Manufacture of high-purity meloxicam via its novel potassium salt monohydrate

Article abstract of DOI:10.1021/op900031h

An improved procedure for the manufacture of 4-hydroxy-2- methyl-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (meloxicam) is described. The key intermediate of this protocol is the new potassium salt monohydrate of meloxicam, which makes possible the efficient removal of impurities, resulting in an environmentally friendly manufacturing process of the high-purity (>99.90%) drug substance.

Full text of DOI:10.1021/op900031h

Organic Process Research & Development 2009, 13, 567–572
Manufacture of High-Purity Meloxicam via Its Novel Potassium Salt Monohydrate
Tibor Mezei,§ Norbert Mesterha´zy,‡ Tibor Bako´,§ Ma´rta Porcs-Makkay,§ Gyula Simig,§ and Bala´zs Volk*,§
Chemical Research DiVision, EGIS Pharmaceuticals Plc., P.O. Box 100, H-1475, Budapest, Hungary, and Pilot Plant for API,
EGIS Pharmaceuticals Plc, P.O. Box 100, H-1475, Budapest, Hungary
Abstract:
An improved procedure for the manufacture of 4-hydroxy-2-
methyl-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazine-3-car-
boxamide 1,1-dioxide (meloxicam) is described. The key interme-
diate of this protocol is the new potassium salt monohydrate of
meloxicam, which makes possible the efficient removal of impuri-
Figure 1. Two representatives of the oxicam family of NSAIDs.
ties, resulting in an environmentally friendly manufacturing
process of the high-purity (>99.90%) drug substance.
launched in 1996 by Boehringer Ingelheim for the treatment
of osteoarthritis and rheumatoid arthritis. The active ingredient
of the drug product is polymorph Form I.6,7 Further known
crystalline forms are Form II,7 Form III,7 Form IV (zwitterionic
form)6 and Form V.7
As regards published synthetic procedures leading to 1, two
viable synthetic pathways are described in the literature for the
synthesis of 1.8-10 The key intermediate of the first route
(Scheme 1, route A) is a 4-hydroxy-2-methyl-2H-1,2-benzothi-
azine-3-carboxylate 1,1-dioxide ester 3,11 which is reacted with
5-methyl-1,3-thiazol-2-amine (4). The second literature proce-
dure (Scheme 1, route B) for the synthesis of meloxicam (1)
proceeds via 4-hydroxy-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-
benzothiazine-3-carboxamide 1,1-dioxide (5), which is methy-
lated in position 2 in the last step, with methyl iodide,8 in the
presence of a base.
Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs)1 are drugs
with analgesic, antipyretic, and in higher doses, anti-inflam-
matory effects: they reduce pain, fever and inflammation. Part
of the popularity of NSAIDs is that, unlike opioids, they do
not produce sedation or respiratory depression and have a very
low addiction rate. Certain NSAIDs, including ibuprofen and
aspirin, have become accepted as relatively safe over-the-counter
drugs.
Most NSAIDs act as nonselective inhibitors of the cyclooxy-
genase enzyme, inhibiting both the cyclooxygenase-1 (COX-
1) and cyclooxygenase-2 (COX-2) isoenzymes,2 thereby in-
hibiting the transformation of arachidonic acid into prostaglandins
that act as messenger molecules in the process of inflammation.
NSAIDs can be classified on the basis of their chemical
structure, meloxicam (1, Figure 1) and the structurally related
piroxicam (2) belong to the class of drugs called oxicams. 1
has been shown, especially at its low therapeutic dose, to
selectively inhibit COX-2 over COX-1.3 It significantly de-
creases symptoms of pain and stiffness in patients. In a
comparative study, 1 exhibited a lower incidence of gastrointes-
tinal side effects than 2,4 and it also proved to be a safe
alternative to conventional NSAIDs.5 Meloxicam (1) was
A common drawback of the literature procedures is the
formation of impurities 6, alkylated at the nitrogen atom of the
thiazole ring. Similar reactions of N-(5-methyl-1,3-thiazol-2-
yl) carboxylic amides, i.e. alkylation of the thiazole nitrogen
(6) Luger, P.; Daneck, K.; Engel, W.; Trummlitz, G.; Wagner, K. Eur.
J. Pharm. Sci. 1996, 4, 175–187.
(7) Coppi, L.; Sanmarti, M. B.; Montserrat, C. C. Crystalline forms of
meloxicam. U.S. Pat. Appl. 2003/109701, 2003. Chem. Abstr. 2003,
139, 26613.
