1
612
Z. ZHANG ET AL.
8
-amino-N-(2–(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)octana- (1.4 mL, 14 mmol) dropwise over 25 min, and the temperature was
ꢀ
1
ꢀ
mide (b-1). yield 77%; m.p. 125–127 C. H NMR (400 MHz, DMSO) maintained below 20 C. The reaction mixture was slowly warmed
ꢀ
d 11.02 (s, 1H), 9.83 (s, 1H), 7.83 (d, J ¼ 6.9 Hz, 2H), 7.78 (s, 1H), to 20 C over 1 h and stirred for overnight. The reaction mixture
7
.49 (q, J ¼ 7.3 Hz, 2H), 5.15 (dd, J ¼ 13.3, 5.1 Hz, 1H), 4.37 (q, was concentrated and the residue was added to water and stirred
J ¼ 17.5 Hz, 2H), 2.98 ꢄ 2.87 (m, 1H), 2.78 (dd, J ¼ 13.4, 6.7 Hz, 2H), for 30 min. The precipitated solid was collected by filtration,
2
1
1
1
2
.62 (d, J ¼ 16.7 Hz, 1H), 2.37 (t, J ¼ 7.4 Hz, 3H), 2.09 ꢄ 2.00 (m, 1H), washed with water, hexanes, and ether, and dried in vacuo to
13
.57 (d, J ¼ 31.9 Hz, 4H), 1.31 (s, 6H). C NMR (101 MHz, DMSO) d afford the target compound (a mixture of E and Z isomers), further
73.34, 171.86, 171.55, 168.31, 134.32, 134.09, 133.13, 129.08, purified by silica gel column chromatography. White solid, yield
ꢀ
1
25.64, 119.41, 60.22, 52.00, 46.94, 36.20, 31.67, 28.92, 28.77, 83.6%; m.p. 186–187 C. H NMR (500 MHz, DMSO) d 8.24 ꢄ 8.13
7.44, 26.16, 25.43, 23.11. HRMS m/z: calcd. for C21
H
29
N O
4 4
(m, 2H), 8.08 (d, J ¼ 7.8 Hz, 1H), 8.00 (d, J ¼ 7.7 Hz, 1H), 7.93 (t,
J ¼ 7.6 Hz, 1H), 7.72 (t, J ¼ 7.5 Hz, 1H), 7.66 (t, J ¼ 9.1 Hz, 1H), 7.00
þ
[M þ H] 401.2229, found 401.2198.
1
3
(
d, J ¼ 6.3 Hz, 1H). C NMR (126 MHz, DMSO) d 166.37, 162.95,
1
45.89, 140.03, 137.19, 135.84, 134.65, 131.40, 125.82, 123.16,
1
1-amino-N-(2–(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)unde-
ꢀ
1
121.38, 117.87, 114.21, 110.08, 103.88, 101.39. HRMS m/z: calcd.
canamide(b-2). yield 84.9%; m.p. 131–133 C. H NMR (400 MHz,
DMSO) d 11.02 (s, 1H), 9.82 (s, 1H), 7.83 (d, J ¼ 7.0 Hz, 2H),
þ
for C H FNO [M þ H] 266.0617, found 266.0623.
1
6
9
2
7
1
6
2
.79 ꢄ 7.72 (m, 1H), 7.53 ꢄ 7.44 (m, 2H), 5.15 (dd, J ¼ 13.3, 5.1 Hz,
H), 4.37 (q, J ¼ 17.5 Hz, 2H), 3.00 ꢄ 2.87 (m, 1H), 2.77 (dd, J ¼ 13.9,
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid
.5 Hz, 2H), 2.62 (d, J ¼ 16.8 Hz, 1H), 2.36 (t, J ¼ 7.4 Hz, 3H), (e). To a stirred suspension of d (3.7 g, 14 mmol) in water (20 mL)
.10 ꢄ 1.97 (m, 1H), 1.66 ꢄ 1.47 (m, 4H), 1.28 (d, J ¼ 11.2 Hz, 12H). was added aqueous sodium hydroxide (2.6 g in 5 mL water) solu-
1
3
ꢀ
C NMR (101 MHz, DMSO) d 173.33, 171.90, 171.53, 168.32, tion and the reaction mixture was heated under nitrogen to 90 C
ꢀ
1
3
2
34.33, 134.12, 133.13, 129.07, 125.66, 119.41, 51.99, 46.95, 39.28, for 1 h. The reaction mixture was partially cooled to 70 C and
6.25, 31.68, 29.29, 29.27, 29.25, 29.14, 28.97, 27.45, 26.24, 25.56, hydrazine hydrate (10 mL, 2.0 mol) added, and the mixture was
3.12. HRMS m/z: calcd. for C24
þ
ꢀ
35
H N
4
O
4
[M þ H] 443.2658, stirred for 18 h at 70 C. The reaction was cooled to ambient tem-
perature and was acidified with 2 M HCl to pH 4. The mixture was
stirred for 10 min and filtered. The resulting solid was washed
with water, followed by diethyl ether and was dried to produce
found 443.2659.
