Synthesis and green metric evaluation of 2-(chloromethyl)-3-methyl-4-(methylsulfonyl)pyridine

Article abstract of DOI:10.13005/ojc/330244

2-[[(2-pyridinyl) methyl] sulfinyl]-1H-benzimidazoles are the prominent motif's that belong to the class of prazoles. These are used in the treatment of gastroesophageal reflux disease (GERD) ulcers and other gastric acid related diseases. The present article describes the modified synthesis of 2-chloromethyl-4-methanesulfonyl-3-methyl pyridine (an intermediate utilized in the synthesis of Dexlansoprazole). The advantages of this modification involves (i) N-oxidation of 2,3-lutidine with catalytic quantity of RuCl₃ in presence of oxygen (ii) One pot synthesis of 2,3-dimethyl-4-(methylthio) pyridine-N-oxide using 30% NaSH, methyl iodide and tetra butyl ammonium hydroxide (iii) Oxidation of methythio pyridine-N-oxide with 30% H₂O₂ followed by N-deoxygenation with RuCl₃.H₂O to produce 2,3-dimethyl-4-(methylsulfonyl)pyridine (iv) Chlorination of the penultimate step using trichloroisocyanuric acid to obtain the desired 2-chloromethyl-4-methanesulfonyl-3-methyl pyridine. Furthermore, green metrics assessment was calculated for the above modified scheme based on the parameters viz., atom economy (AE), reaction mass efficiency (RME) and E-factor. It was observed that, in case of step 4 (oxidation of thiomethyl pyridine-N-oxide), the E-factor value is very less 3.2 which is indicative of less waste generation, when compared to the various steps that are involved in the synthesis.

Full text of DOI:10.13005/ojc/330244

ISSN: 0970-020 X
CODEN: OJCHEG
2017, Vol. 33, No. (2):
Pg. 930-936
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Synthesis and Green Metric Evaluation of
2-(Chloromethyl)-3-Methyl-4-(Methylsulfonyl)Pyridine
ROHIDAS GILBILE*,1,2, RAM BHAVANI2 and RITU VYAS1
1Department of Chemistry, Pacific Academy of Higher Education and Research,
Udaipur-313 024, Rajasthan, India.
2Green Evolution Laboratories, Wangapally Village, Nalgonda, 500 085,
Telangana State, India.
*Corresponding author E-mail: rohidasgilbile2017@gmail.com
http://dx.doi.org/10.13005/ojc/330244
(Received: March 14, 2017; Accepted: April 12, 2017)
ABSTRACT
2-[[(2-pyridinyl) methyl] sulfinyl]-1H-benzimidazoles are the prominent motif’s that belong to
the class of prazoles.These are used in the treatment of gastroesophageal reflux disease (GERD)
ulcers and other gastric acid related diseases.The present article describes the modified synthesis
of 2-chloromethyl-4-methanesulfonyl-3-methyl pyridine (an intermediate utilized in the synthesis of
Dexlansoprazole). The advantages of this modification involves (i) N-oxidation of 2,3-lutidine with
catalytic quantity of RuCl3 in presence of oxygen (ii) One pot synthesis of 2,3-dimethyl-4-(methylthio)
pyridine-N-oxide using 30% NaSH, methyl iodide and tetra butyl ammonium hydroxide (iii) Oxidation
of methythio pyridine–N-oxide with 30% H2O2 followed by N-deoxygenation with RuCl3.H2O to
produce 2,3-dimethyl-4-(methylsulfonyl)pyridine (iv) Chlorination of the penultimate step using
trichloroisocyanuric acid to obtain the desired 2-chloromethyl-4-methanesulfonyl-3-methyl pyridine.
Furthermore, green metrics assessment was calculated for the above modified scheme based on the
parameters viz., atom economy (AE), reaction mass efficiency (RME) and E-factor. It was observed
that, in case of step 4 (oxidation of thiomethyl pyridine-N-oxide), the E-factor value is very less 3.2
which is indicative of less waste generation, when compared to the various steps that are involved
in the synthesis.
Keywords:Atom economy, RME,E-Factor, Green metrics, Prazoles, Synthesis
INTRODUCTION
of the most expansively marketed drugs in the world.
