Efficient and Scalable Process for Synthesis of 5-Nitro-7-azaindole

Article abstract of DOI:10.1021/acs.oprd.5b00181

A simple and straightforward methodology for the synthesis of 5-nitro-7-azaindole 6 has been developed using metal-free cycloisomerization of 5-nitro-3-trimethylsilanylethynyl-pyridin-2-ylamine 18. Large-scale applicability of this newly developed method was successfully demonstrated on multikilogram scale to obtain 5-nitro-7-azaindole 6 in consistent yield and purity.

Full text of DOI:10.1021/acs.oprd.5b00181

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Efficient and Scalable Process for Synthesis of 5-Nitro-7- azaindole
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Prasanna V. Bhat, Ravindra T. Dere, Ravikumar S., Rama Mohan Hindupur and
Hari N. Pati*
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Process Chemistry Division, Advinus Therapeutics Ltd., 21 & 22 Phase II, Peenya
Industrial Area, Bangalore ꢀ 560058, Karnataka, India.
*Corresponding author:
Hari N. Pati
Process Chemistry Division,
Advinus Therapeutics Ltd.,
21 & 22 Phase II, Peenya Industrial Area,
Bangalore ꢀ 560058, Karnataka, India.
eꢀmailꢀ hari.pati@advinus.com
Tel No: (+91)9900212096
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TOC Graphic:
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TMS-acetylene
Cu(I)
Si
O2N
KI/KIO4
H2SO4
O2N
I
O2N
PdCl2(PPh3)2
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TEA/DMF
N
NH2
N
NH2
N
NH2
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morpholine/H2O
O2N
N
H
N
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ABSTRACT: A simple and straightforward methodology for the synthesis of 5ꢀnitroꢀ7ꢀ
azaindole 6 has been developed using metal free cycloisomerization of 5ꢀnitroꢀ3ꢀ
trimethylsilanylethynylꢀpyridinꢀ2ꢀylamine 18. Largeꢀscale applicability of this newly
developed method was successfully demonstrated on multikilogram scale to obtain 5ꢀ
nitroꢀ7ꢀazaindole 6 in consistent yield and purity.
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Keywords: Azaindole, trimethylsilylacetylene, morpholine, cycloisomerization.
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INTRODUCTION
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Azaindole constitutes one of the most important heterocyclic subunits in many
pharmaceutically active compounds. Despite the usefulness in many drug candidates and
molecules for various applications, no truly convenient process for its largeꢀscale
production has been published till day. The extensive use of azaindole intermediates in
pharmaceutically active compounds has stimulated the synthetic developments for their
synthesis. 5ꢀNitroꢀ7ꢀazaindole 6 is one of the key azaindole intermediate used for
compound possessing anticancer activity.1 Ready availability and cost of this key
intermediate is a major concern. Not many reports are available in the literature for its
synthesis. Frequently employed approach for azaindole synthesis begins with substituted
pyridines which subsequently build a pyrrole ring to produce azaindole. However,
electronꢀdeficient nature of the pyridine ring influence the electronics of the ꢀꢀsystem in
such a way that many classical indole formation methods either do not work or result in
poor yields when directly applied to the synthesis of azaindoles and its analogues. For
example, orthoꢀlithiation of aniline and its derivatives is a versatile method for the
synthesis of indoles. In particular, method developed by Hands et al2 is a convenient
method for the synthesis of 7ꢀazaindole analogues. In this method 2ꢀtertꢀ
butylcarbonylaminoꢀ3ꢀmethylpyridine 1 was dilithiated with nꢀBuLi at ꢀ60˚C to obtain
dark red solution of lithiated dianion 2 which on quenching with DMF and HCl lead to 7ꢀ
azaindole 4 in 81% yield (Scheme 1a). But the same strategy did not work for the
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synthesis of 5ꢀnitroꢀ7ꢀazaindole
6
when 5ꢀnitroꢀ2ꢀtertꢀbutylcarbonylaminoꢀ3ꢀ
methylpyridine 5 reacted with nꢀBuLi at ꢀ60˚C (Scheme 1b).