1
2-amino-N-(2–(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)dode-
ꢀ
ꢀ
1
the title compound. White powder. yield 73.1%; m.p. 107–108 C.
canamide (b-3). yield 84.9%; m.p. 137–139 C. H NMR (400 MHz,
DMSO) d 11.02 (s, 1H), 9.82 (s, 1H), 7.83 (d, J ¼ 7.1 Hz, 2H), 7.79 (s,
1
H NMR (500 MHz, DMSO) d 12.65 (s, 1H), 8.30 (d, J ¼ 7.9 Hz, 1H),
8
2
1
.01 (d, J ¼ 8.0 Hz, 1H), 7.92 (t, J ¼ 7.6 Hz, 1H), 7.86 (t, J ¼ 7.0 Hz,
13
2
H), 7.55 ꢄ 7.44 (m, 2H), 5.15 (dd, J ¼ 13.3, 5.1 Hz, 1H), 4.37 (q,
H), 7.65 ꢄ 7.22 (m, 2H), 4.39 (s, 2H). C NMR (126 MHz, DMSO) d
J ¼ 17.5 Hz, 2H), 2.98 ꢄ 2.87 (m, 1H), 2.77 (dd, J ¼ 13.7, 6.7 Hz, 2H),
65.45, 161.38, 159.83, 145.34, 135.36, 134.76, 133.98, 132.31,
2
1
.62 (d, J ¼ 16.9 Hz, 1H), 2.35 (h, J ¼ 9.2 Hz, 3H), 2.10 ꢄ 1.99 (m, 1H),
13
132.01, 129.54, 128.35, 126.54, 125.87, 119.68, 117.53, 36.77. HRMS
.65 ꢄ 1.46 (m, 4H), 1.28 (d, J ¼ 13.5 Hz, 14H). C NMR (101 MHz,
þ
m/z: calcd. For C H FN2O [M þ H] 299.0832, found 299.0833.
1
6
12
3
DMSO) d 173.33, 171.91, 171.53, 168.32, 134.32, 134.12, 133.13,
The preparation of compounds 1–3 followed the procedure of
1
2
29.07, 125.67, 119.41, 52.00, 46.95, 39.28, 36.25, 31.68, 29.39,
9.35, 29.28, 29.26, 29.13, 28.98, 27.44, 26.24, 25.56, 23.12. HRMS
a-1–a-3.
þ
m/z: calcd. for C H N O [M þ H] 457.2855, found 457.2815.
2
5 37 4 4
N-(8-((2–(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-8-
oxooctyl)-2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)ben-
zamide (1). White powder. yield 52.7%; m.p. 141–143 C. H NMR
dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (c). To
a 0.5 M solution of sodium methoxide in methanol (19.8 mL,
ꢀ
1
(
(
7
500 MHz, DMSO-d6) d 12.65 (s, 1H), 11.06 (s, 1H), 9.96 (s, 1H), 8.29
d, J ¼ 7.9 Hz, 2H), 7.98 (d, J ¼ 4.3 Hz, 1H), 7.90 (d, J ¼ 7.1 Hz, 1H),
9
0
.9 mmol) was added dimethyl phosphite (1.3 mL, 14.3 mmol) at
C, and the solution was stirred at 0 C for 10 min. A suspension
ꢀ
ꢀ
.83 (dd, J ¼ 13.5, 6.4 Hz, 2H), 7.57 (d, J ¼ 6.7 Hz, 1H), 7.52 (dd,
of the 3-hydroxyisobenzofuran-1(3H)-one (1.62 g, 7.07 mmol) in
anhydrous methanol (10 mL) was slowly added and the reaction
mixture allowed to warm to room temperature over a period of
J ¼ 13.0, 7.5 Hz, 2H), 7.23 ꢄ 7.18 (m, 1H), 5.18 (dd, J ¼ 13.3, 5.1 Hz,
1
H), 4.34 (s, 2H), 3.24 (dd, J ¼ 12.9, 6.6 Hz, 2H), 2.90 (s, 1H), 2.70 (s,
1
h. The solution was cooled in an ice-bath, and methanesulfonic 3H), 2.40 (t, J ¼ 7.4 Hz, 2H), 1.94 (s, 2H), 1.65 ꢄ 1.48 (m, 4H), 1.33 (s,
13
acid (1.0 mL, 15.5 mmol) was added dropwise. After the addition, 6H).
