Note: Descriptions are shown in the official language in which they were submitted.
~,~6~89~
This invention relates to a process for the syn-
thesis of 1,2-benzothiazine-3-carboxamides, and in parti-
cular to the preparation of N-aryl-2-methyl-4-hydroxy-2H-
1~2-benzothiazine~3-carboxamide l,l-dioxides, a class of ~
compounds useful as anti-inflammatory agents. ~ -;Synthesis of 3,4-dihydro-2-alkyl-4-oxo-2H-1,2- - -
benzothiazine-3-carboxamide l,1-dioxides has been previous-
ly achieved by amination of the corresponding 3 carboxylic
acid ester or by treatment o the parent 3,4-dihydro-2-alkyl-
4-oxo-2H-1,2-benzothiazine 1,1-dioxide with the appropriate
isocyanate (Lombardino, et al., J. Med. Chem., ~, 1171
~1971) and Zinnes, et al., ibid. ~ , 43 (1973) and United
States Patent 3,591,584). In addition, Zinnes, et al , loc
cit., has taught the preparation of 3-carboxamides by treat-
men~of the pyrrolidine enamine of 3~4-dihydro-2-methyl 4-
oxo-2H-1,2-benzothiazine l,l-dioxide with phosgene ~ollowed
by treatment of the resulting 3-carbonyl chloride with an
appropriate amine.
A process for the synthesis of N-aryl-2-alkyl-4-
hydroxy-2H-1,2-benzothiazine-3-carboxamide l,l-dioxides by
treatment of N-aryl-N'-alkyl-N'-(2'-alkoxycarbonylbenzene-
sulfonyl)glycineamides with an alkali or alkaline earth metal
hydride in a reaction-inert solvent at 50-150C. is claimed
in United States 3,853,862.
United State~ 3,714,155 disclose~ 4-hydroxy-2-N-
-2~
,. : ;;.
1~i9 B~
dimethyl-2H-1,2~ben~othlazine-3-caxboxanilids l,l-dioxides
a~ anti-inflammatory ag2n~, syn~he~i~ed by m~thylation o
the correspondlng N-phenyl carboxamide with dime~hylsulate
in th~ presence of sodium hydrids.
It ha~ now been di~cov~red tha~ preparation of
~nti-in~lammatory compound~ o~ the ormula:
o~
0118R
2 .,
~herein R is 2-thiazolyl or 2-pyridyl i~ e~cted by contao~-
ing ~he alkali metal or alkaline earth metal salt~ o a com-
pound of the formula:
OH
~,CONHR
~ H . .
2
with a methylating agent in a reaction-inert solvent at
~-100C.
A pre~erred ~eature o khe pre~ent proces~ i8 the :
uBe of ethanol as the reaction-inert solvent, the alkali
metal 3alt i5 the sodium salt, the methylatlng agent is
methyl iodide and the reaction ternperature i8 about 25C.
Although the aforementioned alkali metal or
alkalina ea~th m~tal salt of the appropriate 4-hydroxy-2H-
1,2-benzoth~azine-3-carboxamide l,l-dioxide can be prepared
and subsequently added to the.reaction-inert ~olven~, lt i~
preerred to prepare 3aid ~alt in eitu ln ~aid ~olvent. Thi~
i~ conveniently e~ected by treating a ~olution o~ tha
~3-
3"3~
requisite N-axyl-4-hydroxy-2H-1,2-henzothia~ine-3-carboxamlde
l,l~dioxide wl~h an equivalen~ amount o~ the alkali metal or
alkaline earth metal hydride, hydroxide or alkoxide. All
alkali metal and alkal~ne earth metal hydrides, hydroxides
andalkoxides are operable ~or the claimed process.
A~ previously mentioned, the presen~ proce 5 ig
best conducted in a reaation-inert solvent. By such a ~olv-
ent, or mixtures thereof, is contemplated those which, under
the conditions of the instant procesR, do not enter into
appreciable reaction with either the starting reagents or
product~, and adequately solubilize the reactant It is
preferred that relativelv polar solvents be employed. Suit-
able solvents or mixtures thereof which are included in this
group are di~lower)alkylsulfoxides, aqueous lower alkanols,
di(lower)alkyl(lower)alkanoic amides and hexa(lower)alkyl-
phosphoramides. Water may also be used in combination with
any of these solvents or mixtures thereof. Favored solvents
for the present process invention are dimethylformamide,
ethanol and dimethylsuloxide. The especially preferred
solvent i8 ethanol. It is also preferred, although not a
requirement, that the employed solvent be water-miscible.