* To whom correspondence should be addressed. Telephone: +36 1 2655874.
Fax: +36 1 2655613. E-mail: volk.balazs@egis.hu.
§ Chemical Research Division.
(8) (a) The basic patent of meloxicam is: Trummlitz, G.; Engel, W.;
Seeger, E.; Engelhardt, G. 4-Hydroxy-2H-1,2-benzothiazin-3-carboxa-
mid-1,1-dioxides. Ger. Pat. DE 2756113, 1979. Chem. Abstr. 1979,
91, 91656. (b) The U.S. equivalent of the basic patent is: Trummlitz,
G.; Engel, W.; Seeger, E.; Engelhardt, G. U.S. Patent 4,233,299, 1980.
(9) The following paper applies the same starting materials (3, 4), but
the amidation step is performed in the presence of BF3 catalyst and
molecular sieves: Zia-ur-Rehman, M.; Choudary, J. A.; Ahmad, S.
Bull. Korean Chem. Soc. 2005, 26, 1771–1775. Chem. Abstr 2006,
145, 83282.
‡ Pilot Plant for API.
(1) (a) Bennett, J. S.; Daugherty, A.; Herrington, D.; Greenland, P.;
Roberts, H.; Taubert, K. A. Circulation 2005, 111, 1713–1716. (b)
Amadio, P., Jr.; Cummings, D.; Amadio, P. B. Postgrad. Med. 1997,
101, 257–271. (c) Winzeler, S.; Rosenstein, B. AAOHN J. 1988, 46,
253–259.
(2) Hawkey, C. J. Lancet 1999, 353, 307–314.
(3) Churchill, L.; Graham, A. G.; Shih, C. K.; Pauletti, D.; Farina, P. R.;
Grob, P. M. Inflammopharmacology 1996, 4, 125–135.
(4) Dequeker, J.; Hawkey, C.; Kahan, A.; Steinbru¨ck, K.; Alegre, C.;
Baumelou, E.; Begaud, B.; Isomaki, H.; Littlejohn, G.; Mau, J.;
Papazoglou, S. Brit. J. Rheumatol. 1998, 37, 946–951.
(5) (a) Hawkey, C.; Kahan, A.; Steinbru¨ck, K.; Alegre, C.; Baumelou,
E.; Begaud, B.; Dequeker, J.; Isomaki, H.; Littlejohn, G.; Mau, J.;
Papazoglou, S. Brit. J. Rheumatol. 1998, 37, 937–945. (b) Huskisson,
E. C.; Ghozlan, R.; Kurthen, R.; Degner, F. L.; Bluhmki, E. Brit.
J. Rheumatol. 1996, 35, 29–34.
(10) A less common synthetic procedure, i.e. transamination of correspond-
ing carboxamides with 5-methyl-1,3-thiazol-2-amine is also mentioned
in the literature: see ref 8a example 10.
(11) For the synthesis of starting materials 3a and 3b, see: (a) Lombardino,
J. G.; Wiseman, E. H.; McLamore, W. M. J. Med. Chem. 1971, 14,
1171–1175. (b) Lombardino, J. G. J. Org. Chem. 1971, 36, 1843–
1845. (c) Lombardino, J. G.; Wiseman, E. H.; Chianini, J. J. Med.
Chem. 1973, 16, 493–496. (d) Reference 9.
10.1021/op900031h CCC: $40.75  2009 American Chemical Society
Published on Web 03/23/2009
Vol. 13, No. 3, 2009 / Organic Process Research & Development
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567

Scheme 1. Literature procedures leading to meloxicam
instead of the amide nitrogen, are precedented in the literature.12,13
The quantity of impurities 6a,b is limited to 0.05%, in the
recently published European Pharmacopoeia monograph of
meloxicam,14 while the total allowed quantity of impurities is
0.3%.
When applying route B, formation of the N-methylated
impurity (6a) can apparently be explained with dimethylation
to a minor extent. On the other hand, when 1 is synthesised
from esters 3 via route A, formation of impurity 6 (R ) Me or
Et, depending on 3) is less evident. Nevertheless, both ester 3
itself or the alcohol (ROH) formed in the condensation reaction
can act as alkylating agents; thus, they can alkylate the primarily
formed 1 under the harsh reaction conditions needed for the
amidation (e.g., xylene, reflux, 24 h). Vigano et al. used ethyl
ester 3b as starting material of the condensation reaction, and
crude 1 obtained was contaminated with 6b in a quantity of
0.23-0.78%.15
is not allowed in the pharmaceutical industry any more. Luger
et al. found tetrahydrofuran to be an appropriate crystallization
solvent for obtaining polymorph Form I,6 however, the detailed
methodology of purification is not disclosed. A recent patent
application claims a laborious process for the recrystallization
of crude 1 from acetone.16 Acetic acid is also described as
recrystallization solvent, but in this case acetic acid solvate is
formed instead of Form I base.17 Since no purity data can be
found in the above processes, their purification potential can
not be evaluated.
