Process improvements for the preparation of insecticide clothianidin

Article abstract of DOI:10.14233/ajchem.2014.15801

This article describes the process improvements for the preparation of the insecticide clothianidin 1. (Z)-1-Methyl-N-nitro-5-propyl-1,3,5-triazinan-2- imine (9) which was obtained by Mannich reaction of (Z)-1-methyl-2- nitroguanidine (5) n-Propylamine an

Full text of DOI:10.14233/ajchem.2014.15801

Asian Journal of Chemistry; Vol. 26, No. 10 (2014), 2815-2819
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15801
Process Improvements for the Preparation of Insecticide Clothianidin
*
QIN WANG, YI WU, KUNYAN WANG, YANXUE SUN, HONGJUN ZHU , JUAN YU and CHAOHANG XU
Department of Applied Chemistry, College of Science, Nanjing University of Technology, Jiangsu Key Laboratory of Industrial Water-
Conservation & Emission Reduction, Nanjing 211816, P.R. China
*
Corresponding author: Tel./Fax: +86 25 83172358; E-mail: zhuhj@njut.edu.cn
Received: 20 May 2013; Accepted: 16 September 2013;
Published online: 10 May 2014;
AJC-15125
This article describes the process improvements for the preparation of the insecticide clothianidin 1. (Z)-1-Methyl-N-nitro-5-propyl-
,3,5-triazinan-2-imine (9) which was obtained by Mannich reaction of (Z)-1-methyl-2-nitroguanidine (5) n-Propylamine and 37 %
1
aqueous formaldehyde solution in 97 % yield. Intermediate 9 was electrophilic substituted with 2-chloro-5-(chloromethyl)thiazole (4) in
the presence of acid-binding agent to give (E)-1-[(2-chlorothiazol-5-yl)methyl]-3-methyl-N-nitro-5-propyl-1,3,5-triazinan-2-imine (10)
in 90 % yield. The target compound 1 was given by the hydrolyzation of 10 in 88 % yield. The optimized conditions for the preparation
of clothianidin were obtained via screening the reaction temperature, reaction time, acid-binding and solvents in three steps. The overall
yield of clothianidin 1 was up to 77 %.
Keywords: Insecticide, Clothianidin, Mannich reaction, Optimization.
Evidence in chronological order, synthetic routes of
clothianidin 1 are divided into two generations. The first-gene-
ration synthetic method for clothianidin 1 has three process
routes (Scheme-I). The first, clothianidin 1 was obtained by
INTRODUCTION
Neonicotinoids have been attracted with wide attention
in both industry and academia because of their outstanding
1
insecticidal activity . Neonicotinoid insecticides have been
electrophilic substitution of (2-chlorothiazol-5-yl)methanamine
(
rapidly developed worldwide for controlling insects because
of their high potency, low mammalian toxicity, broad insec-
ticidal spectra and good systemic properties. Neonicotinoids,
which interact with nicotinic acetylcholine receptors (nAChR),
have a higher affinity for the insect receptor than for the
9
2) and S-methyl-N-methyl-N'-nitroisothiourea (3) in 67 % .
The second, 2-chloro-5-(chloromethyl)thiazole (4) was electro-
philic substitution with N-methyl-N'-nitroguanidine (5) in
the presence of catalytic agent to give clothianidin (1) in 43 %
10,11
yield . The third, (Z)-1-((2-chlorothiazol-5-yl)methyl)-2-
methyl-3-nitroisothiourea (7) was obtained by the electrophilic
substitution of compound 4 and S-methyl-N-nitroisothiourea
2-5
mammalian receptor and are relatively safe toward mammals
and aquatic life. So it has been made in a significant progress
in the cloning of receptor sub-units, their expression in vivo
and the pharmacology of the ligand-gated ion channel
(
6), then was aminomethylation with methylamine to afford
12,13
clothianidin 1 in 58 % yield . The first-generation synthetic
method is associated with several drawbacks, as summarized
below:
6
-8
complexes . Clothianidin 1 was the major active ingredient
of the neonicotinoid class to reach market. So, most research
on neonicotinoids has so far been performing clothianidin, as
the representative. In this work, an improved synthesis method
was introduced for the insecticide clothianidin (E)-1-(2-chloro-
(a) Various steps (steps b, c and d) requires purification
by SiO column chromatography, (b) Yield of compound 1 is
2
low, (c) Preparation of 1 via isothiourea 3, 7 is undesirable
from the point of view of environmental protection,
5
-thiazolylmethyl)-3-methyl-N-nitroguanidine (1, Fig. 1).