Regarding the temperature range, 0-100C. is
operative, with a preferred temperature of about 25C~
Reaction time is not critical and is inherently
dependent on concentration, reaction temperature and reac~
tivity of the starting materials~ In general, when tempera-
tures of about 25C. are e~ployed, the reaction time will
vary be~ween 12-18 hours.
The order of addition of the reactAnts i8 not0 critical, but from a viewpoint of practicality it i~ pre-
~4~
3 ~
~erred tha~ the salt o~ the benzothiazlne l,l~diuxide be
added to the reaction solvent ~ollowed by the addition o
the methylaklng agent~ In those instances wherein the salt
is generated ln situ in the reaction solvent it is preferred
S tha~ addi~ion o~ the benzothiazine 1,1 dioxide ~o ~he reac-
tion solvent be followed by the addition o~ the hydride,
alkoxide or hydroxlde of the desired alkali metal or alkal-
ine earth metal, and this followed by the addition of the
methylating agen~.
Regarding the molar ratio o~ reactants, to ensure
completeness of reaction a~ least one mole of the methylat
ing agent should be employed per mole of salt. Larger
amounts can be used without markedly affecting ~he course
of the reaction and are preferred. This excess, for practical
reasons, aan aomprise as much a a 100-200% excess of said
agent, although larger amounts can be employed.
The methylating agents employed in the present
process are amiliar to those skilled in the axt and are
methyl halides, dimethylsulfate, methyl, alkyl- or aryl-
sulfonate esters or diazomethane. Preferred are methylbromidel methyl iodide, dime~hylsulfate, methyl methyl-
qulfonate and methyl p-tosylate; especially preferred is
; methyl iodideO
As previously mentioned, the compounds of the
presen~ process invention are useful as anti-inflammatory
agents, and United States Patent 3,591,584 teaches how to
use these compounds for this utility~
The intermediates useful in ~he present process
are prepared from ~ompounds known to tho~e ~killed in the
art, and are herein described.
-5-
~ ~t3 ~ ~
The examples which follow are given by WAy of
lllu~tra~lon, and are not to be con~krued as limltation~
of this inventlon, rnany variations o which are p~sible
withln the scope and ~piri~ thereo.
EXAM
N~(2-Thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3- -
carboxamide 1 l-dioxide
A. 2-Benzyl~4-hydroxy-2H-1~2-benzothiazine-3-caxboxylic
Acid Methvl Ester l,l-Dioxide
A solution of 5O1 g of 4-hydroxy-2H-l~2-benzo-
thiazine-3-carboxylic acid methyl ester l,l-dioxide (J. Med.
Chem., 14, 1171 tl971]), 6~8 gO oft-bromotoluene and 20 ml.
of lN aqueous sodium hydroxide in 20 ml. o~ water and 60 ml.
of ethanol i5 allowed to stir at room temperature overnightO
The suspension i9 cooled to 0C. and filtered. The product
is dried in vacuo to give 5O5 g. of the crude product, m.p.
143-153Co Recrystallization from ethanol provided the ~ ?
purified product, 404 go~ mOpo 157-159Co -~
Anal. Calc'd for C17H15O5NS: C, 5902; H, 404; N, 4~7
Found: Cl 59O3; H, 4O4; N, 4~1~
Bo N-~2-Thiazolyl)-4-hydroxy-2-ben~yl-2H-1,2-benzothiazine-
3-carboxamide l,l-Dioxide
A suspension of 5O0 yO o 2~benzyl-4-hydroxy-2H-1,2-
benzothiazine-3-carboxylic acid methyl ester l,l-dioxide and
2-aminothiazole in 500 ml. of dry xylene is heated and the
xylene allowed to distill slowly. After 3 hrs. the distilla- ~ i~
tion is stopped and refluxing is continued overnightO The
solvent volume is returned to prior level and the distilling
continued. When the solvent is reduced to 200 ml., the heat
is removed and the reaction mixture cooled in an ice-bath~
The re~ulting precipitate i8 filtered and dried, 4,7 g3, m~pO
:,,. , ' , .,.' ' ' ' ' : .