2-[[(2-pyridinyl) methyl] sulfinyl]-1H-benzimidazoles
are the prominent motif’s that belong to the class
of prazoles. These are used in the treatment of
gastroesophageal reflux disease (GERD) ulcers
and other gastric acid related diseases.1 Some of the
examples of the proton pump inhibitors with pyridine
A prominent class of drugs that bring out
distinctive and enduring pharmacological effect by
reducing the gastric acid production are the Proton
pump inhibitors (PPIs). Due to their outstanding
efficacy and safety, these drugs are included in list

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GILBILE et al., Orient. J. Chem., Vol. 33(2), 930-936 (2017)
ring nucleus (Figure 1) that are the top selling classes is not solely sufficient to determine the material
of pharmaceuticals and have populated this area2 economy of the reaction, though it useful to choose
are omeprazole (1, Losec), rabeprazole (3, Aciphex), a synthetic pathway. A precise method to evaluate
pantoprazole (2, Protonix), lansoprazole (4, Prevacid) the material economy is the reaction mass efficiency
and dexlansoprazole (5). All these PPI drugs (API’s) (RME) which is the percentage of the mass of the
contain the distinguishing benzimidazole unit flanked reactants that remains in the product (Eq.2)14, 15. It is
with a sulfoxide substituent at the 2-position.
understood that in a chemical reaction/process, the
formation of the product requires, use of reactants
A new inclusion to the proton pump along with the additional required materials such
inhibitor (PPI) class is Lansoprazole, which is as solvents, catalysts and acids and bases used in
acceptable for the treatment of heartburn related the work-up. These are the essential material in the
with non-erosive gastroesophageal reflux disease process, though these materials does not appear
(GERD) and remedial for all grades of erosive in the balanced chemical equation. The Sheldon
16
esophagitis (EE) 3,4. Another prominent class of PPI E-factor, which is defined according to equation
is the ‘Dexlansoprazole (dex)’, it is a dextrorotatory (3), respectively, permits a best measurement of
enantiomer of lansoprazole that was developed by the material economy. The calculation of E factor
Takeda Pharmaceutical Co., Ltd and got approved is solely depends on mass (E factor) and presents
in 2009 by US Food and Drug Administration (FDA). a global standpoint and is calculated as the ratio of
Later on this drug (dex) was accepted by Canada and the total mass of all waste to the mass of the desired
Mexico in 2010 and 2011, respectively5.In the clinical product16. During the E-factor calculations, apart
administration, Dex exhibited lower elimination rate, from considering the amount of the by-products
excellent dominance in higher efficacy and less side (i.e amount of waste), it also take into consideration
effects than S-(-)-lansoprazole (levo)6.
of the amount of (i) non-reacting starting materials,
(ii) auxiliaries, (iii) catalysts or any additives such as
Evaluation of the greenness of chemical acids, bases, salts, (iv) solvents of the reaction or
processes is the outmost significance in green solvents required in the work-up (extraction, washing,
chemistry. In general, it is well known that in order separation, recrystallisation, chromatographic
to measure the efficiency of the process, it has to be support if not recycled, etc.). Sheldon17 has
first optimized and controlled.Managing the process suggested one exception during the calculation of
in green chemistry should be implicit as a choice to E-factor, as inclusion of water in the E-factor equation
select the greenest option. The improvement and leads to exceptionally high E-factor value (aqueous
application of measurable procedures allows us to waste stream), it is expelled from the calculation of
differentiate the greenness of existing solutions with E-factor.
newly developed ones.
