,
CHCl3).
Eth yl 3,5-Diflu or o-4-(4-m or p h olin o)ben zoa te (29b). To
a flame-dried flask containing ethyl 3,4,5-trifluorobenzoate
(28b, 4.45 g, 21.80 mmol) in DMSO (100 mL) was added K2-
HPO4 (15.19 g, 87.20 mmol), and the mixture was heated to
75 °C for 15 h. The reaction mixture is diluted with ethyl
acetate (100 mL), washed with H2O (6 × 100 mL), washed with
saline solution (50 mL), dried over sodium sulfate, concen-
trated in vacuo, and chromatographed on silica gel (230-400
mesh, 200 mL), eluting with hexane/ethyl acetate (95/5). The
appropriate fractions were combined (Rf ) 0.53, TLC, hexane/
ethyl acetate, 75/25) and concentrated in vacuo to give 5.19 g
(88%) of the title compound as a clear colorless oil: IR (neat)
1721, 1511, 1450, 1433, 1381, 1369, 1319, 1264, 1240, 1220,
1211, 1119, 1026, 930, 767 cm-1; MS (ESI+) for C13H15NO3F2
m/z 272.2 (M + H)+. Anal. Calcd for C13H15F2NO3: C, 57.56;
H, 5.57; N, 5.16. Found: C, 57.33; H, 5.56; N, 5.12.
3-F lu or o-4-(4-m or p h olin o)ben zyl Alcoh ol (30a ). A solu-
tion of methyl 3,4-difluorobenzoate (28a , 16.4 g, 95.2 mmol)
in dry DMSO (25 mL) in a sealed tube (screw cap, O-ring,
heavy wall) was heated to 95 °C for 20 h. The reaction mixture
was cooled, diluted with dichloromethane (300 mL), and
transferred to a separatory funnel. The organic layer was
washed with water (2 × 200 mL) and brine (150 mL), dried
over anhydrous sodium sulfate, filtered, and concentrated by
rotary evaporation under reduced pressure to give a crude
solid. Chromatography over silica gel, eluting with 5/1 hexane/
ethyl acetate afforded, after concentration of appropriate
fractions, 18.5 g (81%) of methyl 3-fluoro-4-(4-morpholino)-
benzoate (29a ) as a white solid: mp 89-90 °C. A solution of
29a (3.35 g, 14.0 mmol) in dry THF (50 mL) was added
dropwise to a slurry of lithium aluminum hydride (0.797 g,
21.0 mmol) in dry THF at 0 °C under a nitrogen atmosphere.
When the addition was complete, the cooling bath was removed
and the mixture was stirred at ambient temperature. After
16 h, TLC (2/1 hexane/ethyl acetate) revealed that the reaction
was complete. The mixture was cooled to 0 °C, and the reaction
was carefully quenched with H2O (800 µL), 15% aqueous
NaOH (800 µL), and H2O (2.4 mL). After being stirred for 30
min, the mixture was diluted with ethyl acetate (100 mL),
filtered through Celite (ethyl acetate wash), and concentrated
under reduced pressure to give 3.0 g (100%) of the title
(R)-N-[[4,5-Dih yd r o-3-[4-b r om op h en yl]-5-isoxa zolyl]-
m eth yl]a ceta m id e (23). Following the similar procedure for
the synthesis of (()-N-[[4,5-dihydro-3-[4-bromophenyl]-5-isox-
azolyl]methyl]acetamide (9), (R)-4,5-dihydro[3-(4-bromophe-
nyl)-5-(hydroxymethyl)]isoxazole (21) was converted to the title
compound: mp 219-220 °C; [R]25 -69° (c 0.99, CHCl3); IR
D
(mull) 3285, 1641, 1592, 1558, 1489, 1431, 1399, 1352, 1296,
1076, 1010, 906, 826, 806, 608 cm-1; MS (FAB) m/z (rel
intensity) 297 (MH+, 95), 453 (9), 452 (2), 451 (10), 371 (3),
300 (3), 299 (99), 298 (4), 297 (95), 57 (7), 43 (7). Anal. (C12H13
BrN2O2) C, H, N.
-
(S)-N-[[4,5-Dih yd r o-3-[4-b r om op h en yl]-5-isoxa zolyl]-
m eth yl]a ceta m id e (24). Following the similar procedure for
the synthesis of (()-N-[[4,5-dihydro-3-[4-bromophenyl]-5-isox-
azolyl]methyl]acetamide (9), (S)-4,5-dihydro[3-(4-bromophe-
nyl)-5-(hydroxymethyl)]isoxazole (22) was converted to the title
compound: mp 219-221 °C; [R]25 +71° (c 0.83, CHCl3); IR
D
(mull) 3285, 1641, 1591, 1558, 1489, 1431, 1399, 1352, 1296,
1076, 1010, 906, 826, 806, 608 cm-1; MS (ESI+) for C12H13
-
BrN2O2 m/z 297 (M + H)+. Anal. (C12H13BrN2O2) C, H, N.
compound as a white solid: mp 67-69 °C; MS (EI) for C11H14
-
(R)-N-[[4,5-Dih ydr o-3-[4-[1,2,3,6-tetr ah ydr o-1-(h ydr oxy-
a cet yl)-4-p yr id in yl]p h en yl]-5-isoxa zolyl]m et h yl]a cet -
a m id e (25). Following the general procedure for (()-N-[[4,5-
dihydro-3-[4-[1,2,3,6-tetrahydro-1-(hydroxyacetyl)-4-pyridinyl]-
phenyl]-5-isoxazolyl]methyl]acetamide (15) but substituting
(R)-N-[[4,5-dihydro-3-[4-[1,2,3,6-tetrahydropyridinyl]phenyl]-
5-isoxazolyl]methyl]acetamide (280 mg, 0.94 mmol) for (()-
FNO2 m/z 211 (M+, 85), 153 (85), 69 (53), 60 (31), 57 (54), 55
(37), 45 (35), 44 (99), 43 (83), 42 (74); HRMS (EI) calcd for
C
11H14FNO2 211.1008, found 211.1011.
3-F lu or o-4-(4-m or p h olin o)ben za ld eh yd e (31a ). To a
flame-dried flask containing 4 Å sieves (235 mg, 500 mg/mmol)
in CH2Cl2 (1 mL) was added N-methylmorpholine N-oxide (83