Preparation of triazolobenzodiazepine derivatives as Vasopressin V1a antagonists

Article abstract of DOI:10.1016/j.tetlet.2011.08.011

This Letter describes the synthesis of a number of fused tricyclic and bicyclic triazolobenzodiazepines for the Vasopressin V1a antagonist programme.

Full text of DOI:10.1016/j.tetlet.2011.08.011

Tetrahedron Letters 52 (2011) 5913–5917
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of triazolobenzodiazepine derivatives as Vasopressin
V1a antagonists
⇑
David M. Beal, Justin S. Bryans, Patrick S. Johnson , Julie Newman, Christelle Pasquinet,
⇑
Torren M. Peakman, Thomas Ryckmans, Toby J. Underwood , Simon Wheeler
Pfizer Ltd, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the synthesis of a number of fused tricyclic and bicyclic triazolobenzodiazepines for
the Vasopressin V1a antagonist programme.
Received 2 June 2011
Revised 25 July 2011
Accepted 2 August 2011
Available online 22 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Triazolobenzodiazepines
Tricyclic
Vasopressin V1a
Triazole
Atropisomer
The arginine Vasopressin V1a receptor is expressed mainly in
the liver, vascular smooth muscle cells and the brain. In vascular
smooth muscle cells the V1a receptor regulates vasoconstriction
and contractility. V1a receptor antagonists have been progressed
to the clinic for a range of indications1 including Raynauds syn-
drome and dysmenorrhoea. In this Letter we describe the synthesis
of a number of fused tricyclic compounds as potential Vasopressin
V1a antagonists (Fig. 1). In addition, two alternative routes are
described for lead compounds which allowed rapid exploration
of SAR within this chemical series.
purity profiling and cost was the neat phosphorus oxychloride
method which gave oxadiazole 4 in 80% yield5 and allowed the ex-
cess phosphorus oxychloride to be recovered by simple distillation.
The synthesis of this intermediate proved to be robust and was
scaled to multigram quantities and avoided the use of column
chromatography over the three steps.
With this oxadiazole intermediate in hand we were able to pre-
pare a number of triazolobenzodiazepines in an expedient manner
as described in Scheme 2.
Benzyl alcohol 5 and benzylamine 6 were obtained by lithium
aluminium hydride reduction of the respective commercial ben-
zoic acid6 and benzonitrile.7 Alkylation of chloromethyl oxadiazole
4, with nucleophiles 5 and 6 gave the ether 7 and amine 8 interme-
diates. Cyclisation was achieved using acid catalysis in a high boil-
ing solvent to give triazolo ether 98 and triazolo amine 10 in 65%
and 76% yields, respectively. Subsequent derivatisation of second-
ary amine 10 by either amide coupling or reductive amination
Our initial route to these targets allowed us to synthesize a
number from the common oxadiazole intermediate 4 shown in
Scheme 1.
The formation of the acyl hydrazide 2 proceeded in 73% yield,
from known ester 12 simply by heating with hydrazine hydrate
in methanol. Subsequent reaction with chloroacetyl chloride in
the presence of N-methyl morpholine furnished the bis-acyl hydra-
zide 3 in 84% yield. A number of methods were investigated for the
final dehydration step to give oxadiazole 4. The mildest method
using trifluoroacetic anhydride and pyridine3 was attractive for po-
tential scalability. However, due to isoliphophilic by products
being produced this method was deemed unsuitable. Use of Bur-
gess’ reagent4 gave a good reaction profile but was not pursued
further due to the cost of reagents. The method of choice, due to
N
N
N
N
N
X
n
X = O, N, S
n = 1,2
⇑
Corresponding authors.
E-mail addresses: patrick.s.johnson@pfizer.com (P.S. Johnson), underwoodt@
Cl
rsc.org (T.J. Underwood).
Figure 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.011

