Synthesis of 5-carbonyl-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanoic acid integrin antagonists

Article abstract of DOI:10.1081/SCC-120021037

The 5-carboxy-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanoic acid benzyl ester (I), obtained from condensation of 1,3-dihydro-1,3-dioxo-5-isobenzofurancarboxylic acid with β-alanine benzyl ester p-toluenesulfonate, reacted with an appropriate amine (II) to afford the corresponding amide (IIIa-e), which then hydrogenolyzed by 5% palladium-on-carbon to give target compounds (IVa-e).

Full text of DOI:10.1081/SCC-120021037

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Synthesis of 5-Carbonyl-1,3-dihydro- 1,3-dioxo-2H-
isoindole-2-propanoic Acid Integrin Antagonists
Yong Deng a , Yi Shen b & Yu-Guo Zhong b
a Department of Pharmaceutical Engineering , College of Chemical Engineering , Chengdu,
Sichuan, P.R. China
b Department of Medicinal Chemistry , West China School of Pharmacy , Sichuan University ,
Chengdu, Sichuan, P.R. China
Published online: 17 Aug 2006.
To cite this article: Yong Deng , Yi Shen & Yu-Guo Zhong (2003) Synthesis of 5-Carbonyl-1,3-dihydro- 1,3-dioxo-2H-isoindole-2-
propanoic Acid Integrin Antagonists, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:12, 2109-2117, DOI: 10.1081/SCC-120021037
To link to this article: http://dx.doi.org/10.1081/SCC-120021037
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 12, pp. 2109–2117, 2003
Synthesis of 5-Carbonyl-1,3-dihydro-
1,3-dioxo-2H-isoindole-2-propanoic
Acid Integrin Antagonists
2
2
Yong Deng,1, Yi Shen, and Yu-Guo Zhong
*
1Department of Pharmaceutical Engineering,
2
College of Chemical Engineering, and Department of
Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, Chengdu, Sichuan, P.R. China
ABSTRACT
The 5-carboxy-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanoic acid
benzyl ester (I), obtained fromcondensation of 1,3-dihydro-1,3-
dioxo-5-isobenzofurancarboxylic acid with b-alanine benzyl ester
p-toluenesulfonate, reacted with an appropriate amine (II) to
afford the corresponding amide (IIIa–e) ,which then hydrogenolyzed
by 5% palladium-on-carbon to give target compounds (IVa–e).
*Correspondence: Yong Deng, Department of Pharmaceutical Engineering,
College of Chemical Engineering, Sichuan University, Chengdu, Sichuan,
610065, P.R. China; E-mail: dengyongy@sohu.com.
2109
DOI: 10.1081/SCC-120021037
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2110
Deng, Shen, and Zhong
The growth of malignant tumors has been shown to be dependent
on the development of new blood vessels. Blocking tumor-induced
angiogenesis is an efficient strategy to prevent and cure cancer.[1] It
has been shown that the angiogenic process depends on vascular
endothelial cell migration and invasion, which regulated by cell adhe-
sion receptor. The integrin avb3 is such a cell adhesion receptor.[2]
Recent studies show that the integrin avb3 and extracellular matrix
can recognize each other through Arg-Gly-Asp (RGD) sequence.
Some peptides containing RGD sequence can inhibit embryonic neo-
vascularization and tumor-induced angiogenesis.[3] The investigations of
structure-activity relationships (SAR) of RGD-containing linear pep-
tides and cyclic peptides indicate that the guanidiniumof arginine
and the carboxylate of aspartate are necessary for RGD recognition
by integrin.[4] Recently, the biological research of thalidomide shows
that this severe teratological compound has distinct inhibition of angio-
genesis and tumor metastasis.[5] This mechanism may be related to
down-regulate b3 integrin.[6] The SAR investigations show that the glu-
tarimide ring of thalidomide is not necessary for antimetasis, but phthal-
imide is functional group.[7]
In this article, we use RGD tripeptide and thalidomide as lead struc-
ture to design and synthesize a series of RGD mimetics, containing a
5-carbonyl-1,3-dihydro-1,3-dioxo-2H-isoindole as the central scaffold.
To our knowledge none of the target compounds have been reported in
the literature. These compounds can be obtained by the method described
in the Sch. 1.