The preparation of sodium salt of 1 has been described in
the basic patent of meloxicam.8 Instead of recrystallization,
formation of 1 and subsequent precipitation by acidification
emerged as an alternative procedure for the purification of the
crude product. The salification-reacidification process was first
described in a patent application, using sodium hydroxide.7
However, the authors did not use this step for the purification
of 1, they rather aimed at synthesizing new polymorphs of 1.
HPLC purity of the product is not disclosed in the patent
application. Vigano et al.15 used sodium alcoholates for the
formation of the sodium salt from crude 1, then the methanolic
solution of the sodium salt obtained was reacidified to give 1.
Nevertheless, similarly to recrystallization of 1, this method also
proved to be inefficient for the reduction of the quantity of 6
Removal of derivatives 6 and that of other eventual impuri-
ties is primarily described in the literature by recrystallization
from 1,2-dichloroethane.8 Nonetheless, use of 1,2-dichloroethane
(12) For analogous thiazole N-alkylation leading to N-[3-alkyl-1,3-thiazol-
2(3H)-ylidene]-carboxamide derivatives with Z configuration, see: (a)
Ohta, H.; Ishizaka, T.; Tatsuzuki, M.; Yoshinaga, M.; Iida, I.;
Tomishima, Y.; Toda, Y.; Saito, S. Bioorg. Med. Chem. Lett. 2007,
17, 6299–6304. (b) Manaka, A.; Ishii, T.; Takahashi, K.; Sato, M.
Tetrahedron Lett. 2005, 46, 419–422.
(13) For papers discussing the simultaneous formation of products alkylated
at the carboxamide nitrogen and the thiazole nitrogen atoms, see: (a)
Hadida Ruah, S. S.; Grootenhuis, P. D. J.; Miller, M. T.; Hamilton,
M. Preparation of mainly N-thiazolyl carboxamides as modulators of
ATP-binding cassette transporters. PCT Pat. Appl. WO 2005/075435,
2005. Chem. Abstr. 2005, 143, 229835; example 28, (E)-(Z) isomerism
not discussed. (b) Masuda, N.; Yamamoto, O.; Fujii, M.; Ohgami, T.;
Moritomo, A.; Kontani, T.; Kageyama, S.; Ohta, M. Synth. Commun.
2005, 35, 2305–2316.
(16) Venkataraman, S.; Kumar, M. K.; Purandhar, K.; Reddy, B. K.; Reddy,
L A.; Kondaiah, G. C.; Sreenath, K. Process for the preparation of
crystalline form of meloxicam. U.S. Patent Appl. 2006/025408, 2006.
Chem. Abstr. 2006, 144, 177433.
(17) (a) Trummlitz, G.; Sieger, P.; Werthmann, U.; Soyka, R.; Luger, P.
Novel modification of 2H-1,2-benzothiazine-3-carboxamide-4-hy-
droxy-2-methyl-N-(5-methyl-2-thiazolyl)-1,1-dioxide (meloxicam) in
form of a crystalline acetic acid solvate and use as drug. Ger. Pat.
Appl. DE 10245882, 2004. Chem. Abstr. 2004, 140, 390403. (b) The
PCT equivalent of this German patent application is: Trummlitz, G.;
Sieger, P.; Werthmann, U.; Soyka, R.; Luger, P. PCT Pat. Appl. WO
2004/031183, 2004.
(14) European Pharmacopoeia (Ph. Eur.) Suppl. 6.3, 2009; 2373.
(15) Vigano, E.; Landonio, E. Process for the purification of meloxicam.
Eur. Pat. EP 1645559, 2006. Chem. Abstr. 2006, 144, 350700.
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below the very strict level (0.05%) specified in the European
Pharmacopoeia monograph.14 Therefore, an additional refluxing
of the suspension of 1 in acetone had to be applied. The yield
of the salification-acidification step and that of the final
purification is not disclosed.
Results and Discussion
Since 3a is a common intermediate of meloxicam (1) and
piroxicam (2) and this latter had already been manufactured at
our company, we aimed at optimizing the synthetic route starting
from 3a. Moreover, an efficient, robust, and green purification
method of crude 1 was also sought.