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H
O
1a
Li
N
5.5M HCl
reflux
n-BuLi
DMF
5.5M HCl
N
N
N
NH
N
N
NH
H
4
9
1
2
O
O
Li
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O
1b
O2N
n-BuLi
O2N
DMF
5.5M HCl
reflux
N
NH
5.5M HCl
N
N
5
O
6
H
No reaction
1c
Br
Br
Br
DMF-DMA
n-BuLi
N
N
N
N
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N
7
NH2
8
H
N
1d
O2N
O2N
O2N
n-BuLi
DMF-DMA
N
N
NH2
N
11
N
N
6
H
10
N
No reaction
1e
H2
Raney Ni
HNO3
H2SO4
H2SO4
N
N
N
N
N
N
H
4
13
NO2
12
H
O2N
Pd-C
H2N
O2N
H2
Dowtherm A
N
Pd-C
EtOH
N
N
N
N
H
N
6
H
14
H
15
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1f
TMS-acetylene
Cu(I)
PdCl2(PPh3)2
Si
5
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7
8
O2N
KI/KIO4
H2SO4
O2N
I
O2N
TEA/DMF
N
NH2
N
NH2
N
NH2
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microwave
190oC, 30min
O2N
N
N
H
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Scheme 1: Reported synthetic routes to 5-nitro-7-azaindole 6
Recently, simple cost effective synthesis of 5ꢀhalogenated azaindole 9 was reported by
two step process without using heavy metal catalyst (Scheme 1c).3 We attempted this
method to synthesize 5ꢀnitroꢀ7ꢀazaindole 6 using commercially available 3ꢀmethylꢀ5ꢀ
nitroꢀpyridinꢀ2ꢀylamine 10 in place of its 5ꢀhalogen analogue (Scheme 1d). 3ꢀmethylꢀ5ꢀ
nitroꢀpyridinꢀ2ꢀylamine 10 was converted to N,NꢀdimethylꢀN'ꢀ(3ꢀmethylꢀ5ꢀnitroꢀpyridinꢀ
2ꢀyl)ꢀformamidine 11 by reacting with dimethylformamide dimethylacetal in good yield.
However, cycloisomerization reaction on N,NꢀdimethylꢀN'ꢀ(3ꢀmethylꢀ5ꢀnitroꢀpyridinꢀ2ꢀ
yl)ꢀformamidine 11 using similar conditions did not offer corresponding 5ꢀnitroꢀ7ꢀ
azaindole 6. We explored different bases such as lithium diisopropylamide, lithium
bis(trimethylsilyl) amide, sodium bis(trimethylsilyl) amide, sodium methoxide for this
cycloisomerization reaction. However, none of the bases afforded desired 5ꢀnitroꢀ7ꢀ
azaindole 6. It may be due to the presence of nitro group at 5ꢀposition on pyridine which
alters the reactivity due to its electron withdrawing nature. Another reliable and general
method for indole formation is Fischer cyclization. However, it often gives poor results
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when pyridinyl hydrazines are used as substrates owing to the requirement of drastic
reaction conditions.1b, 1c Other methods reported in the literature for the synthesis of 5ꢀ
nitroꢀ7ꢀazaindole 6 suffer from various disadvantages and are not suitable for largeꢀscale
production. In 1959, Robison et al4 reported first synthesis of 5ꢀnitroꢀ7ꢀ azaindole 6 using
7ꢀazaindoline 12 (Scheme 1e) which was prepared by reduction of 7ꢀazaindole 4. In this
procedure, 7ꢀazaindoline 12 behaves like a substituted 2ꢀaminopyridine which undergoes
nitration reaction at 5ꢀposition of the pyridine ring without accompanying reaction at the
3ꢀposition. Nitration using a mixture of fuming HNO3 and concentrated H2SO4 at ꢀ5°C
first gives 1ꢀnitroꢀ7ꢀazaindoline 13 which on treatment with concentrated H2SO4 gives
desired 5ꢀnitroꢀ7ꢀazaindoline 14. 5ꢀNitroꢀ7ꢀazaindoline 14 on catalytic hydrogenation
using Dowtherm offered 5ꢀnitroꢀ7ꢀazaindole 6 in 21% overall yield. This process raises
safety concerns and hence not suitable for largeꢀscale production of 5ꢀnitroꢀ7ꢀazaindole 6.