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Acid Integrin Antagonists
2111
5-Carboxy-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanoic
acid
benzyl ester (I) is prepared by the reaction of 5-isobenzofuran-
carboxylic acid with b-alanine benzyl ester p-toluenesulfonate in
toluene in the presence of triethylamine. Ester I is converted to an
activated carboxylic acid intermediate using DCC and HOBT or
SOCl2, and the intermediate subsequently reacted with an appropriate
amine (II) to afford the corresponding amide (III). In our hands, the
DCC/HOBT method gave low yields and suffered from stringent
reaction conditions and tedious work-up. Therefore we activate car-
boxylic acid with SOCl2. Compound III on further treatment with 5%
Pd/C in methanol gives the target compounds (IV) in excellent yield.
All compounds gave the explored elemental analyses, IR, 1H NMR,
and MS spectra.
EXPERIMENTAL
Melting points were observed in an open capillary tube and uncor-
rected. Elemental analyses were performed on a Carlo-Erba 1106
Elemental Analysis instrument. IR spectra were recorded using KBr
1
pellets on a Nicolet 560 FTIR spectrophotometer and H NMR spectra
on a Varin INOVA-400 instrument using (CD3)2SO or CDCl3 as
solvent and Me4Si as internal standard. MS were measured on a
HP5988A spectrometer. b-Alanine benzyl ester p-toluenesulfonate[8] and
2-(methylaminomethyl)benzimidazole[9] were prepared according to
literature procedures. All commercially available reagents were used
without purification unless otherwise noted. All experiments run at the
same scale.
5-Carboxy-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanoic
Acid Benzyl Ester (I)
A mixture of 1.93 g (0.01 mol) of 1,3-dihydro-1,3-dioxo-5-isobenzo-
furancarboxylic acid, 3.52 g (0.01 mol) of b-alanine benzyl ester p-tolu-
enesulfonate, 75 mL of toluene and 2.30 g (0.023 mol) of triethylamine
was heated under reflux. The liberated water was removed azeotropically
and trapped with the aid of a Stark and Dean distilling receiver. After 5 h,
the volatile material was removed from the mixture at 70ꢀC under

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2112
Deng, Shen, and Zhong
reduced pressure (ꢁ0.085 Mpa). The solid residue was stirred with 30 mL
of cold water and 5 mL of hydrochloric acid. The mixture was filtered,
washed with cold water and recrystallized fromethanol–water (2:1). 3.0 g
of compound I, white needles, was obtained. Yield: 85%. M.p.
109–110ꢀC. 1H NMR (CDCl3) ꢀ 8.5 (2H, m, Ar-H6, Ar-H4), 7.93
(1H, d, J ¼ 7.7 Hz, Ar-H7), 7.30 (5H, s, CH2Ph), 5.10 (2H, s, CH2Ph),
4.10 (2H, t, J ¼ 7.0 Hz, CH2), 2.80 (2H, t, J ¼ 7.0 Hz, CH2). IR (KBr, ꢁ,
cmꢁ1): 3465 (O-H), 1774 (C¼O), 1724 (C¼O), 1621 (C¼O). MS (m/z):
354 (M þ 1). Anal. calcd. for C19H15NO6: C, 64.59; H, 4.28; N, 3.96.
Found: C, 64.30; H, 4.30; N, 3.86.
General Procedure for Preparation of III a–e
A mixture of ester I (3.53 g, 0.01 mol) and 80 mL thionyl chloride was
refluxed for 3.5 h. The excess thionyl chloride was evaporated at 40ꢀC
under reduced pressure (ꢁ0.08 Mpa) to yield crude product as a off-
brown oil, suitable for most uses. This was dissolved in dry dichloro-
methane (100 mL) and the solution added dropwise over a period of
60 min to a stirred solution of amine (II) (0.015 mol), triethylamine
(6.2 mL), and pyridine (10 mL) in dry dichloromethane (200 mL) at
0–5ꢀC. The reaction mixture was allowed to warm to room temperature
and stand for 12 h. It then was washed with 10% Na2CO3 (2 ꢂ 40 mL)
and brine (1 ꢂ 50 mL) and dried over Na2SO4. The solution was filtered,
the solvent was evaporated, and the crude product was recrystallized
fromacetone–ether (1:1) to yield white crystals of compound III.
The physical and spectral data are shown in below.
5-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-1,3-dihydro-
1,3-dioxo-2H-isoindole-2-propanoic Acid Benzyl Ester (IIIa)
Yield: 65%. M.p.: 165–166ꢀC. H NMR (DMSO-d6) ꢀ 12.39 (1H,
1
brs, imidazole-NH), 9.62 (1H, t, J ¼ 5.4 Hz, NHCH2), 8.41 (1H, s, Ar-
H4), 8.36 (1H, d, J ¼ 7.8 Hz, Ar-H6), 8.00 (1H, d, J ¼ 7.8 Hz, Ar-H7), 7.5
(2H, m, benzimidazole-H4,7), 7.32 (5H, s, CH2Ph), 7.2 (2H, m, benzimi-
dazole-H5,6), 5.07 (2H, s, CH2Ph), 4.95 (2H, d, J ¼ 5.4 Hz, NHCH2), 3.89
(2H, t, J ¼ 7.0 Hz, CH2), 2.78 (2H, t, J ¼ 7.0 Hz, CH2). IR (KBr, ꢁ, cmꢁ1):
3323 (N-H), 1775 (C¼O), 1716 (C¼O), 1645 (C¼O). MS (m/z): 482 (M,
basic peak). Anal. calcd. for C27H22N4O5: C, 67.21; H, 4.60; N, 11.61.
Found: C, 67.42; H, 4.55; N, 11.52.

