An innovative and efficient method to synthesize meloxicam in one-step procedure with respect to the green chemistry

Article abstract of DOI:10.1007/s13738-018-1525-6

An improved procedure for the synthesis of meloxicam drug (methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazol-2-amine-3-carboxylate 1,1-dioxide) was described in one-step using mainly impregnated montmorillonite K10 (MK10) with ZnCl₂ as a heterogeneous catalyst. This innovative method was compared to the last described procedure employed in the manufacture of this anti-inflammatory drug by means of some metrics used in a first step of the evaluation process of the environmental impact of a chemical transformation. Apart from the yield, which was 90%, atom economy, waste, environmental factor, reaction mass efficiency and stoichiometric factor were calculated as 91.6%, 8.4%, 0, 8.1% and 1%, respectively. Interpretation of these metrics was given and highlighted the fact that the strategy used in the current study may be considered as an environmental-friendly and sustainable method that fits well in the green chemistry concepts.

Full text of DOI:10.1007/s13738-018-1525-6

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1525-6
ORIGINAL PAPER
An innovative and efficient method to synthesize meloxicam in one-
step procedure with respect to the green chemistry
Pierrick Dufrénoy1,2,5 · Alina Ghinet1,2,3 · Marie Hechelski4 · Adam Daïch5 · Christophe Waterlot4
Received: 3 April 2018 / Accepted: 11 October 2018
© Iranian Chemical Society 2018
Abstract
An improved procedure for the synthesis of meloxicam drug (methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazol-2-amine-
3-carboxylate 1,1-dioxide) was described in one-step using mainly impregnated montmorillonite K10 (MK10) with ZnCl2 as
a heterogeneous catalyst. This innovative method was compared to the last described procedure employed in the manufacture
of this anti-inflammatory drug by means of some metrics used in a first step of the evaluation process of the environmental
impact of a chemical transformation. Apart from the yield, which was 90%, atom economy, waste, environmental factor,
reaction mass efficiency and stoichiometric factor were calculated as 91.6%, 8.4%, 0, 8.1% and 1%, respectively. Interpreta-
tion of these metrics was given and highlighted the fact that the strategy used in the current study may be considered as an
environmental-friendly and sustainable method that fits well in the green chemistry concepts.
Keywords Meloxicam · Green chemistry · Metrics · Heterogeneous catalyst · Montmorillonite K10
Introduction
chemical reactions. This problem is not only a great inter-
est for organic chemistry researchers. Indeed, since the
Pollution Prevention Act of 1990, scientists, industrialists
and operators have had to develop together methodologies
encouraging the design of environmentally benign processes
and products, including also the reduction of the cost of
their production and the limitation of energy, to ensure
constant improvement of the synthetic processes towards
a concept of green chemistry. In that sense, new chemis-
try concepts using microwaves irradiation [1, 2] and ultra-
sounds [3–5] have been developed in research laboratory, as
well as solvent-free reactions [6, 7], innovative supported
reagents like alumina, aluminosilicates, amorphous silica-
alumina (SiO2–Al2O3), carbon, Celite, graphite, Kieselguhr,
molecular sieves, oxides different than SiO2–Al2O3, porous,
mesoporous and microporous solid supports, silica-gel, clays
and pillared clays [8–47].
Since two decades, the main concerns for chemistry
researchers are to develop organic synthetic routes with
the aim to find quicker, cleaner, cheaper synthesis process.
