Solid phase synthesis of tetrahydro-1,4-benzodiazepin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2003.09.108

A novel solid phase route to tetrahydro-1,4-benzodiazepin-2-ones is described which involves construction of a core template in solution followed by diverse derivatization on solid phase.

Full text of DOI:10.1016/j.tetlet.2003.09.108

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8493–8495
Solid phase synthesis of tetrahydro-1,4-benzodiazepin-2-ones
Neal D. Hone,* William Wilson and John C. Reader
Millennium Pharmaceuticals Ltd, Granta Park, Great Abington, Cambridge CB1 6ET, UK
Received 9 July 2003; revised 4 September 2003; accepted 12 September 2003
Abstract—A novel solid phase route to tetrahydro-1,4-benzodiazepin-2-ones is described which involves construction of a core
template in solution followed by diverse derivatization on solid phase.
© 2003 Elsevier Ltd. All rights reserved.
The 1,4-benzodiazepine-2,5-dione template has found
widespread therapeutic use across a range of disease
states. The closely related 1,4-benzodiazepin-2-one
nucleus is less utilised yet has demonstrated anticonvul-
sant,1 anti-HIV2 and anti-coagulant3 activity. We
wished to access a diverse range of these compounds
for testing throughout a number of discovery pro-
grammes. Two solid phase approaches have been dis-
closed,4 and although our initial attempts at multistep
solid phase routes showed some promise, products were
generally of poor quality. In an alternative approach,
the 1,4-benzodiazepin-2-one core was prepared in solu-
tion. This was followed by loading onto solid phase and
subsequent derivatization, yielding compounds of
greatly improved purity.
4-(Bromomethyl)-3-nitrobenzoic acid 1 was treated
with methanolic HCl to provide the ester 2 (Scheme 1).
Reaction of 2 with glycine methyl ester gave the sec-
ondary amine 3 which was Boc protected (4) using
di-t-butyl dicarbonate. Nitro reduction of 4 was
achieved through catalytic hydrogenation to give the
aniline 5 which was cyclised in boiling toluene to give
the 1,4-benzodiazepin-2-one ester 6. No column chro-
matography was required throughout the synthesis and
the final product crystallised from toluene on addition
of ether and cooling in 50% overall yield.
Exposure of 6 to aqueous hydroxide led to degradation
of the molecule, but the methyl ester could be success-
fully cleaved using potassium trimethylsilanolate in
Scheme 1. Reagents and conditions: (i) HCl–MeOH, rt, 18 h; (ii) glycine methyl ester hydrochloride (3 equiv.), DIEA (4 equiv.),
DMF, rt, 18 h; (iii) Boc-O-Boc, DCM, rt, 18 h; (iv) H2, Pd, rt, 1 atm., 72 h, THF–MeOH (4:1); (v) toluene, D, 72 h, then Et2O
rt.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.108