. .
9~
193-200C. Recrystallization from ethanol gave 3.7 g. of
the pure product, m.p. 198-200C.
Anal- Calc'd for Cl9H16N34S2 C,
Found: C, 55.1; H, 3.6; N, 9.9.
C. N-(2-Thiazolyl)-4-hydroxy-2H-1,2-benzothiazine-3-carbox-
amide l,l-dioxide
A solution of 1.4 g. N-(2-thiazolyl)-4-hydroxy-2-
benzyl-2H-1,2-benzothia~ine-3-carboxamide l,l-dioxide and
1.0 g. of 10% palladium in 200 ml. of 2:1 v:v chloro~orm-
methanol is shaken in a hydrogen atmosphere at an initial
pressure of 40 p.s.i. After 2 hrs. the catalyst is filtered
and fresh catalyst (1.0 g.) is added to the filtrate and the
hydrogenation continued for an additional 2 hrs.
The catalyst is filtered and the filtrate evapor-
~ ted in vacuo to dryness. The yellow residual product is15
purified by recrystallization from ethanol.
D. N-(2-Thiazolyl)-4-hydroxy-2-methyl-2H~1,2-benzothiazine-
3-carboxamide l,l-dioxide
_
To 4.2 g. of N-(2-thiazolyl)-4-hydroxy-2H-1,2-
benzothiazin~-3-carboxamide l,l-dioxide in 11 ml. of water,
40 ml. of ethanol and 12 ml. of lN aqueous sodium hydroxide
is added 2.4 ml. of methyl iodide, and the resulting reaction
mixture allowed to stir at room temperature for 18 hrs. The
mixture is cooled to 0C. and the precipitated product fil-
tered, dried under reduced pressure and recrystallized from
xylene.
EXAMPLE 2
N-(2-Pyridyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-
carboxamide l,l-Dioxide
. ~
. N-(2-Pyridyl)-4-hydroxy-2-benzyl-2H-1,2-benzothiazine-3-
carboxamlde 1, l-dioxlde _ _ __ _
In a manner similar to Example l-B, 10 g. of 2-
. .
.
benzyl-4-hydroxy-~H-1,2-b~nzothiazine-3-carboxylic acid
methyl ester l,l-dioxide and 3.3 g o 2-aminopyridine in
1 l.of dry xylene i5 heated at such a rate that the xylene
slowly distills. After a total of 7 hrs. of distilling, the
solvent being replaced with fresh xylene every ~ hours, the
reaction is refluxed overniyht. Then the volume is reduced
to 350 ml. The reaction mlxture is cooled in an ice~bath,
and the precipitated product filtered and dried ln vacuo.
The crude material is employed in the next reaction without
further purification.
B N-(2-Pyridyl)-4-hydroxy-2H-1,2-benzothiazine-3-aarbox-
amide 1,l-dioxide
Palladium-on-charcoal ~lOg) (1,5 g.) is added to
a solutlon of 1.2 g. of N-(2-pyridyl)-4-hydroxy-2-benzyl-2H-
1,2-benzothiazine-3-carboxamide l,l-dioxide in 175 ml. of
2:1 v:v chloroform-methanol, and the resulting suspen~ion
shaken in a hydrogen atmosphere for 4 hrs. at an initial
pressure of 45 p.s.i. The spent catalyst is filtèred and ~-
the filtrate concentrated to dryne~s. The residual product
is recry~tallizefl from ethanol.
