A short and efficient synthesis of novel N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides

Article abstract of DOI:10.1007/s007060170090

Several novel N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides were prepared by acyl coupling of 2-aminobenzophenones with α-(benzotriazol-1-yl)-N-acylglycines followed by displacement of the benzotriazole ring with ammonia and cycl

Full text of DOI:10.1007/s007060170090

Monatshefte fuÈr Chemie 132, 747±752 (2001)
A Short and Ef®cient Synthesis of Novel
N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-
benzodiazepin-3-yl)-2-carboxamides
Ali Khalaj1;Ã, Morteza Pirali1, Hogatollah Matloubi2,
and Reza Dowlatabadi1;a
1
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences,
Tehran, Iran
2
Atomic Energy Organization of Iran, Nuclear Research Center, Tehran, Iran
Summary. Several novel N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carbox-
amides were prepared by acyl coupling of 2-aminobenzophenones with ꢀ-(benzotriazol-1-yl)-N-
acylglycines followed by displacement of the benzotriazole ring with ammonia and cyclization of the
resulting monoacyl aminals. In addition to high yields and shorter reaction sequences due to avoiding
deprotection and acylation of the protected 3-amino-1,4-benzodiazepin-2-one intermediates, the
present approach did not involve the use of toxic and odoriferous materials as is the case with other
methods.
Keywords. 3-Substituted 1,4-benzodiazepin-2-ones; ꢀ-(Benzotriazol-1-yl)-N-acylglycines; Chole-
cystokinin antagonists.
Introduction
Since the isolation and identi®cation of asperlicin [1] as a non-peptide antagonist of
the peptide hormone cholecystokinin (CCK), various 3-substituted benzodiazepines
have been designed as agonists and/or antagonists of the peripheral (CCK-A) and/or
central (CCK-B) receptor subtypes [2±4]. The development of devazepide [5], FK
480 [3], etc. as CCK-A antagonists for the treatment of pancreatitis, irritable bowel
syndrome, and pancreatic cancer [3] and CCK-A agonists such as GW 5823 for the
suppression of food intake [2] have demonstrated the signi®cance of these
investigations. These potent compounds, which display both high selectivity and
good oral activity, are currently under clinical investigations [2±3]. In connection
with ongoing work aimed at the synthesis and evaluation of novel N-(2,3-dihydro-2-
oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides as CCK-A antagonists
and in view of problems and limitations associated with the preparation of
analogous compounds, a general convenient synthesis of the title compounds is
reported in this paper.
Ã
Corresponding author
a
Part of PhD thesis

748
A. Khalaj et al.
Results and Discussion
3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepin-2-ones are usually prepared by acy-
lation of 3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (1) either with
acyl chlorides or with free acids in the presence of a coupling agent such as 1-(3-
(dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (EDC)[6]. Reported
methods for the synthesis of 1 are based on the preparation and transformation of
benzodiazepine-N-oxide [7±8], elimination-addition reactions of 2-(N-acetoxyace-
tamido)-20-benzoylacetanilide [9±10], construction of the N1-substituted 1,4-benzo-
diazepine nucleus followed by introduction of the 3-amino group [11], acyl
coupling of ꢀ-(isopropylthio)- or ꢀ-(benzotriazol-1-yl)-N-(benzyloxycarbonyl)-
glycine with 2-aminobenzophenone followed by displacement of the ꢀ-substituent
with ammonia, cyclization of the resulting protected monoacyl aminal, and removal
of the blocking group [11±12]. These methods suffer from a number of drawbacks
including low yields and/or lengthy reaction sequences [7±10], inadequacy for large
scale preparations [6], use of highly toxic and odoriferous materials [11], and
protection/deprotection steps [11±12].
Scheme 1

