CA1069894A

CA1069894A - Process for preparing 2-methyl-4-hydroxy-1-2-benzothiazine-3-carboxamide 1,1-dioxides

Info

Publication number: CA1069894A
Application number: CA267,358A
Authority: CA
Inventors: Joseph G. Lombardino
Original assignee: Pfizer Corp SRL
Current assignee: Pfizer Corp SRL
Priority date: 1976-01-12
Filing date: 1976-12-07
Publication date: 1980-01-15
Also published as: CH594650A5; AR210628A1; ES454502A1; SU634672A3; SE421792B; DK579876A; LU76466A1; AT349483B; DD130145A5; NL7614135A; SE7613691L; ATA915876A; FI763680A; PL102554B1; JPS5293777A; FI63231B; HU173509B

Abstract

ABSTRACT OF THE DISCLOSURE
A process for the synthesis of N-aryl-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides by methylation of an alkali or alkaline earth metal salt of N-aryl-4-hydxoxy-2H-1,2-benæothiazine-3-carboxamide 1,1-dioxides in a reaction-inert solvent at 0-100°C., said products being anti-inflammatory agents.

Description

~,~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~

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 . .

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 not 0 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.

~ ~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.

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.

... . .
:
`'- ~ ' ~ ' ' : ' ~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.

~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.

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 Ca(OH)2 (CH3)2NCH0 35 CH3I
LiOH C2H50H-H20 35 (CH30)2S02 .~. , - . .

:

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the formula:

...I

and its alkali metal and alkaline earth metal salts wherein R
is 2-thiazolyl or 2-pyridyl, comprising contacting an alkali metal or alkaline earth metal salt of a compound of the formula:

...II

with at least one mole of a methylating agent in a reaction-inert solvent at 0-100°C and when required preparing the pharmaceutical-ly acceptable salt.

2. A process according to claim 1, wherein the reaction-inert solvent is ethanol, the alkali metal salt is sodium, the methylating agent is methyl iodide and the reaction temperature is about 25°C.

3. A process according to claim 1 or 2, wherein R is 2-thiazolyl.

4. A process according to claim 1 or 2, wherein R is 2-pyridyl.