In this way, many efforts have been made to avoid or to
reduce the use of (1) certain catalysts considered as pol-
lutants, (2) organic solvents and molecules that are able to
cause problems for environment and human health but also
(3) the generation of hazardous substances in the course of
* Christophe Waterlot
christophe.waterlot@yncrea.fr
1
Laboratoire de chimie durable et santé, Yncrea Hauts-de-
France, HEI, 13 rue de Toul, 59046 Lille Cedex, France
2
Faculté de médecine, Pôle recherche, Inserm U995,
Meloxicam is a non-steroidal anti-inflammatory drug
(NSAID) of the oxicam family, with anti-inflammatory,
analgesic and antipyretic properties largely used in human
and veterinary medicine. The representative molecules of
the family of oxicams are: tenoxicam 1, piroxicam 2 and
meloxicam 3 (Fig. 1). Meloxicam is the active pharmaceu-
tical ingredient in the marketed drug Mobic® for human
or Metacam® for veterinary use. This compound is used
in short-term symptomatic treatment of acute attacks of
LIRIC, Université de Lille, CHU de Lille, Place Verdun,
59045 Lille Cedex, France
3
Faculty of Chemistry, ‘Alexandru Ioan Cuza’ University
of Iasi, Bd. Carol I nr. 11, 700506 Iasi, Romania
4
Laboratoire Génie Civil et géoEnvironnement (LGCgE),
Yncrea Hauts-de-France, 48 boulevard Vauban,
59046 Lille cedex, France
5
Normandie Univ., UNILEHAVRE, FR 3038 CNRS,
URCOM EA 3221, UFR Sciences & Techniques, 25 rue
Philipe Lebon, BP: 1123, F-76063 Le Havre Cedex, France
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
sulfasalazine coupled with TNF-α treatment on patients with
ankylosing spondylitis. The phase III clinical trials in pro-
gress on meloxicam alone or in combination study: (1) the
comparison lidocaine–prilocaine vs. meloxicam in the treat-
ment of postpartum perineal pain; (2) the evaluation of the
safety and tolerability of preoperative dosing of meloxicam
in subjects undergoing colorectal surgery; (3) the combina-
tion of meloxicam and traditional Chinese medicine Fangji
Huangqi pill on KOA.
Meloxicam 3 is the most studied representative of the
oxicam family. In the current work, we investigated a clean
and efficient synthesis of this molecule and compared it to
the other procedures described in the literature to propose
the simplest synthetic pathway to this active pharmaceutical
ingredient from a green chemistry perspective.
Fig. 1 Structure of representative members of the oxicams family:
tenoxicam 1, piroxicam 2 and target meloxicam 3
Screening of reaction conditions
osteoarthritis and in long-term symptomatic treatment of
rheumatoid arthritis and ankylosing spondylitis. Its mecha-
nism of action involves the inhibition of cyclooxygenases
(COX) with, however, an inhibition selectivity on COX-2
even if it only appears at the recommended minimum dos-
ages. This inhibition results, as for the other NSAIDs, in
the inhibition of the biosynthesis of prostaglandins, known
mediators of the inflammation.
The first innovative route was proposed by Zia-ur-Rehman
et al. (2005) in which N-methyl benzothiazine alkyl (methyl,
ethyl or isopropyl) carboxylate (4a–c) and 5-methyl-1,3-thi-
azol-2-amine (or 5-methyl-2-aminothiazole) (5) were con-
densed together under an inert medium in presence of boron
trifluoride (BF3.Et2O), used as Lewis acid catalyst, to give
meloxicam 3 in good yield (Scheme 1) [49].
New therapeutic approaches are currently investigated for
the use of meloxicam alone or in combination. Eight clini-
cal trials are currently under way: four phase II, three phase
III studies and one unspecified phase study using meloxi-
cam are in progress [48]. Phase II studies are focused on:
(1) meloxicam in association with filgrastim to assess the
safety and efficacy of mobilizing autologous peripheral
blood stem cells (PBSCs) from multiple myeloma (MM)
and non-Hodgkin’s lymphoma (NHL) patients planning to
undergo high-dose chemotherapy with stem cell support; (2)
the evaluation of meloxicam on the mobilization of hemato-
poietic stem cells to see if it provides a benefit to people
receiving Autologous Hematopoietic Stem Cell Transplan-
tation (AHSCT); (3) the efficacy of meloxicam on knee
osteoarthritis (KOA) and (4) association of meloxicam and
In more recent days, Mezei et al. have proposed an
original approach (Scheme 2) [50]. The authors produced
crude meloxicam 3a starting from methyl 4-hydroxy-2-me-
thyl-2H-1,2-benzothiazol-2-amine-3-carboxylate 1,1-diox-
ide 4a and 5-methyl-2-aminothiazole 5 under argon atmos-
phere and in the presence of charcoal. Due to the presence
of charcoal in the crude meloxicam along with by-product
6 (12% yield), the authors decided to produce meloxicam
potassium salt monohydrate 7 by adding a KOH solution in
the crude mixture to discard the charcoal and the undissolved
residues. The solution was further treated with a KOH solu-
tion and the compound 7 was filtered and washed with water.