Figure 2. Molecular diagram of 7 with the numbering of atoms.
Atomic displacement ellipsoids are drawn at the 50% prob-
ability level.
The first step, i.e. amidation of ester 3a with amine 4 was
published in the basic patent of meloxicam8 in good yield and
under industrially applicable reaction conditions. Since the
patent had already expired, we could apply practically the same
method, without major modifications. We found in accordance
with literature data15 that, depending on the reaction time,
5-20% of impurity 6a was formed in the amidation reaction.
Despite the numerous papers dealing with meloxicam, the
synthesis and characterization of impurity 6a, to the best of our
knowledge, have not been published in the literature. Hereby,
we have synthesised an authentic sample of 6a Via N-alkylation
of 1, at the thiazole nitrogen atom, and characterized it using
spectroscopic methods. The fact that the newly introduced
methyl group is attached to the thiazole N atom and not to the
amide nitrogen was proved by NOE and MS fragmentation
experiments. Irradiation of the thiazole C(4′)-H atom at 7.43
ppm resulted in interactions not only with the thiazole
C(5′)-CH3 moiety at 2.32 ppm, but also with another signal
at 3.74 ppm, which later can be assigned to the N(3′)-CH3 group.
The m/z ) 113 fragment (C5H7NS) in the MS spectrum, which
corresponds to the N-methylated thiazole ring, also supports
this statement. Determination of the geometry of the double
bond in 6a would necessitate structure determination by single-
crystal X-ray diffraction; however, we did not succeed in
obtaining appropriate crystals from 6a. It is noteworthy that
impurity 6a has been published in the Ph. Eur. monograph14 in
the form of (Z) isomer, although no published data prove either
the position of the newly introduced methyl group or the
geometry of the newly formed double bond.
preliminary experiments were performed with various KOH
amounts and concentrations. It was found that the amount of
precipitated 7 increased strongly with increasing excess of KOH.
On the other hand, a very high excess of KOH was considered
to be disadvantageous because of the treatment of mother liquor
and the sulfated ash test of the drug substance. For technological
reasons, more concentrated solutions were preferred. As a result
of these experiments, use of 5 equiv of KOH in a 23 w/w%
KOH solution (30 g KOH in 100 mL water) proved to be
optimal. Thus, to the clear yellow solution obtained after the
filtration, a 23 w/w% KOH solution containing 5 equiv of KOH
was added, and the precipitated yellow crystals of 7 were filtered
off in high yield (81%, calculated for starting material 3a) with
an HPLC purity >99.90%, the amount of impurity 6a being
below 0.03%. Our experiments revealed that the solubility of
7 in aqueous KOH solutions showed a maximum at a
concentration of 0.5 w/w%. Therefore, 7 was dissolved in a
mixture of 0.5 w/w% aqueous KOH solution and ethanol, and
then hydrochloric acid was subsequently added until pH ) 6,
resulting in high-purity 1, as Form I polymorph. HPLC purity
of the drug substance 1 thus obtained exceeded 99.95%, and
the amount of impurity 6a was below 0.03%. The efficiency
of this purification procedure is best demonstrated by the fact
that even a crude batch of 1 containing 12% of impurity 6a led
to a pure drug substance, which fulfilled the strict requirements
of the European Pharmacopoeia.14
Meloxicam potassium salt monohydrate (7, Figure 2) is a
1
novel salt. Its structure was confirmed by H NMR, MS, and
For the further purification of crude 1, obtained in the
amidation step, recrystallization from 1,2-dichloroethane has
been first performed as a reference method.8 However, it was
found that the recrystallized product contained impurity 6a in
a quantity exceeding 0.2%.
When seeking an efficient purification method, we found
surprisingly that potassium salt of 1 crystallized from aqueous
KOH solution in its monohydrate form (7, Figure 2), in high
purity. This observation led us to a very simple and robust
process. Crude meloxicam obtained from 3a was first treated
with an equimolar amount of KOH in an aqueous solution.
Since the solubility of 7 in water increased substantially between
ambient temperature and 50 °C but there was no further
significant increase up to 80 °C, 50 °C was found to be the
optimal temperature. While 7 remained in the solution, impurity
6a did not form a potassium salt and could be removed by
filtration. For salting out 7 with an excess of potassium ion,
IR spectra, single-crystal X-ray diffraction, and elemental
analysis; furthermore, it was characterized by DTG and DSC
measurements. The water content was measured by the con-
ventional Karl Fischer method, and DTG corresponds to the
calculated value of the monohydrate form. The salt is thermally
stable; loss of water does not occur below its melting point
(170-171 °C).
