Synthesis of 3-carboxylic derivatives of 1,5-benzodiazepines

Article abstract of DOI:10.1002/jhet.5570380315

A series of 3-carboxylic derivatives of disubstituted 1,5-benzodiazepines (5-9) was synthesized by heterocyclisation from 1,2-diaminobenzene (1) with dibenzoylmethane (2) followed by bromination on position 3 and by introduction of the carboxylic group or

Full text of DOI:10.1002/jhet.5570380315

May-Jun 2001
Synthesis of 3-Carboxylic Derivatives of 1,5-Benzodiazepines
O. Mansour[a], B. Szymonski[a], F. Thomasson[b], J. M. Morand[a] and M. Cussac[a]*
641
[a] Laboratoire de Chimie Thérapeutique; [b] Service Commun de RMN;
Département de Pharmacochimie Moléculaire, UMR 5063-CNRS,
Faculté de Pharmacie - Université J. Fourier - 38706 La Tronche Cedex – France
Received July 27, 2000
A series of 3-carboxylic derivatives of disubstituted 1,5-benzodiazepines (5-9) was synthesized by hetero-
cyclisation from 1,2-diaminobenzene (1) with dibenzoylmethane (2) followed by bromination on position 3
and by introduction of the carboxylic group or introduction of the malonic moiety. Reduction of the hetero-
cycle gave the perhydro derivative diethyl (2,4-diphenyl-1,2,4,5-tetrahydro-3H-1,5-benzodiazepin-3-
yl)malonate (9).
J. Heterocyclic Chem., 38, 641 (2001).
Calcium channel blockers as diltiazem [1-2] and
It was not possible to obtain the heterocyclization from
1,2-diaminobenzene and a diaryl β-diketone when this
β-diketone bears also an ester or a cyano or a carboxylic
moiety on the α-atom. Therefore the carboxylic moiety
had to be introduced by carboxylation of the 3-bromo
derivative via an organometallic reaction. However the
introduction of the ester (ethoxycarbonyl) group or the
endothelin antagonists namely SB-209670 [3] and BMS-
182874 are protective cardiovascular agents acting by
coronary vasodilatation and activation of coronary blood
flow [4-6] (Chart 1). Comparison of their structures
prompted us to design novel protective agents with a
mixed structure.
cyano moiety in this 3-position was always unsuccessful
even from 3-unsubstituted-1,5-benzodiazepine structure or
from 3-bromo -1,5-benzodiazepine structure.
The preparation of 3-carboxylic derivatives of 2,4-
diphenyl-3H-1,5-benzodiazepine was achieved by cycliza-
tion of 1,2-diaminobenzene (1) with dibenzoylmethane (2)
which afforded 2,4-diphenyl-3H-1,5-benzodiazepine (3).
Its bromination by N-bromosuccinimide gave
3-bromo-2,4-diphenyl-1,5-3H-benzodiazepine (4). The
introduction of the carboxylic moiety in the 3 position was
obtained from (4) by the Grignard reaction using solid car-
bon dioxide to give 2,4-diphenyl-3H-1,5-benzodiazepin-3-
carboxylic acid (5). Malonic derivatives were obtained by
condensation of (4) with diethyl malonate to give the
diethyl ester of (2,4-diphenyl-3H-1,5-benzodiazepin-3-
yl)malonic acid (6). Partial saponification of this diester
gave the monoacid derivative (7). The diacid (8) was
obtained by longer hydrolysis.
We wish to describe herein the synthesis of 3-carboxylic
derivatives of diaryl substituted -1,5-benzodiazepines
which at present are being tested for their coronary
vasodilator properties.
Among thousands of benzodiazepinic compounds, those
bearing a carboxylic group or derived moiety are very few.
The best known are chlorazepic acid and ethyl loflazepate
which are anxiolytics having a 1,4-benzodiazepine struc-
ture. 1,5-Benzodiazepine derivatives are much fewer, and
none bearing a carboxylic or an ester group at the 3-posi-
tion is described.
The 1,5-benzodiazepine heterocycle was constructed in a
one pot operation from 1,2-diaminobenzene (1) by cycliza-
tion with dibenzoylmethane (2) (Chart 2). The carboxylic
or the ester group in the 3-position of 1,5-benzodiazepine
compounds could be introduced during the construction of
the heterocyclic moiety as in the 1,4-benzodiazepine series
or by substitution of a 3-bromo-1,5-benzodiazepine deriva-
tive to give the corresponding monocarboxylic acid or the
malonic acid or the malonic ester derivative.