This precipitate was dissolved again in a KOH solution in
presence of charcoal under stirring. The mixture was filtered
off and the solution was acidified with HCl under stirring.
Scheme 1 Condensation of
substituted alkyl carboxylate
and 5-methyl-2-aminothiazole
(Route 1; [49]). Reagents and
conditions: (i) 1.2 equiv. of
amine, 0.02 equiv. of boron
trifluoride, xylene, nitrogen
atmosphere, reflux, 16 h, 76%
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Journal of the Iranian Chemical Society
Scheme 2 Condensation of substituted methyl carboxylate and
5-methyl-2-aminothiazole in presence of charcoal (Route 2; [50]);
reagents and conditions: (ii) charcoal, xylene, reflux, 24 h; (iii) 0.82
equiv. of KOH (0.5 w/w% aqueous solution), 50 °C, 1 h, then 4.12
equiv. of KOH (23 w/w% aqueous solution), 10 °C, 2 h; (iv) 1.6
equiv. of KOH (0.5 w/w% aqueous solution), EtOH, 40–45 °C, 0.5 h,
charcoal, HCl aqueous solution, 30 °C, 0.5 h, then stirring at 10 °C,
2 h
The precipitate was filtered, washed with water and dried in
vacuo to obtain purified meloxicam 3 [50].
Innovative synthesis methods were developed to produce
meloxicam 3 under cleaner and cheaper conditions. These
methods were based on the use of heterogeneous catalysts,
which were prepared using MK10 as a solid support, instead
of ZnCl2. The syntheses of meloxicam 3 were performed fol-
lowing the procedure described above with 0.05 equivalents
of (1) commercial MK10 (Fig. 3, Route 3b), (2) catalyst 1
(Cat 1) constituted by MK10 impregnated with ZnCl2 and
prepared according to the procedure described by Waterlot
et al. (Scheme 3, Route 3c) [37].
For the current study, our objective was to highlight inno-
vative and green synthetic pathway to produce meloxicam
3 and to compare our results with the most recent effec-
tive pathway described in the literature [50]. In this way, we
studied alternative methods with the aim of (i) improving
the reaction yield, (ii) reducing the cost of the reaction and
its time-consuming and (iii) limiting the waste production
compared to the most recent described methodology. Our
first procedure was conducted by mixing 1 equivalent of
methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazol-2-amine-
3-carboxylate 1,1-dioxide 4a and 1 equivalent of 5-methyl-
2-aminothiazole 5 in the presence of 0.05 equivalents of
ZnCl2 (Scheme 3, Route 3a). The mixture was refluxed for
24 h in o-xylene. After the reaction, the solvent was evapo-
rated and the mixture was washed with water to destroy the
Lewis acid ZnCl2. The crude organic product was extracted
by CH2Cl2 and the mixture was purified by flash chromatog-
raphy (EtOAc:n-Heptane, 00:100 to 50:50).
Green chemistry metrics: results
and discussion
The efficiency of chemical processes is evaluated by metrics
to quantify technical and environmental improvements that
can be made when new synthetic pathways and new technolo-
gies are proposed. In the concept of sustainable chemistry, the
green chemistry metrics facilitate the adoption of the innova-
tive process by the scientific community and industrialists. It
Catalyst
Scheme 3 Condensation of substituted methyl carboxylate and 5-methyl-2-aminothiazole in presence of ZnCl2 or heterogeneous catalysts. Rea-
gents and conditions: (v) Route 3a: 0.05 equiv. of ZnCl2; Route 3b: 0.05 equiv. of MK10; Route 3c: 0.05 equiv. of Cat 1, o-xylene, reflux, 24 h
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Journal of the Iranian Chemical Society
is well adopted that yield is the most common parameter to
evaluate the efficiency of a chemical process. However, even
if this parameter is the most simple, it is not always the most
appropriate in green chemistry since the operator cannot evalu-
ate changes in relation with the utilization, the modification or
the formation of toxic compounds as well as process hazards.