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Acid Integrin Antagonists
2113
5-[[[(2-Benzimidazolyl)ethyl]amino]carbonyl]-1,3-dihydro-1,3-
dioxo-2H-isoindole-2-propanoic Acid Benzyl Ester (IIIb)
Yield: 76.5%. M.p.: 181–182ꢀC. 1H NMR (DMSO-d6) ꢀ 12.35
(1H, brs, imidazole-NH), 9.09 (1H, t, J ¼ 4.95 Hz, NHCH2), 8.28
(1H, s, Ar-H4), 8.25 (1H, d, J ¼ 8.00 Hz, Ar-H6), 7.94 (1H,
d, J ¼ 8.00 Hz, Ar-H7), 7.4 (2H, m, benzimidazole-H4,7), 7.29
(5H, s, CH2Ph), 7.1 (2H, m, benzimidazole-H5.6), 5.04 (2H, s,
CH2Ph), 3.86 (2H, t, J ¼ 7.00 Hz, NCH2), 3.74 (2H, q, J ¼ 7.05 Hz,
NHCH2), 3.11 (2H, t, J ¼ 7.05 Hz, CH2CH2NH), 2.76 (2H, t,
J ¼ 7.00 Hz, CH2COO). IR (KBr, ꢁ, cmꢁ1): 3322 (N-H), 1775 (C¼O),
1715 (C¼O), 1636 (C¼O). MS (m/z): 496 (M). Anal. calcd. for
C28H24N4O5: C, 67.73; H, 4.87; N, 11.28. Found: C, 67.58; H, 4.92;
N, 11.42.
5-[[[N-(2-Benzimidazolyl)methyl-N-methyl]amino]carbonyl]-
1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanoic Acid
Benzyl Ester (IIIc)
Yield: 75%. M.p.: 101–102ꢀC. 1H NMR (CDCl3) ꢀ 7.92 (1H, s,
Ar-H4), 7.85 (1H, d, J ¼ 8.20 Hz, Ar-H6), 7.80 (1H, d, J ¼ 8.20 Hz,
Ar-H7), 7.6 (2H, m, benzimidazole-H4,7), 7.30 (5H, s, CH2Ph), 7.3 (2H,
m, benzimidazole-H5,6), 5.09 (2H, s, CH2Ph), 4.88 (2H, s, NCH3CH2),
4.02 (2H, t, J ¼ 7.0 Hz, NCH2), 3.13 (3H, s, NCH3), 2.78 (2H, t,
J ¼ 7.0 Hz, CH2COO). IR (KBr, ꢁ, cmꢁ1): 3435 (N-H), 1774 (C¼O),
1711 (C¼O), 1629 (C¼O). MS (m/z): 496 (M). Anal. calcd. for
C28H24N4O5: C, 67.73; H, 4.87; N, 11.28. Found: C, 67.54; H, 4.81;
N, 11.12.
5-[1-[4-(2-Pyrimidinyl)piperazinyl]carbonyl]-1,3-dihydro-1,3-
dioxo-2H-isoindole-2-propanoic Acid Benzyl Ester (IIId)
Yield: 81%. M.p.: 123–124ꢀC. 1H NMR (CDCl3) ꢀ 8.35 (1H, s,
Ar-H4), 8.32 (1H, d, J ¼ 7.50 Hz, Ar-H6), 7.9 (2H, m, pyrimidine-H5,6),
7.96 (1H, d, J ¼ 7.5 Hz, Ar-H7), 7.32 (5H, s, CH3Ph), 6.57 (1H, t,
J ¼ 4.70 Hz, pyrimidine-H5), 5.10 (2H, s, CH2Ph), 4.03 (2H, t,
J ¼ 7.0 Hz, NCH2), 3.8 (6H, m, piperizine), 3.4 (2H, m, piperizine), 2.79
(2H, t, J ¼ 7.0 Hz, CH2COO). IR (KBr, ꢁ, cmꢁ1): 1771 (C¼O), 1715