C NMR (126 MHz, DMSO-d6) d 173.35, 172.52, 171.97,
most of the solvent is evaporated under reduced pressure with 171.54, 168.36, 163.94, 159.89, 157.28, 145.44, 134.74, 134.34,
gentle heating and the residue is partitioned between dichlorome- 133.97, 133.11, 132.71, 132.00, 130.40, 129.51, 129.03, 128.33,
thane (100 mL) and cold water (5.0 mL). The organics was washed 126.52, 125.97, 125.72, 124.81, 119.38, 116.66, 52.04, 38.68, 36.93,
with brine (50 mL), and concentrated. The residue was dried under 36.25, 31.67, 30.87, 29.34, 29.10, 26.73, 25.54, 23.12, 21.56. HRMS
vacuum and recrystallized from dichloromethane/ether to yield m/z: calcd. for C37
the title compound. Light yellow solid, yield 89.3%; m.p. 87–88 C.
H
38FN
6
O
6
[M þ H]þ 681.2837, found 681.2838.
ꢀ
1
H NMR (500 MHz, DMSO) d 7.96 (d, J ¼ 7.7 Hz, 1H), 7.88 (t, N-(11-((2–(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-11-
J ¼ 7.5 Hz, 1H), 7.76 ꢄ 7.71 (m, 1H), 7.69 (d, J ¼ 7.4 Hz, 1H), 6.38 (d,
oxoundecyl)-2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-
J ¼ 11.1 Hz, 1H), 3.84 (d, J ¼ 10.9 Hz, 3H), 3.64 (d, J ¼ 10.7 Hz, 3H).
ꢀ
1
benzamide (2). White powder. yield 45.4%; m.p. 130–131 C.
NMR (500 MHz, DMSO-d6) d 12.62 (s, 1H), 11.05 (s, 1H), 9.78 (s,
H
1
3
C NMR (126 MHz, DMSO) d 169.88, 144.52, 135.27, 130.39,
1
C
25.97, 124.83, 123.95, 75.84, 54.34, 40.01. HRMS m/z: calcd. for
1H), 8.28 (d, J ¼ 7.8 Hz, 1H), 8.25 (s, 1H), 7.97 (d, J ¼ 7.9 Hz, 1H),
7.89 (t, J ¼ 8.3 Hz, 1H), 7.83 (t, J ¼ 8.2 Hz, 2H), 7.55 (d, J ¼ 6.8 Hz,
1H), 7.51 (d, J ¼ 5.3 Hz, 1H), 7.47 ꢄ 7.42 (m, 1H), 7.23 ꢄ 7.17 (m,
þ
10
H
12 5
O P [M þ H] 243.0422, found 243.0420.
2
-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrile
1H), 5.18 (dd, J ¼ 13.3, 5.1 Hz, 1H), 4.33 (s, 2H), 3.40 (s, 3H), 3.22
(
d). To a mixture of c (3.5 g, 14 mmol) and 2-fluoro-5-formylbenzo- (dd, J ¼ 13.0, 6.7 Hz, 2H), 2.99 ꢄ 2.90 (m, 1H), 2.63 (d, J ¼ 17.0 Hz,
nitrile (2.1 g, 14 mmol) in THF (50 mL) was added triethylamine 1H), 2.36 (d, J ¼ 7.6 Hz, 2H), 2.00 (s, 1H), 1.63 ꢄ 1.46 (m, 4H), 1.28