Some associated metrics, developed in this sense, are the atom
economy, the carbon efficiency, the reaction mass efficiency,
the environmental factor and the stoichiometric factor.
was isolated in good yield (81.7%). Due to (1) the release of
HCl vapours resulting from the reaction between ZnCl2 and
water molecules in the atmosphere and (2) the final workup
to destroy this catalyst, heterogeneous catalysts were further
tested. The first was MK10, a well-known clay belonging to the
smectite group, which presents Bronsted and Lewis acid sites
(Route 3b). Unfortunately, meloxicam 3 was obtained in a very
low yield (29%). We decided to increase the number of Lewis
acid’s sites of the MK10 by synthesizing impregnated MK10
with ZnCl2 (Zn-MK10) following the procedure described by
Waterlot et al. [37]. The yield of the reaction reached 90%,
which is considered in practice as an excellent yield.
Yield
The mass, the molar mass and the number of mole of reactants
and products involved in the three steps described in Scheme 2
are summarised in Table 1. From these data, it was established
that yields of potassium salt 7 and meloxicam 3 were 80.9% and
97%, respectively. The overall yield of this multistep synthesis
was obtained by multiplying yields from each step and was
78.5%. In practice, this result is considered as a good yield.
However, taking into account the general procedure, this value
may be different due to the fact that the yield of individual step
depends on the experimental conditions and the operators.
Aminolysis reactions may be performed without any cata-
lyst. The direct condensation between methyl ester 4a and
amine 5 without using any catalyst was much less effective
and provided the target product 3 in only 34% yield. That
explains why we decided to use ZnCl2 as Lewis acid in a first
step and then, we attempted to replace this homogeneous cata-
lyst by heterogeneous catalysts. Meloxicam 3 was produced
in only one step whatever the catalyst chosen (Scheme 3) and
the global results are presented in Table 2. As shown in this
table, meloxicam 3 was produced using ZnCl2 (Route 3a) and
In view of the low meloxicam’s yield via the Route 3b
(Scheme 3), this synthetic pathway was not considered in the
following part of the current study.
Atom economy (AE) and Sheldon’s E‑factor
The atom economy is a theoretical value described in the
literature [51] and was expressed in percentage by Eq. 1.
From this metric, it may be defined the percentage of reac-
tants engaged in the reaction process that may be considered
as waste materials.
Molecular weight of the isolated product
AE =
× 100.
Sum of the molecular weights of the reactants
(1)
From the atom economy, and therefore, the waste mate-
rials, the E-factor, introduced by Sheldon [52], may be
calculated following Eq. 2. For researchers and industri-
als, this metric may measure how much material enters
Table 1 Molar mass, mass of reactants and products, mol number and yield associated with the manufacturing of meloxicam according to Mezei
et al. [50]
Chemical formula of reactants
and products
C11H11NO5S (6) C4H6N2S (5) Crude
KOH
KOH HCl C14H13N3O4S2
C14H13N3O4S2 C14H12KNO4S2·H2O
(3)
(3a)
(8)
Molar mass of reactants and
269
114
15
56
407.52 56
36.5
351
products (g mol−1
)
Mass of reactants and products 35
43
(g): step (ii)
Mol number of reactants and
products: step (ii)
0.130
0.132
Mass of reactants and products
43
36
42.9
(g): step (iii)
Mol number of reactants and
products: step (iii)
0.643
0.105
Mass of reactants and products
34.1
7.5
8.8
28.5
0.081
97.0
(g): step (iv)
Mol number of reactants and
products: step (iv)
Yield (%)
0.084 0.134 0.241
80.9
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Journal of the Iranian Chemical Society
Table 2 Molar mass, mass of reactants and products, mol number and yield associated with the synthesis of meloxicam described in the current
study
Chemical formula Route 3a
of reactants and
Route 3b
Route 3c
C11H11NO5S (6) C4H6N2S (5) ZnCl2
C14H13N3O4S2 (3) MK10 C14H13N3O4S2 (3) Zn-MK10 C14H13N3O4S2 (3)
products
Molar mass of
reactants and
products (g
269
114
136.39
351
351
351
mol−1
)
Mass of reactants 200
and products
(mg)
87
5
213.21
30
75.8
30
235
Mol number of
reactants and
products
7.43E−04
7.63E−04
3.67E−05 6.07E−04
81.7
2.16E−04
29.0
6.70E−04
90.0
Yield (%)
Reaction mass efficiency (RME)
Table 3 Metrics associated to the determination of the environmental
factor (E-factor)
The reaction mass efficiency was based on the Curzons’s
definition [53] and was calculated from Eq. 3.
