A rapid synthetic method of pyridobenzodiazepines

Article abstract of DOI:10.1007/s11164-010-0135-4

A new one-pot Bischler-Napeiralski type cyclization reaction between pyridine-1,2-diamines and various carboxylic acids with PPA as catalyst to prepare pyridobenzodiazepines is proposed. In the new synthetic route, the reaction time is only one-third of t

Full text of DOI:10.1007/s11164-010-0135-4

Res Chem Intermed (2010) 36:253–258
DOI 10.1007/s11164-010-0135-4
A rapid synthetic method of pyridobenzodiazepines
•
Fuqiang Shi Xu Bai Qun Dang Long Zhang
•
•
Received: 20 November 2009 / Accepted: 27 January 2010 / Published online: 12 March 2010
Ó Springer Science+Business Media B.V. 2010
Abstract A new one-pot Bischler–Napeiralski type cyclization reaction between
pyridine-1,2-diamines and various carboxylic acids with PPA as catalyst to prepare
pyridobenzodiazepines is proposed. In the new synthetic route, the reaction time is
only one-third of the methods reported. The synthetic strategy provides an efficient
way to prepare novel structurally diversified heterocyclic compounds of pyr-
idobenzodiazepine family with potential pharmaceutical or biological activities.
Keywords Pyridobenzodiazepines ꢀ Cyclization ꢀ PPA ꢀ Catalyst ꢀ
Bischler–Napeiralski reaction
Heterocyclic compounds are always considered privileged structures in medicinal
chemistry due to their various biological effects. Pyridobenzodizepine derivatives,
as the prototypical privileged substructures, possess high biological and pharma-
cological activities [1]. For example, 5,11-dihydro-benzo[e]pyrido[2,3-b][1,4]dia-
zepin-6-ones has diverse therapeutic activities including inhibition of HIV-1 reverse
transcriptase and muscarinic receptor inhibition. Pirenzepine (1, Fig. 1), prototyp-
ical the M1 selective muscarinic antagonist, is currently marketed as an antiulcer
drug providing safe and unproblematic treatment of duodenal ulcers and gastritis for
F. Shi (&) ꢀ L. Zhang (&)
Jilin Provincial Engineering Laboratory for the Complex Utilization of Petroresource and Biomass,
2055 Yanan St., Changchun, 130012 Jilin, People’s Republic of China
e-mail: shifq@yahoo.com.cn
L. Zhang
e-mail: zhanglongzhl@163.com
X. Bai ꢀ Q. Dang
The Center for Combinatorial Chemistry and Drug Discovery, Jilin University, 75 Haiwai St.,
Changchun, 130012 Jilin, People’s Republic of China
123

254
F. Shi et al.
H
N
O
H
N
O
H
N
O
N
N
N
N
N
N
N
O
O
N
N
H
N
Et2
N
3
1
H
2
N
N
N
N
N
N
Cl
N
N
H
N
N
H
5
4
Fig. 1 Some pyridobenzodizepine derivatives with biological and pharmacological activities
many years; AF-DX 116 (2) is the inhibitor of cardio (M2) selective muscarinic
receptor, which shows in vitro a 10-fold higher affinity for receptors of heart than
for those of the cortex (M1); [2–4] Nevirapine (3), the first non-nucleoside inhibitors
of HIV-1 RT, is employed in the treatment of AIDS and AIDS-related complex
(ARC) [5–9]. Moreover, as clozapine-like analogs, 8-chloro-6-(40-methyl-l-piper-
azinyl)-11H-pyrido[2,3-b] [1,4] benzodiazepine (4) and 8-methyl-6-(40-methyl-1-
piperaziny1)-11H-pyrido[2,3-b][1,4] benzodiazepine (5) showed the behavioral
features for neuroleptics [10, 11]. Pyridobenzodizepine derivatives have been
extensively studied as potential agents to modulate activities of the central nervous
system and vasopressin V2 receptor [12, 13].
Recently, we reported the synthesis of C6-aryl and alkyl substituted pyr-
idobenzodiazepines, which relied on Bischler–Napeiralski-type cyclization reac-
tions as the key transformation step, and the reaction conditions of four equivalents
of POCl3 in refluxing acetonitrile were identified for the conversion of pyridines 8
(or 9) to pyridobenzodiazepines 10 (or 11), However, this method requires a long
reaction time [14]. The reaction scheme (1) is shown below.
Here, we report a more effective method of ready access to pyridobenzodiaze-
pines with various carbon-derived substituents at the 6-position of the central
heterocycle core.
R1
Y
R1
Y
R4
R4-COOH
N
NH2
NO2
Cl
X
Y
X
R3
POCl3/CH3CN
N
R2
X
N
R2
R3
6, X=CH , Y=N
7, X=N , Y=CH
8, X=CH , Y=N
9, X=N , Y=CH
10, X=CH , Y=N
11, X=N , Y=CH
Scheme 1 Efficient alternative route to pyridobenzodiazepine
123

