4598 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 23
Ohnmacht et al.
heated at 45 °C for 18 h, poured onto water (350 mL), and
extracted with Et2O. The combined extracts were washed with
saturated brine, dried (MgSO4), evaporated to an orange solid
(3.01 g), and chromatographed (CHCl3) to yield 32 as a pale
yellow solid (0.46 g, 17%): mp 191-2.5 °C; 1H NMR (300 MHz,
DMSO-d6) 1.58 (s, 3H, CH3), 7.63-7.76 (m, 3H, aromatic),
8.02-8.07 (d, 3H, aromatic) 8.34 (dd, 1H, J ) 2.2, 8.6 Hz,
aromatic), 8.59 (s, 1H, NH), 8.61 (d, 1H, J ) 2.3 Hz, aromatic);
MS (CI, CH4) 419 (M + 1). Anal. (C16H13F3N2O6S) C, H, N.
Met h od A3: N-[4-[(4-Nit r op h en yl)su lfon yl]p h en yl]-
3,3,3,-tr iflu or o-2-h yd r oxy-2-m eth ylp r op a n a m id e (36). To
a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-methylpro-
panoic acid (1.00 g, 6.3 mmol) in toluene (10 mL) was added
thionyl chloride (0.75 g, 6.3 mmol) and the mixture heated at
reflux for 3 h. The reaction mixture was cooled to room
temperature and added to a mixture of 4-[(4-nitrophenyl)-
sulfonyl]aniline (1.75 g, 6.3 mmol) in toluene (20 mL) and the
reaction mixture heated at reflux overnight. The toluene was
removed in vacuo, and the resulting solid was recrystallized
from ethyl acetate. Unreacted 4-[(4-nitrophenyl)sulfonyl]-
aniline was recovered by filtration as the desired product
remained in the filtrate. The filtrate was concentrated and
the product purified by flash chromatography (0-10% v/v ethyl
ether in methylene chloride) to yield 36 (1.02 g, 39%): mp
213-215 °C; 1H-NMR (250 MHz, DMSO-d6) 1.58 (s, 3H, CH3)
7.58 (s, 1H, OH), 8.00-8.06 (m, 4H, aromatic), 8.20 (dd, 2H, J
) 7.0, 1.9 Hz, aromatic), 8.40 (dd, 2H, J ) 7.0, 1.8 Hz,
aromatic), 10.48 (s, 1H, NH); MS (CI, CH4) 419 (M + 1). Anal.
(C16H13F3N2O6S) C, H, N.
Met h od A4: N-[4-[(N′,N′-Dip h en yla m in o)su lfon yl]-
p h e n y l]-3,3,3-t r iflu o r o -2-h y d r o x y -2-m e t h y lp r o p a n -
a m id e (40). To a stirred, cooled (-20 °C) solution of 4-(di-
methylamino)pyridine (0.125 g, 1.02 mmol) in methylene
chloride (10 mL) was added thionyl chloride (0.12 g, 0.83 mmol)
and the mixture stirred for 10 min. 3,3,3-Trifluoro-2-hydroxy-
2-methylpropanoic acid (0.13 g, 0.83 mmol) was added and the
mixture stirred at -20 °C for 30 min. A solution of 4-(di-
methylamino)pyridine (0.125 g, 1.02 mmol) and N,N-diphenyl-
4-aminobenzenesulfonamide (0.27 g, 0.83 mmol) in methylene
chloride (4 mL) was added and the reaction mixture stirred
at -20 °C for 10 min and at room temperature for 2 h and
heated at reflux for 48 h. The cooled solution was treated with
water (50 mL) and extracted with methylene chloride. The
crude material was chromatographed (methylene chloride/
ethyl ether, 12:1) to yield 40 as a colorless solid (0.19 g, 50%):
mp 217-20 °C; 1H NMR (250 MHz, DMSO-d6) 1.60 (s, 3H,
CH3), 3.32 (br s, 1H, OH), 7.28-7.42 (m, 9H, aromatic), 7.58-
7.65 (m, 3H, aromatic), 8.00-8.03 (m, 2H, aromatic); MS (CI,
CH4) 465 (M + 1). Anal. (C22H19F3N2O4S) C, H, N.