Conclusion
The novel meloxicam potassium salt monohydrate is a
valuable intermediate in the synthesis of high-purity meloxicam
drug substance. The solubility of this salt form can be
extensively altered with pH and K+ concentration of the aqueous
solution. On the contrary, the most crucial and common
impurity of meloxicam, i.e. N-methylated derivative 6a, being
present in crude meloxicam in a relatively large quantity, does
not form a water-soluble potassium salt under the same
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569

conditions; thus, it can be efficiently removed. The new
manufacturing process18 is not only simple, efficient, and high-
yielding, but it is also environmentally friendly, since it applies
aqueous media for the purification of the drug substance, thereby
circumventing recrystallization from chlorinated organic solvents.
was filtered, the filter cake was washed with xylene (50 mL)
and ethanol (80 mL) and dried at room temperature to give a
mixture of the title product and charcoal (total mass: 43.0 g).
The crude product contained ∼12% of 6a.
Pilot-Plant Process. A 630-L enamel-lined autoclave was
equipped with a cambered paddle stirrer, a pressure gauge, a
thermometer, an oil heating jacket, a valve for inert gas inlet,
and a receiver with a flush-out valve. Into the autoclave, purged
with argon gas, were introduced 5-methyl-1,3-thiazol-2-amine
(4, 15.6 kg, 136.2 mol), charcoal (6.0 kg), 4-hydroxy-2-methyl-
2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (3a, 36.0 kg,
133.7 mol), and finally xylene (450 L). The suspension was
heated to reflux (138-142 °C) under argon atmosphere and
stirred for 24 h. Meanwhile, the methanol formed in the
condensation reaction was distilled off with xylene; the low
intensity of distillation was maintained with the temperature-
controlled oil heating. The total quantity of the distilled xylene/
methanol mixture was 125-150 L. After 24 h reaction time,
the suspension was cooled to 30-35 °C and centrifuged, and
the filter cake was washed on the centrifuge with xylene (50
L). The obtained crude substance, containing charcoal, was
suspended in the autoclave with ethanol (85 L) for 30 min at
30-35 °C, then it was centrifuged; finally the filter cake was
washed on the centrifuge with ethanol (30 L) to give 50-60
kg charcoal-containing substance.
Experimental Section
General Remarks. All melting points were determined on
a Bu¨chi 535 capillary melting point apparatus and are uncor-
rected. IR spectra were obtained on a Bruker IFS-113v FT
spectrometer in KBr pellets. Elemental analyses were performed
1
on a Perkin-Elmer 2400 analyzer. H and 13C NMR spectra
were recorded in DMSO-d6 on a Varian Unity Inova 500
spectrometer (500 and 125 MHz for 1H and 13C NMR spectra,
respectively), using TMS as internal standard. Chemical shifts
(δ) and coupling constants (J) are given in ppm and in Hz,
respectively. For the NOE measurements, the difference pulsed
field gradient nuclear Overhauser enhancement (DPFGNOE)
pulse sequence was applied. Mass spectrometry measurements
were run on Thermo Finnigan LCQ Advantage ion trap MS/
MS instrument, coupled with an HP1090 HPLC (column:
Phenomenex MercuryMS Luna C18(2) 20 mm × 4.0 mm, 3
µm, acetonitrile/water gradient method: 5-95% acetonitrile/3
min, 0.1% formic acid), in positive electrospray ionization mode
(4.5 kV spray voltage, 150-1000 mass range, 45% normalized
collision energy). For purity determination, HPLC measure-
ments were run on a Kromasil 100-5 C-18 column (150 mm
× 4.6 mm, 5 µm) with linear gradient elution at a flow rate of
1 mL/min. Eluent A: 20 mM KH2PO4 buffer solution (pH )
6.8)/methanol ) 70/30 (v/v); eluent B: 20 mM KH2PO4 buffer
solution (pH ) 6.8)/methanol ) 30/70 (v/v); 0 min: 100%
eluent A, 30 min: 100% eluent B. Column temperature was 30
°C, UV detection occurred at λ ) 260 and 350 nm. TG
measurements were run on a Perkin-Elmer Pyris 1 TG apparatus
at a heating rate of 10 °C/min, with a 10 mg of sample, Al
sample holder and N2 as flushing gas. DSC was performed with
a Perkin-Elmer DSC 7 calorimeter at a heating rate of 10 °C/
min, with a 2 mg sample, Al sample holder, without flushing
gas. Water content was measured using the traditional Karl
Fischer method. Conditions of the single-crystal X-ray measure-
ment are described in detail in the Supporting Information.
