A. B. Beeler et al. / Bioorg. Med. Chem. 11 (2003) 5229–5234
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ducing the crude oxalate salt of 8, crystallized from
acetonitrile–ether (2.75 g, 75% yield). Mp 174–175 ꢀC;
1H NMR (400 MHz, CDCl3, free base) d 7.57 (d, J=7.4
Hz, 2H), 7.15–7.30 (m, 8H), 4.21 (dq, J=7.1Hz, J=1.2
Hz, 2H), 3.52 (d, J=12.7 Hz, 1H), 3.23 (d, J=12.7 Hz,
1H), 2.75 (m, 2,), 2.53 (m, 2H), 2.13 (s, 3H), 1.17 (dt,
J=7.1Hz, J=1.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3) d 163.98 (t, J=28.0 Hz), 140.20, 137.24, 129.73,
128.9, 128.41, 128.14, 127.97, 127.23, 115.33 (t, J=255
Hz), 80.12 (t, J=24.5 Hz), 62.90, 62.77, 54.34, 41.44,
29.25, 14.20; Exact mass calcd for C21H26F2NO3
(MH+) 378.1881, found: 378.1895. Anal. calcd for
C23H27F2NO7 (8-(COOH)2): C, 59.10; H, 5.82; N, 3.00,
found: C, 59.06; H, 5.91; N, 2.94.
evaporated to dryness under high vacuum. The residue
was treated with 1N NaOH (10 mL) and extracted with
EtOAc several times. The organic portion was dried
over magnesium sulfate and solvent removed under
vacuum. The crude product was dissolved in anhydrous
ether, an ethereal solution of HCl was added, and 4-
HCl was recrystallized from methanol–ether (20 mg,
18%): mp 203–205 ꢀC; H NMR (400 MHz, CD3OD) d
1
7.56–7.43 (m 5H), 6.53 (t, 1H, J=3.2), 4.16 (s, 2H), 4.08
(t, 2H, J=10.8), 3.15 (s 3H); 13C NMR (MeOD) d
134.22 (t, J=23.9). 132.92, 129.24, 128.74, 127.71,
127.01, 115.63, 55.8 (t, J=34.3), 52.32, 42.67; Exact
mass calcd for C12H14F2N (MH+) 210.1094, found:
210.0960. Anal. calcd for C12H14ClF2N: C, 58.66; H,
5.74; N, 5.70 found: C, 58.86; H, 5.54; N, 5.60.
3,3-Difluoro-4-hydroxy-1-methyl-4-phenyl-piperidin-2-
one (9). The free base of 8 (1.6 mmol, 0.60 g) was dis-
solved in methanol (15 mL) and a catalytic amount of
Pd(OH)2 (50 mg, 10% Pd content) was added. The
solution was vacuum purged several times, and allowed
to react under a blanket of hydrogen gas (1atm) for 24
h at room temperature. The solution was filtered to
remove catalyst, and the solvent evaporated to yield an
amorphous solid that was recrystallized from EtOAc–
hexane yielding lactam 9 (0.360 g, 95%): mp 163–
165 ꢀC; 1H NMR (400 MHz, CD3OD) d 7.60 (d, J=7.54
Hz, 2H), 7.36 (m, 3H), 3.71(m, 1H), 3.36 (dd, J=12
Hz, J=5.6 Hz, 1H), 3.00 (s, 3H), 2.87 (m, 1H), 2.11 (m,
1H). 13C NMR (100 MHz, CD3OD) 163.32 (dd, J=31.3
Hz, J=27.9), 139.38, 128.39, 128.08, 127.08 (d, J=1
Hz), 111.70 (dd, J=254.2, J=243.3), 73.40 (dd,
J=24.9, J=20.4), 45.41, 33.92, 30.85 (d, J=4.5). Exact
mass calcd for C12H14F2NO+2 (MH+) 242.0993, found
242.0983. Anal. calcd for C12H13F2NO2: C, 59.75; H,
5.43; N, 5.81, found: C, 59.38; H, 5.37; N, 5.66.
3-Fluoro-4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester (12). To a round bottomed flask
containing magnesium powder (0.22 g, 9.1mmol) and
anhydrous THF (50 mL) at 0 ꢀC was added bromo-
benzene (0.960 mL, 9.1mmol). After the magnesium
had been consumed (1h), fluoroketone 11 (1.8 g, 8.3
mmol) dissolved in THF (10 mL) was added, and the
mixture was warmed to room temperature allowed to
stir for an additional 4 h. The reaction was quenched
with water (10 mL) and diluted with diethyl ether. The
organic layer was washed successively with water and
brine, dried over sodium sulfate, evaporated to dryness,
and chromatographed over silica gel (1:1 EtOAc–hex-
anes) yielding 1.1 g of a white amorphous solid (46%).