A rapid synthetic method of pyridobenzodiazepines
255
Experimental section
General considerations
All commercial reagents were used as received without additional purification.
Melting points were uncorrected. Mass spectra and HPLC (ELSD) data were
recorded on an Agilent 1100 LC/MS-ELSD (Altech) system using a 4.6 9 50 mm
column (5 lm) with a linear gradient of 30–90% (v/v) acetonitrile–water with
0.035% trifluoroacetic acid (TFA) over 5 min with a flow rate of 3.5 mL/min.
Analytical TLC was performed using 2.5 9 5 cm plates coated with a 0.25-mm
thickness of silica gel GF254. Column chromatography was performed using silica
1
gel G (200–300 mesh). All H NMR spectra (300 or 500 MHz) are reported as
follows: chemical shifts in ppm downfield from TMS as internal standard (d scale)
and CDCl3 as the solvent. Multiplicities are indicated as the following: multiplicity
[br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and
coupling constant (Hz)]. All 13C NMR spectra (75 or 125 MHz) were determined
with complete proton decoupling and reported in ppm.
New synthetic route of pyridobenzodiazepine (10)
The synthetic scheme (2) of pyridobenzodiazepine (10) proposed is shown below.
In the new synthetic route, PPA is exployed as the catalyst to speed the reaction.
The preparation of 2-substituted pyridines 8 which is starting material for the
proposed synthetic route to pyridobenzodiazepines, is prepared from 2-chloro-3-
nitropyridine (6) as depicted in [14].
PPA (0.75 mmol, 254 mg), precursors 8 (0.5 mmol) and acid (0.75 mmol) were
dissolved in POCl3 (5 mL). After heated at 95 °C in an oil bath for due time, the
mixture was poured into ice-water (20 mL) and treated with 5 N aqueous NaOH to
pH 9–10, then extracted with EtOAc (3 9 20 mL). The combined organic phase
was washed with saturated NaHCO3 and brine, dried with anhydrous Na2SO4,
concentrated in vacuo, and purified by flash chromatography with petroleum ether/
EtOAc (10:1, v/v) as eluent to afford products 10. Various pyridobenzodiazepines
prepared are shown below.
11-Methyl-6-phenylpyrido[2,3-b][1,4]benzodiazepine (10a). Yellow solid, yield:
88%, mp 109.0–110.7 °C. 1H NMR (CDCl3, 300 MHz): d 8.09 (d, J = 3.0 Hz, 1H),
7.77 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.42–7.47 (m, 4H), 7.15 (d,
J = 8.1 Hz, 1H), 7.01–7.06 (m, 3H), 3.35 (s, 3H). 13C NMR (CDCl3, 75 MHz): d
170.6, 156.0, 155.0, 144.5, 140.2, 137.0, 135.1, 131.8, 131.0, 130.3, 129.5, 128.6,
127.9, 122.6, 119.6, 118.4, 35.5. ES-MS: 286.1 [(M ? H?)].
R
Scheme 2 The synthetic
scheme of pyridobenzodiazepine
N
N
NH2
N
R-COOH
PPA/POCl3
95oC
N
8
10
123