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In recent times, reports on synthesis of 5ꢀnitroꢀ7ꢀazaindole 6 mentioned microwave
irradiation and metal mediated cycloisomerization reaction conditions.5 Orthoaminohalo
pyridines can be coupled with a terminal alkyne by Sonagashira reaction in high yields
which on intramolecular cyclization gives required azaindole derivatives. Pearson et al6
adopted this strategy and reported microwave assisted CuI catalysed synthesis of 5ꢀ
aminoꢀ7ꢀazaindole 6 in overall 66% yield and demonstrated its use up to 10 gm scale
synthesis (Scheme 1f). However, isolation and purification of 5ꢀnitroꢀ7ꢀazaiondole 6 was
found to be problematic and 5ꢀaminoꢀ7ꢀazaindole 15 was isolated in 4 steps. We found
this procedure promising for scaleꢀup as it involved iodination of relatively inexpensive
2ꢀaminoꢀ5ꢀnitropyridine 16 followed by Sonogashira coupling of 3ꢀiodoꢀ5ꢀnitroꢀpyridinꢀ
2ꢀylamine 17 with trimethylsilyl acetylene to get terminal alkyne which on
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intramolecular cyclization provided required compound. In this context, to generate a
large quantity of 5ꢀnitroꢀ7ꢀazaindole 6 we decided to develop a robust process for its
synthesis in multikilogram scale without performing chromatographic purifications.
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ANTECEDENTS AND RESULTS
In the beginning, commercially available 2ꢀaminoꢀ5ꢀnitropyridine 16 was iodinated at 3ꢀ
position using Batkowski procedure7 to obtain 3ꢀiodoꢀ5ꢀnitroꢀpyridinꢀ2ꢀylamine 17 in
90% yields. During iodination reaction, it was observed that excessive evolution of iodine
resulted in the condensation of iodine on condenser surface leading to complications in
the reaction. To overcome this problem, we performed a few experiments by varying
equivalents of KI and duration of KI addition. It was observed that evolution of iodine
was comparatively less when 0.8 equivalent of KI was added dropwise for about 2 h. The
reaction mixture was refluxed over 1h after KI addition to ensure complete consumption
of the starting material. After the completion of the reaction, pH was adjusted to 7ꢀ8 by
adding NaHCO3 solution. The precipitated yellow solid was collected by filtration in
excellent purity (>98% area by HPLC). After iodination reaction, next task that
confronted us was to synthesize 5ꢀnitroꢀ3ꢀtrimethylsilanylethynylꢀpyridinꢀ2ꢀylamine 18
using Sonogashira coupling.8 As per the reported method,5 a mixture of 3ꢀiodoꢀ5ꢀnitroꢀ
pyridinꢀ2ꢀylamine 17, triethyl amine (25.0 vol) in tetrahydrofuran (4.0 vol) and N, Nꢀ
diethylacetamide (8.0 vol) was degassed for 30 min. Bis(triphenylphosphino)
palladium(II) chloride (0.02 eq.) and copper (I) iodide (0.02 eq.) were added followed by
the addition of trimethylsilylacetylene (1.5 eq.) in dropwise manner to obtain 5ꢀnitroꢀ3ꢀ
trimethylsilanylethynylꢀpyridinꢀ2ꢀylamine 18 in 81% yield after column chromatography.
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However, isolation and purification of the compound was problematic. To overcome this
problem, we reacted 3ꢀiodoꢀ5ꢀnitroꢀpyridinꢀ2ꢀylamine 17 with trimethylsilylacetylene
(1.2 eq.) in triethyl amine (4.0 vol) and DMF (1.0 vol) in the presence of
bis(triphenylphosphino) palladium(II) chloride (0.02 eq.) and CuI (0.02 eq.) to get the
required product by simple filtration in good yield. Encouraged by these results, we
decided to optimize the molar equivalents of the catalysts bis(triphenylphosphino)
palladium(II) chloride and copper(I) iodide to minimize the residual metal contamination
in the product. Two different sets of the experiments were carried out at 5.0 g scale by
varying amount of bis(triphenylphosphino) palladium(II) chloride from 0.001 to 0.02
equivalents and keeping amount of copper(I) iodide fixed to 0.02 equivalents. The
results of these reactions are summarized in Table 1. It was found that the yield of the
product was not affected at all when the equivalents of bis(triphenylphosphino)
palladium(II) chloride was reduced to 0.002 (entries 1ꢀ6). However, further reduction in
the molar equivalents resulted in the lower yield of the product even in 5 h stirring (entry
7). In the second set, same experiments were carried out by keeping the amount of
bis(triphenylphosphino) palladium(II) chloride constant (0.002 equivalents) and varying
the equivalents of copper(I) iodide from 0.006 to 0.02 equivalents. It is evident from the
data summarized in Table 1 that Sonogashira coupling reaction offered compound 5ꢀ
nitroꢀ3ꢀtrimethylsilanylethynylꢀpyridinꢀ2ꢀylamine 18 in 89% yield after 3 h of reaction
using catalysts bis(triphenylphosphino) palladium(II) chloride and copper(I) iodide in
0.002:0.008 molar ratio. It is noteworthy to mention here that the precipitated compound
5ꢀnitroꢀ3ꢀtrimethylsilanylethynylꢀpyridinꢀ2ꢀylamine 18 is readily isolated by filtration.