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D. M. Beal et al. / Tetrahedron Letters 52 (2011) 5913–5917
NH2NH2.H2O, MeOH,
65 oC, 18 h
O
O
N
N
N
OEt
73%
N
N
H
NH2
1
2
O
Cl
Cl
84%
NMM,CH2Cl2,
20 oC, 3 h
N
O
N
N
POCl3, 100 oC, 4 h
O
O
Cl
N
N
4
80%
N
N
H
N
H
Cl
3
Scheme 1.
OH NH2
NaH, THF
20 oC, 3 h
p
TSA, xylene
N
N
O
5
N
N
O
Cl
N
N
N
N
N
N
N
140 o
C, 18 h
N
N
x = o, 65%
x = NH, 76%
or
X
Cl
X
NH2 NH2
4
H2N
Cl
7, X=O, 72%
8, X = NH, 75%
9, X=O, 65%
10, X=NH, 76%
Cl
THF
50 oC, 18 h
6
Cl
Scheme 2.
CH2O, CH2Cl2,
NaBH(OAc)3
20 oC, 15 min
N
N
N
N
N
N
N
N
N
AcCl, CH2Cl2
20 oC, 3 h
N
N
N
N
N
N
O
73%
92%
NH
N
N
12
10
11
Cl
Cl
Cl
Scheme 3.
N
JAB=13.8 Hz
Tcoal=293 K
vA-vB=359 Hz
N
N
allowed rapid analogue generation, furnishing useful SAR data, as
exemplified in Scheme 3.
N
N
Due to concerns about atropisomerism with these tria-
zolobenzodiazepine templates we carried out further NMR stud-
ies on compound 12.9 The free energy of activation for rotation
about the aryl-triazole bond was estimated from variable tem-
perature 1H NMR experiments conducted in tetrachloroethane-
d2 from 248 to 343 K. The hydrogens of the two methylene
groups in the seven-membered ring each form a pair of AB
systems at low temperature that coalesce to two A2 systems at
higher temperature (Fig. 2). From the geminal coupling constants
and frequency separation measured at low temperature (248 K)
and the observed temperature of coalescence (Tcoal) an approxi-
mate value of kcoal was calculated10 as 801 sꢀ1. Using this value
for kcoal in the Eyring equation gives an estimate of the free
energy of activation of 55 kJ molꢀ1, which is lower than that
required to satisfy the condition for the existence of atropisomer-
ism.11 In the case of ether 9 the two methylene groups in the
seven-membered ring appeared as two A2 systems in the 1H
N
JAB=12.8 Hz
Tcoal=283 K
vA-vB=214 Hz
Cl
Figure 2.
NMR spectrum at room temperature. Although broadening was
observed at lower temperatures (253 K) the free energy of activa-
tion for rotation about the aryl-triazole bond is clearly lower than
that in 12.
An alternative route was required which allowed rapid manip-
ulation of the piperidine functionality. Formation of thiolactam 16
gave the ability to introduce hydrazide 2, and analogues, at a late
stage allowing additional SAR studies shown in Scheme 4.

D. M. Beal et al. / Tetrahedron Letters 52 (2011) 5913–5917
5915
O
CO2tBu
NH2
Cl
NH2 NH2
HN
NH
KOtBu, THF, 20 oC, 2 h
87%
THF, 65 oC, 20 h
81%
Cl
CO2tBu
N
H
Cl
6
13
14
Cl
CH2O, NaBH(OAc)3
CH2Cl2, AcOH
79%
O
20 oC, 30 min
NH2
N
R
N
H
S
N
O
R
P4S10, Na2CO3,THF
N
nBuOH, 100 oC, 20 h
HN
N
HN
20 oC, 18 h
N
N
Acyl Hydrazide=2, 65%
93%
Cl
16
12
Cl
15
Cl
Scheme 4.
O
HS
CO2H
H2, PtO2, EtOH
Br
NO2
CO2H
NO2
HN
S
40 psi, 20 oC, 1 h
NaOH, H2O, (CH3)2CO
20 oC, 20 h
S
70%
40%
16
Cl
N
18
17 Cl
Cl
i) P4S10, Na2CO3,
THF, 20 oC, 18 h
N
N
N
58% (2 steps)
ii) 2, nBuOH
100 oC, 20 h
N
S+
O
30% H2O2/H2O, (CF3)2CHOH
20 oC, 1 h
41%
N
N
N
N
Cl
21
N
30% H2O2/H2O, TFA
20 oC, 1 h
S
N
N
N
N
19
66%
Cl
N
O
S
O
20
Cl
Scheme 5.
Alkylation of benzylamine 6 with the sterically hindered chloro-
acetic tert-butyl ester gave secondary amine 13 in 81% yield. Cyc-
lisation under basic conditions and subsequent reductive amina-
tion with formaldehyde gave lactam 15 in 79% yield. Formation
of more reactive thiolactam using phosphorus pentasulfide fur-
nished the desired intermediate 16 in 93% yield.12 Triazole forma-
tion then occurred by simply heating thiolactam 16 with
hydrazides such as compound 2, giving compound 12.13
This second route also allowed us to access alternative tethered
analogues such as the sulfur linked compounds 19, 20 and 21 as
outlined in Scheme 5.
ether 19 in an overall yield of 58%. Standard oxidation conditions15
gave sulfone 20.16 However by using 1,1,1,3,3,3-hexafloro-2-pro-
panol as a solvent we were able to obtain sulfoxide 21.17 This par-
tial reaction is believed to be due to H-bonding stabilization
between the solvent and the sulfoxide.18
Variable temperature 1H NMR spectroscopy showed that the
sulfur analogues 19, 20 and 21 existed as atropisomers. Thus the
hydrogens of the methylene groups on the seven-membered ring
appear as AB systems even at 355 K. Sulfoxide 21 was observed
as a mixture of diastereoisomers by 1H NMR spectroscopy in a
2:1 ratio.
Reduction of the nitro intermediate 17 directly gave lactam
18.14 Treatment with phosphorus pentasulfide gave the thiolactam
which reacted smoothly with hydrazide 2 to furnish triazolo thio-
Pleasingly, the methodology from the first route (Scheme 2) al-
lowed us to explore larger, eight- and nine-membered, ring sys-
tems (Scheme 6).

