Inhibitors of Stromelysin DiscoVered by SAR by NMR
J. Am. Chem. Soc., Vol. 119, No. 25, 1997 5825
during which time the mixture became homogenous. The reaction
mixture was cooled to ambient temperature and concentrated in Vacuo.
The residue was taken up in 1:1 CH2Cl2/THF. In a separate flask,
NMM (3.5 mL, 32 mmol) was added to a solution of hydroxylamine
hydrochloride (2.1 g, 30 mmol) in water (10 mL). THF (20 mL) was
then added and the hydroxylamine solution was poured into the acid
chloride solution, and the reaction mixture vigorously stirred for 2 h.
The reaction mixture was partitioned between saturated aqueous NH4-
Cl and CH2Cl2. The organic phase was dried over MgSO4, filtered,
and concentrated in Vacuo to give 4-(4-phenylphenoxy)butanohydrox-
amic acid (1.45 g, 57% overall yield) as a white solid: mp 131-132
°C; 1H NMR (DMSO-d6) δ 1.94 (m, 2H), 2.14 (t, 2H, J ) 7 Hz), 4.01
(t, 2H, J ) 6 Hz), 7.02 (d, 2H, J ) 8 Hz), 7.29 (t, 1H, J ) 6 Hz), 7.43
(t, 2H, J ) 6 Hz), 7.62 (m, 4H), 8.71 (s, 1H), 10.44 (s, 1H); MS (DCI/
NH3) 289 (M + NH4+, 100), 272 (M+H+, 35), 255 (30). Anal. Calcd
for C16H17NO3: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.55; H, 6.95;
N, 4.86.
5-(4-Phenylphenoxy)pentanohydroxamic Acid (48). A mixture
in acetone of 4-phenylphenol (0.85 g, 5.0 mmol) and potassium
carbonate (0.76 g, 5.5 mmol) was stirred for 30 min. Neat methyl
5-bromovalerate (0.78 mL, 5.5 mmol) was added dropwise via syringe,
and the reaction mixture was stirred for 2 h at ambient temperature
and overnight at reflux. Catalytic KI was then added, and the reaction
mixture was heated overnight at reflux. An additional 10 drops of
methyl 5-bromovalerate was then added, and reflux was continued for
8 h. The reaction mixture was cooled to ambient temperature and
filtered. The collected solid was washed with acetone, and the
combined filtrate and washings were concentrated in Vacuo. The
residue was partitioned between Et2O and water. The aqueous phase
was extracted with Et2O. The combined organic layers were dried over
Na2SO4, filtered, and concentrated in Vacuo to give methyl 5-(4-
phenylphenoxy)pentanoate (1.66 g) as a white powder.
(6 mL), adding of NMM (2.50 mL, 23.0 mmol), and then diluting with
THF (20 mL). After 2 h, the mixture was partitioned between aqueous
NH4Cl and CH2Cl2. The organics were dried (MgSO4) and concentrated
to give a white solid (1.97 g). Recrystallization from hot CH3CN (100
mL) provided 1.11 g of the final compound (39% overall yield) as a
1
white solid: mp 191-193 °C; H NMR (DMSO-d6) δ 4.54 (s, 2H),
7.08 (d, 2H, J ) 8.8 Hz), 7.73 (d, 2H, J ) 8.4 Hz), 7.87 (q, 4H, J )
5.5 Hz), 9.01 (s, 1H), 10.88 (s, 1H); 13C NMR (DMSO-d6) δ 65.85,
109.27, 115.32, 119.02, 126.95, 128.31, 131.07, 132.80, 144.14, 158.44,
164.15; IR (KBr) 3400, 3230, 2960, 2220, 1640, 1600, 1490, 1255
cm-1; MS (DCI/NH3) 303 (M + NH4+NH3+, 5), 286 (M + NH4+, 20),
270 (M + NH4 - O+, 100). Anal. Calcd for C15H12N2O3: C, 67.16;
H, 4.51; N, 10.44. Found: C, 67.04; H, 4.51; N, 10.23.