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This optimized method yielded product 5ꢀnitroꢀ3ꢀtrimethylsilanylethynylꢀpyridinꢀ2ꢀ
5
6
ylamine 18 in excellent yield with high purity (>98 % area by HPLC).
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Table 1: Results of Sonogashira reaction carried out at different concentration of
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Pd(PPh3)2Cl2 and CuI
b
Pd(PPh3)2Cl2
Yield(%)a
Entry
CuI
Time
Sonogashira coupling using different molar equivalents of Pd(PPh3)2Cl2
1
2
3
4
5
6
7
0.02
0.01
0.02
0.02
0.02
0.02
0.02
0.02
0.02
3
3
3
3
3
3
5
85
84
85
87
86
84
68
0.008
0.006
0.004
0.002
0.001
Sonogashira coupling using different molar equivalents of CuI
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0.002
0.002
0.002
0.002
0.002
0.002
0.02
0.01
3
3
3
4
2
4
86
87
89
65
74
88
9
10
11
12
13
0.008
0.006
0.008
0.008
a Isolated yield.
b We have tested only palladium catalyst bis(triphenylphosphino) palladium(II) chloride.
After successfully optimizing first two steps, the main obstacle was to carry out
cycloisomerization reaction to get final compound 6. Going through various
cycloisomerization reactions reported in the literature, it occurred to us that the
cycloisomerization reaction should be possible under basic conditions other than reported
microwave irradiation. As a first attempt, we initiated cycloisomerization reaction trials
of acetylene derivative 18 using catalytic copper (I) iodide in DMF, without using basic
reagent. But these trials failed to give the required product. Under this cycloisomerization
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reaction conditions mainly desilylated compound was isolated. After failing to cyclize
compound 18 using Cu(I) in DMF, we carried out further cycloisomerization reaction
trials using various bases and results are summarized in Table 2. When we attempted
reaction using weak inorganic bases like NaHCO3, K2CO3 (entry 4 and 6) and organic
bases like triethylamine (entry 1, 2 and 3) could not activate the cyclization reaction
whereas with strong bases like potassium tertꢀbutoxide in tertꢀbutyl alcohol we were able
to get required compound 5ꢀnitroꢀ7ꢀazaindole 6 in 50% yield. Similar reaction using 1M
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tetraꢀnꢀbutyl ammonium fluoride (TBAF) in THF at 80°C afford required product in 52%
yield after 24h (entry 8). However, the quality and purity of the obtained product 6 was
not good and required column chromatography for its purification. Reactions using
hindered base 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) in toluene afford the required
product in 57% yield (Table 2) (entry 7). On the other hand, reaction using organic bases
like pyrrolidine, morpholine gave the required product with 60% and 65% yields,
respectively (entry 9 and 10).
Table 2: Results of cyclization reactions carried out using different bases
Yield(%)a
No reaction
No reaction
No reaction
No reaction
Entry
Base
Et3N
Et3N
Et3N
K2CO3
Solvent
toluene
THF
Time (h)
Temp (˚C)
110
1
2
3
4
24
24
24
24
65
MeCN
80
toluene
110
5
6
t BuOK
NaHCO3
DBU
t BuOH
toluene
toluene
THF
24
24
24
24
24
24
80
90
50
No reaction
7
110
65
57
52
60
65
8
TBAF
pyrrolidine
morpholine
9
pyrrolidine
pyrrolidine
90
10
90
a Isolated yield.
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Moderateꢀtoꢀgood yields were achieved for a variety of bases like DBU, pyrrolidine,
morpholine. However, the methodology presented clear limitations especially in terms of
applicability. After significant efforts, it appeared that a further improvement of these
conditions was not straightforward. To develop a more general method suitable for largeꢀ
scale synthesis we tried to find some solvent if that added to pyrrolidine or morpholine,
could help the cyclization and enhance the interaction of the substrates. In our quest to
develop scalable method, we carried out cycloisomerization reaction using
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pyrrolidine/water (1:1) molar ratio at 90°C over 24h and isolated required product in 67%
yield. Similar reaction using morpholine/water (1:1) molar ratio at 90°C gave compound
6 in 73% yields after 24h. Among the different bases and solvents used for cyclization
morpholine/water system emerged as the best of choice.
