Note: Descriptions are shown in the official language in which they were submitted.
I 18l~g
This invention is concerned with a process for the prepara-tion of
2-methoxyethyl 4-hydroxy-2-methyl-2~1-1,2-benzothiazine-3-carboxylate 1,1-
dioxide,
q~l ~
~ ~o/~C~13
~ NCH3 ~1)
~0
an ester having special value in the synthesis of piroxicam ~4-hydroxy-2-
methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide l,l-dioxide)
(II)
~ CH3 ~
an antiinflammatory agent of established value in the medicinal art. It
will be noted that in past practice, the acyl radical of compounds of this
type has been sometimes written as
O O
and such compounds alternatively named as 3,4-dihydro-2-methyl-4-oxo-2H-
1,2-benzothiazine l,l-dioxide derivatives. Those skilled in the art will
1~
l g
understand that these are equivalent tautomeric forms of the same compound.
The present invention is intended to encompass both tautomeric forms while
writing only one o~ them as a matter of conven:ience.
Piroxicam was originally disclosed by Lombarclino (United States
Patent 3~591,584). One of the processes or the synthesis of piroxicam
disclosed therein is to react a 3-carboxylic acid ester with 2-aminopyridine.
More specifically, the ester is disclosed as a (Cl-C12) alkyl ester or
phenyl (Cl-C3) alkyl ester. The specific ester described is the methyl
ester, viz.,
~H O
O ~CH3 (III)
~NCH3
0~ ~0
(See also Lombardino et al., J. Med~ Chem. 1~, pp. 1171-1175 ~1971)). A
disadvantage in this otherwise useful process for piroxicam lies in the variable
formation of quantitïes of a highly co]ored byproduct. This highly colored
byproduct, which is removed only by multiple recrystallizations with major
product loss, lends an unacceptable, strong yellow color to the prioxicam
bulk product, even when present at very low levels (e.g., 0.5-1%). This
2~ byproduct has been isolated and determined to have the following structure:
I~CH3 ~IV)
I~ ~
O O
It has been shown that (IV) is actuall~ formed as a byproduct in the reaction,
rather ~han being derived from a contaminant in the precursor. How this
-2-
compound is actually formed in the reaction mixture is not fully understood,
although methods which are direc-ted to rapid removal of the methanol byproduct
as it is formed in the reaction appear to reduce the incidence of piroxicam
batches havin~ unacceptable color. However, these methods are of uncertaitl
dependability and a goal has been to find an ester which is read:ily available
by synthesis and which does not give rise to an ether such as ~IV) as a
troublesome byproduct during conversion to piroxicam.
Alternative syntheses of piroxicam which have been disclosed in the
literature include reaction of 3,4-dihydro-2-methyl-~-oxo-2E-l-1,2-benzothiazine
10 l,l-dioxide with 2-pyridyl isocyanate ~Lombardino, United States Patent
3,591,584), transamidation of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-
carboxanilides wi.th 2-aminopyridine (Lombardino~ United States Patent
3,891,637), cyclization of
~ ~C02(Cl-C3)alkyl
~--So2NCH2CONH~3
CH3
(Lombardino, United States Patent 3,853,862), coupling of a 4-~Cl-C3)alkoxy-
20 2-methyl-2H-1,2-benzothiazine-3-carboxylic acid l,l-dioxide with 2-aminopyridine
followed by hydrolysis of the enolic ether linkage ~Lombardino United States
Patent 3,892,740), coupling of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-
carboxylic acid, via the acid chloride, with 2-aminopyridine ~Hammen, United
States Patent 4,100,347) and methylation Gf 4-hydroxy-N-2-pyridyl-2H-l,
2-benzothiazine-3-carboxamide (Canada Patent 1,069,894).
Another ester related to the methoxyethyl ester of the present
in~lention which has been specifically described in the literature is ethyl
I t8~
~I-hydro~y-2-metllyl-2H-l,2-benzothiazine-3-carboxylate l,l-dioxide (Rasmussen,
United States Patent 3,501,466; see also Zinnes et al., Un;ted States Patent
3,816,628~.
The 2-methoxyethyl ester ~ as been synthesized. In the known
process of converti.ng a corresponding 3-carboxylic acid ester to pi-~oxicam,
this ester has been substituted for the prior art methyl ester (III). Use
of the novel ester ~I) has the surprising advan-tage that the piroxicam so
produced contains no detectable level o-f the expected, highly-colored ether
byproduct ~4-(2-methoxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-
carboxamide)~ of the formula
C 2CH20CH3,~
N ~V)
CH3
O O
analogous ~o the ethor ~IV).