Crude Meloxicam (1). Laboratory Method. Under argon
atmosphere, xylene (350 mL) was introduced into a flask, which
was equipped with a condenser and a receiver. Methyl 4-hy-
droxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide
(3a, 35.0 g, 0.130 mol), 5-methyl-1,3-thiazol-2-amine (4, 15.0 g,
0.131 mol), and charcoal (6.0 g) were added under stirring. The
suspension was heated to reflux temperature over a period of
30 min and was kept at this temperature for 24 h. Heating was
maintained with an oil bath at such an intensity that only a
minimal amount (2-3 mL/h) of distillate was formed and
collected in the receiver during the reaction. The reaction
mixture was cooled to ambient temperature. The crude product
Meloxicam Potassium Salt Monohydrate (7). Laboratory
Method. To the mixture (43.0 g) of crude 1 and charcoal, which
was obtained in the above reaction, 0.5 w/w% aqueous KOH
solution (1200 mL, 0.107 mol) was added, and the suspension
was stirred at 50 °C for 1 h. The undissolved residues were
filtered off with a G4 glass filter. To the clear yellow filtrate, a
solution of KOH (30 g KOH in 100 mL of water, 23 w/w%,
0.536 mol) was added dropwise, over a period of 30 min.
During the addition, a yellow product precipitated. The suspen-
sion was stirred at 10 °C for 2 h and filtered. The precipitate
filtered off was washed with distilled water (150 mL) and dried
at room temperature to give 42.9 g (81%, calculated for 3a) of
yellow crystals. Mp 170-171 °C. Water content by the Karl
Fischer method: 4.6% (calcd 4.6%). Loss of mass by TG
between 175 and 245 °C: 4.75%. HPLC purity: >99.90%. IR
(KBr, cm-1): ν 3462, 3364, 2919, 1603, 1560, 1517, 1392,
1
1325, 1168, 1151. H NMR (DMSO-d6, TMS, 500 MHz): δ
14.39 (s, 1H, NH), 8.04 (d, 1H, J ) 7.7 Hz, H-5), 7.72 (t, 1H,
J ) 7.9 Hz, H-6), 7.64 (d, 1H, J ) 7.9 Hz, H-8), 7.62 (t, 1H,
J ) 7.7 Hz, H-7), 7.00 (d, 1H, J ) 1.3 Hz, H-4′), 2.77 (s, 3H,
N-CH3), 2.32 (d, 3H, J ) 1.1 Hz, Ar-CH3) ppm. 13C NMR
(DMSO-d6, TMS, 125 MHz): δ 166.11 (C-4), 163.44 (C)O),
157.77 (C-2′), 136.08 (C-4a), 135.67 (C-8a), 134.47 (C-4′),
132.06 (C-6), 130.14 (C-7), 127.14 (C-5), 123.84 (C-5′), 122.62
(C-8), 107.82 (C-3), 39.26 (N-CH3), 11.41 (Ar-CH3) ppm.
Elemental analysis for C14H12KN3O4S2 ·H2O (407.52): calcu-
lated C 41.26, H 3.46, N 10.31, S 15.74%; found C 41.20, H
3.52, N 10.21, S 15.61%.
Pilot-Plant Process. A 1400-L enamel-lined autoclave was
equipped with a turbine stirrer, a steam heating jacket
(water-methanol cooling), a pressure gauge, and a thermom-
eter. Potassium hydroxide (6.30 kg, 112.3 mol) was dissolved
in water (1260 L) under stirring. To this 0.5 w/w % aqueous
(18) Mezei, T.; Simig, Gy.; Molna´r, E.; Luka´cs, Gy.; Porcs-Makkay, M.;
Volk, B.; Hoffmanne´ Fekete, V.; Nagy, K. Mesterha´zy, N.; Krasznai,
´
Gy.; Vereczkeyne´ Dona´th, Gy.; Ko¨rtve´lyessy, Gy.; Pe´csi, E. Process
for preparation of high-purity meloxicam and meloxicam potassium
salt. PCT Pat. Appl. WO 2006/064298, 2006. Chem. Abstr. 2006, 145,
83359.