Synthesis of Substituted 1H-Benzodiazepins
749
In the course of our investigations on the design and synthesis of the CCK-A
antagonists, a shorter and more ef®cient reaction sequence for the preparation of
novel N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides
6a±g was developed through installing the desired acyl group of the ®nal product as
a protecting group of ꢀ-(benzotriazol-1-yl)-glycine. The novel ꢀ-(benzotriazol-1-
yl)-N-acylglycine synthons 2a±d were prepared by condensation of benzotriazole,
glyoxylic acid, and the corresponding amides with azeotropic removal of water
[13]. Acyl coupling of these new synthons with 2-aminobenzophenones 4 and
subsequent displacement of the benzotriazole moiety with ammonia followed by
cyclization of the resulting amino ketone intermediate 5 (Scheme 1) gave the
desired 3-substituted benzodiazepines 6a±g.
By the synthetic sequences described, the known compound 6a [14] was
prepared in 77% overall yield, whereas the novel compounds 6b±g were obtained in
59±72% overall yield. A major advantage of the present approach, which was
developed by the modi®cation of the published procedures for the preparation of
analogous 3-substituted 1,4-benzodiazepin-2-ones [11±12], is shortening the syn-
thetic route from ®ve to three steps by eliminating the deprotection and acylation of
the protected 3-aminobenzodiazepinone intermediates. The biological activities of
6b±g are currently under investigation.
Experimental
1
Melting points were determined on a Reichert hot plate apparatus and are uncorrected. H and 13C
1
NMR spectra were recorded on a Varian Unity Plus 400 spectrometer (399.866 MHz for H NMR
and 100.556 MHz for 13C NMR) using DMSO-d6 as solvent. Chemical shifts (ꢁ) are reported in ppm
relative to TMS as internal standard. Mass spectra were obtained on a Finnigan TSQ-70 instrument.
Infrared spectra were recorded on a Nicolet Magna IR 550 spectrometer.
General procedure for the preparation of ꢀ-(benzotriazol-1-yl)-N-acylglycines 2a±d
Benzotriazole (2.38 g, 20 mmol), 1.84 g glyoxylic acid monohydrate (20 mmol), and 20 mmol of the
appropriate amide in 100 cm3 toluene were re¯uxed in a Dean-Stark apparatus for 3 h. Compounds
2a and 2b which precipitated upon cooling were puri®ed by washing with ether, crystallization from
methanol/ether, and drying under high vacuum. For isolation of compounds 2c and 2d, the reaction
mixture was cooled to room temperature, the solvent was decanted, and the residue was triturated with
5 cm3 of methanol. The resulting precipitates were puri®ed by crystallization from methanol/ether.
2-(1H-Benzotriazol-1-yl)-2-(benzoylamino)acetic acid (2a; C15H12N4O3)
Yield: 5.44 g (92%); m.p.: 195±197ꢀC; 1H NMR (400 MHz): ꢁ ˆ 7:42 (t, 1H, J ˆ 7:6 Hz), 7.47±7.52
(m, 3H), 7.56±7.60 (m, 2H), 7.91±7.94 (m, 2H), 8.05±8.12 (m, 2H), 10.17 (d, 1H, J ˆ 7:6 Hz) ppm;
13C NMR (100 MHz): ꢁ ˆ 63:87, 111.54, 119.21, 124.24, 127.76, 127.85, 128.51, 132.33, 132.68,
145.19, 166.80, 167.12 ppm; IR (KBr): ꢂ ˆ 1150, 1277, 1523, 1659, 1722, 3323 cm 1; MS (70 eV):
‡
m=z ˆ 296 (M ).
2-(1H-Benzotriazol-1-yl)-(2-thienylamino)acetic acid (2b; C13H10N4O3S)
Yield: 5.31 g (88%); m.p.: 205±207ꢀC; 1H NMR (400 MHz): ꢁ ˆ 7:20 (t, 1H, J ˆ 4 Hz), 7.44 (t, 1H,
J ˆ 7:6 Hz), 7.56 (d, 1H, J ˆ 4 Hz), 7.60 (t, 1H, J ˆ 7:6 Hz), 7.87 (d, 1H, J ˆ 8 Hz), 8.05 (d, 1H,