Molecular weight of product
------------------------------------------------ X 100
Sum of all molecular weight of reactans
In the early 1990s, U.S. Environmental
(1)
AE =
Protection Agency, has introduced the concept of
green chemistry which is defined as ‘‘the utilization
of a set of principles that minimizes or eliminates
the use or production of unsafe substances in the
design, manufacture and application of chemical
products’’. An integrated set of twelve principles
was recognized in order to explicate ways to extend
environmentally friendly chemistry 7-10 along with
sustainable chemistry metrics.11-12 Thus the concept
of atom economy paved the way to green chemistry
by emphasizing the significance of the incorporation
of all the atoms in the reaction product13. Atom
economy (molecular weight ratio of the final
product divided by the sum of all reactants, Eq.1)
mass of product (g)
--------------------------------
sum of mass of reactants (g)
X 100
(2)
RME =
mass reactants - mass product
-----------------------------------
mass products
mass input materials - massproduct
------------------------------------
mass product
(3)
=
E factor =
Keeping in view of the importance of
prazole drugs and related pyridine intermediates,
we intend to describe here the modified synthesis of
2-chloromethyl-4-methanesulfonyl-3-methyl pyridine
(3)18 (an intermediate utilized in the synthesis of
Dexlansoprazole) and evaluate the green metrics

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GILBILE et al., Orient. J. Chem., Vol. 33(2), 930-936 (2017)
parameters such as atom economy (AE), reaction
mass efficiency (RME) and E-factor for the various
steps involved in the synthesis.
in the desired 4-chloro-2,3- dimethyl-pyridine-N-
oxide 3 in 49% yield. Nucleophillic substitution with
NaSH followed by alkylation with MeI in presence
of 40% tetra butyl ammonium hydroxide 23 resulted
in the formation of 2,3-dimethyl-4-(methylthio)
pyridine-N-oxide 4 in 85% yield. In this method,
the aqueous tetra-n-butyl ammonium hydroxide
solution (TBAOH) was applied as a strong base, as
a reaction medium and as a phase transfer catalyst.
Oxidation of methythio-pyridine 4 was achieved in
presence of 30% H2O224 (portion wise addition in
intervals of 2h, 6h and 10h) at 75oC for 24h gave
4-Methanesulfonyl-2,3-dimethyl-pyridine-1-oxide 5 in
85% yield. This method of oxidation with 30% H2O2
is measured as a highly atom-economic, solvent
and catalyst free oxidation. N-deoxygenation of 5
in presence of RuCl3x3H2O25 in acetonitrile at 85oC
for 1h resulted in the formation of 2,3-dimethyl-
4-(methylsulfonyl)pyridine 6 in 85% yield. This
method is mild, competent and avoidance of harsh
reagents and is of reasonably a broad scope for
the deoxygenation of N-oxides. Allylic chlorination
of 6 with trichloroisocyanuric acid26 in chloroform at
reflux for 1h gave the desired 2-(chloromethyl)-3-
methyl-4-(methylsulfonyl)pyridine 7 in 82% yield. As
trichloroisocyanuric acid (TCCA) is safe in handling
and due to its efficient expulsion of chlorine (for use
in reactions all three chlorine atoms are active) in
the chemical process, it is used as a chlorination
and oxidation reactions also on large scale. TCCA
is more atom economical and is also highly soluble
in organic solvents and is more economical, when
compared to N-Chlorosuccinamide (the most-used
N-haloamide), thus making it the better reagent for
large-scale use.
RESULTS AND DISCUSSIONS
The traditional method for the synthesis
of 2-chlromethyl-pyridine precursor are prepared
from the starting materials19,20viz., 2,3,5-trimethyl
pyridine, 2,3-dimethyl pyridine (for the synthesis
of omeprazole, rabeprazole, lansoprazole and
dexlansoprazole), which is nitrated in the 4th
position to form the 4-nitropyridine derivative. The
4- nitro pyridine precursor is treated with sodium
methoxide and acetic anhydride to generate
methoxide ion which replaces the nitro group. The
methyl group at the second position is converted
to the acetoxymethyl group using acetic anhydride.
This acetoxy methyl group in turn is hydrolysed and
chlorinated using thionyl chloride to generate the
2-chloromethyl pyridine precursor.
