Journal of Medicinal Chemistry
ARTICLE
in heptane (2 L), washed four times with 1 N NaOH (250 mL) and
brine, and dried (MgSO4). The organic layer was filtered and concen-
trated to dryness to afford the title product as a colorless oil (54 g, 78%
fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-1H-tetrazol-1-yl)-
acetate. H NMR (500 MHz, DMSO-d6): δ 7.64 (dd, 1H), 7.29 (dd,
1H), 6.82 (td, 1H), 5.79 (s, 2H), 4.94ꢀ4.89 (m, 1H), 4.19 (q, 2H),
3.86ꢀ3.80 (m, 2H), 3.75ꢀ3.69 (m, 2H), 2.12ꢀ2.06 (m, 2H), 1.901.84
(m, 2H), 1.20 (t, 3H).
1
1
yield). H NMR (500 MHz, acetone-d6): δ 7.58 (dd, 1H), 7.00 (dd,
1H), 6.70 (td, 1H), 4.64ꢀ4.58 (m, 1H), 3.12ꢀ3.06 (m, 2H), 2.73ꢀ2.66
To
a solution of ethyl (5-{5-[4-(2-bromo-5-fluorophenoxy)-
(m, 2 H), 2.02ꢀ1.94 (m, 2H), 1.69ꢀ1.60 (m, 2H).
piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-2H-tetrazol-2-yl)acetate (2.57 g,
5.02 mmol) in a mixture of THF/MeOH (30 mL) (2:1) (v/v) was
added 1 N NaOH (10 mL) at room temperature. After 5 min, the
reaction mixture was poured into 1 N HCl, extracted with EtOAc,
washed with brine, dried (Na2SO4), filtered, and concentrated. The
residue was triturated with a mixture of Et2O/hexanes to give the desired
material (6) as a white solid (2.23 g, 92% yield); mp: 243ꢀ245 °C
(decomp). 1H NMR (400 MHz, DMSO-d6): δ 13.89 (br s, 1H), 7.65
(dd, 1H, J = 8.8, 6.3 Hz), 7.30 (dd, 1H, J = 9.0, 3.0 Hz), 6.83 (td, 1H, J =
9.0, 3.0 Hz), 5.84 (s, 2H), 4.95ꢀ4.88 (m, 1H), 3.86ꢀ3.78 (m, 2H),
3.74ꢀ3.66 (m, 2H), 2.15ꢀ2.07 (m, 2H), 1.92ꢀ1.84 (m, 2H). 13C NMR
(126 MHz, DMSO-d6): δ 172.8, 167.6, 162.8 (d, JCF = 244 Hz), 158.3,
5-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2-
carbonitrile (14). To a solution of 4-(2-bromo-5-fluorophenoxy)-
piperidine (13) (14.4 g, 52.7 mmol) in 1,4-dioxane (80 mL) was added
N,N-diisopropylethylamine (20 mL, 115 mmol), followed by 5-bromo-
1,3,4-thiadiazole-2-carbonitrile (12) (10.0 g, 52.7 mmol). The mixture
was stirred 1 h at room temperature. The reaction mixture was then
poured into saturated aqueous NH4C1, extracted with EtOAc, washed
with brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude material was purified by column chromatography on
silica gel (eluting with a gradient from 10 to 40% EtOAc/hexanes) to
afford the desired product as a colorless oil (15.6 g, 77% yield). 1H NMR
(500 MHz, acetone-d6): δ 7.63 (dd, 1H), 7.14 (dd, 1H), 6.78 (td, 1H),
5.04ꢀ4.99 (m, 1H), 4.00ꢀ3.95 (m, 2H), 3.89ꢀ3.84 (m, 2H), 2.27ꢀ
2.21 (m, 2H), 2.11ꢀ2.05 (m, 2H).
154.6 (d, JCF = 10.7 Hz), 144.8, 134.3 (d, JCF = 9.9 Hz), 109.6 (d, JCF
=
22.6 Hz), 107.5 (d, JCF = 4.3 Hz), 104.2 (d, JCF = 26.8 Hz), 72.8, 54.5,
47.2 (2C), 29.4 (2C); the regioconfiguration of the acetic acid moiety
was assigned by a 15N gHMBC experiment (JHN = 5 Hz) on the sodium
salt of 5 with observation of three long-range couplings between the
methylene protons at δ 5.00 ppm and tetrazole nitrogens at δ 393.8,
314.9, and 303.0 ppm (15N-benzamide external ref δ 110 ppm) and was
confirmed by X-ray crystallography. HRMS (ESI) (m/z): (M + H)+
calcd for C16H16BrFN7O3S, 486.0178; found, 486.0182.
Ethyl 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-
carboxylate (17). To a suspension of 4-(2-bromo-5-fluorophenoxy)-
piperidine (13) (20 g, 73 mmol), hydroxycarbonimidic dibromide (16)
(13 g, 64 mmol), and ethyl propiolate (15) (38 g, 422 mmol) in EtOAc/
H2O (390 mL/65 mL) was added KHCO3 (19.4 g, 194 mmol). The
mixture was stirred for 12 h at room temperature. The organic layer was
then separated, dried over anhydrous Na2SO4, and concentrated. Chro-
matography over silica gel and elution with hexanes/EtOAc (1:1) and
swishing in hexanes/Et2O (3:2) to give the title compound as a white
powder (5.0 g, 19% yield). 1H NMR (400 MHz, acetone-d6): δ 7.62 (dd,
1H), 7.11 (dd, 1H), 6.97 (s, 1H), 6.76 (td, 1H), 4.91ꢀ4.86 (m, 1H),
4.39 (q, 2H), 3.71ꢀ3.63 (m, 2H), 3.49ꢀ3.41 (m, 2H), 2.17ꢀ2.09
(m, 2H), 1.99ꢀ1.88 (m, 2H), 1.38 (t, 3H).
4-(2-Bromo-5-fluorophenoxy)-1-[5-(2>H-tetrazol-5-yl)-1,3,4-thia-
diazol-2-yl]piperidine (5). A suspension of 5-[4-(2-bromo-5-fluorophe-
noxy)piperidin-l-y1]-1,3,4-thiadiazole-2-carbonitrile (14) (15.6 g, 40.7
mmol), NaN3 (13.2 g, 204 mmol), and pyridinium hydrochloride
(9.47 g, 82.0 mmol) in NMP (70 mL) was heated at 130 °C for 4 h.
The reaction mixture was cooled to room temperature and poured into
aqueous 0.5 N HC1, extracted with EtOAc, and washed three times with
aqueous 0.5 N HC1 and with aqueous brine solution. The organic layer
was dried (Na2SO4) and filtered. Evaporation of the solvent was
followed by trituration in a mixture of MeOH/Et2O/heptane (1:1:6)
(v/v). After filtration of the solid, the material was triturated again in this
solvent system to finally afford the desired product (5) as a white solid
(15.3 g, 88% yield); mp: 213-215 °C. 1H NMR (400 MHz, acetone-d6):
δ 7.64 (dd, 1H, J = 9.0, 6.5 Hz), 7.16 (dd, 1H, J = 9.0, 3.0 Hz), 6.79 (td,
1H, J = 9.0, 3.0 Hz), 5.04ꢀ5.00 (m, 1H), 4.02ꢀ3.94 (m, 2H), 3.89ꢀ3.81
(m, 2H), 2.29ꢀ2.20 (m, 2H), 2.12ꢀ2.03 (m, 2H). 13C NMR (126
MHz, DMSO-d6): δ 173.3, 162.8 (d, JCF = 243 Hz), 154.6 (d, JCF = 10.9
Hz), 149.7 (broad peak), 143.3, 134.2 (d, JCF = 10.0 Hz), 109.6 (d, JCF
=
22.7 Hz), 107.5 (d, JCF = 3.0 Hz), 104.2 (d, JCF = 26.4 Hz), 72.8, 47.2
(2C), 29.4 (2C). HRMS (ESI) (m/z): (M + H)+ calcd for
C14H14BrFN7OS, 428.0122; found, 428.0131.
3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-carbox-
amide (18). To a suspension of ethyl 3-[4-(2-bromo-5-fluorophenoxy)-
piperidin-1-yl]isoxazole-5-carboxylate (17) (2.0 g, 4.84 mmol) in
MeOH (10 mL) and THF (10 mL) was added ammonium hydroxide
(28 wt %, 20 mL, 144 mmol) at room temperature. The mixture was
stirred at room temperature overnight stirring. A precipitate appeared
after about 15 min and became more abundant after overnight. Volatile
materials were then removed in vacuo. The residue was diluted with
water and extracted with EtOAc. The EtOAc extract was washed with
diluted brine, dried (Na2SO4), and concentrated. The residue was
triturated in Et2O/hexanes (1:1) to give the title compound as a white
powder (1.7 g, 91% yield). 1H NMR (400 MHz, acetone-d6): δ 7.62 (dd,
1H), 7.52 (s, 1H), 7.11 (m, 2H), 6.80ꢀ6.71 (m, 2H), 4.91ꢀ4.85 (m,
1H), 3.69ꢀ3.61 (m, 2H), 3.46ꢀ3.38 (m, 2H), 2.17ꢀ2.09 (m, 2H),
1.99ꢀ1.88 (m, 2H).
(5-{5-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadia-
zol-2-yl}-2H-tetrazol-2-yl)acetic Acid (6). A solution of 4-(2-bromo-5-
fluorophenoxy)-1-[5-(2H-tetrazol-5-yl)-1,3,4-thiadiazol-2-yl]piperidine
(5) (4.54 g, 10.66 mmol) in DMF (20 mL) was treated with NaH (60%
in oil) (512 mg, 12.80 mmol) at ꢀ78 °C. The mixture was warmed to
0 °C for 10ꢀ15 min, cooled again to ꢀ78 °C, and ethyl bromoacetate
(1.6 mL, 14.37 mmol) was added dropwise. The final reaction mixture
was warmed and stirred at room temperature overnight. The reaction
mixture was poured into aqueous 1 N HCl and extracted with EtOAc.
The organic layers was washed with 1 N HCl and brine, dried (Na2SO4),
and filtered. Solvents were removed in vacuo to afford the crude product,
which was purified by column chromatography on silica gel (eluting with
a gradient from 10 to 50% EtOAc/hexanes). The two isomers were
triturated with a mixture of Et2O/heptane. The more polar isomer
(Rf = 0.3 (50% EtOAc/hexanes)), obtained as an off-white solid (2.60 g,
48% yield), was the desired isomer ethyl (5-{5-[4-(2-bromo-5-fluor-
ophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-2H-tetrazol-2-yl)acetate.
1H NMR (500 MHz, DMSO-d6): δ 7.64 (dd, 1H), 7.29 (dd, 1H),
6.82 (td, 1H), 5.98 (s, 2H), 4.93ꢀ4.89 (m, 1H), 4.24 (q, 2H), 3.84ꢀ3.77
(m, 2H), 3.72ꢀ3.66 (m, 2H), 2.13ꢀ2.06 (m, 2H), 1.901.83 (m, 2H),
1.24 (t, 3H).
3-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-carbo-
nitrile (19). Trifluoroacetic anhydride (0.8 mL, 5.7 mmol) was added to
a suspension of 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-
5-carboxamide (18) (1.6 g, 4.2 mmol) and Et3N (1.5 mL, 10.8 mmol) in
CH2Cl2 (20 mL) at iceꢀwater bath temperature. After addition was
completed, the cooling bath was removed and the mixture was stirred
at room temperature for 2 h. The mixture was quenched with water
(10ꢀ15 mL), followed by saturated NaHCO3 (15ꢀ20 mL), and
extracted with CH2Cl2 (2 ꢁ 30 mL). The combined CH2Cl2 extracts
The less polar isomer (Rf = 0.5 (50% EtOAc/hexanes)), obtained as a
white solid (2.55 g, 47% yield), was ethyl (5-{5-[4-(2-bromo-5-
5092
dx.doi.org/10.1021/jm200319u |J. Med. Chem. 2011, 54, 5082–5096