104 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
Bergeron et al.
pressure, and the solution was acidified with 1 N HCl to pH
2. The resulting brown precipitate was filtered, and the solid
was washed with H2O (40 mL) and EtOH (20 mL). The crude
product was dissolved in saturated NaHCO3 (700 mL), and
the aqueous solution was washed with EtOAc (2 × 200 mL).
The aqueous layer was filtered through a fine frit and acidified
with 1 N HCl to pH 2. The precipitated product was collected.
The latter aqueous layer was extracted with EtOAc (4 × 400
mL), and the extracts were concentrated in vacuo. The residue
was combined with the precipitated product and dried under
high vacuum at 40 °C for 12 h to give 4.08 g (66%) of 5 as a
yellow solid, mp 266-268 °C dec (lit. mp of (R)-enantiomer
vacuum, the residue was dissolved in H2O (120 mL), and
evaporation was repeated. Distilled H2O (120 mL) was added
to the solid, and solvent was removed by lyophilization to give
12.96 g (quantitative) of 10 as a green solid: NMR (D2O) δ
2.30 (s, 3 H), 2.33-2.46 (m, 1 H), 2.67-2.82 (m, 1 H), 3.59-
3.68 (m, 2 H), 5.10 (dd, 1 H, J ) 10, 6), 7.04 (d, 1 H, J ) 8),
7.52-7.58 (m, 1 H), 7.59-7.62 (m, 1 H). Anal. (C12H14ClNO3)
C, H, N.
4,5-Dih yd r o-2-(2-h yd r oxyp h en ylm eth yl)th ia zole-4(S)-
ca r boxylic Acid (11). NaHCO3 (1.90 g, 22.6 mmol) was added
in portions to a solution of D-cysteine hydrochloride monohy-
drate (3.95 g, 22.5 mmol) in water (20 mL). Phosphate buffer
(40 mL), degassed CH3OH (60 mL), and 2-hydroxyphenylac-
etonitrile32 (2.00 g, 15.0 mmol) were added, and the mixture
was refluxed under Ar for 25 h. Volatile components were
removed under reduced pressure, and saturated NaHCO3 (100
mL) was added. The aqueous layer was washed with EtOAc
(3 × 50 mL), acidified with 1 N HCl to pH 3, and extracted
with EtOAc (3 × 50 mL). The combined organic extracts were
evaporated in vacuo. Purification of the residue on a Sephadex
LH-20 column, eluting with 15% EtOH in toluene, afforded
1.91 g (54%) of 11 as a colorless solid, mp 129 °C: [R]22D -13.7°
(c 1.00, CH3OH); NMR (CD3OD) δ 2.88 (dd, 1 H, J ) 5.7, 13.8),
2.96 (dd, 1 H, J ) 4.8, 13.8), 3.54 (d, 1 H, J ) 14.7), 3.65 (d, 1
H, J ) 14.7), 4.63 (m, 1 H), 6.80 (m, 2 H), 7.12 (m, 2 H); HRMS
calcd for C11H11NO3S (M+) 237.0460, found 237.0476.
261-262 °C44): [R]23 +27.0° (c 1.02, DMF); NMR (DMSO-d6)
D
δ 3.61 (m, 2 H), 5.38 (dd, 1 H, J ) 7.2, 9.4), 6.31 (d, 1 H, J )
2.3), 6.38 (dd, 1 H, J ) 2.3, 8.6), 7.25 (d, 1 H, J ) 8.6), 10.25
(br s, 1 H), 12.60 (br s, 1 H), 13.15 (br s, 1 H). Anal. (C10H9-
NO4S) C, H, N.
4,5-Dih yd r o-2-(2-h yd r oxy-3-m eth oxyp h en yl)th ia zole-
4(S)-ca r boxylic Acid (6). D-Cysteine (2.78 g, 22.9 mmol) was
added to a solution of 17 (2.28 g, 15.3 mmol) in a mixture of
degassed CH3OH (30 mL) and phosphate buffer (20 mL). The
mixture was stirred at 70 °C under Ar for 17 h. Volatile
components were removed under reduced pressure; the sus-
pension was acidified with 1 N HCl to pH 2.5 and extracted
with EtOAc (3 × 200 mL). Solvent was removed by rotary
evaporation. Purification of the residue on a Sephadex LH-20
column, eluting with 4% EtOH/toluene, yielded 3.50 g (90%)
4,5-Dih yd r o-2-(2-h yd r oxyp h en yl)t h ia zole-4(S)-a cet ic
Acid (12). Degassed 6 N HCl (100 mL) was added to 25 (3.18
g, 9.53 mmol), and the reaction mixture was heated at reflux
under a nitrogen balloon with periodic venting for 1 day.