Isolated weight of the isolated product
Atom economy
(%)
Waste (%)
E-factor
RME =
× 100.
Route 2
Route 3a
Route 3c
36.4
67.6
91.6
63.6
32.4
8.4
2.1
2.4E−02
0.0
Sum of the weights of the reactants
(3)
Although Mezei et al. [50] produced meloxicam 3 via
a multistep synthesis, they presented their results from
crude meloxicam product. This point is very important
since this Curzons’s metric requires the assumption
that 100% of the product in a reaction is engaged in the
subsequent reaction. The reaction mass efficiency of
the Mezei’s reaction was 20.9%. This value means that
79.1% of the weights of the reactants used in the reaction
Scheme 2 is not inserted in the meloxicam 3. This result
correlated well with the high percentage of waste (63.6%;
Table 3). In contrast, RME values were 73.1% and 81.9%
for the routes 3a and 3c, respectively. Once again, the
best result was obtained using the impregnated Zn-MK10
catalyst and highlighted that only 8.1% of the weights of
the reactants engaged in the reaction was not inserted in
the meloxicam 3, reflecting the very low quantity of waste
(8.4%, Table 3).
the production site and how much leaves as product and/
or waste materials.
Mass of waste
E-factor =
.
(2)
Mass of product
The three metrics were calculated from the Routes 2, 3a
and 3c and the results are presented in Table 3. Compared to
the multistep synthesis described in Mezei et al. [50], the atom
economy related to synthesis of meloxicam 3 using ZnCl2 was
1.86-fold higher (67.6% vs. 36.4%). The best AE was obtained
using the impregnated Zn-MK10 (91.6%) and was 2.5-fold
higher than the AE obtained by Mezei et al. [50]. For the Route
3c, this result means that only 8.4% of the atomic mass of the
reactants used in the reaction will constitute waste, whereas in
Mezei et al. [50], 63.6% of the engaged reactants may be con-
sidered as waste. Although the E-factor values were very low
for each route, the best E-factor was obtained for the Route 3c.
This result may be explained by the properties of the hetero-
geneous catalyst Zn-MK10. This catalyst was recovered after
solid–liquid filtration and it was reused five times without sig-
nificant loss of activity.
Stoichiometric factor (SF)
The stoichiometric factor highlights the difference between
the reaction conducted in the process studied and this reac-
tion when the reactants should be used in stoichiometric
condition [53].
Sum of the weights of the reactants − sum of the weights of the reactants in a stoichiometric process
(4)
SF = 1 +
× 100.
Sum of the weights of the reactants in a stoichiometric process
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Journal of the Iranian Chemical Society
The SF metric was calculated for the reaction described
in Scheme 2. The value of 1.29 indicated that 29% of the
weight of the reactants in the process described by Mezei
et al. [50] were used in excess. This result is in relation with
the use of KOH to produce the meloxicam potassium salt
and the treatment of this salt by KOH and HCl to obtain
meloxicam 3. In view of our both processes, ZnCl2 was used
under catalytic conditions (1:10; Route 3a) and the impreg-
nated Zn-MK10 was a reusable catalyst used under catalytic
conditions too (Route 3c). Consequently, the SF values were
1 for both syntheses ways indicating that no limiting and
excess reactants were used in our innovative process.
performed with a CombiFlash Rf Companion (Teledyne-Isco
System) using RediSep packed columns. IR spectra were
recorded on a Varian 640-IR FT-IR Spectrometer.
