Potent Isoxazoline GPIIb/ IIIa Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 55
in 9:1 MeOH/pyridine (30 mL) was heated at reflux for 18 h.
The mixture was cooled to room temperature and concentrated
to dryness. The residue was dissolved in EtOAc, washed with
0.1 M HCl, water, saturated CuSO4, water, and saturated
NaCl, and dried over MgSO4. After filtration and washing the
solid with EtOAc, the filtrate was concentrated in vacuo and
placed under vacuum until constant weight was achieved to
give 3.19 g (96%) of oxime 8b as a white solid: mp 140.1-
141.8 °C; 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.48 (d, J
) 8.8 Hz, 2H), 6.86 (d, J ) 8.8 Hz, 2H), 4.14 (bs, 2H), 3.80 (d,
J ) 6.2 Hz, 2H), 2.71 (bt, J ) 12.4 Hz, 2H), 1.95 (m, 1H), 1.80
(bd, J ) 12.4 Hz, 2H), 1.45 (s, 9H), 1.26 (m, 2H).
resulting suspension was heated at reflux for 5 h, cooled to
room temperature, and diluted with EtOAc. It was washed
with 0.1 M HCl, water, and saturated NaCl, dried (MgSO4),
and concentrated in vacuo. The resulting solid was crystal-
lized from CH2Cl2/hexanes to give 357 mg (77%) of isoxazoline
9b as a white solid: mp 139.1-140.9 °C; 1H NMR (300 MHz,
CDCl3) δ 7.59 (d, J ) 8.8 Hz, 2H), 6.90 (d, J ) 8.8 Hz, 2H),
5.08 (m, 1H), 4.10 (bd, J ) 13.2 Hz, 2H), 4.04 (t, J ) 5.9 Hz,
2H), 3.73 (s, 3H), 3.53 (dd, J ) 16.5, 10.1 Hz, 1H), 3.10 (dd, J
) 16.8, 7.1 Hz, 1H), 2.88 (dd, J ) 16.1, 5.9 Hz, 1H), 2.71 (bt,
J ) 12.8 Hz, 2H), 2.64 (dd, J ) 15.8, 7.7 Hz, 1H), 1.72 (m,
5H), 1.46 (s, 9H), 1.08 (m, 2H); CIMS (NH3) m/ z 464 (M +
NH4+, 1), 447 (M + H+, 31), 391 (M + H - C4H8+, 100). Anal.
(C24H34N2O6) C, H, N.
P r ep a r a tion of Oxim in oyl Ch lor id e 38a . To a solution
of 8a (955 mg, 2.74 mmol) in DMF (5 mL) was added NCS
(366 mg, 2.74 mmol) in three portions. After 3 h, the solution
was diluted with EtOAc, washed with water and saturated
NaCl, dried (MgSO4), and concentrated in vacuo. The result-
ing solid was crystallized from ether/hexanes to give 548 mg
(52%) of the oximinoyl chloride as a white solid: mp 119.3-
Also prepared in this fashion from 38b was 9c: white solid,
1
537 mg (60%); mp 97.9-99.9 °C; H NMR (300 MHz, CDCl3)
δ 7.57 (d, J ) 9.0 Hz, 2H), 6.87 (d, J ) 9.0 Hz, 2H), 4.74 (m,
1H), 4.15 (bd, J ) 13.2 Hz, 2H), 3.81 (d, J ) 6.2 Hz, 2H), 3.67
(s, 3H), 3.40 (dd, J ) 16.5, 10.2 Hz, 1H), 2.95 (dd, J ) 16.5,
7.3 Hz, 1H), 2.73 (dt, J ) 13.2, 1.1 Hz, 2H), 2.52 (t, J ) 7.3
Hz, 2H), 1.98 (q, J ) 7.0 Hz, 2H, overlapping m, 1H), 1.81
(bd, J ) 12.8 Hz, 2H), 1.45 (s, 9H), 1.26 (dq, J ) 12.4, 3.7 Hz,
2H); CIMS (NH3) m/ z 464 (M + NH4+, 2), 447 (M + H+, 31),
408 (M + NH4 - C4H8+, 11), 391 (M + H - C4H8+, 100). Anal.
(C24H34N2O6) C, H, N.
1
119.9 °C; H NMR (300 MHz, CDCl3) δ 8.37 (bs, 1H), 7.77 (d,
J ) 8.8 Hz, 2H), 6.88 (d, J ) 8.8 Hz, 2H), 4.12 (bd, J ) 13.2
Hz, 2H), 4.04 (t, J ) 6.2 Hz, 2H), 2.72 (bt, J ) 12.1 Hz, 2H),
1.70 (m, 5H), 1.46 (s, 9H), 1.10 (m, 2H); CIMS (NH3) m/ z 400
(M + NH4+, 18), (M + NH4 - HCl+, 100). Anal. (C19H27
ClN2O4) C, H, N, Cl.