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2114
Deng, Shen, and Zhong
(C¼O), 1629 (C¼O). MS (m/z): 499 (M). Anal. calcd. for C27H25N5O5:
C, 64.92; H, 5.04; N, 14.02. Found: C, 64.66; H, 9.09; N, 13.88.
5-[[1-[4-(Phenylmethyl)piperazinyl]]carbonyl]-1,3-dihydro-1,3-
dioxo-2H-isoindole-2-propanoic Acid Benzyl Ester
Hydrochloric Acid (IIIe)
Yield: 78.0%. M.p.: 229–230ꢀC. H NMR (DMSO-d6) ꢀ 7.97 (1H, s,
1
Ar-H4), 7.93 (1H, d, J ¼ 7.6 Hz, Ar-H6), 7.87 (1H, d, J ¼ 7.6 Hz, Ar-H7),
7.61 (2H, s, PhCH2), 7.48 (3H, s, PhCH2), 7.32 (5H, s, OCH2Ph), 5.06
(2H, s, OCH2Ph), 4.56 (1/2H, brs, PhCH2N þ), 4.33 (3/2H, s, PhCH2Nþ),
¼
¼
3.88 (2H, t, J ¼ 7.20 Hz, NCH2), 3.4 (8H, m, piperizine), 2.77 (2H, t,
J ¼ 7.20 Hz, CH2COO). IR (KBr, ꢁ, cmꢁ1): 3432 (N-H), 1774 (C¼O),
1716 (C¼O), 1638 (C¼O). MS (m/z): 512 (M ꢁ Cl). Anal. calcd. for
C30H30ClN3O5: C, 65.75; H, 5.52; N, 7.67. Found: C, 65.98; H, 5.43;
N, 7.84.
General Procedure for the Preparation of Compounds IV a–e
A mixture of III (0.01 mol) and 5% Pd/C (0.8 g) in methanol (80 mL)
was treated with H2 at atmospheric pressure for 6 h. The mixture was
filtered through Celite, and the filtrate was concentrated in vacuo
(ꢁ0.085 Mpa). The residue was recrystallized fromethanol, then white
powder of the products was given. The physical and spectral data of
compounds IVa–e are reported below.
5-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-1,3-dihydro-
1,3-dioxo-2H-isoindole-2-propanoic Acid (IVa)
Yield: 85%. M.p.: 272–273ꢀC. H NMR (DMSO-d6) ꢀ 12.34 (1H,
1
brs, benzimidazole-NH), 9.59 (1H, t, J ¼ 5.4 Hz, NHCH2), 8.41 (1H, s,
Ar-H4), 8.36 (1H, d, J ¼ 7.8 Hz, Ar-H6), 8.02 (1H, d, J ¼ 7.8 Hz, Ar-H7),
7.5 (2H, m, benzimidazole-H4,7), 7.1 (2H, m, benzimidazole-H5,6), 4.74
(2H, d, J ¼ 5.4 Hz, NHCH2), 3.82 (2H, t, J ¼ 7.2 Hz, NCH2), 2.64 (2H, t,
J ¼ 7.2 Hz, CH2COO). IR (KBr, ꢁ, cmꢁ1): 3430 (N-H), 3372 (O-H), 1774
(C¼O), 1712 (C¼O), 1653 (C¼O). MS (m/z): 393 (M þ 1). Anal. calcd.
for C20H16N4O5: C, 61.23; H, 4.08; N, 14.29. Found: C, 61.46; H, 4.15;
N, 14.05.