Synthesis of 2-chloromethyl-4-
methanesulfonyl-3-methyl pyridine 7, is depicted in
scheme-1 is the modified version of the previously
reported literature method18.N-oxidaton of 2,3-
lutidine in presence of 5 mol% of RuCl3X3H2O21
and bubbling of oxygen in dichloromethane at room
temperature for 8h yielded 2,3-Dimethyl-pyridine-
N-oxide 2 in 93% yield. This method of N-oxidation
of pyridine substrate catalyzed by ruthenium with
molecular oxygen as the prime oxidant, resulted in
the high yield under optimal reaction conditions.The
advantage of this method is (i) the easy separation of
the catalysts, (ii) simple workup and environmentally
acceptable makes this method a convenient
approach. Chlorination of N-oxide 2 was carried
out by bubbling chlorine gas22 in dichloromethane at
25oC for 3h (in two equal intervals of 1.5 h) resulted
Reaction Conditions
a) RuCl3·3H2O, O2, dichlor methane, r.t., 8h;
b) Cl2, dicloromethane, 25oC, 3 h; c) i. 30% NaSH,
O
S
O
S
OCH3
N
N
F
H3CO
O
S
O(CH2)3OCH3
N
OCH3
N
H
N
H
F
O
MeO
N
H
N
N
N
Pantoprazole, 2
Rabeprazole 3
Omeprazole,1
O
OCH2CF3
N
O
OCH2CF3
N
S
S
N
H
N
H
N
N
Lansoprazole, 4
Dexlansoprazole, 5
Fig. 1: chemical structure of the proton pump inhibitors 1-5

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GILBILE et al., Orient. J. Chem., Vol. 33(2), 930-936 (2017)
tetra-butyl ammonium hydroxide, 70oC, 5h. ii. tetra- –SO2CH3 and –CH3 flanked to the pyridine ring
butyl ammonium hydroxide, MeI, 15-20oC, 8h;d) 30% nucleus. The molecular ion of the compound in the
aq.H2O2, 75oC, 24h;e) RuCl3·3H2O, acetonitrile, 85oC, mass spectra with m/z, 220.1 (M+1) further supports
1h; f) trichloroisocyanuric acid, chloroform, reflux, the confirmation of the desired product.
1h;
In view of the significant importance of
Thestructuralelucidationoftheintermediates green metrics evaluation, we have calculated the
and the final 2-chloromethyl-4-methanesulfonyl-3- atom economy (AE), reaction mass efficiency (RME)
methyl pyridine 7 was characterized by the various and E-factor for the various steps that are involved
spectroscopic techniques like1H NMR, mass and IR in the synthesis of 2-(chloromethyl)-3-methyl-4-
data.As an example, the 1H NMR of 2-(chloromethyl)- (methylsulfonyl)pyridine 7. The calculation of these
3-methyl-4-(methylsulfonyl)pyridine7 is described parameters is tabulated in Table-1. In general, the
here, the protons resonating at d 8.68 ppm and % of AE is less than 100% due to the formation of
7.90 ppm as doublets with two proton integration is various by-products involved in the individual steps,
assigned to the pyridine ring protons and the proton while the variation in RME is recognized to the factors
resonating d 4.82 ppm as singlet is assigned to the such as number of reactants involved in the reaction,
methylene proton (-CH2Cl) while the singlet signals usage of excess molar equivalents of reactants and
at 3.15 ppm and 2.83 ppm is assigned to the groups poor yields of the products.
Table 1: AE, RME and E-factor for the
various steps involved in the synthesis of
2-(chloromethyl)-3-methyl-4(methylsulfonyl)
pyridine
Among the various steps, step 1 indicates,
higher % of yield, AE and RME values i.e., 99,
97, 93% respectively, though these parameters
measures the effectiveness of the reaction but in
terms of E-factor value (12.48) it is less efficient.
The high value of E-factor value is attributed to the
usage of voluminous amounts of solvent (during
work up of the reactions), purification techniques
(crystallization / column chromatography) and drying
agents. In case of step 4, even though the values of
AE, RME and yield (74%, 62% and 85%) are at lower
end when compare to step 1, the E-factor value is
3.2, the lower value of E-factor is indicative of the
less waste generation when compared to step 1.
Similarly, the variation of AE, RME and E-factor for
the remaining steps (Table 1) is explained based on
the above criteria. The E-factor value for the various
steps involved in the synthesis is observed in the
Compound Step AE Yield RME * E-factor
No.