3-[4-(4-Cyanophenyl)phenoxy]propanohydroxamic Acid (50). To
a solution of 4-cyano-4′-hydroxybiphenyl (3.30 g, 16.9 mmol) in THF
(76 mL) and DMF (10 mL) was added potassium tert-butoxide (2.00
g, 16.9 mmol). Neat â-propiolactone (1.30 mL, 18.6 mmol) was added
dropwise. The resulting yellow suspension was stirred overnight at
ambient temperature and then reduced in volume in Vacuo. The residue
was taken up in EtOAc and extracted twice with 5% aqueous NaHCO3
with NaCl added. The combined aqueous phases were washed with
ether and then acidified to approximately pH 2. A white precipitate
formed, which was filtered off and dried in Vacuo to give 3-(4-(4-
cyanophenyl)phenoxy)propionic acid (2.48 g, 60%) as a white pow-
1
der: mp 160-164 °C; H NMR (DMSO-d6) δ 2.72 (t, 2H, J ) 5.9
Hz), 4.23 (t, 2H, J ) 6.1 Hz), 7.06 (d, 2H, J ) 8.5 Hz), 7.72 (d, 2H,
J ) 8.8 Hz), 7.85 (d, 2H, J ) 8.5 Hz), 7.88 (d, 2H, J ) 8.5 Hz); IR
(neat) 3044, 2976, 2950, 2220, 1702, 1603, 1496, 1254, 1244, 1182,
1043, 824 cm-1; MS (DCI/NH3) 267 (M + NH4 - H2O)+, 285 (M +
NH4)+, 302 (M + NH4 + NH3)+
. Anal. Calcd for: C16H13-
NO3‚0.10H2O: C, 71.42; H, 4.94; N, 5.20. Found: C, 71.22; H, 4.75;
N, 5.01.
A 1.00 g portion of the acid (3.74 mmol) was refluxed in thionyl
chloride (10 mL) for 2 h. The excess thionyl chloride was removed in
Vacuo, and the resulting acid chloride was dissolved in THF (10 mL).
A solution of hydroxylamine was prepared by dissolving hydroxylamine
hydrochloride (0.178 g, 2.5 mmol) in distilled water (6 mL) and
treatment with NMM (0.3 mL, 2.7 mmol). The soution was diluted
with THF (10 mL) and added to the acid chloride solution. After 2.5
h, the reaction mixture was partitioned between CH2Cl2 and aqueous
NH4Cl solution, and the organic phase was dried over Na2SO4. Solvent
removal, followed by trituration with CH3CN with 0.1% TFA (20 mL)
A portion of this material (1.42 g, 5.0 mmol) was dissolved in
methanol (7.5 mL) and treated with 2 M aqueous NaOH (7.5 mL, 15
mmol). After 7 h, the mixture was evaporated to dryness, and the
residues were partitioned between water and Et2O. The aqueous phase
was acidified to pH 2 with concentrated HCl and extracted successively
with EtOAc and CH2Cl2. The combined organic phases were dried
(MgSO4) and evaporated to provide a white solid (1.11 g, 82%).
A portion of this material (0.270 g, 1.0 mmol) was dissolved in CH2-
Cl2 (5 mL) and then treated with DMF (10 µL) and oxalyl chloride
(96 µL, 1.1 mmol). After 2 h, a solution of hydroxylamine hydro-
chloride (0.139 g, 2.00 mmol) and Et3N (279 µL, 2.0 mmol) in THF/
water (1 mL each) was added, and the mixture was stirred a further 2
h at ambient temperature. The mixture was partitioned between 100
mL each of water and of CH2Cl2. The organic phase was discarded,
and the aqueous phase was acidified to pH 7 with concentrated HCl
and extracted with 3 × 100 mL CH2Cl2. The combined CH2Cl2 extracts
were dried (Na2SO4) and concentrated to give a white solid (0.090 g,
1
gave 0.61 g (58%) of a white powder: mp 114-118 °C; H NMR
(DMSO-d6) δ 2.45 (t, 2H, J ) 5.9 Hz), 4.25 (t, 2H, J ) 5.9 Hz), 7.06
(d, 2H, J ) 8.8 Hz), 7.72 (d, 2H, J ) 8.8 Hz), 7.85 (d, 2H, J ) 8.5
Hz), 7.88 (d, 2H, J ) 8.5 Hz), 8.87 (s, 1H), 10.56 (s, 1H). IR (neat)
3241, 2244, 2235, 1629, 1606, 1496, 1257, 815 cm-1; MS (DCI/NH3)
300 (M + NH4)+, 317 (M + NH4 + NH3)+. Anal. Calcd for
C16H14N2O3‚0.60 H2O: C, 65.56; H, 5.23; N, 9.56. Found: C, 65.41;
H, 4.85; N, 9.83.