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N. D. Hone et al. / Tetrahedron Letters 44 (2003) 8493–8495
Scheme 2. Reagents and conditions: (i) TMSOK (3 equiv.), THF, 40°C, 2 h; (ii) oxime resin, DIC, DMAP (10%); (iii) alkyl halide
(5 equiv.), DBU (5 equiv.), DMF, 0–35°C, 20 min; (iv) 50% TFA in DCM, rt, 30 min; (v) electrophile (5 equiv.), DIEA (5 equiv.),
DCM, rt, 1 h; (vi) amine (5 equiv.), DCE, 75°C, 18 h.
THF to provide the acid 7 (Scheme 2). This was loaded
onto oxime resin5 using DIC-DMAP, the reaction per-
formed in batches of approximately 40 g. The amide
nitrogen of 8 was alkylated using activated alkyl
halides6 and DBU in DMF. This reaction was exother-
mic and led to product loss from the resin on prolonged
treatment. Optimal conditions involved cooling prior to
exposure to the alkylating mixture and terminating the
reaction after 20 min. The alkylation step was per-
formed on 30 g resin batches. It was observed that
alkylations using 100 mg resin required three treat-
ments to achieve reaction completion. The tertiary
amides 9 were Boc-deprotected using TFA (30 g resin
scale) and the resultant secondary amines 10 derivatized
with a range of electrophiles7 to give 11. Each resin
combination was then cleaved with amine solutions8 in
1,2-DCE at 75°C overnight to provide 1344 individual
compounds 12.9 Derivatizations and cleavages were
performed using 120 mg resin. Average crude yield was
65% and average crude purity by HPLC-MS was 62%
(using diode array detection). All library members were
purified by HPLC10 to an average of 10% yield at 89%
average purity.
6. Alkyl halides used were methyl iodide, bromoacetamide,
benzyl bromide, 3-methoxybenzyl bromide, 4-chlorobenz-
yl bromide and 4-cyanobenzyl bromide. The unalkylated
amide 8 was also taken through steps iv–vi.
7. Electrophiles used were acetic anhydride, cyclohexanecar-
bonyl chloride, 3-cyclopentylpropionyl chloride, benzoyl
chloride, 4-chlorobenzoyl chloride, 2-fluorobenzoyl chlo-
ride, 2-cyanobenzenesulphonyl chloride, 4-cyanobenzoyl
chloride, 4-methoxybenzoyl chloride, 2-furoyl chloride,
isoxazole-5-carbonyl chloride, 4-methoxybenzenesulphon-
yl chloride, benzenesulphonyl chloride, 4-chlorobenz-
enesulphonyl chloride, 3,5-difluorobenzenesulphonyl
chloride, ethyl isocyanate, cyclopentyl isocyanate, allyl
isocyanate, ethyl chloroformate, benzyl isocyanate, benz-
yl bromide, 4-chlorobenzyl bromide and 3-methoxybenz-
yl bromide. The underivatised amine was also taken
through step vi.
8. Amines used were ammonia, n-propylamine, N,N-
dimethylethylenediamine, ethanolamine, pyrrolidine,
morpholine, 2-methoxyethylamine and benzylamine.
9. Typical experimental procedures: Oxime resin loading—
The acid 7 (38.74 g, 127 mmol) was dissolved in dry
DMF (100 ml) and oxime resin (1.3 mmol/g, 48.6 g, 63
mmol) added. Sufficient dry DCM was then added to
attain a thin slurry. DMAP (0.77 g, 6.3 mmol) was added
followed by DIC (16.22 g, 129 mmol) and the mixture
stirred at room temperature overnight. The resin was
then washed with DMF, MeOH, DCM, MeOH, DCM,
MeOH and dried in vacuo to provide 8 (65.1 g). Alkyla-
tion—resin 8 (1.3 mmol/g, 30 g, 39 mmol) was suspended
in sufficient dry DMF to form a thin slurry and the
mixture cooled to 0°C using an ice-water bath. DBU (29
ml, 194 mmol) was added, followed by methyl iodide
[caution: Highly toxic, potential carcinogen] (12.14 ml, 195
mmol), and the mixture stirred at a temperature between
30–40°C, maintained using the ice bath. After 20 min the
resin was washed with DMF, MeOH, DCM, MeOH,
DCM, MeOH and dried in vacuo to give 9 (R1=Me)
(30.2 g). Boc deprotection—resin 9 (1.3 mmol/g, 30 g, 39
mmol) was suspended in 50% TFA in DCM and stirred
at room temperature for 1 h. The resin was then washed
with DCM, MeOH, DCM, MeOH and dried in vacuo to
provide resin 10 (26 g). Acylation—resin 10 (1.3 mmol/g,
References
1. Hardy, J.-C.; Bouquerel, J.; Nemecek, P.; Peyronel, J.-F.
Pat. Appl. WO 98-FR1638 19980724.
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Knaep, F.; Pauwels, R.; Andries, K.; De Clercq, E.;
Janssen, M. A. C.; Janssen, P. A. J. Bioorg. Med. Chem.
1999, 7, 2427–2436.
3. Nakagawa, T.; Tokumasu, M.; Tashiro, M.; Takahashi,
M.; Kayahara, T.; Takehana, S.; Kajigaya, Y.; Yoshida,
K.; Sakurai, K. Pat. WO 0226732 A1 20020404.
4. (a) Bhalay, G.; Blaney, P.; Palmer, V. H.; Baxter, A. D.
Tetrahedron Lett. 1997, 38, 8375–8378; (b) Wu, Z.;
Ercole, F.; FitzGerald, M.; Perera, S.; Riley, P.; Cambell,
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5. Novabiochem 1.3 mmol/g 1% DVB polystyrene.

N. D. Hone et al. / Tetrahedron Letters 44 (2003) 8493–8495
8495
120 mg, 0.16 mmol) was placed into the well of an ACT
Advantage reaction block, swelled with dry DCM (2 ml)
and drained. A solution of DIEA (135 ml, 0.78 mmol) in
dry DCM (0.5 ml) was added, followed by a solution of
2-furoyl chloride (102 mg, 0.78 mmol) in dry DCM (1 ml)
and the suspension vortexed at room temperature for 1 h.
The resin was then washed with DCM, MeOH, DCM,
MeOH and DCM to provide the resin 11. Cleavage—the
resin 11 was washed with 1,2-DCE then n-propylamine
(64 ml, 0.78 mmol) in dry 1,2-DCE (1.5 ml) added and the
mixture heated to 75°C for 18 h with intermittent vortex-
ing. The mixture was cooled to room temperature and the
well vented into a collection vial. The resin was washed
with a further 1.5 ml DCM and the washings vented into
the collection vial. The contents of the vial were evapo-
rated to dryness using a vacuum centrifuge to provide the
1,4-benzodiazepin-2-one 12 (R1=Me, R2=2-furoyl, R3=
n-propyl, R4=H) (32 mg, 86% yield based on original
resin loading, purity by HPLC using diode array detec-
tion=89%). 1H NMR (400 MHz, CDCl3) 7.75 (1H, s),
7.53 (1H, d, J=7.8), 7.44 (1H, br s), 7.37–7.25 (1H, m),
7.03 (1H, d, J=3.5), 6.59 (1H, br s), 6.43 (1H, br s), 4.69
(2H, br s), 4.25 (2H, br s), 3.4–3.31 (5H, m), 1.63–1.52
(2H, m), 0.90 (3H, t, J=7.4). m/z (ES+) 356 (MH+).
10. Purification was performed using Gilson preparative sys-
tems and Phenomenex Luna 150×21.2 mm C8 columns.
Mobile phases were A; 10 mM NH4OAc in MeOH and
B; 10 mM NH4OAc in water. The gradient was 5% B,
0–3 min; 5–100% B, 3–25 min; 100% B, 25–27 min;
100–5% B, 27–27.5 min.