7 4 9
The 2-methoxyethyl ester ~I) of the present invention is readily
prepared from saccharin-2-acetate ester (2-methoxyethyl-3-oxo-2H-1,2-benziso-
thiazoline-2-acetate l,l-dioxide, formula (VI)) by the following sequence oE
reactions
11
CH2COOCH2CH20CH3 (VI)
~ O
CH3CH2CH2~ ¦ rearrangement
0
q ~
OOCH2CI~20CH3 ~VII)
~ methylation
q
9H
~ ~ COOCH2CH20CH3 ~I)
0~ ~0
The rearrangement is carried out by treating the intermediate saccharin-2-
acetic acid ester with an alkoxide, preferably a 2-methoxyethoxide such as
sodium 2-methoxyethoxide in order to avoid the complication o:E transester-
ification, in a polar organi.c solvent such as dimethyl sulfoxide or
dimetllylformamicle. Methylation is accomplished by a methylating agent~
such as dimethyl sulfate or a methyl halide, conveniently methyl iodide, in
a reaction-inert solvent such as a lower ketone, a lower alkanol, formamide,
dimethylformamide or dimethylsulfoxide.
The saccharin-2-acetic acid ester required as starting material
in the above sequence is prepared from saccharin and 2-methoxyethyl chlor-
oacetate in analogy to the method for preparation o the corresponding methyl
ester (Chemische Berichte 30, p. 1267 (1897))J or, less directly, by hydrolysis
of said methyl ester to the corresponding saccharin acetic acid and coupling,
such as via the acid chlorideJ wi~h 2-methoxyethanol.
The reaction of the methoxy ester (I) with 2-aminopyridine to
produce piroxicam,
~1 8 ,~
,~ ~ ~ \ N ~II)
~\ ~ S~ NC 3 H
is generally conducted by mixing the t~o components together in a reaction-
inert solvent system at or near room temperature, and then heating the resultant
system at 115-175 degrees Celsius for a period of about one-half to several
hours. Al~hough it is only necessary that these two reactants be present
in substantially equimolar amounts in order ~o effect the reaction3 a slight
excess of one or the other (and preferably the more readily available amine
base reagent) is not harmful in this respect and may even serve to shift the
ammonGlysis reaction to completion. Preferred reaction-inert organic solvents
for use in the ammonolysis reaction include such lo~er N,N-dialkylalkanamides
as dimethylformamide, dimethylace~amide and the like, as well as such aromatic
--6--
~ ~3 i7~9
hydrocarbon solvents as benzene, toluene, xylene and so forth. In any event,
it is found most helpful and usually sui~able to distill of:E the volatile
alcohol byproduct as it is formed in the reaction and -thereby shift the
am~lonolysis equillbrium to completion in -this manner. In the presen-t
instance, the most highly preferred so]vent is xylene, since byprod~lct
2-methoxyethanol is ef-flclently removed as a lower bolllng azeotrope. The
volume of xylene can be maintained by the addition of more xylene during
distillation. After removal of the alcohol and completion of the reaction,
the resulting piroxicam is conveniently recovered by cooling and simple
filtration of the crystallized product. If desired, the piroxicam is recry-
stallized from dimethylacetamide/acetone/water.
The present invention is illustrated by the following examples.
However, it should be understood that the invention is not limited to the
specific details of these examples.
~XAMPLE I
~-~2-Methoxyethoxy)~2-methyl-N-2-pyridyl-2H-
1,2-benzothiazine-3-carboxamide l,l-Dioxide
~04-(2-methoxyethyl)piroxicam)
(V)
In a flame dried flask maintained under a dry nitrogen atmosphere,
piroxicam (1~814 g., 5.47 mmoles) was dissolved in 13 ml. of dry dime-thyl-
form~mide. Sodium hydride (0.131 g., 5~47 mmoles) was added slowly in
portions and the resulting mixture heated at 40-45 degrees Celsius for abo~l-t
3 hours, until such time as ~he sodium hydride had completely reacted. 2-
Methoxyethyl chloride ~1.0 ml., 0.94 mmoles) and sodium iodide (0.821 g.,
7 ~l ~
5.~7 mmoles) were then aclded and the reaction then heated at 89 degrees
Celsius for 51 hours. The cooled reaction mixture was dlluted with about
50 g. of ice and extracted with five 10 ml. portions of me-thylerle chloride.