1
32% yield): mp 151.5-153.5 °C; H NMR (DMSO-d6) δ 10.36 (S,
4-[4-(4-Cyanophenyl)phenoxy]butanohydroxamic Acid (51). To
a suspension in dry DMF of 4-cyano-4′-hydroxybiphenyl (2.02 g,.10.4
mmol) and cesium carbonate (4.49 g, 14.1 mmol) was added ethyl
4-bromobutyrate (2.66 g, 13.6 mmol), and the reaction mixture was
stirred for 18 h at ambient temperature. The reaction mixture was
diluted with Et2O and extracted with pH 7 buffer. The organic phase
was washed twice with brine, dried over MgSO4, filtered, and
concentrated in Vacuo to give 3.30 g white solid.
The crude ester was treated with lithium hydroxide hydrate (0.635
g, 15.1 mmol) in 2:1 dioxane/water (30 mL) for 18 h at ambient
temperature and concentrated in Vacuo. The resulting white solids were
shaken with Et2O and aqueous Na2CO3. The organic phase was
discarded and the aqueous phase was acidified with concentrated HCl,
and the resulting precipitate collected and vaccum dried to give 2.03 g
of the acid.
A portion of the acid (1.00 g, 3.56 mmol) in thionyl chloride (10
mL) was heated at reflux for 90 min. The reaction mixture was cooled
to ambient temperature and concentrated in Vacuo, and the residue was
taken up in 1:1 CH2Cl2/THF (10 mL). In a separate flask, NMM (0.55
mL, 5.0 mmol) was added to a solution of hydroxylamine hydrochloride
(0.345 g, 4.96 mmol) in water (4 mL). THF (10 mL) was then added
and the hydroxylamine solution was poured into the acid chloride
1H), 8.66 (d, 1H, J ) 1.5 Hz), 7.65-7.55 (c, 4H), 7.46-7.39 (c, 2H),
7.34-7.26 (c, 2H), 4.00 (t, 2H, J ) 6 Hz), 2.03 (t, 2H, J ) 6 Hz),
1.80-1.58 (c, 4H); IR (KBr) 3200, 3040, 2920, 2860, 1660, 1640, 1620,
1610, 1520, 1490, 1470, 1290, 1270, 1250, 1200, 1180, 1030, 840,
780, 690 cm-1; MS (DCI/NH3) 269 (M - 16), 286 (M + H)+, 303 (M
+ NH4)+. Anal. Calcd for C17H19NO3‚0.25 H2O: C, 70.44; H, 6.78;
N, 4.83. Found: C, 70.71; H, 6.82; N, 4.98.
2-[4-(4-Cyanophenyl)phenoxy]ethanohydroxamic Acid (49). To
a suspension of 4-cyano-4′-hydroxybiphenyl (2.07 g, 10.6 mmol) and
cesium carbonate (5.37 g, 16.5 mmol) in dry DMF (25 mL) was added
tert-butyl bromoacetate (1.70 mL, 11.5 mmol). After stirring 18 h at
ambient temperature, the mixture was diluted with Et2O (200 mL) and
extracted successively with NaHCO3 and brine. The organic phase
was dried (MgSO4) and concentrated to give an off-white solid (3.26
g). This material was treated for 90 min at 0 °C with 80% TFA/20%
CH2Cl2 (25 mL), and the mixture was partitioned between brine and
CH2Cl2. The organics were dried (MgSO4) and concentrated to give a
white solid (3.36 g). This material was suspended in thionyl chloride
(20 mL) and heated to reflux for 2 h, then cooled and vacuum dried.
The resulting acid chloride was redissolved in THF (20 mL) and treated
with a solution of hydroxylamine. Hydroxylamine was generated by
dissolving hydroxylamine hydrochloride (1.50 g, 21.6 mmol) in water