The heterocyclic moiety of the diester (6) could be
reduced by sodium cyanoborohydride by a procedure

642
O. Mansour, B. Szymonski, F. Thomasson, J. M. Morand and M. Cussac
Vol. 38
2,4-Diphenyl-3H-1,5-benzodiazepine (3).
adapted from Ohkawa et al. [8] giving diethyl (2,4-
diphenyl-1,5-benzoperhydroazepin-3-yl) malonate (9).
In theory, the reduction of (6) that contains 2 double
bonds, in the case of an attack by H ion from sodium
cyanoborohydride on the same side of the double bonde,
A mixture of 1,2-diaminobenzene (1) (12.9 g, 120 mmoles)
and dibenzoylmethane (2) (22.4 g, 100 mmoles) was heated at
170-180° for 4 hours. After evaporation of the mixture and mix-
ing with diethyl ether a precipitate was obtained. The crude prod-
uct was collected, dried, and recrystallized from ethanol to give
9.86 g (44%) of 2,4-diphenyl-3H-1,5-benzodiazepine (3), mp
-
could lead to (9) that should be a mixture of the cis isomers
-
which are enantiomers. In the case of an attak of H to
1
138° (lit. 140° [9]); H nmr (deuteriochloroform) : δ 3.74 (br s,
each side of the heterocycle, a mixture of 4 diastereoiso-
mers (2 enantiomer pairs) could be obtained because of the
prochirality of the carbon–3 in the compound (6), which
becomes a chiral carbon in the compound (9).
2H, 3-H ), 7.36 (dd, 2H, 6-,9-H, J = 6.1, 3.5 Hz), 7.41- 7.43 (m,
2
6H, m, p- phenyl protons), 7.63 (dd, 2H, 7-,8-H, J = 6.1, 3.5 Hz) ,
7.96-8.01 (m, 4H, o-phenyl protons) ; ir (potassium bromide) :
-1
1580 (C=N) cm .
Experimentally we have isolated only one product
with good yield (85%) which has lead us to believe that the
reduction follows the first hypothesis.
3-Bromo-2,4-diphenyl-3H-1,5-benzodiazepine (4).
A mixture of 2,4-diphenyl-3H-1,5-benzodiazepine (3) (0.6 g, 2
mmoles) in tetrachlorocarbone (2.4 ml) and N-bromosuccinimide
(0.48 g, 2.6 mmoles) was refluxed without benzoyl peroxid under
nitrogen atmosphere for 16 hours. After cooling to room temper-
ature, the crude product was filtered, dried, and recrystallized
from dry ether to give 0.54 g (90%) of 3-bromo-2,4-diphenyl-
EXPERIMENTAL
Melting points were determined with a Buchi 510 capillary appa-
ratus and are uncorrected. The ir spectra were recorded on a Unicam
SP 1100 infrared spectrophotometer using potassium bromide plates
1
3H-1,5-benzodiazepine (4), mp 120°; H nmr (deuteriochloro-
form): δ 7.02 (s, 1H, 3-H), 7.46-7.51 (m, 8H, 6-, 9-H, m, p-
phenyl protons), 7.71 (dd, 2H, 7-, 8-H, J = 6.1, 3.5 Hz), 7.90-7.95
(m, 4H, o-phenyl protons); ir (potassium bromide): 1580 (C=N),
-1
1
for solid products. The frequencies are expressed in cm . H and
13
C-nmr spectra were obtained on a Bruker AC 200 spectrometer in
-1
deuteriochloroform or dimethylsulfoxide-d solution. Chemical
730 (C-Br) cm .
6
shifts are given in δ (ppm) units relative to the internal reference
tetramethylsilane. The abbreviations of signal patterns are as fol-
lows: s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br:
broad. Elemental analyses (C, H, N, Br, O) were carried out in the
Service Central d'Analyses, Centre National de la Recherche
Scientifique, 69 390 Vernaison, France and were within ± 0,4% of
theoretical values unless otherwise noted. Reaction progress and
purity of products were checked by carrying out tlc using silica gel
Merck 60 F254; the spots were visualised by uv and iodine vapour.
Anal. Calcd. for C
7.49. Found: C, 67.37; H, 4.00; Br, 21.02; N, 7.46.
H BrN : C, 67.45; H, 4.04; Br, 21.36; N,
21 15 2
2,4-Diphenyl-3H-1,5-benzodiazepin-3-carboxylic acid (5).