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potassium hydroxide solution was introduced the charcoal-
containing substance obtained in the above reaction, and the
mixture was stirred until complete dissolution (∼1.5 h) at
50-55 °C. The charcoal and undissolved residues were filtered
off with a pressure filter, into a 3000-L enamel-lined autoclave,
which was equipped with a cambered paddle stirrer, a steam
heating jacket (water-methanol cooling), a pressure gauge, and
a thermometer. The filter cake was washed with warm (50-55
°C) water (150 L). To the yellow filtrate, a previously prepared
aqueous KOH solution (30.9 kg KOH in 105 L water) was
added over a period of 1 h, and meloxicam potassium salt
monohydrate precipitated as a yellow solid. After the addition,
the suspension was cooled to 10-15 °C at a cooling intensity
of 15 °C/h and centrifuged, and the cake was washed on the
centrifuge with cold (10-15 °C) water (150 L). The obtained
wet meloxicam potassium salt monohydrate weighed 35-45
kg. The wet product was dried in a vacuum tray dryer at 80-85
°C for 20 h to give 36-38 kg (66-69%, calculated for 3a) of
yellow solid. The end-point of drying was determined by a loss
on drying control (e1.0%). The quality of the meloxicam
potassium salt monohydrate was controlled by TLC (total
impurity e1.0%) and HPLC (assay g99.5%).
Meloxicam (1), Polymorph Form I. Laboratory Method.
Meloxicam potassium salt monohydrate (7, 34.1 g, 83.7 mmol)
was dissolved in a mixture of 0.5 w/w% aqueous potassium
hydroxide solution (1500 mL, 134 mmol) and ethanol (25 mL).
The solution was stirred at 40-45 °C for 30 min. Charcoal
(2.0 g) was added to the yellow solution, and it was filtered off
with a G4 filter after an intense stirring of 10 min. To the filtrate,
HCl solution (20 mL of cc. HCl + 80 mL of water) was added
at 30 °C over 30 min. The suspension was stirred at 10 °C for
2 h and was filtered; the product was washed with distilled water
(200 mL) and dried in Vacuo (10 mmHg) at 80 °C for 6 h;
28.5 g (97%, calculated for 7) title product was obtained. Mp
246-248 °C (lit. mp 254 °C,8 254-255 °C19). IR,7,17,201H
NMR,8,20 and XRPD7 are in accordance with literature data.
Elemental analysis for C14H13N3O4S2 (351.41): calculated C
47.85, H 3.73, N 11.96, S 18.25%; found C 47.80, H 3.82, N
11.87, S 18.20%. HPLC purity: > 99.90%, Imp. C, D’ 0.05%,
any other impurity e0.1%. The purity of the product obtained
meets the requirements of Ph. Eur. 6.3.14
cooling), and a thermometer. The filter cake was washed
with warm (50-55 °C) water (2 × 55 L). A previously
prepared aqueous hydrochloric acid solution (16 L of
concentrated HCl in 64 L water) was added to this solution
at 65-70 °C, over a period of 50-70 min. During the
addition, a yellow solid precipitated. After the addition,
the suspension was heated to reflux and kept at this
temperature for 2-2.5 h, and then it was cooled to 25-30
°C and centrifuge; the filter cake was washed on the
centrifuge with water (82 L). The obtained crude wet
meloxicam was suspended in the autoclave in a mixture
of ethanol (84 L) and purified water (82 L), for 1 h at
25-30 °C. Then it was centrifuged, and the filter cake
was washed on the centrifuge with ethanol (56 L). The
thus obtained wet meloxicam weighed 20-24 kg. The wet
product was dried in a vacuum tray dryer at 78-80 °C
for 24 h. The end-point of drying was determined by a
loss on drying control (e0.10%). The dried meloxicam
was sieved to give the obtained meloxicam end-product
19-21 kg (83-91%, calculated for 7) of the title product.
Identification of the product was performed by IR and UV
spectra; the quality was controlled by assay by titration
(99.0-100.5%) and HPLC.
N-[3,5-Dimethyl-1,3-thiazol-2(3H)-ylidene]-4-hydroxy-2-
methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (6a),
Meloxicam Imp. C.14 Method A. Meloxicam (1, 24.0 g, 68.0
mmol) was suspended in DMSO (400 mL). To this
suspension were added an aqueous solution of KOH (10.0
g, 122 mmol in 10 mL water) and methyl iodide (6.0 mL,
96 mmol), and stirring at 25 °C was continued for 24 h.