-
Also prepared in this fashion from 8b was oximinoyl chloride
Also prepared in this fashion from 38b was 9d : white solid,
1
38b: white solid, 1.17 g (33%); mp 178.0-179.8 °C; H NMR
1
329 mg (68%); H NMR (300 MHz, CDCl3) δ 7.58 (d, J ) 8.8
(300 MHz, CDCl3) δ 7.75 (d, J ) 9.0 Hz, 2H), 6.86 (d, J ) 9.0
Hz, 2H), 4.17 (bd, J ) 12.4 Hz, 2H), 3.80 (d, J ) 6.2 Hz, 2H),
2.74 (dt, J ) 12.8, 1.8 Hz, 2H), 1.95 (m, 1H), 1.81 (bd, J )
12.1 Hz, 2H), 1.46 (s, 9H), 1.27 (dq, J ) 12.5, 4.0 Hz, 2H);
CIMS (NH3) did not afford product-derived M + NH4+ or M +
H+ ions.
Hz, 2H), 6.88 (d, J ) 8.8 Hz, 2H), 5.04 (m, 1H), 4.15 (bd, J )
13.2 Hz, 2H), 3.81 (d, J ) 6.2 Hz, 2H), 3.71 (s, 3H), 3.54 (dd,
J ) 16.8, 10.3 Hz, 1H), 3.08 (dd, J ) 16.8, 7.3 Hz, 1H), 2.86
(dd, J ) 16.1, 5.9 Hz, 1H), 2.73 (dt, J ) 12.8, 1.8 Hz, 2H), 2.62
(dd, J ) 15.8, 7.7 Hz, 1H), 1.95 (m, 1H), 1.81 (bd, J ) 13.2 Hz,
2H), 1.45 (s, 9H), 1.25 (dq, J ) 12.8, 4.4 Hz, 2H); CIMS (NH3)
m/ z 450 (M + NH4+, 100), 433 (M + H+, 25), 394 (M + NH4 -
C4H8+, 20).
Also prepared in this fashion from 31 was 39: white solid,
572 mg (93%); mp >300 °C; 1H NMR (300 MHz, CDCl3) δ 12.89
(s, 1H), 7.96 (m, 4H); CIMS (NH3) m/ z 198 (M + NH4+, 80),
181 (M + H+, 30), 136 (100). Anal. (C8H5ClN2O) C, H, N, Cl.
P r ep a r a tion of Isoxa zolin e 9a . To a solution of 38a (500
mg, 1.43 mmol) and methyl 4-pentenoate (245 mg, 2.15 mmol)
in CH2Cl2 (7 mL) was added a 5% solution of NaOCl (Clorox;
5 mL, 3.5 mmol). The mixture was stirred rapidly at room
temperature for 18 h, diluted with water, and washed with
CH2Cl2. The combined organic was dried over MgSO4. After
filtration and washing the solid with EtOAc, the filtrate was
concentrated in vacuo giving a yellow solid. Crystallization
from EtOAc/hexanes afforded 500 mg (76%) of isoxazoline 9a
as a white solid: mp 104.1-104.8 °C; 1H NMR (300 MHz,
CDCl3) δ 7.58 (d, J ) 8.8 Hz, 2H), 6.90 (d, J ) 8.8 Hz, 2H),
4.75 (m, 1H), 4.10 (bs, 2H), 4.04 (t, J ) 5.9 Hz, 2H), 3.69 (s,
3H), 3.42 (dd, J ) 16.5, 10.3 Hz, 1H), 2.97 (dd, J ) 16.5, 7.3
Hz, 1H), 2.71 (bt, J ) 12.5 Hz, 2H), 2.53 (t, J ) 7.3 Hz, 2H),
Also prepared in this fashion from 39 was 32. The crude
product was purified using flash chromatography (0-50%
EtOAc/hexanes), giving 3.68 g (81%) as a white solid: mp
120.1-120.5 °C; 1H NMR (300 MHz, CDCl3) δ 7.72 (AB
quartet, ∆ ) 22.7 Hz, J ) 8.4 Hz, 4H), 5.16 (m, 1H), 3.72 (s,
3H), 3.54 (dd, J ) 16.8, 10.6 Hz, 1H), 3.13 (dd, J ) 16.8, 7.7
Hz, 1H), 2.90 (dd, J ) 16.1, 5.7 Hz, 1H), 2.67 (dd, J ) 16.1,
7.7 Hz, 1H); CIMS (NH3) m/ z 262 (M + NH4+, 100), 245 (M +
H+, 45). Anal. (C13H12N2O3) C, H, N.