750
A. Khalaj et al.
J ˆ 7:6 Hz), 8.07 (d, 1H, J ˆ 4 Hz), 8.09 (d, 1H, J ˆ 7:6 Hz), 10.31 (d, 1H, J ˆ 8 Hz) ppm; 13C
NMR (100 MHz): ꢁ ˆ 63:69, 111.52, 119.19, 124.23, 127.69, 128.32, 130.24, 132.25, 132.70,
137.62, 145.13, 161.44, 166.92 ppm; IR (KBr): ꢂ ˆ 1156, 1402, 1549, 1622, 1759, 3218 cm 1; MS
‡
(70 eV): m=z ˆ 302 (M ).
2-(1H-Benzotriazol-1-yl)-2-(2-furanylamino)acetic acid (2c: C13H10N4O4)
Yield: 4.63 g (81%); m.p.: 185±187ꢀC; 1H NMR (400 MHz): ꢁ ˆ 6:65 (dd, 1H, J ˆ 1:6 Hz,
J ˆ 0:8 Hz), 7.35 (dd, 1H, J ˆ 1:6 Hz, J ˆ 0:4 Hz), 7.42 (t, 1H, J ˆ 7:6 Hz), 7.47 (d, 1H, J ˆ 8 Hz),
7.57 (t, 1H, J ˆ 7:6 Hz), 7.90 (dd, 1H, J ˆ 0:8 Hz, J ˆ 0:4 Hz), 8.06 (t, 2H, J ˆ 7:6 Hz), 10.08 (d,
1H, J ˆ 8 Hz) ppm; 13C NMR (100 MHz): ꢁ ˆ 63:39, 111.69, 112.37, 115.96, 119.30, 124.45,
127.88, 132.30, 145.29, 146.19, 146.52, 157.97, 166.94 ppm; IR (KBr): ꢂ ˆ 1406, 1655, 1733,
‡
3144 cm 1; MS (70 eV): m=z ˆ 286 (M ).
2-(1H-Benzotriazol-1-yl)-(1H-pyrrol-2-ylamino)acetic acid (2d; C13H11N5O3)
Yield: 4.16 g (73%); m.p.: 195±196ꢀC; 1H NMR (400 MHz): ꢁ ˆ 7:07 (t, 1H, J ˆ 4 Hz), 7.35 (t, 1H,
J ˆ 7:6 Hz), 7.41 (d, 1H, J ˆ 8 Hz), 7.49 (t, 1H, J ˆ 7:6 Hz), 7.62 (d, 1H, J ˆ 4 Hz), 7.80 (br, 1H),
7.96 (d, 1H, J ˆ 4 Hz), 7.99±8.02 (m, 2H), 10.02 (d, 1H, J ˆ 8 Hz) ppm; 13C NMR (100 MHz):
ꢁ ˆ 63:48, 111.18, 118.92, 123.80, 127.28, 127.70, 130.15, 131.72, 132.12, 137.55, 145.15, 161.42,
‡
166.64 ppm; IR (KBr): ꢂ ˆ 1408, 1659, 1749, 3176 cm 1; MS (70 eV): m=z ˆ 285 (M ).
General procedure for the preparation of N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-
yl)-2-carboxamides 6a±g
Oxalyl chloride (0.86 cm3, 10 mmol) and 0.1 cm3 anhydrous DMF were added to a solution of
10 mmol of 2 in 40 cm3 of anhydrous THF under N2 at 0±5ꢀC, and the mixture was stirred below 5ꢀC
for 2 h. A solution of 1.97 g 2-aminobenzophenone (10 mmol) and 2.1 cm3 anhydrous N-methyl-
morpholine in 15 cm3 of anhydrous THF was added to the stirred mixture at 5ꢀC over 30 min;
thereafter, the reaction mixture was allowed to reach room temperature. The reaction slurry was
®ltered, and the mother liquor was saturated with ammonia gas, diluted with 80 cm3 of methanol, and
again saturated with ammonia gas for approximately 30 min. After evaporation of the solvent under
reduced pressure, the residue was dissolved in 50 cm3 of ethyl acetate, washed successively with 1 N
aqueous NaOH solution and brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. Following the treatment of the resulting crude amino ketone intermediate with a
solution of 3.3 g ammonium acetate in 40 cm3 glacial acetic acid, the reaction solution was stirred
under N2 overnight. The solvent was evaporated under reduced pressure, the residue was suspended
in 10 cm3 ethyl acetate and 50 cm3 diethyl ether, and the pH of the mixture adjusted to approximately
8.5 by addition of 1 N aqueous NaOH solution. The crude products, which precipitated upon
cooling the suspension, were crystallized from ethyl acetate/diethyl ether to give the pure compounds
6a±g.
N-(2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-benzamide (6a; C22H17N3O2)
1
Yield: 2.73 g (77%); m.p.: 233±235ꢀC; H NMR (400 MHz): ꢁ ˆ 5:21 (d, 1H, J ˆ 6:8 Hz), 7.03±
7.25 (m, 3H), 7.43±7.58 (m, 9H), 7.99 (d, 2H, J ˆ 6:8 Hz), 9.27 (d, 1H, J ˆ 6:8 Hz) ppm; 13C NMR
(100 MHz): ꢁ ˆ 68:49, 120.17, 122.73, 125.71, 126.68, 127.65, 127.91, 129.03, 129.57, 129.74,
130.82, 131.05, 133.55, 138.36, 143.77, 165.52, 165.67, 166.48 ppm; IR (KBr): ꢂ ˆ 523, 770, 1260,
‡
1383, 1527, 1660, 1705, 2889, 3319, 3462 cm 1; MS (70 eV): m=z ˆ 355 (M ).