%
(%)
%
2
3
4
5
6
7
1
2
3
4
5
6
99
81
36
74
45
42
93
74
85
85
85
82
97
59
31
62
39
59
12.48
14.14
16.35
3.2
28.5
27.04
* E-factor calculation presented under experimental
section
Cl
N
SCH3
SO2CH3
a
b
c
d
Step 1
Step 2
N
Step 3
N
Step 4
N
N
O
O
O
O
1
2
3
4
5
SO2CH3
SO2CH3
e
f
Cl
Step 5
Step 6
N
N
7
6
Scheme 1: Modified synthesis of 2-chloromethyl-4-methanesulfonyl-3-methyl pyridine 7

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GILBILE et al., Orient. J. Chem., Vol. 33(2), 930-936 (2017)
following increasing pattern, step 4 (E-factor-3.2) >
step 1 (E-factor-12.48) > step 2 (E-factor-14.14)>
step 3 (E-factor-16.35)> step 6 (E-factor-27.04)>step
5 (E-factor-28.5). Thus, the E-factor value clearly
gives information on the waste generation involved
in the various steps on a laboratory scale. Based on
this information, a process chemist can explore to
modify the technology before going further for much
higher batch size.
E-factor = 12.4; Not accounted for column
chromatography;
[5g (compound 1) + 0.48 g (RuCl3.3H2O)
+ 66.5 g (dichloromethane) – 5.34 g (compound 2,
product x yield)] / 5.34 g.
4-chloro-2,3-dimethyl-pyridine-N-oxide 3
A quantified chlorine gas (5g, 70.48
mmol) was bubbled for 1.5 h, into a stirred solution
of 2,3-Lutidine-N-oxide 2 (17.18g, 140 mmol) in
dichloromethane (60 mL) that was cooled to 25oC.
After the conversion had reached 50% conversion
(judged by T.L.C), 50% sodium hydroxide solution
(11.5 g, 2.79 mol) was added slowly for 30 minutes
(maintaining reaction mixture at <25°C). A second
lot of chlorine gas (5g, 70.48 mmol) was again
bubbled introduced for 1.5 hours at < 25°C, until the
total conversion of product is attained (monitored
by T.L.C). Water (25 mL) was added to the above
reaction mixture and the pH was adjusted to 6.8
using sodium hydroxide solution (aq. 50%, 2.76 g).
The aqueous phase was separated and extracted
with dichloromethane (2 X 20 mL ).The organic layer
was concentrated under reduced pressure to afford
a thick residue, that was dissolved in ethylacetate
(55 mL) at room temperature and stirred at 10oC for
2 h, the precipitated solids were filtered and further
washed with ethylacetate (25 mL) and dried to obtain
4-chloro-2,3- dimethyl-pyridine-N-oxide (3). Yield:
10.77g, 49%. 1H NMR (300 MHz, CDCl3): d 8.09 (d,
J = 6.9 Hz, 1H), 7.26 (d, J = 4.2 Hz, 1H), 2.56 (s,
3H), 2.40 (s, 3H); ESI-MS: m/z, 158.01 (M+H)+; IR
(KBr):nmax3430, 3088, 2518, 1638, 1415, 1389, 1263,
1207, 1140, 1080, 839, 722, 632, 566, 491;
MATERIALS AND METHODS
All the chemical and solvents used for
the synthesis were analytical standard from Fluka
or Merck. For thin-layer chromatography (TLC)
analysis, E.Merck AL silica gel 60 F254 plates were
utilized and spots were visualized under UV light.
The mass spectrawas recorded on Agilent ion trap
MS and Infrared (IR) spectra were recorded on a
Perkin Elmer FT-IR spectrometer. 1H NMR spectra
was recorded in CDCl3 and DMSO-d6 with a 400
MHz (Varian Mercury plus) instrument. TMS was
used as an internal standard and the chemical shift
values were reported in ´ (ppm) and the signals
were reported as s (singlet), d (doublet), dd (doublet
of doublet), t (triplet), q (quartet), m (multiplet) and
coupling constants are measured in Hz. Melting
point (mp) determinations were performed by using
Mel-temp apparatus and are uncorrected.
