Efficient synthesis of novel benzo-[e]-[1,4]-diazepine derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00402-6

Following two efficient synthetic routes a novel series of benzo-[e]-[1,4]-diazepine derivatives, bearing an unusual Z exo-methylencarbamoyl side chain at the C-5 position, have been prepared to identify new antagonists of the glycine binding site associa

Full text of DOI:10.1016/S0040-4039(01)00402-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3227–3230
Efficient synthesis of novel benzo-[e]-[1,4]-diazepine derivatives
Tommaso Messeri, Giorgio Pentassuglia and Romano Di Fabio*
GlaxoWellcome S.p.A., Medicines Research Center, Via Fleming 4, I-37135 Verona, Italy
Received 25 January 2001; revised 1 March 2001; accepted 8 March 2001
Abstract—Following two efficient synthetic routes a novel series of benzo-[e]-[1,4]-diazepine derivatives, bearing an unusual Z
exo-methylencarbamoyl side chain at the C-5 position, have been prepared to identify new antagonists of the glycine binding site
associated with NMDA receptor. © 2001 Published by Elsevier Science Ltd.
The role of excitatory amino acids (EAA) in pathologi-
cal conditions, such as stroke, head trauma and neu-
ronal spinal injury has been widely investigated.1 In
give the corresponding amide 5. Finally, reduction of
the nitro group afforded the desired aniline derivative 6
quantitatively.
particular, the overstimulation of the N-methyl-D-
aspartate (NMDA) receptor, through the modulation
of the glycine binding site, has been proposed as a
useful way forward to counteract excitotoxicity.2 In this
event, different classes of glycine antagonists3 have been
investigated in the last decade as potential neuroprotec-
tive agents. Our recent exploration of the indole-2-car-
boxylate template resulted in the identification of
potent glycine antagonist compounds.4,5 In particular,
GV150526A 1, shown in Fig. 1, reached phase III
clinical trials in man as a potential anti-stroke agent.
To prepare the first compound of the series, the C-3
unsubstituted compound 2a, reaction of 6 with bromo-
acetyl bromide in the presence of pyridine gave com-
pound 8a which was then transformed into the corre-
sponding azido derivative 9a in 50% yield. The crucial
cyclization step was accomplished either by an aza-
Wittig type reaction in the presence of PPh3 or by
catalytic hydrogenation, followed by the in situ cycliza-
tion of the amino intermediate to give, in both cases,
2a in good yield as a chemically stable compound.
Remarkably, the cyclization reaction proceeded with
complete stereocontrol in the formation of the double
bond, to give the desired Z-exo-2-carbamoylmethylene
side chain only.9
To identify new glycine antagonists, novel benzodi-
azepine derivatives of general structure 2 (Fig. 1), bear-
ing a Z exo a-b-unsaturated side chain in the position
C-5, were designed by receptor mapping techniques
based on the known pharmacophore model of the
glycine binding site.4b
To prepare C-3 substituted derivatives, the amidation
reaction was repeated with racemic N-Cbz amino acids
7b–f,10 activated as acyl chlorides, affording derivatives
8b–f in variable yields. The one-pot removal of the
N-CBz protecting group, followed by cyclization of
compounds 8b–f, gave the Z-exo benzodiazepines 2b–f
in good yield, confirming the previous observation in
terms of chemical stability of the exo derivatives with
To prepare this novel template two synthetic strategies,
shown in Schemes 1 and 3, respectively, were explored.
In the first route (Scheme 1) the key intermediate 6 was
obtained from the commercially available benzoic acid
derivative 3 in a three-step sequence and high total
yield. Reaction of the acyl chloride derived from 3 with
the potassium salt of the mono ethyl malonate ester in
the presence of MgCl2 and TEA7 gave compound 4,8
which was reacted with aniline in m-xylene at reflux to
Keywords: glycine antagonists; synthesis; benzo-[e]-[1,4]-diazepines.