Further, the second-generation synthetic method was
constructed via alkylation of the nitroimino-hexahydro-triazine
NO2
N
14
(
9) with heteroaryl-methyl chlorides (10) (Scheme-II) . This
S
method also has some shortcomings, viz., (a) Step c requires
chromatographic separation, (b) Low reproducibility of the
electrophilic substitution reaction might be a significant issue
for large-scale synthesis and (c) Low yield in each step.
N
H
NH
Cl
1
CH3
N
Fig. 1. Structure of compound 1

2
816 Wang et al.
Asian J. Chem.
NO2
N
SCH3
S
S
a
N
H
NH
Cl
NH2
Cl
O N
2
N
C
+ CH SH
3
+
CH3
N
N
NHCH3
3
2
1
(67%)
NO2
N
S
NH2
S
Cl
Cl
b
Cl
N
H
NH
HCl
+
O2N
N
C
+
CH3
N
NHCH3
N
4
5
1
(43%)
SCH3
S
c
Cl
Cl
O N
2
N
C
+
N
NH2
6
4
NO2
NO
2
N
N
S
S
Cl
N
H
SCH
3
d
Cl
N
H
NH
CH3
+
CH SH
3
N
N
7
1 (58%)
Reagents and conditions: (a) EtOH, reflux, 6 h, SiO column chromatography, (b) CsCl (cat.), PTC, DMF, 25 °C, 24 h, SiO column chromat-
2
2
ography, (c) CsCl (cat.), PTC, EtOH, 50 °C, 18 h, SiO column chromatography, 75.00 % yield, (d) K CO , CH NH , DMF, 40 °C, 12 h, SiO
2
2
3
3
2
2
column chromatography, 77.33 %.
Scheme-I: First-generation synthetic method
NO2
N
N
N
NO2
NO2
c
N
N
HetCH Cl
a
b
HN
2
C
C
H CS
3
NH2
H N
2
NH
CH3
8
5
(94%)
9
(92%)
NO2
NO2
NH
N
N
S
S
N
NH
d
Cl
N
H
1
3
Cl
5
N
N
CH
3
N
1
(86%)
10 (90%)
S
Cl
Het =
N
Reagents and conditions: (a) CH NH , EtOH, 80 °C, 16 h, then cool to 25 °C, (b) n-PrNH , EtOH, 37 % aqueous formaldehyde solution,
3
2
2
5
0 °C, 5 h, then cool to 25 °C, (c) HetCH Cl, K CO , DMF, 50 °C, 16-20 h, SiO column chromatography, (d) aq 1N HCl, EtOH, 25 °C, 24h
2 2 3 2
Scheme-II: Second generation synthetic method

Vol. 26, No. 10 (2014)
Process Improvements for the Preparation of Insecticide Clothianidin 2817
heptane (20 mL). The wet cake was dried under vacuum at
Under those circumstances, the development of a suitable
process for 1 with higher overall yield and without SiO
2
column
40-45 °C afford the desired product 1 (Tables 4 and 5) as a
10
1
chromatography purification was demanded. Our efforts has
been focusing on designing a safe and efficient synthesis
method of 1 that incorporates the following key characteristics:
white solid. m.p. 174-175 °C (Lit. 174-175 °C); H NMR
(500 MHz, DMSO-d ): 9.11 (bs, 1H), 7.94 (bs, 1H), 7.59 (s,
1H), 4.50 (bd, J = 4.75 Hz, 2H), 2.81 (bd, J = 4.75Hz, 3H);
6
13
(
1) group-protecting technology, (2) optimized conditions.
C NMR (DMSO-d
28.3.
6
, 100 MHz): δ 157.3, 150.7, 139.9, 37.2,
During this research, N-methyl-N'-nitroguanidine (5) could
be purchased as a commercially available compound. The
process improvements for the preparation of the insecticide
clothianidin 1 was introduced in this work.