Synthesis of Substituted 1H-Benzodiazepins
751
N-(2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-thiophen-2-carboxamide
(6b; C20H15N3O2S)
1
Yield: 2.67 g (74%); m.p.: 219±221ꢀC; H NMR (400 MHz): ꢁ ˆ 5:48 (d, 1H, J ˆ 7:6 Hz), 7.20 (t,
1H, J ˆ 4 Hz), 7.24±7.36 (m, 3H), 7.44±7.54 (m, 6H), 7.63±7.67 (m, 1H), 7.81 (d, 1H, J ˆ 5:2 Hz),
9.64 (d, 1H, J ˆ 7:6 Hz) ppm; 13C NMR (100 MHz): ꢁ ˆ 68:91, 121.42, 123.25, 126.30, 128.06,
128.14, 128.29, 129.49, 130.58, 131.42, 131.54, 132.21, 138.12, 138.82, 139.22, 161.19, 167.16,
168.02 ppm; IR (KBr): ꢂ ˆ 707, 1178, 1271, 1501, 1650, 1696, 2889, 3088, 3329 cm 1; MS (70 eV):
‡
m=z ˆ 361 (M ).
N-(2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-furan-2-carboxamide
(6c; C20H15N3O3)
1
Yield: 2.28 g (66%); m.p.: 207±209ꢀC; H NMR (400 MHz): ꢁ ˆ 5:69 (d, 1H, J ˆ 8 Hz), 6.51 (dd,
1H, J ˆ 3:6 Hz, J ˆ 1:6 Hz), 7.13±7.24 (m, 3H), 7.32±7.36 (m, 3H), 7.41±7.54 (m, 5H), 8.15 (d, 1H,
J ˆ 8 Hz) ppm; 13C NMR (100 MHz): ꢁ ˆ 67:04, 112.00, 114.97, 121.56, 123.82, 127.40, 128.05,
129.79, 130.45, 131.16, 132.02, 137.64, 138.59, 144.41, 147.50, 158.11, 168.31, 168.64 ppm; IR
(KBr): ꢂ ˆ 523, 764, 1189, 1378, 1511, 1647, 1706, 2361, 2889, 3155, 3406 cm 1; MS (70 eV):
‡
m=z ˆ 345 (M ).
N-(2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-pyrrol-2-carboxamide
(6d; C20H16N4O2)
Yield: 2.03 g (59%); m.p.: 212±214ꢀC; 1H NMR (400 MHz): ꢁ ˆ 5:36 (d, 1H, J ˆ 6:8 Hz), 5.58 (d,
1H, J ˆ 8:4 Hz), 7.03±7.10 (m, 3H), 7.45±7.55 (m, 7H), 7.58 (d, 1H, J ˆ 3:6 Hz), 7.66 (d, 1H,
J ˆ 6:8 Hz) ppm; 13C NMR (100 MHz): ꢁ ˆ 62:10, 127.88, 127.95, 128.96, 129.14, 129.38, 130.88,
131.24, 131.41, 137.74, 137.84, 142.46, 162.13, 162.24, 169.12, 169.55 ppm; IR (KBr): ꢂ ˆ 704,
‡
1122, 1429, 1542, 1614, 1650, 1745, 2361, 3176, 3360 cm 1; MS (70 eV): m=z ˆ 344 (M ).