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Acid Integrin Antagonists
2115
5-[[[(2-Benzimidazolyl)ethyl]amino]carbonyl]-1,3-dihydro-1,3-
dioxo-2H-isoindole-2-propanoic Acid (IVb)
Yield: 82%. M.p.: 263–264ꢀC. H NMR (DMSO-d6) ꢀ 12.32 (2H,
brs, COOH, benzimidazole-NH), 9.09 (1H, t, J ¼ 5.3 Hz, NHCH2), 8.29
(1H, s, Ar-H4), 8.25 (1H, d, J ¼ 7.50 Hz, Ar-H6), 7.96 (1H, d, J ¼ 7.5 Hz,
Ar-H7), 7.4 (2H, m, benzimidazole-H4,7), 7.1 (2H, m, benzimidazole-
1
H
5,6), 3.80 (2H, t, J ¼ 7.20 Hz, NCH2), 3.75 (2H, q, J ¼ 7.12 Hz,
NHCH2), 3.13 (2H, t, J ¼ 7.12 Hz, CH2CH2NH), 2.61 (2H, t,
J ¼ 7.20 Hz, CH2COO), IR (KBr, ꢁ, cmꢁ1): 3435 (N-H), 3385 (O-H),
1773 (C¼O), 1712 (C¼O), 1653 (C¼O). MS (m/z): 406 (M). Anal.
calcd. for C21H18N4O5: C, 62.07; H, 4.43; N, 13.79. Found: C, 61.90;
H, 4.50; N, 13.98.
5-[[[N-(2-Benzimidazolyl)methyl-N-methyl]amino]carbonyl]-
1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanoic Acid (IVc)
Yield: 78.0%. m.p.: 264–265ꢀC. H NMR (DMSO-d6) ꢀ 12.45 (2H,
1
brs, COOH, benzimidazole-NH), 8.02 (1H, s, Ar-H4), 7.96 (1H, d,
J ¼ 8.0 Hz, Ar-H6), 7.91 (1H, d, J ¼ 8.0 Hz, Ar-H7), 7.5 (2H, m, benz-
imidazole-H4,7), 7.2 (2H, m, benzimidazole-H5,6), 4.94 (1H, s,
CH2NCH3), 4.65 (1H, s, CH2NCH3), 3.8 (2H, m, NCH2), 3.05 (3/2H,
s, CH2NCH3), 3.00 (3/2H, s, CH2NCH3), 2.6 (2H, m, CH2OOH), IR:
3425 (N-H), 3383 (O-H), 1771 (C¼O), 1713 (C¼O), 1632 (C¼O). MS
(m/z): 407 (M þ 1). Anal. calcd. for C21H18N4O5: C, 62.07; H, 4.43; N,
13.79. Found: C, 62.25; H, 4.36; N, 13.65.
5-[1-[4-(2-Pyrimidinyl)piperazinyl]carbonyl]-1,3-dihydro-1,3-
dioxo-2H-isoindole-2-propanoic Acid (IVd)
Yield: 72.2%. M.p.: 157–158ꢀC. H NMR (DMSO-d6) ꢀ 12.30 (1H,
1
brs, COOH), 8.38 (2H, d, J ¼ 4.70 Hz, pyrimidine-H4,6), 7.97 (1H, s, Ar-
H4), 7.92 (1H, d, J ¼ 7.60 Hz, Ar-H7), 7.85 (1H, d, J ¼ 7.60 Hz, Ar-H6),
6.68 (1H, t, J ¼ 4.70 Hz, pyrimidine-H5), 3.82 (2H, t, J ¼ 7.10 Hz, NCH2),
3.8 (8H, m, piperizine), 2.62 (2H, t, J ¼ 7.10 Hz, CH2COOH). IR (KBr, ꢁ,
cmꢁ1): 3395 (O-H), 1773 (C¼O), 1723 (C¼O), 1611 (C¼O). MS (m/z):
410 (M þ 1). Anal. calcd. for C20H19N5O5: C, 58.68; H, 4.65; N, 17.11.
Found: C, 58.90; H, 4.60; N, 17.32.

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2116
Deng, Shen, and Zhong
5-[(1-Piperazinyl)carbonyl]-1,3-dihydro-1,3-dioxo-2H-
isoindole-2-propanoic Acid (IVe)
Yield: 74.5%. M.p.: 210–211ꢀC. H NMR (DMSO-d6) ꢀ 10.29 (3H,
1
brs, COOH, ¼ NHþ2 ), 7.97 (1H, d, J ¼ 1.2 Hz, Ar-H4), 7.95 (1H, d,
J ¼ 7.80 Hz, Ar-H7), 7.88 (1H, dd, J1 ¼ 1.2 Hz, J2 ¼ 7.8 Hz, Ar-H6), 3.81
(2H, t, J ¼ 7.20 Hz, NCH2), 3.3 (8H, m, piperizine), 2.62 (2H, t,
J ¼ 7.20 Hz, CH2COOH). IR (KBr, ꢁ, cmꢁ1): 3446 (N-H), 1767 (C¼O),
1707 (C¼O), 1621 (C¼O). MS (m/z): 332 (M ꢁ Cl). Anal. calcd.
for C16H17N3O5 HCl: C, 52.25; H, 4.93; N, 11.43. Found: C, 52.11; H,
4.82; N, 11.20.
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Received in the USA September 16, 2002

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