Solvent was removed under high vacuum, degassed H2O (50
mL) was added, and evaporation was repeated to give 1.55 g
(95%) of 26,33 which was used directly. Degassed phosphate
buffer (55 mL) and distilled CH3OH (86 mL) were added to
26 (1.54 g, 9.0 mmol) and 2-cyanophenol (1.04 g, 8.77 mmol).
The pH was raised to 7 with 50% (w/w) NaOH (40 drops), and
the reaction mixture was heated at 50 °C for 1 day under N2.
After the bulk of solvents were removed by rotary evaporation,
0.5 M citric acid (100 mL) was added, followed by extraction
with EtOAc (5 × 20 mL). The organic extracts were washed
with H2O (25 mL) and brine (25 mL), and solvent was taken
off in vacuo. Purification of the concentrate on a Sephadex LH-
20 column, eluting with 3% EtOH/toluene, produced 0.17 g
of 6 as a yellow solid, mp 65 °C: [R]22 +31.8° (c 1.15, CH3-
D
OH); NMR (CD3OD) δ 3.69 (d, 2 H, J ) 9), 5.42 (t, 1 H, J ) 9),
6.87 (t, 1 H, J ) 8), 7.09 (m, 2 H). Anal. (C11H11NO4S) C, H,
N.
2-(4-Ca r b oxy-2-h yd r oxyp h en yl)-4,5-d ih yd r ot h ia zole-
4(S)-ca r boxylic Acid (7). D-Cysteine (780 mg, 6.44 mmol)
was added to a solution of 18 (700 mg, 4.29 mmol) in a mixture
of degassed CH3OH (30 mL) and phosphate buffer (20 mL).
The pH was adjusted to 6 with 1 N NaOH, and the mixture
was stirred at 70 °C under Ar for 23 h. Volatile components
were removed under reduced pressure, and the suspension was
acidified with 1 N HCl to pH 2. The aqueous layer was
extracted with EtOAc (4 × 100 mL). The combined organic
extracts were evaporated in vacuo. Purification of the residue
on a Sephadex LH-20 column, eluting with 6% EtOH/toluene,
gave 604 mg (53%) of 7 as a yellow solid, mp 240 °C dec: [R]22
D
(8%) of 12 as a yellow solid, mp 157-158.5 °C: [R]21 -23.7°
+19.6° (c 1.02, CH3OH); NMR (DMSO-d6) δ 3.67 (dd, 1 H, J )
7.6, 11.4), 3.76 (dd, 1 H, J ) 9.7, 11.4), 5.52 (dd, 1 H, J ) 7.6,
9.7), 7.49 (m, 2 H), 7.60 (d, 1 H, J ) 8.1), 12.60 (br s, 1 H),
13.30 (br s, 2 H). Anal. (C11H9NO5S) C, H, N.
D
(c 1.34, CH3OH); NMR δ 2.76 (dd, 1 H, J ) 16, 8), 2.98 (dd, 1
H, J ) 16, 6), 3.16 (dd, 1 H, J ) 11, 7), 3.61 (dd, 1 H, J ) 11,
8), 4.2 (br s, 2 H), 5.05-5.16 (m, 1 H), 6.85-7.03 (m, 2 H),
7.33-7.45 (m, 2 H). Anal. (C11H11NO3S) C, H, N.
