VOL. 39 APRIL, 209–212
JOURNAL OF CHEMICAL RESEARCH 2015
RESEARCH PAPER 209
A two-step continuous flow synthesis of 4-nitropyridine
Zhidong Wana, Zheng Fanga, Zhao Yangb, Chengkou Liua, Jiajia Gua and Kai Guoc,d*
aSchool of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, P.R. China
bCollege of Pharmacy, China Pharmaceutical of University, Tongjiaxiang No. 24, Nanjing 211816, P.R. China
cCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, P.R. China
dState Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing 210009, P.R. China
4-Nitropyridine, a key intermediate in medicinal products, was successfully prepared from pyridine N-oxide in a two-step -approach.
Pyridine N-oxide was nitrated with HNO3 and H2SO4 to give 4-nitropyridine N-oxide, followed by reaction with PCl3 to give the final product.
The continuous flow methodology was used to minimise accumulation of the highly energetic and potentially explosive nitration product
to enable the safe scale-up of 4-nitropyridine with no 2-nitropyridine by-product. By employing continuous extraction in the nitration step
and applying the optimised conditions, a throughput of 0.716 kg 4-nitropyridine product per day from pyridine N-oxide with 83% yield and
high selectivity in a continuous flow system was achieved.
Keywords: 4-nitropyridine, continuous flow system, nitration reactions, continuous extraction, microreaction technology
4-Nitropyridine can be an excellent starting material for the
preparation of pyridine derivatives, which are important
synthetic intermediates for new pesticides and medicines.1,2 The
pathway to 4-nitropyridine via the pyridine N-oxide involves
two steps,3, 4 including a nitration step and a reduction step.
The nitration reaction is a key step and with the use of HNO3 –
H2SO4 mixed acid as the nitration reagent is usually exothermic
and at higher temperatures, which can result in polynitration.5, 6
In addition, the scale-up of the synthesis of nitration products
in batch can lead to the formation of hot spots and, as a further
result, to the formation of undesired by-products and low
productivity due to inefficient mixing and poor heat transfer.7
Employing microreaction technology is one way to increase
the process safety and efficiency of fast highly exothermic
reactions.8-17 In recent years, microreaction technology
has emerged as a useful approach for the synthesis of fine
chemicals and key pharmaceutical intermediates where
either the poor selectivity of the product is inevitable in
batch or there are situations where the reactions are highly
exothermic.11-13 Compared with reactions in batch mode, one
major advantage of the microreactor is the submillimetre
dimensions of flow structures, which permits chemical
reactions to proceed with higher quality, on account of highly
efficient mixing and excellent heat absorption. As a result,
reaction temperature control can be accurate and thus avoid
hot spots often the cause of the formation of by-products,
and with respect to traditional batch procedures, hazardous
reactions can be handled more safely. Some of the important
initial studies include the following: (1) Ducry and Roberge5
have reported the nitration of phenol in continuous flow with
a glass reactor (channel width <0.5 mm and 2.0 mL internal
volume). The nitration of phenol in a microreactor yields a
better fraction of the mononitration product of phenol and,
as a further consequence, a reduction in the formation of
polymerised products. (2) The nitration of toluene using HNO3
–H2SO4 mixed acid (T=65 °C, t=15 min, conversion of more
than 98%), and with Ac2O/H2SO4/HNO3 as the nitrating agent
(T=300 °C, t=70 min, conversion of 100%) in the CYTOS
microreaction system was reported by Gerhard et al.14 [NOTE:
There may be significant additional safety implications
when AC2O and HNO3 are involved together in a nitrating
agent.15-17](3) The nitration of 3-alkylpyrazoles on 100 g scale
with a productivity of 0.82 g h-1 was developed by Pelleter and
Renaud18 as a continuous process. (4) Kulkarni et al.19,20 have
reported the nitration of benzaldehyde and salicylic acid in
continuous flow in equipment involving syringe pumps and
self-made apparatus.
We now describe how all of these challenges have been
overcome by careful selection of the reaction conditions, we
report an efficient two-step flow synthesis of 4-nitropyridine
(1). The investigated method includes two reaction steps: at
first, pyridine N-oxide (2) was converted into 4-nitropyridine
N-oxide (3) by heating it with a mixture of fuming nitric
acid and conc. sulfuric acid. Secondly, the reaction of
4-nitropyridine N-oxide (3) with PCl3 led to the formation of
4-nitropyridine (1) (Scheme 1).
Experimental
Batch model: The experiments were carried out not only in batch
mode but also in continuous mode. To confirm our approach, the
initial experiments in batch mode were mainly conducted based
3,
4
on the literature
which provides us with information about
the reaction rate (which was monitored by HPLC), especially an
opportunity to check whether the reaction is homogeneous.
Continuous flow procedure: An overview of the two-step
continuous flow process is depicted in Scheme 2. The reaction takes
place by pumping pyridine N-oxide (2, 20 g, 0.212 mol) dissolved
in conc.H2SO4 (200 mL) through one HPLC pump (TBp 5010T,
Shanghai Tanto Biotech Co., Ltd. flow rate: 0.23 mL min-1), and
the fuming HNO3 (40 mL, 0.96 mol) in H2SO4(200 mL) through a
N
O2
N
O2
HN
H
O3 / 2SO4
P l
C 3
N
O
N
O
N
1
2
3
( )
( )
( )
Scheme 1 Reaction sequence for the preparation of 4-nitropyridine.
* Correspondent. E-mail: guok@ njtech.edu.cn