Carboxylation of (4) was performed with experimental condi-
tions adapted from the literature [7]. A mixture of magnesium (0.08
g, 3.3 mmoles), 3-bromo-2,4-diphenyl-3H-1,5-benzodiazepine (4)
(1g, 2.66 mmoles) and tetrahydrofuran (6 ml) was refluxed under a
nitrogen atmosphere for 4 hours. After cooling to room temperature,

May-Jun 2001
Synthesis of 3-Carboxylic Derivatives of 1,5-Benzodiazepines
643
solid carbon dioxyde was introduced for 45 minutes, then water (2
ml) was added. The reaction mixture was acidified by 10% (v/v)
hydrochloric acid, extracted by ethyl acetate. The aqueous solution
was evaporated. The residue was washed with methanol. After
evaporation of the solvent an unstable product was obtained, 0.55 g
(55%) of 2,4-diphenyl-3H-1,5-benzodiazepine-3-carboxylic acid
mmole) in ethanol:tetrahydrofuran (1:1; v/v) (2.4 ml).
Neutralisation was performed by addition of 2.4 N hydrochloric
acid in ethanol until a yellow color persisted. After addition of 1.5
ml of water, the crude product was extracted by chloroform. The
organic phase was evaporated to give 0.15 g (85%) of diethyl (2,4-
diphenyl-1,2,4,5-tetrahydro-3H-1,5-benzodiazepin-3-yl)malonate
1
1
(5), mp 200°; H nmr (methanol-d ): δ 5.1 (s, 1H, 3-H), 6.61 (dd,
(9), mp 192°; H nmr (deuteriochloroform): δ 1.20 (t, 6H, 2CH ,
4
3
2H, 6-, 9-H, J = 5.9, 3.4 Hz), 7.13 (dd, 2H, 7-, 8-H, J = 5.9, 3.4 Hz),
J = 7.1 Hz), 3.27 (d, 1H, -CH(COOEt) , J = 3.1 Hz), 3.57 (ddd, 1H,
2
7.56–7.61 (m, 4H, o-phenyl protons), 7.67 – 7.74 (6H, m, m, p-
3-H, J = 6.5, 3.1 Hz), 4.06 (q, 4H, 2CH , J = 7.1 Hz), 4.80 (br d, 2H,
2
phenyl protons); ir (potassium bromide): 1420 (CO -), 1580 (C=N),
1640 (C=O), 3500 (OH) cm .
2-, 4-H, J = 6.5 Hz), 6.48 (dd, 2H, 6-, 9-H, J = 5.8, 3.4 Hz), 6.65 (dd,
2H, 7-, 8-H, J = 5.8, 3.4 Hz), 7.26 – 7.39 (m, 6H, m, p-phenyl pro-
2
-1
tons), 7.55 (br dd, 4H, o-phenyl protons); ms: (chemical ionization)
Diethyl (2,4-Diphenyl-3H-1,5-benzodiazepin-3-yl)malonate (6).
+
m/z 459 (M+1), 299 (M -CH(COOEt) ); ir (potassium bromide):
2
-1
A mixture of 3-bromo-2,4-diphenyl-3H-1,5-benzodiazepin (4)
(3.75 g, 10 mmoles), diethyl malonate (1.5 ml, 10 mmoles) and
sodium ethanolate (15 ml) (2.5 M) was heated at 60-65° for 24
hours. After cooling to room temperature, the reaction mixture
was dried. Then, an adequate amount of water was added. After
extraction by chloroform, the collected extracts were dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The crude product was chromatographed on a silica gel
column with ethyl acetate:petroleum ether (1:1; v/v) to get 0.97 g
(26%) of diethyl (2,4-diphenyl-3H-1,5-benzodiazepin-3-yl)mal-
1310 (C-N), 1600 (NH), 1750 (C=O), 3460 (NH) cm .
Anal. Calcd for C
H N O : C, 73.34; H, 6.59; N, 6.11; O,
28 30 2 4
13.96. Found: C, 73.23; H, 6.64; N, 6.03; O, 14.10 .
2-(2,4-Diphenyl-3H-1,5-benzodiazepin-3-yl)-2-ethoxycarbonyl-
malonic Acid (7).