P r ep a r a tion of Ca r boxylic Acid 41a . To a solution of
9a (350 mg, 0.760 mmol) in THF (5 mL) was added 0.5 M LiOH
(3 mL, 1.5 mmol). The reaction mixture was stirred at room
temperature for 4 h, the pH was adjusted to 3 using 0.1 M
HCl, and the mixture was extracted with CH2Cl2. The
combined organic extracts were dried over MgSO4 and filtered,
the solid was washed with EtOAc, and the filtrate was
concentrated in vacuo. Purification of the residue using flash
chromatography (CHCl3-20% MeOH/CHCl3 gradient) afforded
261 mg (77%) of carboxylic acid 41a after crystallization from
EtOAc/hexanes as a white solid: mp 119.4-119.6 °C; 1H NMR
(300 MHz, CDCl3) δ 7.59 (d, J ) 8.6 Hz, 2H), 6.90 (d, J ) 8.6
Hz, 2H), 4.08 (bs, 2H), 4.04 (bt, J ) 5.9 Hz, 2H), 3.44 (dd, J )
16.5, 10.3 Hz, 1H), 2.98 (dd, J ) 16.5, 7.3 Hz, 1H), 2.71 (bt, J
) 12.1 Hz, 2H), 2.59 (t, J ) 7.3 Hz, 2H), 2.00 (m, 2H), 1.72
(m, 4H), 1.46 (s, 9H), 1.19 (m, 2H); MS (ESI) m/ z 447 (M +
H+, 100). Anal. (C24H34N2O6‚0.33 H2O) C, H, N.
Also prepared in this fashion from 9b was 41b: white solid,
34 mg (74%); mp 169.1-170.6 °C; 1H NMR (300 MHz, CDCl3)
δ 7.60 (d, J ) 8.8 Hz, 2H), 6.91 (d, J ) 8.8 Hz, 2H), 5.10 (m,
1H), 4.08 (m, 2H, coincident with t, J ) 5.9 Hz, 2H), 3.55 (dd,
J ) 16.5, 10.2 Hz, 1H), 3.11 (dd, J ) 16.8, 7.0 Hz, 1H), 2.93
(dd, J ) 16.1, 6.2 Hz, 1H), 2.71 (m, 3H), 2.00 (m, 2H), 1.72 (m,
5H), 1.46 (s, 9H); CIMS (NH3) m/ z 450 (M + NH4+, 100), 433
(M + H+, 7). Anal. (C23H32N2O6) C, H, N.
Also prepared in this fashion from 9c was 41c: crystallized
from CH2Cl2/hexanes to give 163 mg (67%) as a white solid;
mp 146.5-147.7 °C; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J )
8.8 Hz, 2H), 6.88 (d, J ) 8.8 Hz, 2H), 4.75 (m, 1H), 3.81 (d, J
) 6.2 Hz, 2H), 3.41 (dd, J ) 16.5, 10.3 Hz, 1H), 2.95 (dd, J )
16.5, 7.3 Hz, 1H), 2.75 (bt, J ) 12.4 Hz, 2H), 2.57 (t, J ) 7.3
Hz, 2H), 1.97 (m, 3H), 1.81 (bd, J ) 12.1 Hz, 2H), 1.45 (s, 9H),
2.01 (q, J ) 7.3 Hz, 2H), 1.72 (m, 4H), 1.46 (s, 9H), 1.17 (m,
+
2H); CIMS (NH3) m/ z 478 (M
(C25H36N2O6) C, H, N.
+
NH4
,
100). Anal.
Also prepared in this fashion from 38a was 9e: white solid,
1
409 mg (66%); mp 71.8-73.1 °C; H NMR (300 MHz, CDCl3)
δ 7.61 (d, J ) 8.6 Hz, 2H), 6.91 (d, J ) 8.6 Hz, 2H), 5.17 (dd,
J ) 10.2, 7.7 Hz, 1H), 4.10 (bs, 2H), 4.04 (t, J ) 5.9 Hz, 2H),
3.82 (s, 3H), 3.64 (s, 1H), 3.61 (d, J ) 3.3 Hz, 1H), 2.71 (bt, J
) 12.4 Hz, 2H), 1.72 (m, 4H), 1.46 (s, 9H, coincident with m,
1H), 1.17 (m, 2H); MS (ESI) m/ z 433 (M + H+, 39), 377 (M +
H - C4H8+, 100), 333 (M + H - C4H8CO2+, 42). Anal.
(C23H32N2O6) C, H, N.
Also prepared in this fashion from 22 and methyl 3-butenoate
was 40, except that 22 was added to the reaction mixture over
15 h. The crude isoxazoline was purified using flash chroma-
tography (10-50% EtOAc/hexanes), giving 10.35 g (42%) of a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 4.89 (m, 1H), 4.09
(bd, J ) 5.5 Hz, 2H), 3.71 (s, 3H), 3.13 (dd, J ) 16.8, 9.9 Hz,
1H), 2.79 (dd, J ) 15.8, 6.0 Hz, 1H), 2.67 (m, 3H), 2.55 (dd, J
) 15.8, 7.7 Hz, 1H), 2.38 (t, J ) 7.3 Hz, 2H), 1.68 (bd, J )
10.6 Hz, 2H), 1.52 (m, 2H), 1.45 (s, 9H, coincident with m, 1H),
1.10 (dq, J ) 11.7, 3.7 Hz, 2H); MS (ESI) m/ z 355 (M + H+,
100). Anal. (C18H30N2O5) C, H, N.
P r ep a r a tion of Isoxa zolin e 9b. To a solution of 38a (400
mg, 1.045 mmol) and methyl 3-butenoate (200 mg, 2.00 mmol)
in benzene (5 mL) was added Et3N (0.15 mL, 1.1 mmol). The