Note: Descriptions are shown in the official language in which they were submitted.
-1- 72222-77
A method for the preparation oE a pharmac0utically usable
benzothiazine dioxide, and an intermediate for use in the
method
The present invention relates to a method for the preparation
of a pharmaceutically useful 2-methyl-4-hydroxy-2H-1,2-
benzothiazine-l,l-dioxide-3-(N-2-pyridyl)-carboxamide, i.e.
piroxicam, having the formula
OH
~-CH 3
and to a new intermediate, 2-methyl~4-mesyloxy-2H-1,2-
benzothiazine-l,l~dioxide-3-carboxylic acid, for carrying
out the said reaction. The formula of the intermediate is
CH3-S02-0
COOH
J S,N-CH3 II
Piroxicam has proved to be a highly usable anti-inflammatory
and analgesic agent which does not have the harmful effects
steroids usually have. Methods for the preparation of
piroxicam have been presented in numerous Finnish and foreign
patent specifications, of which can be mentioned Finnish
Patents 51189, 59592, 62297 and 63573.
The best method with respect of yield is presented in Finnish
Patent 51189. In the method of Patent 51189, the 3-carboxylic
acid ester of 3,4-dihydro-4-oxo-2H-1,2-benzothia~ine-carboxamide-
l,l-dioxide is allowed to react with an at least equimolar amount
of an amine which contains the desired aromatic part, which in
the case of piroxicam is pyridyl. The yield obtained using the
'; J
~2~ 6~;
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~ethod in question is about 70%.
A somewhat better yield is obtained by a similar to but different
from the method according to Finnish Pate~ 51189 only with
respect to the esterized group. Thus, in Pate~t 51189, methyl
ester is used as the ester of the carboxylic acid in the 3-
position, and in the other method methoxyethyl ester is used
instead.
The above-mentioned methods based on an aminolysis reaction of
the respective ester of 1,2 benzothiazine-3-carboxylic acid
ln and 2-aminopyridine are, it is true, suitable for industrial
production owing to their yield and also to their other properties,
but their disadvantages include the use of a high temperature,
involving temperatures of boiling xylene, and a very long reaction
time, which is usually more than 20 hours. Both the temperature
and the long reaction time tend to have a decomposing effect on
the product, in which case -the purification of the product is
difficult and the yield tends to decrease owing to
decomposition. Purification is further complicated especially
because the methods in question produce colored byproducts which
require numerous leachings and recrystallizations, and also other
steps, in order to yield an acceptable final product.
Another method for the preparation of piroxicam that is worth
mentioning is presented in Finnish Patent 63573. In the said
specification the starting material is a compound having
the formula
~ CONHR2
~ S,~-CH3
b2
~2~
wherein Z is isopropoxy and R2 is 2-pyridyl when the product
desired is piroxicam, The compound is contacted with an
inor~anic acid, whereby ~he isopropoxy group is caused to
break off. The total yleld ob~alned by thls method 1~ very
poor, for before the breaking off of the isopropoxy group
the preparation also includes ~he llnking of an aminopyridyl
group to the benzothiazine, which is preceded by the conversion
of the 3-acetyl compound to the respective 3 carboxylic acid
Thus the total yield o~tained is only about 2 ~. The dis-
advantages of the said method are not limited to the poor
yield, for the method includes several steps using detrimental
solvents such as benzene and strong acid such as 32 %
hydrobromic acid, by means of which the isopropyl group is
broken off. The method is not suitable for industrial
production.
The object of the present invention is to provide a method
by which piroxicam can be produced with a very good yield
and by using reaction steps which are both easy to carry
out and rapid to complete. It is also an object to obtain
as pure a final product as possible.
The method of the invention for the preparation of piroxicam,
2~methyl-4-hydroxy-2H-1,2-benzcthiazine-l,l~dioxide-3 (N-2-
pyridyl) carboxamide,
OH
~-HN~3 I
b2
is characterized in that 2-methyl-4-mesyloxy-2H-l,l-
benzothiazine-l,l-dioxide-3-carboxylic acid or its solvate
with dimethyl acetamide
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CH3~SO2-O /CH3 ~
,C0~N (C 3 \ ) II
(n is O or 1)
is reacted with 2-aminopyridine of the formula
H2N - ~ III
in ~he presence o~ thionyl chloride in an inert solvent.
The starting material II and 2-aminopyridine are used in
approximately equimolar amounts, whereas thionyl chloride
can be used in excess, for example about a double amount.