N,N-Dip h en yl-4-a m in oben zen esu lfon a m id e. A stirred
suspension of 4-acetamidobenzenesulfonyl chloride (2.0 g, 8.56
mmol), diphenylamine (2.9 g, 17.1 mmol), 4-pyrrolidinopyri-
dine (0.064g, 0.43 mmol), and triethylamine (1.73 g, 17.1 mmol)
in acetonitrile (5 mL) was refluxed for 72 h. The cooled
mixture was diluted with water (50 mL) and extracted with
ethyl acetate, and the dark oil thus obtained was purified by
column chromatography (methylene chloride/ethyl ether, 8:1)
to give 0.46 g (15%) of tan solid. The solid was dissolved in
hot ethanol (35 mL), 6 N HCl (10 mL) was added, and the
mixture was stirred at 75-80 °C for 3 h. The cooled mixture
was treated with concentrated NH4Cl to pH ) 9 and the solid
filtered off and washed well with water to yield 0.24 g (68%,
10% overall) of N,N-diphenyl-4-aminobenzenesulfonamide: mp
151-3 °C; MS (CI, CH4) 325 (M + 1).
Gen er a l Meth od A5: N-[2-Cya n o-4-(p h en ylca r bon yl)-
p h e n y l]-3,3,3-t r iflu o r o -2-h y d r o x y -2-m e t h y lp r o p a n -
a m id e (48). A stirred solution of 3,3,3-trifluoro-2-hydroxy-
2-methylpropanoic acid (0.15 g, 1.0 mmol) and thionyl chloride
(0.12 g, 1.0 mmol) in methylene chloride (15 mL) was heated
at reflux for 3 h. Triethylamine (0.11 g, 1.1 mmol) was added
to the cooled reaction mixture and the solution heated at reflux
for 30 min. A solution of 4-amino-3-cyanobenzophenone (0.19
g, 0.9 mmol) in tetrahydrofuran (2.5 mL) was added to the
cooled mixture, and the reaction mixture was heated at reflux
for 20 h. The solvents were removed in vacuo, and the residue
was dissolved in ethyl acetate and washed with water. The
organic layer was dried (MgSO4) and concentrated to a clear
oil. Purification by flash chromatography (2% v/v ethyl ether/
methylene chloride) yielded 48 as a white solid (0.11 g, 35%):
mp 202-4 °C; 1H-NMR (300 MHz, DMSO-d6) 1.64 (s, 3H, CH3),
7.57-7.62 (m, 2H, aromatic), 7.70-7.76 (m, 3H, aromatic +
OH), 7.89 (d, 1H, J ) 4.0 Hz, aromatic), 7.96-8.07 (m, 2H,
aromatic), 8.17 (s, 1H, aromatic), 10.46 (s, 1H, NH); MS (CI,
CH4) 363 (M + 1). Anal. (C18H13F3N2O3‚0.5H2O) C, H, N.
Gen er al Meth od B: N-(4-(P h en ylsu lfon yl)-3-cyan oph en -
yl)-3,3,3-tr iflu or o-2-h yd r oxy-2-m eth ylp r op a n a m id e (9).
To a stirred solution of 1.91 g (5.2 mmol) of N-(4-(phenylthio)-
3-cyanophenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropan-
amide and 150 mL of glacial acetic acid was added a solution
of 0.99 g (6.3 mmol) of potassium permanganate and 100 mL
of water in one portion. The mixture was stirred at ambient
temperature for 45 min, poured into 400 mL of water, clarified
with a little solid sodium bisulfite, and extracted with three
250 mL portions of chloroform. The extracts were dried
(MgSO4) and filtered, and the solvent was removed to yield
an oil which was chromatographed on 300 g of silica gel using
a ethyl ether (0%, 10%, 15%, and 20%) in methylene chloride
gradient. The material was further recrystallized from hexane
containing a small amount of ethyl acetate to yield 1.57 g (75%)
of the title propanamide as a white solid: mp 163-165 °C; 1H
NMR (300 MHz, DMSO-d6) 1.59 (s, 3H, CH3), 7.66-7.77 (m,
4H, aromatic, OH), 7.99 (d, 2H, J ) 7.3 Hz, aromatic), 8.32
(d, 1H, J ) 8.6 Hz, aromatic), 8.40-8.43 (m, 2H, aromatic),
10.77 (s, 1H, NH); MS (CI, CH4) 399 (M + 1). Anal.