The organic extracts were com~inedl back washed with seven l5 ml. portions
of water~ washed once with brine, dried over anhydrous magnesium swlfate~
filtered and evaporated to an oil (1.44 g.). The oil was triturated with
ether, yielding solids (0.84 g.), which were recrys~allized ~rom acetonitrile
(yielding 0.57 g.). Recrystallized product (0.45 g.) was chromatographed
on silica gel ~13.5 g.), eluting with 2:3:6 methanol:cyclohe~ane:ethyl
acetate and monitoring by TLC ~same eluant) with phosphomolybdic spray.
Early cuts, containing clean product, were combined, evaporated in vacuo to
solids, Ihe solids were chased with carbon tetrachloride an~ dried under
high vacuum yielding 04-~2-methox~ethyl~piroxicam. ~0.31 g.; m.p. 155-157
degrees Celsius; Rf 0.5 ~2:3:6 methanol:cyclohexane:ethyl acetate); Rf 0.4
~10:4:3 xylene:methallol:water); pnmr/CDC13/delta 3.15 (s, 3H), 3.35 (s, 3H),
3.68 ~m, 2H), 4.23 (m, 2H), 7.2 (m lH), 7.9 (m, 5H), 8.9 (m, 2H), 10.2
(broad s, lH)).
EXAMPLE 2
2-Methox~eth_1 2~ -Ch oroacetate
Maintaining a temperature of -5 to 5 degrees Celsius, 2-chloro-
acetyl chloride ~11.2 g., 0.10 mole) in 15 ml. of methylene chloride was
added dropwise over 1 hour to a cold solution of pyridine ~8.0 g., 0.11 mole)
and 2-methoxyethanol ~7.6 g., 0.10 mole) in 35 ml. of methylene chloride.
The reaction mixture was stirred for a further 1 hour at 0 degrees Celsius,
warmed to room temperature and extracted with two 50 ml. portions of wa~er.
The two aqueous extracts were combined and back-washed with 50 ml. of
(3
chlorofrm- Th~ origlnal organic layer and chloroform back-wash were
combined and ~ashed with 50 ml. o~ 5% copper sulfate. The 5% copper sulfate
wash was backwashed wi~h 25 ml. of chloroform and recomb;ned with the
organic phase. ~inally, khe organic phase was washed with 50 ml. of brine,
treated with activated carbon and anhydrous magnesium sulfate, ~iltered,
concentrated to an oil and distilled to yield 2-methoxyethyl 2-chloroacetate
~14.1 g.; b.p. 80-82 degrees Celsius.)
EXAMPLE 3
2-Methoxyethyl 3-Oxo-2H-1,2-benzisothiazoline-
2-acetate l,l-Dioxide
~2-Methoxyethyl Saccharin-2-acetate)
~I3
Sodium saccharin ~18 g., 0.088 mole) and 2-methoxyethyl 2-chloro-
acetate ~13.4 g. J 0.088 mole) were combined in 40 ml. of dimethylformamide
and heated at 120 degrees Celsius for 4 hours. The reaction mixture was
cooled to 25 degrees Celsius~ poured into 100 ml. of waterJ granulated at
5-10 degrees Celsius l`or 0.5 hour, filtered with water wash and air dried
to yield 2-methoxyethyl saccharin-2-acetate ~23.2 g., 90%; m.p. 91-92 degrees
Celsius; m/e 299; ir~KBr) 2985 cm 1)
EXAMPLE 4
2-Methoxyethyl 4-llydroxy-2H-1,2-
benzothiazine-3-carboxylate l,l-dioxide
Under a dry nitrogen atmosphereJ 2-methoxyethanol (72.9 ml., 0.924
mole) was charged to a stirred, flamedried flask. Sodium spheres (10.6 g.~
0.463 mole; pentane washed and slightly flattened with tweezers) were added
_g_
I L~17~3
portionwise over 2 hours, keeping the temperature of the reaction mix-ture
in the range of 25-~5 degrees Celsius. After an additional 1 hour o-f stirring,
a fur-ther 10 ml. o~ 2-methoxyethanol was added and the reaction mixture
warmed to 57 degrees Celsius. On slight cooling the reaction mix-ture solicl-
ified. The reaction mixture was thinned with 75 mL. o~ dry dime-thylsul~oxicle
and a single remaining particle of soclium metal removed mechanically. The
2-methoxyethyl saccharin-2-acetate (50 g., 0.167 mole) in 70 ml. of warm, dry
dimethylsul~oxide was added dropwise over 20 minutes. The reaction mixture
was stirred for 1 hour at ambient temperature, quenched into a mixture of
concentrated hydrochloric acid ~276 ml.) and water (1.84 1.), maintaining
the temperature of the quench at 20-25 degrees Celsius by an ice-water bath
and rate of addition. The slllrry was granulated at 6-8 degrees Celsius for
1 hour, filtered with cold water wash and dried in air to yield 2-methoxy-
ethyl ~-hydroxy-2H-1l2-benzothiazine-3-carboxylate l,l-dioxide ~32.8 g.,
66%; m.p. 120-122 degrees Celsius; ir(KBr) 3~8, 3226 cm ).