256
F. Shi et al.
11-Methyl-6-(40-methoxyphenyl)pyrido[2,3-b][1,4]benzodiazepine (10b). Yel-
1
low solid, yield: 92%, mp 152.0–154.3 °C. H NMR (CDCl3, 300 MHz): d 8.07
(dd, J = 4.8 Hz, 1.8 Hz, 1H), 7.72–7.77 (m, 2H), 7.54 (dd, J = 7.5 Hz, 1.8 Hz,
1H), 7.44 (td, J = 7.2 Hz, 1.8 Hz, 1H), 7.10–7.16 (m, 2H), 6.99–7.04 (m, 2H),
6.90–6.95 (m, 2H), 3.87 (s, 3H), 3.34 (s, 3H). 13C NMR (CDCl3, 75 MHz): d 170.1,
161.6, 156.0, 155.1, 144.2, 137.3, 134.9, 132.8, 131.8, 131.3, 131.1, 128.6, 122.6,
119.7, 118.4, 113.3, 55.3, 35.5. ES-MS: 316.1 [(M ? H?)].
11-Methyl-6-(30-methyl-phenyl)pyrido[2,3-b][1,4]benzodiazepine (10c). Yellow
1
solid, yield: 96%, mp 110.7–111.4 °C. H NMR (CDCl3, 300 MHz): d 8.10 (dd,
J = 4.8 Hz, 1.8 Hz, 1H), 7.63 (s, 1H), 7.59 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 7.42–7.51
(m, 2H), 7.29–7.33 (m, 2H), 7.15 (d, J = 8.1 Hz, 1H), 6.99–7.09 (m, 3H), 3.37 (s,
3H), 2.41 (s, 3H). 13C NMR (CDCl3, 75 MHz): d 171.0, 156.0, 155.1, 144.5, 140.4,
137.7, 137.1, 135.2, 131.9, 131.1, 130.0, 128.8, 127.9, 127.0, 122.7, 119.7, 118.4,
35.6, 21.4. ES-MS: 300.1 [(M ? H?)].
11-Methyl-6-(40-methyl-phenyl)pyrido[2,3-b][1,4]benzodiazepine (10d). Yellow
1
solid, yield: 86%, mp 170.5–171.5 °C. H NMR (CDCl3, 300 MHz): d 8.08 (dd,
J = 4.8 Hz, 1.8 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.55 (dd, J = 7.5 Hz, 1.8 Hz,
1H), 7.44 (td, J = 8.1 Hz, 1.8 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.14 (d, J =
8.1 Hz, 1H), 7.08 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 6.98–7.03 (m, 2H), 3.34 (s, 3H),
2.41 (s, 3H). 13C NMR (CDCl3, 75 MHz): d 172.0, 155.8, 155.0, 143.9, 141.6,
136.5, 136.4, 135.9, 132.6, 131.8, 130.0, 128.9, 128.2, 123.1, 119.8, 118.9, 35.9,
21.5. ES-MS: 300.0 [(M ? H?)].
11-Methyl-6-(20-methyl-phenyl)pyrido[2,3-b][1,4]benzodiazepine (10e). Yellow
1