RESULTS AND DISCUSSION
Optimization for Mannich reaction: The (Z)-1-methyl-
N-nitro-5-propyl-1,3,5-triazinan-2-imine (9) was prepared by
Mannich reaction of N-methyl-N'-nitroguanidine (5), n-
propylamine and 37 % aqueous formaldehyde solution. The
optimized conditions for preparation of compound 9 were
obtained via screening the temperatures, time and solvents.
Firstly, several tests were performed to optimize the
temperatures (Table-1). When the reaction time was 6 h, using
methanol or ethanol as solvent, temperatures screening was
done among 45, 50, 55 °C and 60 °C (entries 1, 2, 3 and 4; 5,
EXPERIMENTAL
Starting materials, solvents and reagents were purchased
from commercial sources and were used as received without
further purification. Reactions were monitored by reversephase
HPLC on a DIONEX chromatograph. HPLC purity refers to
chromatographic area percentage. NMR spectra were recorded
on a Bruker 400 spectrometer and the chemical shifts were
reported in ppm with the solvent resonance as the internal
1
13
standard ( H, CDCl
3 6 3
: 7.26; DMSO-d : 2.50. C, CDCl : 77.0,
6
, 7 and 8). Results showed that 55 °C (entry 3) gave the best
results in comparison with other temperatures such as 45 °C
entries 1, 5), 50 °C (entries 2, 6) and 60 °C (entries 4, 8). As
DMSO-d : 39.5).
6
Synthesis of (Z)-1-methyl-N-nitro-5-propyl-1,3,5-
triazinan-2-imine (9): A mixture of the N-methyl-N'-nitro-
guanidine (5) (0.1 mol), n-propylamine (0.1 mol) and 15.2 mL
of 37 % aqueous formaldehyde solution (0.2 mol) in methanol
(
expected, better results would be obtained by modifying
reaction temperatures.
(50 mL) were heated to certain temperature for some time.
The reaction progress was monitored by HPLC until the starting
TABLE-1
TEMPERATURES, TIME AND SOLVENTS SCREENING
material was consumed (≤ 0.50 %). After being cooled to
a
FOR MANNICH REACTION
0 °C, the products precipitated out of the reaction mixture.
Filtration afforded the products in pure form (Table-1). m.p.
Solvent
100 mL)
HPLC area (%)
Entry Temp. (°C) Time (h)
(
9
5
1
0
1
5-86 °C (Lit. 84-86 °C); H NMR (300 MHz, DMSO-d
8
9
6
): δ
1
2
3
4
5
6
7
8
9
45
50
55
60
45
50
55
60
55
55
55
55
55
55
55
55
55
55
55
55
55
55
6
6
Methanol
Methanol
Methanol
Methanol
Ethanol
95.62
95.89
97.57
96.01
92.43
93.14
94.10
93.65
97.26
93.72
97.49
94.01
97.53
94.07
95.33
93.64
93.70
93.51
90.79
91.77
84.60
72.30
4.38
4.11
2.43
3.99
7.57
6.86
5.90
6.35
2.74
6.28
2.51
5.99
2.47
5.93
4.67
6.36
6.30
6.49
9.21
8.23
15.40
27.70
.24 (bs, 1H), 4.31 (s, 2H), 4.29 (s, 2H), 2.86 (s, 3H), 2.57 (t,
13
J = 2H), 1.42-1.54 (m, 2H), 0.88 (t, J = 6, 3H). C NMR (100
MHz, DMSO-d ): δ 155.1, 67.7, 59.4, 51.8, 33.9, 20.4, 11.4.
6
6
6
Synthesis of (E)-1-[(2-chlorothiazol-5-yl)methyl]-3-me-
thyl-N-nitro-5-propyl -1,3,5-triazinan- 2-imine (10): A so-
lution of (Z)-1-methyl-N-nitro-5-propyl-1,3,5-triazinan-2-
imine (9) (15.3 g, 0.075 mol), base (0.186 mol) in a solvent
6
6
Ethanol
6
Ethanol
6
Ethanol
24
24
18
18
7
Methanol
Ethanol
(
100 mL) was added over 20 min to the slurry of 2-chloro-5-
chloromethyl) thiazole (4) (15.3 g, 0.075 mol) in typically
10
(
11
Methanol
Ethanol
solvent (50 mL) at < 30 °C. The reaction progress was moni-
tored by HPLC until consumption (20-24 h) of starting mate-
rial (≤ 0.50 %) and then cooled to 10 °C. After the filtration
and the concentration, the crude product was recrystallized
from methanol to afford compounds 10 (Tables 2 and 3). m.p.