(C17H13F3N2O4S) C, H, N.
Gen er a l Meth od C: N-[3-Hyd r oxy-4-(p h en ylsu lfon yl)-
p h e n y l]-3,3,3-t r iflu o r o -2-h y d r o x y -2-m e t h y lp r o p a n -
a m id e (14). To a stirred suspension of 18 (0.75 g, 1.9 mmol)
in dry methylene chloride (22 mL) was added boron tribromide
(3.8 mL of a 1.0 M solution of boron tribromide in methylene
chloride, 3.8 mmol). The resulting solution was stirred at room
temperature for 3 h, diluted with methylene chloride (50 mL),
and washed with water. The organic layer was dried (MgSO4)
and concentrated in vacuo to yield an off-white foam. Puri-
fication by flash column chromatography (10-30% v/v ethyl
acetate in methylene chloride) yielded 14 as a white solid (0.34
g, 46%): mp 155-156 °C; 1H-NMR (250 MHz, DMSO-d6) 1.58
(s, 3H, CH3), 7.30 (dd, 1H, J ) 8.8, 1.8 Hz, aromatic), 7.48 (s,
1H, OH), 7.51-1.66 (m, 4H, aromatic), 7.80-7.86 (m, 3H,
aromatic), 10.19 (s, 1H, NH), 10.60 (s, 1H, OH); MS (CI, CH4)
390 (M + 1). Anal. (C16H14F3NO5S) C, H, N.
Resolu tion of 41. (S)-(-)-N-[4-(P h en ylca r bon yl)p h e-
n yl]-3,3,3-t r iflu or o-2-h yd r oxy-2-m e t h ylp r op a n a m id e
[41(S)]. To a cooled (0 °C), stirred solution of 41 (6.87 g, 20.4
mmol) and triethylamine (3.2 mL, 23 mmol) in methylene
chloride (70 mL) was added 4-(dimethylamino)pyridine (cata-
lytic) followed by the dropwise addition of (1S)-(-)-camphanic
acid chloride (5.00 g. 23.1 mmol). The mixture was stirred
at room temperature for 2 h, diluted with methylene chloride
(70 mL), and washed with water, 3 N HCl (200 mL), and water.
The dried (MgSO4) organics were filtered, and the solvent was
removed in vacuo to yield a white foam. The diastereomers
were separated by repeated flash column chromatography (0-
3% v/v ethyl ether gradient in methylene chloride). The
camphanic ester which eluted first was isolated as a white
foam (3.20 g, 30%). Optical purity of >98% de was determined
by chiral HPLC (Chiralcel OD column, 15% v/v ethanol in
hexane, flow rate: 1 mL/min): 1H-NMR (300 MHz, DMSO-
d6) 0.97 (s, 3H, CH3), 1.037 (s, 3H, CH3), 1.044 (s, 3H, CH3),
1.58-1.61 (m, 1H, aliphatic), 2.00-2.10 (m, 5H, CH3, ali-
phatic), 2.43-2.47 (m, 1H, aliphatic), 7.54-7.59 (m, 2H,
aromatic), 7.66-7.82 (m, 7H, aromatic), 10.34 (s, 1H, NH). To
a suspension of the first eluting camphanic ester (3.20 g, 6.2
mmol) in methanol (40 mL) was added 2 N NaOH (3 mL) and
the yellow solution stirred at room temperature for 1 h. The
methanol was removed in vacuo, the residue treated with
water, and the mixture extracted with methylene chloride (2
× 50 mL). The dried (MgSO4) organics were filtered, the
solvent was removed in vacuo, and the white solid was
recrystallized from methylene chloride/hexane to yield 1.80 g
(86%) of 41(S): mp 171-3 °C; [R]27 ) -18.8°, c ) 1.01 in
D
methanol; optical purity >98% ee by chiral HPLC (Chiralcel
OD column, 15% v/v ethanol in hexane, flow rate 1 mL/min).
The compound was determined to have the (S) configuration