solid, yield: 91%, mp 138.8–141.2 °C. H NMR (CDCl3, 300 MHz): d 8.12 (dd,
J = 4.8 Hz, 1.8 Hz, 1H), 7.57 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 7.51 (dd, J = 7.5 Hz,
1.8 Hz, 1H), 7.35–7.42 (m, 1H), 7.28–7.33 (m, 2H), 7.19–7.22 (m, 1H), 7.09 (d,
J = 7.8 Hz, 1H), 7.00–7.04 (m, 1H), 6.91 (td, J = 7.5 Hz, 0.9 Hz, 1H), 6.82 (dd,
J = 7.8 Hz, 1.8 Hz, 1H), 3.38 (s, 3H), 2.20 (s, 3H). 13C NMR (CDCl3, 75 MHz): d
172.8, 155.1, 155.0, 145.0, 141.3, 136.9, 136.2, 135.6, 132.0, 130.6, 130.3, 129.3,
129.1, 125.7, 123.1, 119.7, 118.2, 35.8, 19.8. ES-MS: 300.1 [(M ? H?)].
11-Methyl-6-(40-nitrophenyl)pyrido[2,3-b][1,4]benzodiazepine (10f). Yellow
1
solid, yield: 40%, mp 195.0–195.4 °C. H NMR (CDCl3, 300 MHz): d 8.27 (d,
J = 9.0 Hz, 2H), 8.15 (dd, J = 4.8 Hz, 1.8 Hz, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.60
(dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.49 (td, J = 7.5 Hz, 1.5 Hz, 1H), 7.17 (d, J = 8.1 Hz,
1H), 7.02–7.08 (m, 2H), 6.96 (dd, J = 7.8 Hz, 1.5 Hz, 1H), 3.36 (s, 3H). 13C NMR
(CDCl3, 75 MHz): d 168.6, 156.4, 154.8, 148.8, 146.1, 145.6, 136.6, 135.8, 132.5,
130.5, 127.8, 123.2, 123.1, 119.9, 119.0, 35.7. ES-MS: 331.0 [(M ? H?)].
11-Methyl-6-(40-fluorophenyl)pyrido[2,3-b][1,4]benzodiazepine (10g). Yellow
1
solid, yield: 75%, mp 155.0–155.8 °C. H NMR (CDCl3, 300 MHz): d 8.10 (dd,
J = 4.8 Hz, 1.8 Hz, 1H), 7.78 (dd, J = 8.7 Hz, 5.4 Hz, 2H), 7.55 (dd, J = 7.8 Hz,
1.5 Hz, 1H), 7.43 (t, J = 6.6 Hz,), 7.00–7.17 (m, 6H), 3.35 (s, 3H). 13C NMR
(CDCl3, 75 MHz): d 169.6, 164.3 (d, J = 249.53 Hz), 156.1, 155.1, 144.7, 137.0,
136.5, 135.2, 132.1 (d, J = 24.08 Hz), 131.7 (d, J = 9.15 Hz), 131.0, 128.4, 122.8,
119.8, 118.6, 115.1 (d, J = 21.75 Hz), 35.6. ES-MS: 304.0 [(M ? H?)].
6,11-Dimethylpyrido[4,5-b][1,4]benzodiazepine (10h). Yellow solid, yield: 72%,
1
mp 119.3–119.7 °C. H NMR (CDCl3, 300 MHz): d 8.06 (d, J = 3.6 Hz, 1H),
123

