SCHEME 4
drochloride ((1R,3R)-5) (5.59 g, 86% yield) as a colorless solid in
three crops. 1H NMR (DMSO-d6) δ 8.68 (br s, 3H), 7.52 (d, 2H, J
) 8.5 Hz), 7.23 (d, 2H, J ) 8.5 Hz), 3.81 (s, 3H), 3.50 (m, 1H),
3.32-3.48 (m, 2H), 2.18-2.26 (m, 2H), 1.93-2.02 (m, 1H),
1.74-1.85 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 172.8,
142.9, 132.4, 130.2, 120.5, 65.4, 55.1, 44.9, 44.8, 38.3, 35.6. Mp
191-192 °C. HRMS m/z calcd for C13H1779BrNO2 is 298.0442,
measured is 298.0439. HRMS m/z calcd for C13H1781BrNO2 is
300.0422, measured is 300.0410.
Preparation of (1S,3S)-Methyl 1-Amino-3-(4-bromophenyl)cy-
clopentanecarboxylate Hydrochloride ((1S,3S)-5). See ref 16.
Preparation of (7S)-7-(4-bromophenyl)-1,3-diazaspiro[4.4]non-
ane-2,4-dione (8). To a round-bottomed flask charged with am-
monium carbonate (268 g, 2.79 mol) and potassium cyanide (44.4
g, 0.681 mol) was added water (1.5 L). The mixture was heated at
80 °C and a solution of (S)-3-(4-bromophenyl)cyclopentanone 2-(S)
(148.09 g, 0.62 mol) in ethanol (1.5 L, 25 mol) was added. The
reaction mixture was heated to reflux for 15 h. The reaction mixture
was then cooled to room temperature. The crude reaction mixture
was filtered and washed with water. The solid was triturated with
ether (1.5 L), filtered, washed with ether, and dried in vacuo to
yield (S)-7-(4-bromophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione
(8) (181 g, 95% yield) as a 1:1 mixture of diastereomers. 1H NMR
(DMSO-d6) δ 10.61 (s, 1H), 8.29 (s, 0.5H), 8.24 (s, 0.5H), 7.49
(d, 2H, J ) 8.4 Hz), 7.27 (d, 1H, J ) 8.5 Hz), 7.24 (d, 1H, J ) 8.5
Hz), 3.14-3.35 (m, 1H), 2.47(dd, 0.5H, J ) 8.3, 13.6 Hz),
1.68-2.27 (m, 5.5H). 13C NMR (100 MHz, DMSO-d6 δ 180.3,
179.9, 157.2, 157.1, 144.14, 144.08, 132.2, 132.1, 130.3, 130.2,
120.1, 68.9, 68.6, 45.9, 45.2, 45.0, 44.3, 37.8, 34.5, 34.0. Mp
192-198 °C. HRMS m/z calcd for C13H1279Br N2O2 (M - H)- is
307.0082, measured is 307.0086. HRMS m/z calcd for
C13H1281BrN2O2 (M - H)- is 309.0062, measured is 309.0111.
Preparation of (5R,7S)-7-(4-Bromophenyl)-3-methyl-1,3-diaza-
spiro[4.4]nonane-2,4-dione ((5R,7S)-9). To a flask containing (S)-
7-(4-bromophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (8) (1:1
mixture of diastereomers, 180 g, 0.583 mol) was added potassium
carbonate (121 g, 0.875 mol) followed by DMF (1 L). After the
mixture was stirred for 15 min at room temperature, methyl iodide
(39.9 mL, 0.642 mol) was added in one portion. The reaction was
stirred at rt for 48 h. The reaction mixture was partially concentrated
in vacuo at 25 °C, removing approximately 400 mL of DMF and
excess methyl iodide. The crude mixture was cooled with an ice
water bath and water (2 L) was added. After the reaction mixture
was stirred for 1 h the resulting colorless precipitate was filtered
and rinsed with water (1 L). The filter cake was dried in vacuo to
provide 220 g of crude (S)-7-(4-bromophenyl)-3-methyl-1,3-
diazaspiro[4.4]nonane-2,4-dione as a 1:1 mixture of diastereomers.
Hydantoin ((5R,7S)-9) can be separated by crystallization as
follows: The material was separated into two batches of 110 g each.
The crude material (110 g) was suspended in MeCN (2.5 L) then
heated to 70 °C until near complete dissolution occurred. The
material was filtered rapidly at 70 °C and rinsed with MeCN (2 ×
500 mL). The combined filtrates were reheated to 65 °C with
stirring. After a clear solution was obtained the mixture was allowed
to cool slowly to 50 °C at which point material began to drop out
of solution. The solution was allowed to slowly cool to 30 °C with
stirring (100 rpm). After aging for 2 h the solution was filtered
and the solid was dried at 65 °C under vacuum to provide (5R,7S)-
7-(4-bromophenyl)-3-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione
((5R,7S)-9) (22.2 g, 20% yield) as a colorless solid. 1H NMR
(DMSO-d6) δ 8.56 (s, 1H), 7.50 (d, 2H, J ) 8.42 Hz), 7.27 (d, 2H,
J ) 8.53 Hz), 3.16-3.31 (m, 1H), 2.84 (s, 3H), 2.46 (dd, 1H, J )
have developed to these intermediates have provided ample
material to conduct SAR studies on this class of molecule, the
results of which will be reported elsewhere.