5916
D. M. Beal et al. / Tetrahedron Letters 52 (2011) 5913–5917
OH
OH
O
Cl
NH2
i)
i)
Cl
22
NaH, THF, 20 oC, 3 h
NH2
24
NaH, THF, 20 oC 3 h
ii) pTSA, xylene,
140 oC, 24 h
ii) pTSA, xylene,
N
N
N
N
N
N
N
N
O
N
140 oC, 2 h
N
N
N
N
N
Cl
12% (2 steps)
21% (2 steps)
O
O
4
NH2
O
Cl
26
25 Cl
5% (2 steps)
Cl
NH2
i)
23
Et3N, THF, 50 oC, 4 h
ii) pTSA, xylene,
140 oC, 2 h
N
N
N
N
N
N
N
N
N
N
N
N
N
CH2O, NaBH(OAc)3, CH2Cl2
20 oC, 15 min
N
Ac2O, Et3N, CH2Cl2
20 oC, 2 h
N
O
N
NH
N
78%
92%
29
Cl
28
27
Cl
Cl
Scheme 6.
NH2
OH
i)
30, (R)
31, (S)
NaH, THF, 20 oC, 2 h
N
N
N
N
N
N
N
ii) pTSA, xylene, 140 oC, 18 h
N
N
Cl
O
32, (R), 68%, ee >99.5
33, (S), 47%, ee >99.5
4
O
Scheme 7.
Alkylation of either alcohol 2219 or alcohol 2420 with oxadiazole
4 and subsequent cyclisation gave the tethered eight-membered
ether 25 and the tethered nine-membered ether 26. A similar reac-
tion sequence was carried out using the amine 2321 to give the
tethered eight-membered amine 27 which was further elaborated
by amide formation or reductive amination to furnish compounds
28 and 29, respectively.
We are also pleased to report that this methodology allows fur-
ther potential in the formation of bicylic six-membered ring sys-
tems, as outlined in Scheme 7. Using chiral amino alcohols 30
and 31 we were able to show the retention of stereochemistry
allowing access to appealing analogues such as 32 and 33.
In summary, we have described the synthesis of attractive tri-
cylic and bicyclic systems as potential Vasopressin V1a antago-
nists. Two reaction sequences have been discussed which allow
expedient exploration of the triazolobenzodiazepine chemical
series. Further exploration has been possible by reduction and
expansion of these ring systems using the same methodology.
4. (a) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973, 38, 26; (b) Brain,
C. T.; Paul, J. M.; Loong, Y.; Oakley, P. J. Tetrahedron Lett. 1999, 40, 3275.
5. 4-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-3,4,5,6-tetrahydro-2H-[1,20]bipyridinyl
(4): The hydrazide 3 (20.4 g, 69 mmol) was suspended in POCl3 (150 ml) at
100 °C for 4 h. The mixture was cooled and the solvent evaporated under
reduced pressure. The residue was dissolved in EtOAc (200 ml) and was added
to H2O (100 ml). The aqueous layer was basified by addition of solid NaHCO3
and the phases were separated. The aqueous layer was extracted with EtOAc
(2 ꢁ 200 ml) and the combined organic layers dried over MgSO4 and
evaporated under reduced pressure. The material was isolated and triturated
with Et2O to give compound 4 as a beige solid (15 g, 80%). 1H NMR (400 MHz,
CD3OD): d = 1.91 (m, 2H), 2.19 (m, 2H), 3.14 (m, 2H), 3.30 (m, 1H), 4.29 (m, 2H),
4.86 (s, 2H), 6.69 (m, 1H), 6.89 (m, 1H), 7.58 (m, 1H), 8.08 (m, 1H). APCI MS m/z
278 [MH]+.
6. Sabbatini, P.; Wellendorph, P.; Hoeg, S.; Pedersen, M. H. F.; Brauner-Osborne,
H.; Martiny, L.; Froelund, B.; Clausen, R. P. J. Med. Chem. 2010, 53, 6506.
7. Pignataro, L.; Carboni, S.; Civera, M.; Colombo, R.; Piarulli, U.; Gennari, C.
Angew. Chem., Int. Ed. 2010, 49, 6633.
8. 8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,20]bipyridinyl-4H,6H-5-oxa-2,3,10b-triaza-
benzo[e]azulene (9): pTSA (5 mg) was added to a solution of compound 7
(100 mg, 0.36 mmol) in xylene (5 ml) and heated at 140 °C for 18 h. The
mixture was cooled and purified by column chromatography on silica gel
loading using EtOAc and eluting with MeOH and NH4OH in CH2Cl2 (5:0.5:95) to
give compound 9 as an off white solid (82 mg, 65%). 1H NMR (400 MHz,
CD3OD): d = 1.97 (m, 2H), 2.09 (m, 2H), 2.98 (m, 2H), 3.17 (m, 1H), 4.32–4.40
(m, 4H), 4.64 (s, 2H), 6.59 (m, 1H), 6.64 (m, 1H), 7.39 (m, 1H), 7.45 (m, 1H),
7.56–7.61 (m, 2H), 8.17 (m, 1H). Anal. Calcd for C20H20ClN5Oꢂ0.27CH2Cl2: C,
60.14; H, 5.11; N, 17.30. Found: C, 60.19; H, 5.17; N, 17.31.
References and notes
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9. 8-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1,20]bipyridinyl-4-yl)-5,6-dihydro-
4H-2,3,5,10b-tetraaza-benzo[e]azulene (12): 1H NMR (400 MHz, CD3OD):