C. N-(2-Pyridyl)-4-hydroxy~2-methyl-2H-1,2-benzothiazine-3- -~
carboxamide 1 _-dioxide
In a manner ~imilar to the procedure of Example
l-D, 8.0 g. of N-(2-pyridyl)-4-hydroxy-2H-1,2-benzothiazine-
3-carboxamide l,l-dioxide in 22 ml. of waterf 80 ml. of
ethanol and 24 ml~ of lN sodium hydroxide is added 3.6 ml.
of methyl iodide. The resulting solution is allowed to ~tir
overnight at room temperature. The suspension is cooled in
an ice bath for 30 min. followed by filtration of the solid.
The product is dried ln vacuo and recry~tallized from methanol/-
dimethylacetamide.
-8-
... . .
:
`'- ~ ' ~ ' ' : '
~o~
EXAMP~E 3
N-(2-~hiazolyl)-4-hydroxy-2-methyl-2H-l~2-benzothlazlne-~~
carboxamlde~ dioxld~ _ _
To 7.0 g. o~ N-~2-thlazolyl)-4-hydroxy-2H-1,2-
benzothiazine-3-carboxamide l,l-dioxide ~ 50 ml. of di-
methylformamide under a nltrogen atmo3phere i~ added 800 mg.
o pota~ium hydride, and the r~ulting reaction mixture
allowed to ~tir un~ll the evolu~ion of hydrogen i~ aomplet~.
The solution is warmed to 50C. and 3.78 g. o dimethyl-
sulfate added dropwise over a 5 min. period. Stirring and10
heating are con~inued ~or 6 hr~. The reaction mixture i~
cooled and diluted with an equal volume o ice and w~ter.
The preaipitated product is iltered, dried and arystallized
from xylene.
EXAMPLE 4
~5
The procedure of Example 3 is repea~ed employing
the indicated ~ource of the base salt, solvent, reaction
temperature and methylating 5
Methylating
~ase Solvenk ~emE~xature,C. _ Agent
LiH ~CH3)2NCHo 10 C~3I
CaH2 ~CH3)2SO ~H3~
NaOCH3 ~CH3)2S0 25 CH3S03CH3
KOH C2H50H-H20 25 ~CH30)S02
~aH2 ~(CH3)2N~3Po 25 C~3Br
2S CsH ~CH3)2N~3P0 80 p CH3C6H4s03cH3
MgH2 (CH3)2NCHO 100 p-CH3c6H4s03cH3
RbH (CH3)2s 25 CH3S03CH3
NaH (CH3)2NCH0 25 CH2N2
E%AMPLE 5
N~ yrid~L~-hydrox~t-2-methvl-2H-1, 2-benzothiazino-3-
_g_
, . .
.
9~
A solution of 3.34 g. o~ N-~2-pyridyl)-4-hydroxy-
2H-1,2-benzothiazine-3-carboxamide l,l~dioxide in 30 ml. o~
dimethylformamide i5 treated with 240 mg. of sodium hydride,
and the resulting reaction mixtur~ allowed to stir at room
temperature for 10 min. Methyl iodide (1.5 g.) is added
dropwi~e with stirring, and the reac~ion mixture hea~ed ~lowly
to 60C. The temperature of the reaction is maintained at
60C. -for 4 hrs. The mixture is cooled to room temperature,
and diluted with approximately 40 g. of ice and water. The
resultant precipitated product is filtered and dried. Re-
crystallization from methanol/dimethylacetamide provides the
purified product.
EXAMPLE 6
The procedure o~ Example 5 is repeated with the ~ -
substitution of the indicat~d base fox sodium hydride, sol-
vent for dimethylformamide, reaction temperature for 60C.
and methylating agent for methyl iodide.
Methylating
Base SolventTemperature, CO Agent
XH ~CH3)2NCHo 40 (CH3)2s2
LiH ~CH3)2SO 10 CH3Br
RbH (CH3~2SO 25 CH3S03CH3
NaOC2H5 C2H50H 60 ¢H3I
CaH2 [(CH3)2N]3Po 80 p-C 3C6H4 3CH3
,
MgH? [(CH3)2N]3PO 100 prC~13C6H4g3CH3
Bah~ [~CH3)2N]3Po 35 2 2
KOH C2H50H-H20 25 CH3I
Ca(OH)2 (CH3)2NCH0 35 CH3I
LiOH C2H50H-H20 35 (CH30)2S02
--10--
.~. , - . .
:
