Journal of Medicinal Chemistry
ARTICLE
pharmacokinetic profiles, and candidates from the series were
successfully progressed into more detailed in vivo studies.
dichloromethane (40 mL) was slowly added trifluoroacetic acid (13 mL).
The reaction was stirred until complete consumption of starting
material (∼50 min, LCMS analysis of crude reaction). The reaction was
immediately diluted with a similar volume of toluene (this step is critical to
ensure no loss of tBu ester during solvent removal), and the volatiles were
removed in vacuo. Further toluene was added, and the mixture
was concentrated to dryness to give 5a as a brown oil that slowly solidified
(3.8 g). This was used in crude form in the next step. LRMS: m/z 455/7
[M þ H]þ.
’ EXPERIMENTAL SECTION
Chemistry. Reagents were obtained from commercial suppliers and
used without purification. Unless otherwise stated, reactions were
carried out at ambient temperature (18-25 °C) and under positive
nitrogen pressure with magnetic stirring. Flash chromatography was
performed on E. Merck 230-400 mesh silica gel 60. Solvent mixtures
used as eluents are volume/volume ratios unless otherwise stated.
Preparative reverse phase (RP) HPLC purifications were performed
on Waters Symmetry, Novapak, or Xterra columns eluting with a
gradient of acetonitrile or methanol in aqueous ammonium acetate,
[4-Chloro-2-[[(3S)-4-[(4-chlorophenyl)acetyl]-3-methyl-1-pipera-
zinyl]methyl]phenoxy]acetic Acid, 1,1-Dimethylethyl Ester (6a) [R1 =
Cl, R2 = tBu, R3 = H, R5 = (3S)-Me, and R6 = 4-Chlorobenzeneacetyl]. To
5a (1.2 g, 2.6 mmol) were added dichloromethane (30 mL), water
(30 mL), and sodium hydrogencarbonate (1.3 g, 15.5 mmol), and the
mixture was vigorously stirred. 4-Chlorobenzeneacetyl chloride (0.58 g,
3.1 mmol) was added dropwise, and the mixture was stirred for 16 h. The
mixture was extracted with dichloromethane, and the combined organics
were washed with water and dried (Na2SO4), and the solvent was
removed in vacuo to give crude 6a as an oil (0.9 g). This was used in the
next step without further purification. An aliquot from an identical
preparation was purified by column chromatography on silica gel,
eluting with iso-hexane/diethyether (1/2-1/3) to give analytically pure
1
ammonia, or trifluoroacetic acid solution. Routine H NMR spectra
were recorded on a Varian UnityInova spectrometer at a proton
frequency of either 300 or 400 MHz. Chemical shifts are expressed in
ppm. Mass spectra were measured on an Agilent 1100 MSD G1946D
spectrometer using electrospray ionization, atmospheric pressure che-
mical ionization, or Agilent Multimode ionization; only ions that
indicate the parent mass are reported.
The purity of all test compounds was determined by RPHPLC
conducted on an Agilent 1100 LC/MS system, using UV detection
and a gradient of 5-95% acetontirile in either aqueous ammonium
acetate (0.1% w/v) (conditions a) or trifluoroacetic acid (0.1% v/v)
(conditions b) over 2.5 min on 2.1 mm ꢀ 5 mm columns packed with
Waters Symmetry C8 or Waters Symmetry C18 or 2.0 mm ꢀ 50 mm
columns packed with Phenomemex Max-RP. Column and solvent
details for each compound are given in the Supporting Information.
All test compounds unless otherwise indicated showed g95% purity.
For all key molecules, high resolution mass spectrometry or micro-
analysis data were also generated.
t
1
6a for characterization. LRMS: m/z 451 [M þ H - Bu]þ. H NMR
(CDCl3) δ: 7.40 (1H, d), 7.28 (2H, d), 7.18 (2H, d), 7.14 (1H, dd), 6.64
(1H, d), 4.81-4.38 (3H, m), 4.03-3.93 (0.5H, m), 3.71-3.63 (2H, m),
3.52 (2H, s), 2.88-2.59 (3H, m), 2.24-1.89 (2.5H, m), 1.47 (9H, s),
1.28 (3H, d).
[4-Chloro-2-[[(3S)-4-[(4-chlorophenyl)acetyl]-3-methyl-1-pipera-
zinyl]methyl]phenoxy]acetic Acid (27). To 6a (0.9 g crude, 1.8 mmol)
was added trifluoroacetic acid (6 mL), and the reaction was stirred for 16
h. Toluene was added, and the volatiles were removed in vacuo. The
crude product was purified by RPHPLC. Solvent removal followed by
redissolution in methanol and evaporation to dryness gave 27 as a white
foam. HPLC analysis: 99.7% purity (conditions b, Phenomemex Max-
RP). LRMS: m/z 451 [M þ H]þ. 1H NMR [dimethyl sulfoxide
(DMSO)-d6] δ: 7.40-7.32 (3H, m), 7.28-7.19 (3H, m), 6.93 (1H,
d), 4.65 (2H, s), 4.54 (1H, m), 4.20 (1H, m), 3.69 (2H, s), 3.53 (2H, s),
3.24 (1H, m), 2.84 (1H, m), 2.69 (1H, m), 2.12 (1H, m), 1.98 (1H, m),
(4-Chloro-2-formylphenoxy)acetic Acid, 1,1-Dimethylethyl Ester
t
(3a) (R1 = Cl, R2 = Bu, and R3 = H). Potassium carbonate (5.0 g, 36
mmol) was added to a solution of 2-hydroxy-5-chlorobenzaldehyde (5.2
g, 33 mmol) and tert-butylbromoacetate (4.8 mL, 33 mmol) in N,N-
dimethylformamide (DMF) (20 mL). The reaction was stirred for 16 h.
Aqueous sodium hydroxide was added (1 N, 100 mL), and the mixture
was extracted with diethyl ether (3ꢀ). The combined organics were
washed with water and brine and dried (MgSO4), and the solvent was
removed in vacuo. The resulting solid was triturated with iso-hexane to
give 3a (7.2 g, 81%). 1H NMR (CDCl3) δ: 10.5 (1H, s), 7.81 (1H, d),
7.47 (1H, dd), 6.82 (1H, d), 4.64 (2H, s), 1.48 (9H, s).
1.19 (3H, m). Anal. (C22H24Cl2N2O4 0.70H2O) C, H, N.
3
4-Chloro-2-iodo-benzeneacetonitrile (34). Borane-THF complex
(24 mL of a 1 M solution in THF, 24 mmol) was added to a solution of
4-chloro-2-iodobenzoic acid (2.4 g, 8.5 mmol) in THF (15 mL), and the
reaction was heated at 50 °C for 1 h. After it was cooled to room
temperature, the reaction mixture was cautiously quenched with metha-
nol, and then, volatiles were removed in vacuo. Methanol was added, and
the volatiles were removed in vacuo (repeated twice) to give a white
solid. This was dissolved in a mixture of dichloromethane (20 mL) and
DMF (1 mL). Thionyl chloride (0.93 mL, 16.8 mmol) was added
dropwise, and the reaction was stirred for 1 h. The solvents were
removed in vacuo, and the residue was partitioned between diethyl ether
and aqueous NaHCO3. The organic layer was separated and dried
(MgSO4), and the solvents were removed in vacuo. The residue was
dissolved in DMF (8 mL), sodium cyanide (0.81 g, 17.0 mmol) was
added, and the reaction mixture was stirred at room temperature for 3 h.
Ice was added, and the solid was collected by filtration to give 34 (2.65 g,
wet) as a beige solid. LRMS: m/z 276 [M - H]-.
(2S)-4-[[5-Chloro-2-[2-(1,1-dimethylethoxy)-2-
oxoethoxy]phenyl]methyl]2-methyl-1-piperazine Carboxylic Acid, 1,1-
Dimethylethyl Ester (4a) [R1 = Cl, R2 = tBu, R3 = H, R4 = BOC, and R5 =
(2S)-Me]. To a solution of (2S)-2-methyl-1-piperazinecarboxylic acid
1,1-dimethylethyl ester (6.7 g, 33.4 mmol) and 3a (9.1 g, 33.6 mmol) in
tetrahydrofuran (THF) (350 mL) was added magnesium sulfate (18 g),
and the reaction was stirred at room temperature for 20 h. Sodium
triacetoxyborohydride (11.7 g, 54 mmol) was added portion-wise, and
the reaction was stirred for 20 h. The reaction was diluted with toluene,
and the volatiles were removed in vacuo. Water was added, and the
mixture was extracted with ethyl acetate (2ꢀ). The combined organics
were washed with brine and dried (Na2SO4), and the solvent was
removed in vacuo. The residue was purified by column chromatography
on silica gel, eluting with iso-hexane/ethyl acetate (6:1-4:1) to give 4a
(9.2 g, 61%). LRMS: m/z 455/7 [M þ H]þ. 1H NMR (CDCl3) δ: 7.44
(1H, d), 7.12 (1H, dd), 6.64 (1H, d), 4.49 (2H, s), 4.20 (1H, bs), 3.80
(1H, d), 3.55 (2H, s), 3.10 (1H, dt), 2.77 (1H, d), 2.65 (1H, d), 2.23
(1H, dd), 2.09 (1H, m), 1.48 (9H, s), 1.46 (9H, s), 1.28 (3H, d).
[4-Chloro-2-[[(3S)-3-methyl-1-piperazinyl]methyl]phenoxy]acetic
Acid, 1,1-DimethylethylEster Trifluoroacetate Salt(5a) [R1 = Cl, R2 = tBu,
R3 = H, R4 = H, and R5 = (3S)-Me]. To a solution of 4a (3.8 g, 8.4 mmol) in
4-Chloro-2-iodophenyl)acetic Acid (35). Nitrile 34 (2.4 g) was
dissolved in aqueous KOH (14 mL of 3.4 M solution) and heated at
100 °C for 24 h. After it was cooled to room temperature, the aqueous
mixture was washed with diethylether (discarded), acidified, and ex-
tracted with ethyl acetate (2ꢀ). The combined organic extracts were
dried (Na2SO4), and the solvents were removed in vacuo to give 35
1
(1.93 g, 82% overall) as a yellow solid. H NMR (CDCl3) δ: 7.85
(1H, d), 7.32 (1H, dd), 7.22 (1H, d), 3.83 (2H, s).
1785
dx.doi.org/10.1021/jm1014549 |J. Med. Chem. 2011, 54, 1779–1788