Before proceeding with largeꢀscale synthetic efforts, we optimized the molar equivalents
of the morpholine and water for optimal yield. Experiments were performed on 10.0 g
scale at 90°C over 24h using different molar equivalents of the morpholine and water.
The results of these experiments are presented in Table 3. Results showed that the yield
of 5ꢀnitroꢀ7ꢀazaindole 6 increased from 73% to 88% on increasing the molar equivalents
of morpholine and water to 10:2 molar ratio (entry 6) further increase in molar
equivalents of morpholine did not result in improvement of the yield beyond 88% (entry
6). It is noteworthy to mention here that 5ꢀnitroꢀ7ꢀazaindole 6 was isolated from the
reaction by filtration as yellow solid in high purity (> 97% area by HPLC). Using this
synthetic route we were able to synthesize 5ꢀnitroꢀ7ꢀazaindole 6 without using column
chromatography and heavy metals for cycloisomerization. This improved synthetic
protocol to produce 5ꢀnitroꢀ7ꢀazaindole 6 was found to be superior to all other protocols
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reported in the literature in terms of applicability and handling of the reaction conditions.
However, we have not tried this synthetic route for the synthesis of substituted 5ꢀ or 6ꢀ
azaindoles.
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Table 3: Results of cyclization reaction carried out at different molar ratio of
morpholine and water
Yield(%)a
Entry
Base/Solvent
pyrrolidine/H2O
morpholine/H2O
morpholine/H2O
morpholine/H2O
morpholine/H2O
morpholine/H2O
morpholine/H2O
Time (h) Molar ratio
1
24
24
24
24
24
24
24
1:1
1:1
67
73
75
79
85
88
88
2
3
6:4
4
7:3
5
8:2
6
10:2
10:3
7
a Isolated yield.
To validate the largeꢀscale applicability of this improved synthesis of 5ꢀnitroꢀ7ꢀazaindole
6, all three synthetic steps were performed in triplicate on 1.0 kg scale (Scheme 2). The
reaction progress was monitored by TLC and HPLC. The results of scaleꢀup batches are
presented in Table 4.
TMS-acetylene
Cu(I)
Si
O2N
KI/KIO4
O2N
I
O2N
PdCl2(PPh3)2
N
NH2
N
NH2
N
NH2
16
morpholine/H2O
O2N
N
H
N
6
Scheme 2: An improved synthesis of 5-nitro-7-azaindole 6
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Table 4: Results of scale-up batches
5
6
7
8
HPLC puritya
(%)
Entry
Batch size Output (kg)
(kg)
Yield(%)
Step-1: Iodination
9
1
2
3
1
1
1
1.70
1.68
1.71
89.47
88.42
90.00
98.40
98.10
98.05
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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Step-2: Sonogashira coupling
4
1
1
1
0.779
0.774
0.765
87.01
88.32
86.93
98.03
98.12
98.00
5
6
Step-3:Cyclization
7
8
9
1
1
1
0.610
0.608
0.609
88.01
87.80
87.90
97.81
97.67
97.89
a
% area by HPLC
CONCLUSION
In conclusion, we have developed a simple and straightforward methodology for the
synthesis of 5ꢀnitroꢀ7ꢀazaindole 6, which involves metal free cycloisomerization of 5ꢀ
nitroꢀ3ꢀtrimethylsilanylethynylꢀpyridinꢀ2ꢀylamine 18. This method is safe, economical,
easy to scaleꢀup and the first of its kind for the synthesis 5ꢀnitroꢀ7ꢀazaindole 6. Largeꢀ
scale applicability of this newly developed method successfully demonstrated by carrying
out reactions on multikilogram scale to obtain 5ꢀnitroꢀ7ꢀazaindole 6 in consistent yield
and purity.
EXPERIMENTAL SECTION
All reagents and solvents were used as received. Starting materials were commercially
available. Reactions were performed under anhydrous conditions unless noted otherwise.