12
13
Methanol
Ethanol
14
15
16
17
18
19
7
5
Methanol
Ethanol
5
4
Methanol
Ethanol
1
0
1
8
7
4-85 °C (Lit. 84-85 °C); H NMR (300 MHz, DMSO-d
.69 (s, 1H), 4.71 (s, 2H), 4.44 (d, 4H), 2.86 (s, 3H), 2.44 (t, J
7.35 Hz, 2H), 1.34 (tq, Jt = Jq = 6 Hz, 2H), 0.78(t, J = 7.33
6
): δ
4
2
Methanol
Ethanol
=
20
21
2
13
Hz, 3H). C NMR (100 MHz, DMSO-d
41.5, 68.5, 64.4, 51.9, 43.1, 34.7, 20.2, 11.2.
Synthesis of (E)-1-(2-chloro-5-thiazolylmethyl)-3-
6
): δ 156.0, 151.6,
0.25
0.25
Methanol
Ethanol
22
1
a
Reaction conditions: N-methyl-N’-nitroguanidine (0.2 mol), n-propyl-
amine (0.2 mol), 37% aqueous formaldehyde solution (0.4 mol).
methyl-N-nitroguanidine (1): Certain quantity of acid was
added to a solution of compound 10 (0.015 mol) in MeOH
(
30 mL) over 20 min at 21-25 °C. The reaction mixture was
Furthermore, reaction time screening was done using 0.25,
2, 2.5, 4, 5, 6, 7, 18 and 24 h (Table-1, entries 3, 7, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22) at 55 °C, the
experimental results were showed in Table-1 and the optimal
reaction time was obtained at 6 h.
stirred at 21-25 °C until raw material 10 cannot be further
consumed by HPLC analysis. Then cooled to 0 °C, the crysta-
llized product out of the reaction mixture. The reaction mixture
was then filtered and the product cake was washed with n-

2
818 Wang et al.
Asian J. Chem.
Besides the temperature and the reaction time, the effect
H
3
PO
4
, H SO
2
4
3 3
, CH COOH, CF COOH and methanesulfonic
of solvent was also investigated. Compared with ethanol, the
experimental results showed that the methanol had a higher
yield (entry 3).
acid (MSA)) were investigated (Table-4). The results indicated
that diluted HCl (entry 1), is more suitable used as the hydro-
lysis catalyst. Furthermore, the influence of different normalities
(0.4, 0.6, 0.8, 1.0, 1.2, 1.4 and 1.6 N) of HCl on the yield of 1
was tested at 20-25 °C (Table-5). The data showed that the
reaction with 0.4 N (entry 1) or 1.6 N (entry 7) HCl for 24 h
gave lower yield and when the reaction was carried out using
1 N HCl for 24 h, optimum results were obtained (entry 4).
In the second-generation synthesis, intermediate 9 was
prepared in 92 % yield. However, we improved the yield to
97.57 % with some modifications of synthetic conditions. The
reaction was stirred in the methanol at 55 °C for 6 h, which
results in the highest yield of compound 9 (as shown in Table-
1
, entry 3).
Optimization of the reaction conditions of electrophilic
TABLE-4
ACID SELECTION FOR THE PREPARATION OF 1
a
substitution:Against the second-generation synthetic method,
a robust, production process for 10 is desired with a higher
overall yield that does not require column chromatography
purification.After the filtration and the concentration, the crude
product was recrystallized from methanol to afford compound
HPLC area (%)
Entry
Acid(30 mL), normality
HCl, 1
1
10
1
2
3
4
5
6
88.20
64.70
70.30
57.80
45.10
46.50
11.80
35.30
29.70
42.20
54.90
53.50
H
H
3
PO
SO
4
, 3
, 2
2
4
1
0 in pure form. The reaction of (Z)-1-methyl-N-nitro-5-
CH
CF
MSA, 1
3
COOH, 1
propyl-1,3,5-triazinan-2-imine 9 and 2-chloro-5-(chloro-
methyl)thiazole 4 was tested in the presence of various kinds
of bases (Table-2). Most of the tested bases gave the complete
conversion of 10, except in the cases of sodium hydroxide
and potassium hydroxide, which could produce a large quantity
of unknown impurities. The results indicated that NaOH and
KOH (entries 4 and 5) could lead the fast decomposition
reaction. The order of the substitution reaction rate was as
3
COOH, 1
a
Reaction conditions: (E)-1-((2-chlorothiazol-5-yl)methyl)-3-methyl-
N-nitro-5- propyl- 1,3,5-triazinan-2-imine (0.038 mol), MeOH, 20-25
°C, 24 h, then cool to 0 °C
TABLE-5
INFLUENCE OF HCL QUANTITY ON YIELD OF 1
a
HPLC area (%)
Unknown
impurity
follows: K CO
2
3
> NaCO
3
> KHCO . Further, solvent screening
3
Entry HCl (mole ratio)
1
10
was done among THF, toluene, DMF, acetonitrile, n-butyl
alcohol and ethanol (Table-3). Results showed that DMF was
the best one.