Synthesis of 4‑hydroxy‑2‑methyl‑N‑(5‑methyl‑2‑thia
zolyl)‑2H‑1,2‑benzothiazine‑3‑carbox‑amide‑1,1‑di‑
oxyde (3) without catalyst
2-Amino-5-methylthiazole (85 mg, 0.7 mmol) was added
to a solution of methyl 2-methyl-4-hydroxy-2H-1,2-benzo-
thiazine-3-carboxylate 1,1-dioxide 4a (200 mg, 0.7 mmol)
in o-xylene (3 mL) and the mixture was stirred at reflux
during 24 h. After cooling to room temperature, the xylene
was evaporated and CH2Cl2 (10 mL) was further added to
the crude. The compound was then purified on flash chro-
matography (EtOAc:n-Heptane, 00:100 to 50:50) to provide
the 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-
benzothiazine-3-carboxamide-1,1-dioxyde (3) in 34% yield.
Conclusion
Since the 12 principles of the green chemistry are known by
researchers and industrials, many efforts have been made to
develop economical, ecological and safe syntheses. The cur-
rent study reported the most recent and innovative syntheses
of meloxicam, a non-steroidal anti-inflammatory drug, the
first based on the use of ZnCl2 and the second using impreg-
nated MK10 (Zn-MK10). Apart from the fact that meloxi-
cam was synthesized in one step using this heterogeneous
catalyst with the best yield (90%), some quantitative tools
used as metrics were used to evaluate the performance of
our synthesis. For this pathway, atom economy waste and
E-factor were 91.6%, 8.4% and 0, respectively. The reaction
mass efficiency highlighted that only 8.1% of the weights
of the reactants engaged in the reaction was not inserted in
the meloxicam 3 produced under a perfect stoichiometric
conditions (stoichiometric factor=1).
Synthesis of 4‑hydroxy‑2‑methyl‑N‑(5‑methyl‑2‑thia
zolyl)‑2H‑1,2‑benzothiazine‑3‑carbox‑amide‑1,1‑di‑
oxyde (3) with ZnCl2 as catalyst
2-Amino-5-methylthiazole (85 mg, 0.7 mmol) and zinc chlo-
ride (5 mg, 0.037 mmol) were added to a solution of methyl
2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate
1,1-dioxide 4a (200 mg, 0.7 mmol) in o-xylene (3 mL) and
the mixture was stirred at reflux during 24 h. After cooling
to room temperature, the xylene was evaporated and CH2Cl2
(10 mL) was further added to the crude and washed with
distilled water (2×10 mL). The organic layer was dried on
Na2SO4, filtered, concentrated in vacuo and the residue was
then purified on flash chromatography (EtOAc:n-heptane,
00:100 to 50:50) to provide the 4-hydroxy-2-methyl-N-(5-
methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-
1,1-dioxyde (3) in 82% yield.
Experimental
Starting materials are commercially available and were used
without further purification (suppliers: Carlo Erba Reagents
S.A.S., Tokyo Chemical Industry Co. Ltd., Fluorochem
Ltd., and Fisher Scientific). Melting point was measured
on a MPA 100 OptiMelt® apparatus and is uncorrected.