The reaction mixture was acidified with glacial acetic acid
(14 mL), then water (200 mL) was added. The resulting
suspension was stirred for 1 h, and the precipitate was
filtered and washed with hexane (100 mL). The yellow
crude product (23.4 g, 94%) was recrystallized from DMF
(100 mL). The product was filtered and washed with EtOH
(50 mL) to give 7.0 g (28%) of pale-yellow crystals. Mp
> 250 °C. IR (KBr, cm-1): ν 3066, 1588 (C)O), 1561,
1
1515, 1418, 1337, 1179. H NMR (DMSO-d6, TMS, 500
MHz): δ 14.93 (bs, 1H, OH), 8.04 (dd, 1H, J ) 7.5, 1.8
Hz, H-8), 7.87 (t, 1H, J ) 7.2 Hz, H-7), 7.86 (dd, 1H, J
) 7.5, 1.5 Hz, H-5), 7.82 (t, 1H, J ) 7.2 Hz, H-6), 7.43
(d, 1H, J ) 1.5 Hz, H-4′), 3.74 (s, 3H, Nth-CH3), 2.91
(s, 3H, SO2NCH3), 2.32 (d, 3H, J ) 1.4 Hz, Cth-CH3)
ppm. NOE (7.43 ppm): 3.74, 2.32 ppm. 13C NMR (DMSO-
d6, TMS, 125 MHz) δ 169.67 (C-4), 164.14 (C-9), 155.45
(C-2′), 134.55 (C-8a), 133.03 (C-6), 132.25 (C-4′), 129.25
(C-4a), 126.13 (C-7), 125.88 (C-5), 123.28 (C-8), 122.39
(C-5′), 115.33 (C-3), 37.80 (SO2NCH3), 36.08 (Nth-CH3),
12.03 (Cth-CH3) ppm. MS (m/z): 366 (M + 1), 155
(C6H7N2OS), 113 (C5H7NS), 100 (C4H6NS). Elemental
analysis for C15H15N3O4S2 (365.40): calculated C 49.29,
H 4.14, N 11.50, S 17.55%; found C 49.18, H 4.09, N
11.46, S 17.43%.
Pilot-Plant Process. A 1250-L enamel-lined autoclave
was equipped with an impeller stirrer, a pressure gauge,
a steam-warm water heating jacket (water-methanol
cooling)- and a thermometer. Meloxicam potassium salt
monohydrate (7, 27.5 kg, 67.50 mol) was stirred at 50-55
°C in a mixture of water (550 L) and ethanol (139 L),
until complete dissolution (∼1 h). Then the solution was
stirred with charcoal (8.25 kg) at this temperature.
Charcoal and undissolved residues were filtered off with
pressure filter into a 1000-L enamel-lined autoclave,
equipped with a cambered paddle stirrer, a pressure gauge,
a steam-warm water heating jacket (water-methanol
(19) Lazer, E. S.; Miao, C. K.; Cywin, Ch. L.; Sorcek, R.; Wong, H.-C.;
Meng, Z.; Potocki, I.; Hoermann, M.; Snow, R. J.; Tschantz, M. A.;
Kelly, T. A.; McNeil, D. W.; Coutts, S. J.; Churchill, L.; Graham,
A. G.; David, E.; Grob, P. M.; Engel, W.; Meier, H.; Trummlitz, G.
J. Med. Chem. 1997, 40, 980–989.
Method B. Meloxicam (1, 2.0 g, 5.7 mmol) and dimethyl
sulfate (0.47 mL, 4.97 mmol) were added to DMF (20
mL), and the suspension was stirred at 100 °C for 2 h. At
this temperature, it became a clear solution. The reaction
(20) Defazio, S.; Cini, R. J. Chem. Soc., Dalton Trans. 2002, 1888–1897.
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mixture was then cooled and stirred at ambient temperature
for 12 h. The precipitate was filtered off and washed with
EtOH (5 mL) to give 0.80 g (44%) of pale-yellow crystals.
To the crude product thus obtained was added EtOH (20
mL). The suspension was refluxed for 10 min, cooled to
room temperature, stirred for 2 h, and filtered to give
0.77 g (37%) of the title product. Spectral data were
identical to those of the product obtained by Method A.
measurements, Mrs. Mónika Mezo¨va´ri for IR spectra and Ms.
Adrienn Hegedu¨s for DSC and TG analyses of the compounds.
Supporting Information Available
Conditions and interpretation of the single-crystal X-ray
measurement of 7, further bond lengths, bond angles, torsion
angles and CIF structure file. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment
We thank Mrs. Eniko¨ Molna´r for technical assistance, Mr.
Csaba Peltz for MS spectra, Dr. Erika Szila´gyi for HPLC
Received for review February 13, 2009.
OP900031H
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