D. M. Beal et al. / Tetrahedron Letters 52 (2011) 5913–5917
5917
d = 2.00 (m, 2H), 2.27 (m, 1H), 2.58 (m, 1H), 3.11 (s, 3H), 3.36 (m, 1H), 3.62 (m,
2H), 4.21 (m, 4H), 4.40 (m, 1H), 4.55 (m, 1H), 7.00 (m, 1H), 7.44 (m, 1H), 7.88
(m, 2H), 7.92 (m, 2H), 8.06 (m, 1H). APCI MS m/z 395 [MH]+. Anal. Calcd for
15. Ben-Haida, A.; Colquhoun, H. M.; Hodge, P.; Raftery, J.; White, A. J. P.; Williams,
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16. 8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,20]bipyridinyl-4-yl)-4H,6H-5-thia-2,3,10b-
triaza-benzo[e]azulene-5,5-dioxide (20): 1H NMR (400 MHz, CDCl3): d = 1.80 (m,
1H), 2.20 (m, 1H), 2.30 (m, 1H), 2.82 (m, 1H), 3.03 (m, 2H), 3.95 (m, 1H), 4.10
(m, 2H), 4.16 (m, 1H), 4.25 (m, 1H), 4.40 (m, 1H), 4.80 (m, 1H), 6.65 (m, 2H),
7.41 (m, 1H), 7.51 (m, 1H), 7.70 (m, 2H), 8.20 (m, 1H). APCI MS m/z 452 [MNa]+.
17. 8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,20]bipyridinyl-4-yl)-4H,6H-5-thia-2,3,10b-
triaza-benzo[e]azulene-5-oxide (21): 1H NMR (400 MHz, CDCl3): d = 1.55 (m,
1H), 1.75 (m, 1H), 2.20 (m, 1H), 2.30 (m, 1H), 2.82 (m, 1H), 3.03 (m, 2H), 3.18
(m, 1H), 3.28 (m, 1H), 3.90 (m, 1H), 4.22 (m, 1H), 4.42 (m, 1H), 5.02 (m, 1H),
6.60 (m, 1H), 6.65 (m, 1H), 7.40 (m, 1H), 7.45 (m, 1H), 7.60 (m, 2H), 8.18 (m,
1H). APCI MS m/z 436 [MNa]+.
C
21H23ClN6ꢂ0.33CH2Cl2: C, 44.37; H, 5.53; N, 14.53. Found: C, 44.30; H, 5.52; N,
14.65.
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4H-2,3,5,10b-tetraaza-benzo[e]azulene (12): To a solution of the thioamide 16
(80 mg, 0.35 mmol) in butan-1-ol (5 ml) was added hydrazide
2 (78 mg,
0.35 mmol) and the mixture heated to 100 °C for 20 h. The reaction mixture
was evaporated under reduced pressure and the residue was purified by
column chromatography on silica gel loading and eluting with MeOH and
NH4OH in CH2Cl2 (10:1:90) to give compound 12 as a brown foam (90 mg,
65%). 1H NMR (400 MHz, CDCl3): d = 2.00 (m, 4H), 2.45 (s, 3H), 2.96 (m, 2H),
3.15 (m, 2H), 3.36 (m, 1H), 3.64 (m, 2H), 4.36 (m, 2H), 6.58 (m, 1H), 6.65 (m,
1H), 7.32 (m, 1H), 7.46 (m, 1H), 7.52 (m, 2H), 8.18 (m, 1H). APCI MS m/z 395
[MH]+.
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