A mixture of diethyl (2,4-diphenyl-3H-1,5-benzodiazepin-3-
yl)malonate (6) (0.60 g, 1.32 mmoles) and sodium ethanolate (5
ml) (2.5 M) was stirred at room temperature for 1 day. After con-
centration the residue was diluted with water and acidified until
pH 5-6. The crude product was extracted with chloroform. After
removal of the solvent, the residue was chromatographed on a sil-
ica gel column with methanol:chloroform (2:8, v/v) to afford 0.12
g (20%) of 2-(2,4-diphenyl-3H-1,5-benzodiazepin-3-yl)-2-
1
onate (6), mp 130°; H nmr (deuteriochloroform): δ 1.07 (t, 6H,
2CH , J = 7.1 Hz), 3.17 (d, 1H, 3-H, J = 11.4 Hz), 4.03 (q, 4H,
3
2CH , J = 7.1 Hz), 6.41 (d, 1H, -CH(COOEt) , J = 11.4 Hz), 7.36
2
2
– 7.42 (m, 8H, m, p-phenyl protons and 6-, 9-H), 7.64 (dd, 2H, 7-
, 8-H, J = 6.1, 3.4 Hz), 8.05 (m, 4H, o-phenyl protons); ms:
1
ethoxycarbonylmalonic acid (7), mp 100°; H nmr (deuteriochlo-
+
(chemical ionization) m/z 455 (M+1), 294 (M -CH(COOEt) );
roform) : δ 0.93 (t, 3H, CH , J = 7.0 Hz), 3.10 (d, 1H, 3-H, J =
2
3
-1
ir (potassium bromide): 1580 (C=N), 1750 (C=O) cm .
11.3 Hz), 3.86 (q, 2H, CH , J = 7.0 Hz), 6.13 (d, 1H, -CH-
2
Anal. Calcd for C
H N O : C, 73.99; H, 5.77; N, 6.16; O,
COOH(COOEt), J = 11.3 Hz), 7.21 – 7.35 (m, 8H, 6-, 9-H,
phenyl protons), 7.52 (dd, 2H, 7-, 8-H, J = 6.0, 3.3), 7.92 (br d,
4H, o-phenyl protons); ir (potassium bromide): 1580 (C=N),
28 26 2 4
14.08 . Found: C, 74.20; H, 5.81; N, 6.27; O, 14.00.
(2,4-Diphenyl-3H-1,5-benzodiazepin-3-yl)malonic Acid (8).
-1
1610 (C=O), 3400 (OH) cm .
A mixture of diethyl (2,4-diphenyl-3H-1,5-benzodiazepin-3-
yl)malonate (6) (0.60 g, 1.32 mmoles) and sodium ethanolate (5 ml)
(2.5 moles of sodium in ethanol) was stirred at room temperature
for 3 days. After evaporation of the solution, the residue was diluted
with water then acidified until pH 5-6. The crude product was
extracted by chloroform. The organic layer was evaporated.
Recrystallization from chloroform gave 0.24 g (40%) of (2,4-
diphenyl-3H-1,5-benzodiazepin-3-yl)malonic acid (8), mp 240°;
REFERENCES AND NOTES
*
Correspondence and reprints: Max Cussac*, Laboratoire de
Chimie Thérapeutique, Faculté de Pharmacie - Université J. Fourier,
38706 La Tronche Cedex – France; Tel. / Fax 33 (0)4 76 63 71 13; E-mail
Max.Cussac@ujf-grenoble.fr.
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Ruffolo, J. Weinstock, J. G. Gleason, C. E. Peishoff and E. H. Ohlstein, J.
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1
H nmr (methanol-d ): δ 2.91 (d, 1H, 3-H, J = 11.2 Hz), 6.35 (d, 1H,
4
-CH(COOH) , J = 11.2 Hz), 7.27 (dd, 2H, 6-, 9-H, J = 6.1, 3.4 Hz),
2
7.30 – 7.34 (m, 6H, m, p-phenyl protons), 7.55 (dd, 2H, 7-, 8-H, J =
6.1, 3.4 Hz), 8.01 – 8.06 (m, 4H, o-phenyl protons); ir (potassium
-1
bromide): 1580 (C=N), 1610 (C=O), 3380 (OH) cm .
Anal. Calcd for C
H
N O : C, 72.35; H, 4.55; N, 7.03; O,
24 18 2 4
16.06. Found: C, 57.48; H, 3.86; N, 5.36; O, 24.5. (1 Na CO + 1
2
3
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H O), confirmed by mass spectrometry.
2
Diethyl (2,4-Diphenyl-1,2,4,5-tetrahydro-3H-1,5-benzodiazepin-
3-yl)malonate (9).
This compound was prepared by selective reduction with
cyanoborohydride according to the procedure described by Ohkawa
et al [8]. Diethyl (2,4-diphenyl-3H-1,5-benzodiazepin-3-yl) mal-
onate (6) (0.18 g, 0.4 mmole) was added under nitrogen atmosphere
at 0° to the mixture of an ethanolic solution on green of bromocresol
(0.05 g/l, 1.12 ml) and sodium cyanoborohydride (0.056 g, 0.88
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