EXPERIMENTAL SECTION
2,3-Dimethyl-pyridine-N-oxide 2
To a solution containing, 2,3-lutidine
1 (5.0g, 46.66 mmol) in dichloromethane (50 mL)
was added RuCl3·3H2O (0.48 g, 5 mol%) and stirred
at room temperature. Oxygen was bubbled into the
reaction mixture at room temperature for 8h. After
the completion of the reaction (judged by T.L.C), the
catalyst was filtered and the filtrate was concentrated
under vacuum to obtain the crude product. The
column chromatography (Stationary phase: basic
alumina, Eluent: 5% Methanol/ dichloromethane)
purification resulted in the pure product 2,3-dimethyl
pyridine N-oxide 2.Yield: 5.34 g , 93%; Pale yellow
viscous liquid; 1H NMR (400 MHz, CDCl3): d 8.23-
8.20 (m, 1H), 7.13-7.10 (m, 2H), 2.50 (s, 3H), 2.33
(s, 3H);
E-factor = 14.14; Not accounting for water
[17.18 g (compound 2) + 10g (Cl2) + 14.26 g (NaOH)
+ 133 g (dichloromethane) + 71.8 g (Ethylacetate) –
16.26 g (product x yield)] / 16.26 g
2,3-dimethyl-4-(methylthio)pyridine-N-oxide 4
A stirred mixture of 4-Chloro-2, 3-dimethyl-
pyridine -1-oxide (10g), 30% aqueous sodium
hydro sulphide (3 Vol, 30mL/ 53.7 g) and tetra butyl
ammonium hydroxide (40% w/w, 2.5 mL/2.48g)
was heated to 70°C for 5h. The reaction mixture
was poured into water (25 mL) and extracted with

935
cyclopentylmethylether (30 mL). After routine work
GILBILE et al., Orient. J. Chem., Vol. 33(2), 930-936 (2017)
[8g (compound 4) + 17.6g (30% H2O2)
up procedure i.e washing with water (3x 20mL), -7.98g (product x yield)] / 7.98
brine solution (25 mL), drying over sodium sulphate
(7g), filtration and concentration yielded the crude 2,3-dimethyl-4-(methylsulfonyl)pyridine 6
compound (9.35g, 95% yield, 60.23mmol).The crude
To a stirred solution of acetonitrile (45 mL)
compound was dissolved in tetra butyl ammonium containing 4-Methanesulfonyl-2, 3-dimethyl-pyridine-
hydroxide (50mL/49.5g, 40% w/w in water) and 1-oxide 5 (5g, 24.84 mmol) was added RuCl3x3H2O
added methyl iodide (10.26g, 72.28 mmol) in several (5.15g, 24.82 mmol) and heated to 85oC for 1h.
portion for 15 minutes at 15-20oC and continued The completion of the reaction was judged by, the
stirring for 8h.The solids obtained during the reaction solvent was concentrated and the obtained residue
was filtered and washed with water (4 X 25 mL), was treated with water (50 mL), made alkaline with
dried at the pump and isolated thiomethyl-N-oxide 25% aqueous ammonia (20 mL) and extracted with
compound. Yield: 9.15g, 85%; IR (KBr):nmax3319, dichloromethane (35 mL). The dichloromethane
3069, 2924, 2171, 1698, 1596, 1444, 1424, 1388, layer was dried over Na2SO4 (8.5g), filtered and
1328, 1242, 1077, 1017, 981, 958, 820, 731, 711, evaporated to obtain the crude product. Puirifcation
634, 567, 497 cm-1;1H NMR (300 MHz, dmso-d6): of the crude product by column chromatography
d 8.11 (d, J = 6.9 Hz, 1H), 7.08 (d, J = 6.9 Hz, 1H), (silica), using (20% ethyl acetate/hexane-200 mL)
2.50 (s, 3H), 2.38 (s, 3H), 2.23 (s, 3H); ESI-MS: m/z, resulted in the formation of desired product 2,3-
170.01 (M+H)+;
dimethyl-4-(methylsulfonyl)pyridine 6. Yield: 4g,
85%.