Nuclear magnetic resonance (NMR) spectra were acquired
Synthesis of 4‑hydroxy‑2‑methyl‑N‑(5‑methyl‑2‑thia
zolyl)‑2H‑1,2‑benzothiazine‑3‑carbox‑amide‑1,1‑di‑
oxyde (3) with MK10 as catalyst
2-Amino-5-methylthiazole (85 mg, 0.7 mmol) and MK10
(30 mg, 0.037 mmol) were added to a solution of methyl
2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate
1,1-dioxide 4a (200 mg, 0.7 mmol) in o-xylene (3 mL) and
the mixture was stirred at reflux during 24 h. After cooling
to room temperature, the mixture was filtered to recover the
MK10, the xylene was evaporated and CH2Cl2 (10 mL) was
added to the crude. The compound was then purified on
flash chromatography (EtOAc:n-heptane, 00:100 to 50:50) to
provide the 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-
2H-1,2-benzothiazine-3-carboxamide-1,1-dioxyde (3) in
29% yield.
1
at 400 MHz for H NMR and at 100 MHz for 13C NMR,
on a Varian 400-MR spectrometer with tetramethylsilane
(TMS) as internal standard, at 25 °C. Chemical shifts (δ)
are expressed in ppm relative to TMS. Splitting patterns
are designed: s, singlet; d, doublet; dd, doublet of doublet;
t, triplet; m, multiplet; sym m, symmetric multiplet; br s,
broaden singlet; br t, broaden triplet. Coupling constants
(J) are reported in Hertz (Hz). Thin layer chromatographies
(TLC) were realized on Macherey Nagel silica gel plates
with fluorescent indicator and were visualized under a UV-
lamp at 254 nm and 365 nm. Column chromatographies were
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Journal of the Iranian Chemical Society
Fig. 2 Infrared spectrum of meloxicam 3
Fig. 3 1H RMN of meloxicam 3
1,1-dioxide 4a (200 mg, 0.7 mmol) in o-xylene (3 mL)
and the mixture was stirred at reflux during 24 h. After
cooling to room temperature, the mixture was filtered
to recover the supported catalyst, the xylene was evap-
orated and CH2Cl2 (10 mL) was added to the crude.
The mixture was then purified on flash chromatogra-
phy (EtOAc:n-heptane, 00:100 to 50:50) to provide the
Synthesis of 4‑hydroxy‑2‑methyl‑N‑(5‑methyl‑2‑thia
zolyl)‑2H‑1,2‑benzothiazine‑3‑carbox‑amide‑1,1‑di‑
oxyde (3) with impregnated MK10 (Zn‑MK10)
as catalyst
2-Amino-5-methylthiazole (85 mg, 0.7 mmol) and Zn-MK10
(30 mg, 0.037 mmol) were added to a solution of methyl
2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate
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Journal of the Iranian Chemical Society
Fig. 4 13C RMN of meloxicam 3
9. A. McKillop, D.W. Young, Synthesis 7, 481 (1979)
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-ben-
zothiazine-3-carboxamide-1,1-dioxyde (3) in 90% yield.
White solid; mp 245–246 °C (CH2Cl2); Rf 0.62
(EtOAc:n-Heptane, 60:40), IR ν cm−1: 3288, 1549, 1344,
1264, 1183 (Fig. 2). 1H NMR (400 MHz, CDCl3) δ (ppm):
2.46 (s, 3H, CH3), 2.89 (s, 3H, CH3), 7.23 (s, 1H, thiazolyl-
H), 7.75 (dquint, J=7.2, 1.6 Hz, 2H, ArH), 7.91 (dd, J=7.4,
2.0 Hz, 1H, ArH), 8.06 (dd, J = 8.2, 1.6 Hz, 1H, ArH)
(Fig. 3). 13C NMR (100 MHz, DMSO-d6) δ (ppm): 11.8
(CH3), 38.0 (CH3), 114.3 (C), 123.3 (CH; C), 126.1 (CH),
129.3 (CH), 132.1 (CH), 132.9 (CH; C), 134.4 (2C), 155.7
(C), 168.4 (C) (Fig. 4).
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Acknowledgements The authors warmly thank Yncréa Hauts-de-
France and the “Fondation de La Catho de Lille” for their financial
support of this study in the frame of « Matériaux Verts Fonctionnels »
program (P.D.’s and M. H.’s PhD scholarships). The authors are also
grateful to the “Université Le Havre Normandie” for technical help.
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