Experimental Section
Preparation of (1R,3R)-1-Amino-3-(4-bromophenyl)cyclopen-
tanecarbonitrile Bi-L-tartrate ((1R,3R)-7). A solution of (R)-3-(4-
bromophenyl)cyclopentanone ((R)-2) (21.5 g, 90.0 mmol) in 7 M
methanolic ammonia solution (220 mL) was treated with ammonium
chloride (9.63 g, 180 mmol) and sodium cyanide (8.82 g, 180
mmol). The reaction was stoppered and stirred at room temperature
for 3 days. The reaction was concentrated, treated with sat. NaHCO3
solution (400 mL), and extracted with EtOAc (400 mL). The EtOAc
layer was washed with sat. NaCl (300 mL) and treated with
L-tartaric acid (13.5 g, 90.0 mmol) and the EtOAc was removed in
vacuo. The resulting white solid was filtered and triturated with
water (9 × 250 mL) until the more soluble isomer was very nearly
gone as indicated by HPLC (ThermoQuest 50 × 4.6 mm, 5 u,
Hypercarb column, part no. 35005-025). The remaining white solid
was dried in vacuo to provide (1R,3R)-1-amino-3-(4-bromophe-
nyl)cyclopentanecarbonitrile 2:1 salt with L-tartaric acid ((1R,3R)-
1
7) (14.5 g, 47% yield). H NMR (DMSO-d6) δ 7.45 (d, 2H, J )
8.3 Hz), 7.23 (d, 2H, J ) 8.4 Hz), 4.01 (s, 1H), 3.30-3.45 (m,
1H), 2.50 (m, 1H), 2.10-2.35 (m, 3H), 1.8-2.0 (m, 2H), 1.6-1.75
(m, 1H). Due to instability (significant amounts of retro-Strecker
reaction were observed on standing in solution) full characterization
of this intermediate was not practical.
Preparation of (1R,3R)-1-Amino-3-(4-bromophenyl)cyclopen-
tanecarboxylic Acid Hydrochloride ((1R,3R)-3). A suspension of
(1R,3R)-1-amino-3-(4-bromo-phenyl)cyclopentanecarbonitrile 2:1
salt with L-tartaric acid ((1R,3R)-7) (14.4 g, 42.4 mmol) in 6 N
hydrochloric acid (72 mL) and p-dioxane (72 mL) was heated at
100 °C. After 24 h the reaction mixture was cooled to rt and the
product was collected by filtration, washed with water (2 × 25
mL), and dried in vacuo to provide the crude amino acid. The crude
product was further purified by trituration with EtOAc (3 × 25
mL) then redried to provide (1R,3R)-1-amino-3-(4-bromophenyl)-
cyclopentanecarboxylic acid hydrochloride ((1R,3R)-3) as a color-
1
less solid (6.29 g, 53% yield). H NMR (DMSO-d6) δ 13.9 (br s,
1H), 8.52 (br s, 3H), 7.51 (d, 2H, J ) 8.5 Hz), 7.23 (d, 2H, J )
8.5 Hz), 3.50 (m, 1H), 2.30-2.42 (m, 2H), 2.10-2.26 (m, 2H),
1.90-2.05 (m, 1H), 1.75-1.88 (m, 1H). 13C NMR (100 MHz,
DMSO-d6) δ 174.6, 143.1, 132.3, 130.1, 120.3, 64.5, 44.02, 43.95,
37.3, 34.7. Mp 224-231 °C. HRMS m/z calcd for C12H15NO279Br
is 284.0286, measured is 284.0278. HRMS m/z calcd for
C12H15NO281Br is 286.0266, measured is 286.0269.
Preparation of (1R,3R)-Methyl 1-Amino-3-(4-bromophenyl)cy-
clopentanecarboxylate Hydrochloride ((1R,3R)-5). To a solution
of (1R,3R)-1-amino-3-(4-methoxyphenyl)cyclopentanecarboxylic
acid hydrochloride ((1R,3R)-3) (6.20 g, 19.4 mmol) in methanol
(150 mL) at 0 °C was added thionyl chloride (8.20 mL, 160 mmol)
at a dropwise rate. The ice bath was removed and the reaction was
heated at 70 °C for 6 h and then was allowed to stir at rt for 15 h.
The reaction was filtered and concentrated. The crude product was
recrystallized from methanol and ether to obtain (1R,3R)-1-amino-
3-(4-bromophenyl)cyclopentanecarboxylic acid methyl ester hy-
(16) The (1S,3S) stereoisomer ((1S,3S)-5) was prepared by using the above
procedures substituting ketone (S)-2 for ketone (R)-2 and D-tartaric acid for
L-tartaric acid. From ketone (S)-2 (9.5 g, 39.7 mmol) was obtained (1S,3S)-
methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate hydrochloride ((1S,3S)-
5) (4.15 g, 31% overall yield). The 1H, 13C, mp, and HRMS matched that obtained
for ((1R,3R)-5). See the Supporting Information for details of chiral purity
analysis.
4888 J. Org. Chem. Vol. 74, No. 13, 2009