E-factor = 16.35;Not accounting for water and brine
solution
E-factor = 28.5;Not accounting for water and column
chromatography
[10g (compound 3) + 53.7g (30% NaSH)
+ 52g (tetra-butyl ammonium hydroxide) + 10.26
5g (compound 5) + 5.15g (RuCl3.3H2O)
g (MeI) + 25.8g (cyclopentylmethyl ether) + 7g + 35.37g (Acetonitrile) + 46.55g (dichlormethane)
(Na2SO4) – 9.15 g (product x yield)] / 9.15g
+ 8.5g (Na2SO4) + 17.6g (25% Aq. Ammonia) – 4g
(product x yiled)] / 4g
4-Methanesulfonyl-2, 3-dimethyl-pyridine-N-
oxide 5
2-(chloromethyl)-3-methyl-4-(methylsulfonyl)
A stirred mixture of 2,3-dimethyl-4- pyridine 7
(methylthio)pyridine 4 (8g, 47.27 mmol) and 30%
To a refluxing solution of CHCl3 (50 mL)
aqueous solution of H2O2 (0.32 g, 9.40 mmol) was containing 2,3-dimethyl-4-(methylsulfonyl)pyridine 6
heated to 75°C for 2 h. Another lot of 30% aqueous (5g, 27 mmol) was added trichloroisocyanuric acid
solution of H2O2 was added (2g, 58.80 mmol ) (2.82 g, 12.1 mmol) in several portions for 60 min
at room temperature and continued at the same and continued reflux for 1h.The reaction mixture was
temperature for 15 min.The reaction mixture became cooled and poured into an ice-water mixture (aliquots
homogenous and additional H2O2 was added (2g, of a 50% aqueous NaOH (10 g) solution were then
58.80 mmol) after 10 h and 0.5g (14.7 mmol) after added to get the pH to 8.5-9.0) and the resulting
6h. Total conversion of the product was attained solution was extracted with chloroform (25 mL).
in 24 h. After cooling the reaction mixture to room The chloroform layer was dried on Na2SO4 (6.5g),
temperature, solids was thrown out which was filtered filtered, and concentrated to dryness. The residue
and dried at the pump to obtain 4-Methanesulfonyl-2, was purified by column chromatography (silica gel,
3-dimethyl-pyridine-N-oxide 5. White solid; Yield: eluant; 10% Methanol in chloroform-300 mL) to
1
7.98g, 85%. H NMR (300 MHz, CDCl3): d 8.36 afford 2-(chloromethyl)-3-methyl-4-(methylsulfonyl)
(d, J = 7.2 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 3.30 pyridine7. Light brown solid; Yield: 4.85g, 82%. 1H
(s, 3H), 2.60 (s, 3H), 2.42 (s, 3H); ESI-MS: m/z, 202 NMR (300 MHz, dmso-d6):d 8.68 (d, J = 5.1 Hz, 1H),
(M+H)+;
7.90 (d, J = 5.1 Hz, 1H), 4.82 (s, 2H), 3.15 (s, 3H),
2.83 (s, 3H); ESI-MS: m/z, 220.1 (M+H)+;
E-factor = 3.2

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GILBILE et al., Orient. J. Chem., Vol. 33(2), 930-936 (2017)
E-factor = 27.04; Not accounted for column
chromatography;
4 (oxidation of thiomethyl pyridine-N-oxide) is
3.2, which is indicative of less waste generation,
when compared to the various steps involved in
the synthesis. The increasing pattern of E-factor
values, “ step 4 (E-factor-3.2) > step 1 (E-factor-
12.48) > step 2 (E-factor-14.14)> step 3 (E-factor-
16.35)> step 6 (E-factor-27.04)>step 5 (E-factor-
28.5)” clearly demonstrates that E-factor value is
least in the case of step 4 while for the remaining
steps it varied between 12.48-28.5. Based on this
information, a process chemist can explore to modify
the technology before going further for much higher
batch size.
[ 5 g ( c o m p o u n d 6 )
+
2 . 8 2 g
(trichloroisocyanuric acid) + 10g (NaOH) + 111.7g
(chloroform) + 6.5g (Na2SO4) – 4.85g (product x
yield)] / 4.85g
CONCLUSION
In summary, the present article describes
the modified synthesis of 2-chloromethyl-4-
methanesulfonyl-3-methyl pyridine 7. The merits
of the synthesis involves, N-oxidation reaction 2,3-
lutidine under mild conditions using RuCl3.3H2O,
one pot synthesis of 4-methylthio-pyridine-N-
oxide, formation of 4-(methylsulfonyl)pyridine-N-
oxide using H2O2 and chlorination reaction using
trichloroisocyanuric acid. Based on the E-factor
assessment, it is concluded that E-factor in step
ACKNOWLEDGEMENTS
One of the authors (RDG) is thankful to the
Director, Green Evolution Laboratories for his helpful
suggestions and constant encouragement.
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