A rapid synthetic method of pyridobenzodiazepines
257
7.32–7.42 (m, 3H), 6.95–7.08 (m, 3H), 3.30 (s, 3H), 2.59 (s, 3H). 13C NMR (CDCl3,
75 MHz): d 171.4, 155.2, 154.6, 144.3, 136.7, 134.6, 131.6, 130.4, 128.2, 123.0,
119.6, 118.1, 35.6, 28.0. ES-MS: 224.2 [(M ? H?)].
11-Methyl-6-(pyridin-30-yl)pyrido[2,3-b][1,4]benzodiazepine (10i). Yellow solid,
1
yield: 84%, mp 119.2–120.8 °C. H NMR (CDCl3, 300 MHz): d 8.95 (s, 1H), 8.70
(d, J = 3.9 Hz, 1H), 8.12 (d, J = 6.3 Hz, 2H), 7.57 (dd, J = 7.8 Hz, 1.5 Hz, 1H),
7.47 (dd, J = 8.4 Hz, 4.5 Hz, 1H), 7.37 (dd, J = 8.1 Hz, 4.8 Hz, 1H), 7.16 (d,
J = 8.1 Hz, 1H), 7.03–7.07 (m, 3H), 3.36 (s, 3H). 13C NMR (CDCl3, 125 MHz): d
167.4, 155.3, 154.1, 145.0, 149.7, 144.2, 135.9, 135.9, 135.0, 134.5, 131.5, 129.7,
126.9, 122.1, 118.9, 117.9, 34.7, 28.7. ES-MS: 287.1 [(M ? H?)].
11-Methyl-6-(thiophen-30-yl)pyrido[4,5-b][1,4]benzodiazepine (10j). Yellow solid,
yield: 58%, mp 154.2–155.4 °C. 1H NMR (CDCl3, 500 MHz): d 8.08 (dd,
J = 5.0 Hz, 2.0 Hz, 1H), 7.66 (dd, J = 5.5 Hz, 1.5 Hz, 1H), 7.60 (dd, J = 3.0 Hz,
1.0 Hz, 1H), 7.53 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.45 (td, J = 7.0 Hz, 1.5 Hz, 1H),
7.35 (dd, J = 5.5 Hz, 3.5 Hz, 1H), 7.31 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.14 (d,
J = 8.5 Hz, 1H,), 7.06 (td, J = 7.0 Hz, 1.0 Hz, 1H), 7.01 (dd, J = 8.0 Hz, 5.0 Hz,
1H), 3.33 (s, 3H). 13C NMR (CDCl3, 125 MHz): d 165.9, 156.2, 155.3, 144.6,
143.5, 137.5, 135.4, 132.2, 130.8, 130.0, 129.1, 128.7, 125.8, 123.0, 120.1, 118.8,
35.8. ES-MS: 292.0 [(M ? H?)].
11-Methyl-6-(furan-20-yl)pyrido[2,3-b][1,4]benzodiazepine (10k). Yellow solid,
yield: 53%, mp 191.4–193.3 °C. 1H NMR (CDCl3, 300 MHz): d 8.09 (d,
J = 3.6 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J = 6.6 Hz, 1H), 7.41–7.49 (m, 2H),
7.07–7.16 (m, 2H), 7.02 (dd, J = 7.8 Hz, 5.1 Hz, 1H), 6.77 (d, J = 3.3 Hz, 1H),
6.54 (d, J = 1.5 Hz, 1H), 3.32 (s, 3H). 13C NMR (CDCl3, 75 MHz): d 159.9, 156.2,
154.9, 152.8, 145.7, 144.6, 137.0, 135.4, 132.2, 130.1, 127.1, 122.9, 119.9, 118.5,
117.3, 111.9, 35.5. ES-MS: 276.1 [(M ? H?)].
Results and discussions
To test the universality of the new preparation method under this condition, a small
pyridobenzodiazepine library was prepared by reaction of 11 carboxylic acids with
pyridine 8 and the results are summarized in Table 1. In general, various carboxylic
acids such as aromatic, aliphatic, and heterocyclic acids reacted well with precursors
8 to give 6,11-disubstituted pyridobenzodiazepines 10a–10k in moderate to high
yields. The outcome and rule of reaction are similar under the existence of POCl3
and acetonitrile, but the reaction time is only one-third of the previous procedure.
Especially, 2H-pyrrole-3-carboxylic acid and furan-2-carboxylic acid do not
perform by previous procedure, while giving higher yields by employing the new
route.
Conclusion
A rapid route to synthesize pyridobenzodizepines in one-pot Bischler–Napeiralski-
type cyclization reaction between pyridine-1,2-diamines and various carboxylic
123

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F. Shi et al.
Table 1 The comparison of preparation conditions of the proposed route with that in [14]
Entry
Pdt
R
Reference [14]
Time (h)
New route
Time (h)
Yield (%)
Yield (%)
1
10a
10b
10c
10d
10e
10f
10g
10h
10i
Ph
30
33
26
28
85
85
36
7
91
96
90
82
93
74
63
72
–
12
12
12
12
12
40
12
2.5
84
10
14
88
92
96
86
91
40
75
72
84
58
53
2
p-MeO–C6H4
m-Me–C6H4
p-Me–C6H4
o-Me–C6H4
p-NO2–C6H4
p-F–C6H4
CH3
3
4
5
6
7
8
9
Pyridin-3-yl
Thiophen-3-yl
Furan-2-yl
–
10
11
10j
10k
24
–
62
–
acids was developed. The current strategy provides new methodologies to enable the
exploration of biological activities for this class of heterocycles.
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