Inert solvents suitable for use include chlorinated hydro-
carbons such as dichloromethane (boiling point about 40C), or1,2-dichlorethane (boiling point 83-84C), acetonitrile
~boiling point about 82C), etc. The reaction is conveniently
carxied out at a temperature of about 40 to 85C, particularly
by reflux at a boiling point of the solvent. The reaction
usually reaches completion within 2-3 hours. When desired, it
is also possible to use in the reaction a tertiary amine such
as 2,6-dimethyl pyridine, a]though it has very little effect
on the reaction.
When the method of the invention is used for the preparation
of piroxicam, the entire reaction takes place under quite
mild conditions. Thus the reaction with 2-aminopyridine occurs
at a moderate temperature and rapidly. Likewise, the mesyl
group can be removed under very mild conditions, for the
breaking off takes place immediately after the acylation
reaction, by using a dilute NaOH solution.
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Owing to the low temperature, the short reaction time, and
the mild conditions the piroxicam obtained as the final
product is very pure, whereupon several of the steps used for
purification in known methods can be eliminated. Likewise, owing
to the factors mentioned above, the yield is high, on average
86~. The method of the invention further includes one
surprising feature, namely that an acid acceptor is not
necessarily needed in the method at all. Evidently the N,N-
dimethyl acetamide used, which forms a solvate with the
starting material, being an aprotic solvent, effectively
catalyses the acylation reaction of 2-aminopyridine, whereupon
the acid acceptor becomes unnecessary.
The invention also relates to an intermediate of the formula
CH3-S02-0
COOH II
N-CH
2
which is a new compound. Especially for the method according
to the present invention it is advantageous that the said
intermediate forms a solvate with dimethyl acetamide.
The preparation of the intermediate~starting material) is best
carried out by hydrogenating benzyl 2-methyl-4-mesyloxy-
2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate o~ the formula
C ~ COOCH2 ~ IV
2
in the presence of a hydrogenation catalyst in an inert solvent
~or example N,N-dimethylacetamide. The starting material
i~
~6f~6~i
- 5a - 4680-325
benzyl-2-methyl-4-mesyloxy-1,2-benzothiazine-1,1-dioxide-3-
carboxylate, for its part can be prepared, with an almost
~"
i6
theoretical yield, by m~sylat$on by conventlonal ~rocedures
from the respectlve 4-hydroxy compound.
Benzyl-2~methyl-4~hydroxy-1,2-benzothiaz~ne~ dloxlde-3-
carboxylate is a known compound which has been presented ln,
for example,EP Patent Application 82303978.9, publication
number 77 603.
The following examples illustrate the invention without
confining it in any way.
Example 1
2-methyl-3-carboxy-4-mesyloxy-2H-1/2-benzothiazine~
dioxide-N,N-dimethylacetamide solvate
A solution which contained 42.3 g (0.1 mole) of benzyl-2-
methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-
carboxylate ~m.p. 110-112 C), 8.7 g (0.1 mole) of N,N-
dimethyl acetamiae, and 2 g of 10 % palladium charcoal
catalyst was hydrogenated for 3 hours at normal pressure and
room temperature. The catalyst was filtered off and the
solvent was distilled off at a lowered pressure, whereby
41.8 ~ (99.5 % of the theoretical amount) of the desired
product ~m.p. 102-104 C) was obtained.
Example 2
2-methyl-4-hydroxy-2H-1,2-benzothiazine-1l1-dioxide-3-(N-2-
pyridyl)-carboxamide (piroxicam3
To a solution which contained 16.8 g (0.040 mole) of the
intermediate prepared in Example 1 and 4.0 g ~0.043 mole)
of 2-aminopyridine in 200 ml of boiling 1,2-dichlorethane,
and possibly 4.3 g (0.40 mole) of 2,6-dimethylpyridine, was
added 9.5 9 (0.08 mole) thionyl chloride whlle stirring,
ln the course of 0.5 hours. The mixture was refluxed for
2 hours, whereafter the mixture was cooled to about 40 C,
and about 500 ml of 0,5 N NaOH solution was added to it
gradually while stirring. The stirring was continued for
another 0.5 hour at a temperature of 40 C. ~hereafter the
aqueous layer was separated, and it was washed with methylPne
chloride, filtered and made mildly acidic by means of acetic
acid, whereupon the desired product crystallized. The product
was filtered and dried, whereby 11.4 g (86 % of the
theoretical amount) of the desired product, m.p. 198-200 C
(purity > 98 %), was obtained.