1H NMR (CDCl3) d 7.48–7.31m (aromatic), 4.95 (ddd,
1H J=2.1, 2.1, 20 Hz), 4.35 (bs, 1H), 3.94 (bs, 1H), 3.25
(m, 2H), 2.53 (s, 1H), 1.88 (m, 2H), 1.49 (s, 9H). This
product contained an impurity that co-eluted with the
product, and was carried through the next step without
further purification. The Grignard product (0.750 g, 2.5
mmol) was dissolved in anhydrous pyridine (2.0 mL)
and POCl3 (300 mL) was added dropwise over 20 min at
0 ꢀC. The resulting orange solution was stirred for 24 h
and quenched with water. The solution was diluted with
EtOAc, washed with saturated sodium carbonate,
water, and brine, respectively. The organic layer was
dried over sodium sulfate, concentrated under vacuum,
and chromatographed (silica gel, 30:70 EtOAc–hexanes)
resulting in a yellow oil (75 mg, 10%). 1H NMR
(CDCl3) d 7.45–7.24 (m, 5H), 4.12 (bs, 2H), 3.60 (bs,
3,3-Difluoro-4-hydroxy-1-methyl-4-phenyl-piperidine (10).
Lactam 9 (1.25 mmol, 0.3 g) and sodium borohydride
(12.5 mol, 0.475 g) were dissolved in 5 mL dioxane, and
trifluoroacetic acid (12.5 mol, 1.43 g, 0.93 mL) was
added very slowly at 0 ꢀC. The reaction was refluxed for
24 h. The resulting solution was cooled to 0 ꢀC, quen-
ched with water (10 mL), and basified to pH 8 with 1 N
aq NaOH. The resulting solution was extracted several
times with EtOAc, and evaporated to dryness. The
crude product was reconstituted in diethyl ether, and an
ethereal solution of HCl was added to produce com-
pound 10 as the hydrochloride salt. Recrystallization
from acetonitrile yielded 10-HCl (0.21g, 65%): mp 269–
270 ꢀC; 1H NMR (400 MHz, CD3OD) d 7.62 (d, J=7.4,
2H), 7.38 (m, 3H), 3.90 (m, 2H), 3.60 (M, 2H), 3.06 (s,
3H), 2.83 (m, 1H), 2.15 (m, 1H); 13C NMR (100 MHz,
CD3OD) d 138.24, 128.64, 128.16, 127.28, 118.0 (dd,
J=254.8, J=243.6) 71.03 (t, J=20.5), 53.62 (t,
J=26.2), 49.94, 43.07, 32.57; Exact mass calcd for
C12H16F2NO (MH+) 228.1200, found: 228.1224. Anal.
calcd for C12H16ClF2NO: C, 54.65; H, 6.12; N 5.31
Found: C, 54.55; H, 6.41; N 5.40.
2H), 2.51(m, 2H), 1.51(s, 9H);
13C NMR (CDCl3) d
154.88, 136.06, 128.96, 128.70, 127.85, 127.67, 126.63,
112.94, 80.73, 60.78, 28.82. Exact mass calcd for
C16H21FNO2 (MH+) 278.1556, found: 278.1562.
5-Fluoro-1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine
(5). N-Boc derivative 12 (60 mg, 0.22 mmol) was dis-
solved in THF (5 mL) and diisobutylaluminum hydride
(1M in THF, 770 mL, 0.78 mmol) was added dropwise
at À78 ꢀC. This solution was allowed to warm to room
temperature and stirred for 72 h. The solution was
quenched with water, diluted with EtOAc, washed suc-
cessively with water and brine, dried over sodium sul-
fate, and evaporated to dryness. The resulting crude
product was dissolved in anhydrous ether and an anhy-
drous ethereal solution of HCl was added. Recrystalli-
zation from methanol–ether yielded 5-HCl (22 mg,
3,3-Difluoro-1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine
(4). Compound 10 (100 mg, 0.438 mmol) was dissolved
in 0.40 mL of pyridine and POCl3 (4.3 mmol) was added
dropwise at 0 ꢀC. The reaction was stirred for 2 h and