EXAMPLE 5
2-Methoxyethyl ~-Hydroxy-2-methyl-21~-1,2-
benzothiazine-3-carboxylate l,l-Dioxide
~I)
2-Methoxyethyl ~-hydroxy-2E~-lJ2-benzothiazine-3-carboxylate 1,1-
dioxide ~31.0 g., 0.1035 mole) was combined with 230 ml. of acetone and cooled
to 10 degrees Celsius. Methyl iodide ~21.9 g., 0.155 mole) was added,
followed by the dropwise addition, over 10 minutes, of sodi~ hydroxide
~103.5 ml. of lN). The cooling bath was removed and the reaction mixture
allowed to slowly warm to room temperature ~about ~5 minutes~, then heated
-].0-
7 ~ '3
at 35 degrees Celsius for 2 hours and finally at 39-40 degrees Celsius for
16 hours. The reaction mixture was cooled to room temperature, diluted with
200 ml. of acetone, treated with activated carbon, flltered and concentrated
in vacuo at 0-5 degrees Celsius to about 50 ml. The resulting slurry was
filtered, and solids washed witZ~ ice-water and then dried in vacuo to yield
2 m0thoxyethyl 4-hydroxy-2-methyl-2H-1l2-benzothiazine-3-carboxylate 1,1-
dioxide (29.26 g., 90%; m.p. 106-107.5 degrees Celsius; m/e 313; ir~KBr)
3345, 2~41, 1684, 1351, 1053 cm 1~.
EX~IPLE 6
4-~lydroxy-2-methyl-N-2-pyridyl-2~1-1,2
benzothiazine-3-carboxamide l,l-Dioxide
(Piroxicam)
~II)
2-Methoxyethyl 4-hydrox~-2H-1,2-ben~othiazine-3-carboxylate 1,1-
dioxide ~28 g., 0.08~ mole) and 2-aminopyridine ~9.26 g., 0.098 mole) were
combined with 500 ml. of xylene in a 1 liter flask equipped with an additional
funnel and a reflux, variable take-off distillation head. The stirred reaction
mixture was heated to relux and the xylene distilled at the rate of approx-
imately 100 ml./hour, while maintaining the pot volume almost constant bythe addition of fresh xylene. After 6 hours, the head temperature, which had
been relatively constant at 134 degrees Celsius, rose to 142 degrees Celsius
and reflux rate slowed. The reaction mixture was then cooled in an ice-bath
and the precipitated solids recovered by filtration, with hexane for transfer
and wash, and dried at 45 degrees Celsius in vacuo to yield piroxicam ~28.5 g.,
96%; m,p. 167-174 degrees Celsius). This product was examined by high
perform~nce liquid chromatography using 60:40 O.lM Na2~1P0~ adjusted to p}l 7.5
-Ll-
7 ~1 g
with citric acicl:methanol on Micro-Bonda pak C18 (Trademark of Waters
Associates for a standard hplc column packing consisting of siloxy sub-
stituted silica coated on micro-glass beads.) Under the conditions employed,
piroxicam has a rete.ntion time of about 6 m.inutes, whereas the potential
contaminant, 04-methoxyethylpiroxicam, has a retention time of 16.5 minutes.
None of the potential contc~minant was detected in the product o the present
Example .
For purposes o:E recrystallization, the above piroxicam ~25 g.)
was taken up in 190 ml. of dime~.hylacetamide at 70-75 degrees Celsius,
treated with 1.26 g. of activated carbon at 75-80 degrees Celsius and
filt0red through diatomaceous earth with 55 ml. of warm dimethylacetamide
for transfer and wash. A mixture of 173 ml. of ace~one and 173 ml. of watex
was cooled to 5-10 degrees Celsius. The carbon-treated filtrate was added
slowly over 10-15 minutes to the chilled aqueous acetone, and the resulting
crystals granulated at 0-5 degrees Celsius for 5 minutes. Recrystallized
piroxicam was recovered by filtration with 154 ml. of cold methanol for
ui~
tran~sfer and wash. Yield: 18.75 g,, 75%; ir~ r~ mull) identical with
authentic piroxicam.
Tradc mar ~-
-12~