1
2
3
4
5
6
7
0.4
0.6
0.8
1.0
1.2
1.4
1.6
57.80
64.70
76.30
88.20
85.14
79.56
70.47
37.65
30.52
19.03
7.31
4.55
4.78
4.67
4.49
TABLE-2
BASES SCREENING FOR ELECTROPHILIC
7.03
7.83
8.92
11.52
17.96
a
SUBSTITUTION STEP
11.57
a
HPLC area (%)
Reaction conditions: (E)-1-((2-chlorothiazol-5-yl)methyl)-3-methyl-
N-nitro-5- propyl-1,3,5-triazinan-2-imine (0.038 mol), MeOH (30
mL), 20-25 °C, 24 h, then cool to 0 °C
Entry
Bases
KHCO3 12.90
9
4
10
79.03
90.01
80.20
0
Uknown impurity
1
2
3
4
5
7.17
4.36
9.30
0.29
0.04
0.90
0.30
K CO3
2
4.70
10.10
0.70
NaCO3
0.40
Conclusion
KOH
99.01
99.71
NaOH
0.25
0
An efficient three-step process was developed for the
synthesis of clothianidin and the overall yield of the target
product was increased from 66.90 to 77.00 % under the
optimized conditions. The present work also described the
procedure for the preparation of key intermediates such as
a
Reaction conditions: (Z)-1-methyl-N-nitro-5-propyl-1,3,5-triazinan-2-
imine (0.076 mol), 2-chloro-5-(chloromethyl)thiazole (0.091 mol),
DMF (100 mL), 50 °C, 20–24 h.
TABLE-3
SOLVENT SELECTION FOR THE PREPARATION OF 10
a
(
Z)-1-methyl-N-nitro-5-propyl-1,3,5-triazinan-2-imine (9) and
E)-1-((2-chlorothiazol-5-yl)methyl)-3-methyl-N-nitro-5-
(
propyl-1,3,5-triazinan-2-imine (10). Furthermore, effective
Entry
Solvents (100 mL)
THF
Conversion (% ; HPLC)
1
2
3
4
5
6
55.80
59.70
90.01
81.90
74.13
61.33
purification of product makes the process easier to scaling-
up.
Toluene
DMF
Acetonitrile
n-butyl alcohol
Ethyl alcohol
ACKNOWLEDGEMENTS
a
Reaction conditions: (Z)-1-methyl-N-nitro-5-propyl-1,3,5-triazinan-2-
imine (0.076 mol), 2-chloro-5-(chloromethyl)thiazole (0.091 mol), 50
C, 24 h
The authors thank the National Key Technology R&D
Program of the Ministry of Science and Technology
°
(
2011BAE06A07-04), the Technology R&D Program of
Jiangsu Province (BE2012363), the Postgraduate Innovation
fund of Jiangsu Province (2010, CX10B_178Z1) for financial
support. Thanks are also due to Jiankui Zhou, Jingjing Shen
and Chen Chen for helpful discussions.
Optimization of the reaction conditions of synthesis of
: To complete the synthesis of the target compounds 1, the
N-CH -N bonds should be cleaved in the compounds 10. The
hydrolysis abilities of different kinds of acids such as HCl,
1
2

Vol. 26, No. 10 (2014)
Process Improvements for the Preparation of Insecticide Clothianidin 2819
7
.
K. Matsuda, S.D. Buckingham, D. Kleier, J.J. Rauh, M. Grauso and
D.B. Sattelle, Trends Pharmacol. Sci., 22, 573 (2001).
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