* Corresponding author. Fax: 0039-045-9218196; e-mail: rdf26781@
glaxowellcome.co.uk
Figure 1.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00402-6

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T. Messeri et al. / Tetrahedron Letters 42 (2001) 3227–3230
Scheme 1. (a) SOCl2, then EtOOCCH2COOK, MgCl2, Et3N, CH3CN; (b) PhNH2, m-xylene, reflux; (c) Fe, CaCl2, EtOH; (d)
BrCH2COBr, Et2O (for 8a) or RCHXCOOH (7b–f), PCl5, THF/pyridine; (e) NaN3, DMSO; (f) PPh3, THF or Pd/CaCO3, H2 (1
atm), MeOH; (g) HBr/AcOH, CH2Cl2 or TMSBr, PhSCH3; (h) Me3SiONa, THF.6
Scheme 2. (a) RNH2, EDCl, HOBT; (b) HCOOH (for 11a) or TFA/CH2Cl2 (for 11b).
respect to the corresponding endo analogues, which
were never isolated.
After deprotection of the amine moiety, the free amino
derivative cyclized under mild acid conditions (AcOH
or SiO2) to yield the benzodiazepine derivative 16,
which was then converted into the desired N-phenyl
amide 2h in the presence of aniline and Al(CH3)3.
The synthesis of the unnatural aminoacids 7c and 7e is
shown in Scheme 2. Thus, formation of the desired
amides of aminomalonate monoester 10,11 followed by
acid hydrolysis of the t-butyl ester afforded the final
intermediates 7c and 7e.
The corresponding unsaturated derivative 2i was
obtained from compound 16 in two steps: reaction with
MnO2 to give the ethyl ester intermediate 17 followed
by treatment with aniline and Al(CH3)3. It is worth
underlining that when the same oxidation reaction was
carried out on compound 2h a complex mixture of
by-products was obtained.
A different approach for the synthesis of this novel
class of benzodiazepine derivatives was also developed.
As an example, the preparation of the C-3 phenyl
derivative 2h is described in Scheme 3. Commercially
available 5-chloro-2-amino benzoic acid 12 was reacted
with racemic N-Cbz-phenylglycine to obtain the amido
derivative 13. When this intermediate was heated in
acetic anhydride, benzoxazinone intermediate 14 was
obtained in high yield. Reaction with the potassium salt
of the mono ethyl malonate ester in the presence of
TEA and MgCl2 gave the key b-ketoester derivative 15
in high yield.12
In summary, two efficient synthetic routes have been
developed to prepare a series of novel benzodiaze-
pine derivatives,13 bearing a chemically stable enamine
Z exo double bond at position C-5, as compounds
specifically designed to identify new classes of glycine
antagonists.

T. Messeri et al. / Tetrahedron Letters 42 (2001) 3227–3230
3229
Scheme 3. (a) PhCH(NHCbz)COCl, THF; (b) Ac2O; (c) EtOOCCH2COOK, MgCl2, Et3N, CH3CN; (d) HBr/AcOH, CH2Cl2,
then AcOH or SiO2, EtOAC; (e) PhNH2, Al(CH3)3, m-xylene/CH2Cl2; (f) MnO2, toluene; (g) PhNH2, Al(CH3)3, toluene.
Acknowledgements
4. (a) Di Fabio, R.; Cugola, A.; Donati, D.; Feriani, A.;
Gaviraghi, G.; Ratti, E.; Trist, D. G.; Reggiani, A. Drugs
Fut. 1998, 23, 61; (b) Di Fabio, R.; Capelli, A. M.; Conti,
N.; Cugola, A.; Feriani, A.; Gastaldi, P.; Gaviraghi, G.;
Hewkin, C. T.; Micheli, F.; Missio, A.; Mugnaini, M.;
Pecunioso, A.; Quaglia, A. M.; Ratti, E.; Rossi, L.;
Tedesco, G.; Trist, D. G.; Reggiani, A. J. Med. Chem.
1997, 40, 841.
The authors would like to thank Dr. C. Marchioro and
1
her group for the H NMR spectra and Dr. M. Ham-
dan and his group for MS spectra.
References
5. For the synthesis and the biological characterization of
other series of indole-2-carboxylate derivatives, see: (a)
Hewkin, C. T.; Di Fabio, R.; Conti, N.; Cugola, A.;
Gastaldi, P.; Micheli, F.; Quaglia, A. M. Arch. Pharm.
Med. Chem. 1999, 332, 55. (b) Micheli, F.; Di Fabio, R.;
Capelli, A. M.; Cugola, A.; Curcuruto, O.; Feriani, A.;
Gastaldi, P.; Gaviraghi, G.; Marchioro, C.; Orlandi, A.;
Pozzan, A.; Quaglia, A. M.; Reggiani, A.; van Amster-
dam, F. Arch. Pharm. Med. Chem. 1999, 332, 73. (c)
Giacobbe, S. A.; Di Fabio, R.; Baraldi, D.; Cugola, A.;
Donati, D. Synth. Commun. 1999, 29, 3125. (d) Di Fabio,
R.; Conti, N.; De Magistris, E.; Feriani, A.; Provera, S.;
Sabbatini, F. M.; Reggiani, A.; Rovatti; L.; Barnaby, R.
J. J. Med. Chem. 1999, 42, 3486. (e) Giacobbe, S. A.;
Baraldi, D.; Di Fabio, R. Biorg. Med. Chem. Lett. 1998,
8, 1689.
1. (a) McCollough, J. Br. J. Clin. Pharmacol. 1992, 34, 106;
(b) Meldrum, B.; Garthwaite, J. Trends Pharmacol. 1990,
11, 379; (c) Choi, D. W. J. Neurosci. 1990, 10, 2493; (d)
Meldrum, B. Cerebrovasc. Brain Metab. Rev. 1990, 2, 27.
2. Reviews: (a) Zivin, J. A. Drugs 1997, 54, suppl. 383, 8. (b)
Huetter, J. E. Biochem. Pharmacol. 1991, 41, 9. (c) Thom-
son, A. M. Prog. Neurobiol. 1990, 35, 53. (d) Palfreyman,
M. G.; Baron, B. M. In Excitatory Amino Acid Antago-
nists; Meldrum, B., Ed.; Blackwell: Oxford, 1991; Chap-
ter 6, pp. 101–129.
3. (a) Di Fabio, R.; Gaviraghi, G.; Reggiani, A. La Chimica
e l’Industria 1996, 78, 283–289; (b) Leeson, P. D.; Iversen,
L. L. J. Med. Chem. 1994, 37, 4053; (c) Kemp, J. A.;
Leeson, P. D. TiPS 1993, 14, 20; (d) Iversen, L. L.;
Kemp, J. A. In The NMDA Receptor, 2nd ed.;
Collingridge, G. L.; Watkins, J. C., Eds.; IRL Press:
Oxford, UK, 1994; Chapter 20, pp. 469–486.
6. Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984,
25, 5831.

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T. Messeri et al. / Tetrahedron Letters 42 (2001) 3227–3230
7. Clay, R. J.; Collom, T. A.; Karrick, L. G.; Wemple, J.
Synthesis 1993, 290.
8. Cecchetti, V.; Fravolini, A.; Sabatini, S.; Tabarrini, O.;
10.66 (bs, 1H); 10.18 (bs, 1H); 10.12 (bd, 1H); 9.52 (bs,
1H); 7.66–7.52 (m, 5H); 7.37 (m, 1H); 7.33 (m, 2H); 7.24
(m, 2H); 7.21 (bs, 1H); 7.08 (m, 1H); 6.94 (m, 1H); 4.93
1
(s, 1H); 4.75 (bs, 1H); [M+H]+ (m/z): 447. (2d) H NMR
Xin, T. Eur. J. Med. Chem. 1998, 33, 899.
9. The Z configuration was assigned by NOE experiments.
10. (a) Delle Monache, G.; Di Giovanni, M. C.; Maggio, F.;
Misiti, D.; Zappia, G. Synthesis 1995, 1155; (b) Krysian,
D. J. Tetrahedron Lett. 1996, 37, 3303; (c) Goldberg, S.
I.; Crosby, J. M.; Iusem, N. D.; Younes, U. E. J. Am.
Chem. Soc. 1987, 109, 823.
(300 MHz) l (acetone-d6): 10.37 (bd, 1H); 9.56 (s, 1H);
8.83 (s, 1H); 7.68 (dd, 2H); 7.62 (d, 1H); 7.26 (m, 4H);
6.98 (tt, 1H); 5.03 (s, 1H); 4.92 (bs, 1H); 4.30 (bs, 2H);
1.28 (bs, 3H). [M+H]+ (m/z): 401. 2e) 1H NMR (300
MHz) l (DMSO-d6): 10.57 (bs, 1H); 9.99 (bd, 1H); 9.50
(bs, 1H); 8.55 (bs, 1H); 7.57 (m, 2H); 7.44–7.10 (m, 10H);
6.93 (m, 1H); 5.13 (s, 2H); 4.90 (s, 1H); 4.64 (bs, 1H);
4.20–3.94 (m, 2H). [M+H]+ (m/z): 520. (2g) 1H NMR
(300 MHz) l (DMSO-d6): 10.33 (bs, 1H); 9.52 (d, 1H);
9.20 (s, 1H); 7.53 (d, 2H); 7.38 (d, 1H); 7.18 (t, 2H); 6.86
(m, 3H); 4.68 (s, 1H); 3.86 (m, 1H); 2.50 (m, 1H); 2.10
(m, 1H). [M]+ (m/z): 407. (2h) 1H NMR (300 MHz) l
(acetone-d6): 10.49 (bs, 1H); 9.48 (bs, 1H); 8.82 (bs, 1H);
7.65 (d, 2H); 7.64–7.28 (m, 8H); 7.26 (t, 2H); 6.97 (t, 1H);
5.29 (bs, 1H); 5.03 (s, 1H); [M+H]+ (m/z): 404. (2i) 1H
NMR (300 MHz) l (DMSO-d6): 11.37 (bs, 1H); 10.09
(bs, 1H); 7.89 (d, 2H); 7.54 (d, 1H); 7.55–7.45 (m, 3H);
7.33 (dd, 1H); 7.30 (t, 2H); 7.24 (d, 1H); 7.02 (tt, 1H);
6.61 (d, 2H); 5.64 (s, 1H). [M+H]+ (m/z): 402.
11. Matt, T.; Seebach, D. Helv. Chim. Acta 1998, 81, 1845.
12. For a similar approach to prepare b-ketoester derivatives,
see: El-Khamry. Adbel Momen, A.; El-Nagdy, S.;
Habashy, M. M.; El-Bassiouny, F. A. Pharmazie 1989,
44, 312.
1
13. (2a) H NMR (300 MHz) l (DMSO-d6): 10.30 (bs, 1H);
9.64 (t, 1H); 9.47 (bs, 1H); 7.58 (d, 1H); 7.56 (d, 2H); 7.30
(m, 1H); 7.23 (t, 2H); 7.15 (bs, 1H); 6.92 (t, 1H); 4.85 (s,
1H); 3.79 (bs, 2H); [M+H]+ (m/z): 328. (2b) 1H NMR
(300 MHz) l (acetone-d6): 10.05 (d, 1H); 9.43 (s, 1H);
8.75 (s, 1H); 7.67 (d, 2H); 7.64 (d, 1H); 7.31(m, 1H); 7.30
(s, 1H); 7.25 (t, 2H); 6.96 (m, 1H); 4.94 (s, 1H); 4.10 (m,
1H); 4.00 (m, 1H); 3.97 (m, 1H); 3.92 (m, 1H); [M+H]+
(m/z): 358. (2c) 1H NMR (300 MHz) l (DMSO-d6):
.
.