3-(Benzoylamino)-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (6e; C22H16ClN3O2)
1
Yield: 2.80 g (72%); m.p.: 217±219ꢀC; H NMR (400 MHz): ꢁ ˆ 5:39 (d, 1H, J ˆ 7:2 Hz), 7.26±
7.31 (m, 2H), 7.46±7.60 (m, 9H), 8.17 (d, 2H, J ˆ 7:6 Hz), 9.42 (d, 1H, J ˆ 7:2 Hz) ppm; 13C NMR
(100 MHz): ꢁ ˆ 69:14, 123.79, 126.49, 127.62, 127.78, 128.29, 128.38, 129.47, 130.69, 131.62,
131.97, 133.63, 137.86, 138.94, 165.65, 166.31, 167.58 ppm; IR (KBr): ꢂ ˆ 530, 702, 835, 1393,
‡
1481, 1657, 1699, 2955, 3473 cm 1; MS (70 eV): m=z ˆ 389 (M ).
7-Chloro-1,3-dihydro-5-phenyl-3-(2-thienylcarbonylamino)-2H-1,4-benzodiazepin-2-one
(6f; C20H14ClN3O2S)
1
Yield: 2.76 g (70%); m.p.: 173±175ꢀC; H NMR (400 MHz): ꢁ ˆ 5:69 (d, 1H, J ˆ 7:6 Hz), 7.11±
7.14 (m, 2H), 7.35±7.54 (m, 8H), 7.73 (d, 1H, J ˆ 3:6 Hz), 7.78 (d, 1H, J ˆ 7:6 Hz) ppm; 13C NMR
(100 MHz): ꢁ ˆ 67:66, 123.13, 127.81, 128.37, 128.71, 129.03, 129.79, 130.65, 130.85, 132.35,
133.12, 136.09, 136.15, 137.88, 161.74, 167.30, 168.54 ppm; IR (KBr): ꢂ ˆ 532, 702, 1281, 1490,
‡
1537, 1644, 1706, 2356, 2930, 3416 cm 1; MS (70 eV): m=z ˆ 395 (M ).
7-Chloro-1,3-dihydro-3-(2-furanylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one
(6g; C20H14ClN3O3)
1
Yield: 2.35 g (62%); m.p.: 164±166ꢀC; H NMR (400 MHz): ꢁ ˆ 5:70 (d, 1H, J ˆ 8 Hz), 6.54 (dd,
1H, J ˆ 3:6 Hz, J ˆ 1:6 Hz), 7.16±7.21 (m, 2H), 7.37±7.55 (m, 8H), 8.03 (d, 1H, J ˆ 8 Hz) ppm;

752
A. Khalaj et al.: Synthesis of Substituted 1H-Benzodiazepins
13C NMR (100 MHz): ꢁ ˆ 67:13, 112.15, 115.15, 123.07, 128.44, 128.86, 129.80, 130.70, 130.96,
132.38, 136.14, 137.98, 144.52, 147.55, 158.10, 167.09, 168.29 ppm; IR (KBr): ꢂ ˆ 513, 810, 1020,
‡
1404, 1573, 1650, 1706, 2361, 3457 cm 1; MS (70 eV): m=z ˆ 379 (M ).
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Received September 20, 2000. Accepted (revised) November 29, 2000