2-(3-H yd r oxyp yr id in -2-yl)t h ia zole-4-ca r b oxylic Acid
(8). Compound 19 (1.00 g, 4.23 mmol) was stirred with 1 N
NaOH (60 mL) and CH3OH (80 mL) for 5 h at room temper-
ature. After the bulk of the CH3OH was removed by rotary
evaporation, the concentrate was cooled to 0 °C and acidified
to a pH of 2 with 85% H3PO4. The precipitate was filtered,
washed with water (2×), and recrystallized with aqueous
EtOH to give 0.80 g (85%) of 8 as a yellow solid: NMR (DMSO-
d6) δ 6.1 (br s, 2 OH), 7.35-7.60 (m, 2 H), 8.11-8.26 (m, 1 H),
8.50 (s, 1 H). Anal. (C9H6N2O3S) C, H, N.
4,5-Dih ydr o-2-(2-h ydr oxyph en yl)th iazole-4(S)-pr opan o-
ic Acid (13). Degassed phosphate buffer (45 mL) and distilled
CH3OH (50 mL) were added to 30 (1.58 g, 8.5 mmol) and
2-cyanophenol (0.953 g, 8.00 mmol). The pH was raised to 6
with 50% (w/w) NaOH (44 drops), and the reaction mixture
was heated at 45 °C for 2.5 days under N2. After the bulk of
solvents were removed by rotary evaporation, the concentrate
was acidified to a pH of 2 with aqueous citric acid and
extracted with EtOAc (6 × 50 mL). The organic extracts were
washed with H2O (2×) and brine, and solvent was taken off
in vacuo. Purification of the concentrate on a Sephadex LH-
20 column, eluting with 2% EtOH/toluene, produced 0.701 g
4,5-Dih yd r o-2-(2-h yd r oxyp h en yl)-1H-im id a zole-4-ca r -
boxylic Acid (9).29 To an ice-cooled solution of D,L-2,3-
diaminopropionic acid monohydrochloride (141 mg, 1.0 mmol)
and triethylamine (111 mg, 1.1 mmol) in CH3OH (8 mL) was
added a solution of ethyl 2-hydroxybenzimidate hydrochloride28
(200 mg, 0.99 mmol) in CH3OH (4 mL). The reaction mixture
was refluxed for 5 h, and the solvent was removed in vacuo.
Silica gel flash chromatography (CH3OH:CH2Cl2 ) 3:7) gave
108 mg (53%) of 9 as a colorless solid, mp 162 °C: NMR
(DMSO-d6) δ 3.86 (dd, 1 H, J ) 7, 12), 3.40 (m, 1 H), 4.50 (dd,
1 H, J ) 7, 11), 6.86 (m, 2 H), 7.35 (m, 1 H), 7.69 (m, 1 H);
(35%) of 13 as a light-green solid, mp 108-108.5 °C: [R]21
D
-70.6° (c 0.622, CHCl3); NMR δ 2.11 (q, 2 H, J ) 8), 2.64 (t, 2
H, J ) 7), 3.04 (dd, 1 H, J ) 11, 9), 3.49 (dd, 1 H, J ) 11, 9),
4.70-4.82 (m, 1 H), 6.84-7.01 (m, 2 H), 7.31-7.43 (m, 2 H).
Anal. (C12H13NO3S) C, H, N.
4,5-Dih yd r o-2-(3-h yd r oxyq u in olin -2-yl)t h ia zole-4(R)-
ca r boxylic Acid (14). Phosphate buffer (7 mL) was added to
33 (0.34 g, 2.00 mmol) and L-cysteine (0.73 g, 6.0 mmol) in
distilled CH3OH (20 mL). The reaction mixture was heated at
60 °C for 1 day, and the volatiles were removed in vacuo. The
residue was taken up in KHCO3 (30 mL), and the solid was
filtered. The filtrate was extracted with Et2O (3 × 20 mL),
and the aqueous portion was acidified to a pH of 3 with 1 N
HCl. Solid was filtered and dissolved in H2O (10 mL), which
C
10H10N2O3 MS (EI) 206 (M+, 61%), 161 (M+ -CO2H, 100%).
3,4-Dih ydr o-5-(2-h ydr oxy-5-m eth ylp h en yl)-2H-p yr r ole-
2-ca r boxylic Acid Hyd r och lor id e (10). Concentrated HCl
(140 mL) was added to 22 (18.08 g, 48 mmol), and the reaction
mixture was heated at reflux under a nitrogen balloon with
periodic venting for 15 h. Solvent was removed under high