Reactions were followed by TLC analysis on Merck TLC aluminium sheets with silica
gel 60 F254. The purities of compounds were assessed by analytical HPLC. LC/MS
analysis was run on an Agilent 1200 MSD system with an Inertsil ODSꢀ3V (250 *4.6
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mm, 5 µm particle size). Chromatograms for electrospray ionization (ESI) positive and
negative base peak intensity and a UV total absorption chromatogram from 220ꢀ300 nm
were generated, and values for m/z are given; generally, only ions that indicate the parent
mass are reported, and unless otherwise stated, the value quoted is (M + H)+ for positiveꢀ
ion mode and (M ꢀ H)ꢀ for negativeꢀion mode. Nuclear magnetic resonance (1H NMR and
13C NMR) spectra were recorded on a 400 MHz (VARIAN AVANCE 400 AS)
spectrometer. Chemical shift data for the proton and carbon resonances were reported in
parts per million (δ) relative to internal standards (CH3)4Si (δ 0.0). All coupling constants
(J) are given in Hz. The purities of the final compounds were determined with Agilent
1200 HPLC system.
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Preparation of 3-iodo-5-nitro-pyridin-2-amine 17: To a solution of 5ꢀnitropyridinꢀ2ꢀ
amine 16 (1.0 kg, 7.1 mol) in H2SO4 (2M, 12L) was added potassium periodate (0.6 kg,
2.5 mol) portionwise (100 g lot in 5 min interval) at room temperature in 30 minutes. The
reaction mixture was refluxed and aqueous potassium iodide (1.2 kg, 7.1 mol) was added
dropwise over 2h. The reaction mixture was refluxed for 1.5h. Reaction mixture was
cooled to room temperature and was neutralized by solid sodium bicarbonate. To the
reaction mass sodium thiosulphate was added with stirring. Yellow colour solid separated
out and was filtered dried to get 3ꢀiodoꢀ5ꢀnitroꢀpyridinꢀ2ꢀamine 17 (1.68 kg, 88.42%).
1HNMR (400MHz, DMSOꢀd6): δ 7.15 (bs, 2H), 8.56 (d, J = 2.8 Hz, 1H), 8.84 (d, J = 2.8
Hz, 1H); MS (ESI): m/z = 266.1 [M + H]+; HPLC purity : 98.8% area (254.0 nm).
Preparation of 5-nitro-3-(2-trimethylsilylethynyl) pyridin-2-amine 18: A mixture of
3ꢀiodoꢀ5ꢀnitropyridinꢀ2ꢀamine 17 (1.0 kg, 3.7 mol), triethyl amine (4.0 L), N, Nꢀ
dimethylformamide (1.0 L) was degassed for 30 minutes with nitrogen. Copper (I) iodide
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(0.05 kg, 0.03 mol) and bis(triphenylphosphino) palladium(II) chloride (0.05 kg, 0.007
mol) was added to the reaction mass. The reaction mixture was stirred and
trimethylsilylacetylene (0.43 kg, 4.4 mol) was added dropwise. The reaction mixture was
stirred for 3h. Yellow colour solid separated out was filtered, washed with water (2.0 L)
and dried to get 5ꢀnitroꢀ3ꢀ(2ꢀtrimethylsilylethynyl) pyridinꢀ2ꢀamine 18 (0.77 kg,
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1
87.01%). HNMR (400MHz, DMSOꢀd6): δ 0.25 (s, 9 H), 7.15 (bs, 2H), 8.18 (d, J = 3.2
Hz, 1H), 8.85 (d, J = 2.4 Hz, 1H) ); MS (ESI): m/z = 236.4 [M + H]+; HPLC purity : 98.6
% area (254.0 nm).
Preparation of 5-nitro-7-azaindole 6: To
a
solution of 5ꢀnitroꢀ3ꢀ(2ꢀ
trimethylsilylethynyl) pyridinꢀ2ꢀamine 18 (1.0 kg, 4.25 mol) in water (230 mL, 12.75
mol) was added morpholine (3.7 kg, 42.5 mol). The mixture was stirred at 90°C for 24h.
Then the mixture was cooled to room temperature and diluted with water (2.0 L) and
yellow colour solid was separated out was filtered, washed with water and dried to get 5ꢀ
1
nitroꢀ7ꢀazaindole 6 (0.6 kg, 87.8%). HNMR (400MHz, DMSOꢀd6): δ 6.74 (d, J = 3.2
Hz, 1H), 7.71 (s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 9.10 (d, J = 2.4 Hz, 1H), 12.49 (s, 1H);
MS (ESI): m/z = 164.2 [M + H]+; HPLC purity : 99.1 % area (254.0 nm).
ACKNOWLEDGEMENT
The authors thank Advinus Therapeutics Ltd., Bangalore for providing the facilities and
financial support.
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REFERENCES
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