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Патент USA US3040052

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United States Patent 0 ice
1
1
3,049,042
Patented June 19, 1962
2
cold water and stirred until a ?ne yellow colored suspen
sion is obtained. The solid is ?ltered, dried and stirred
into 600 ml. of ether. The yellow ether solution is de—
icanted from any insoluble material, washed with water,
dried over magnesium sulfate and concentrated from the
steam bath to a volume of about 50 ml. This ether solu
3,040,042
BENZOTHIADIAZINES
Harry Louis Yale and Jack Bernstein, New Brunswick,
N.J., assignors to Olin Mathieson Chemical Corpora
tion, New York, N.Y., a corporation of Virginia
No Drawing. Filed Nov. 25, 1957, Ser. No. 698,377
14 Claims. (Cl. 260-—243)
tion contains 5-amino-a,a,ct-tri?uoro-2,4-toluenedisulfon
yl chloride, which can be isolated as a crystalline solid.
This invention relates to new benzothiadiazine deriva
tives, and more particularly to new tri?uoromethyl-benzo
The ether solution containing the 5-amino-a,a,a-tri?u
10 oro-2,4-toluenedisulfonyl chloride is cooled in an ice bath
thiadiazinesulfonamide derivatives, one tautomeric form
of which may be represented by the formula
and treated slowly with 50 ml. or" concentrated aqueous
ammonia. A vigorous reaction occurs. Finally, the mix
ture is heated one hour on the steam bath and cooled to
NHisoi
give about 8 g. of 5-amino-a,a,a-tri?uoro-2,4-toluenedisul
15 fonarnide, MJP. about 236—238° after recrystallization
$11
CF
CH
from water.
%
([1) Preparation of 6-(z‘ri?uoromethyl) -1,2,4-benzothia
N
as Well as alkali metal salts thereof.
The new benzothiadiazines of this invention are physi
ologically active compounds which possess both diuretic
I diazine-7-szilf0namide 1,1-dioxida-A‘mixture of 8 g. of‘
5-amino-u,a,a-tri?uoro-2,4-toluenedisulfonamide and 200
20 ml. of 98-100% formic acid is re?uxed for two hours.
100 m1. of formic acid is distilled and the residual solu
tion is diluted with water. The product separates and is
and anti-hypertensive activities. Thus, these compounds
are administrable parenterally and (preferably) orally in
collected on a ?lter. Recrystallization from water gives
the treatment of congestive heart failure, being uniquely
6 - (tri?uoromethyl) - 1,2,4 — benzothiadiazine - 7 ~ $111
suitable for this and other conditions where both the di 25 fonamide 1,1-dioxide, »M.P. about 305-306°.
uretic and anti-hypertensive activities are desirable.
EXAMPLE 2
The compounds of this invention are prepared by the
process of this invention which essentially comprises:
Potassium Salt of 6-(Trz'?noromethyl)-1,2,4-Benz0thia
(a) reacting an aminohenzotri?uoride with chlorosulfonic
diazine-7-Salf0namide 1 ,1 -Di0xide
acid in the presence of an alkali metal chloride \(eg. ‘so 30
To
a
solution
of 6.6 g. of 85% potassium hydroxide in
dium chloride) to yield amino-oi,a,a-trirluorotoluenedisul
100
ml.
of
95%
ethanol is added gradually with shaking
fonyl chloride derivatives, which are new intermediates
1.65 g. of 6-(tri?uoromethyl)-l,2,4-benzothiadiazine-7
of this invention, the reaction preferably being conducted
sulfcnamide 1,1-dioxide. The solid dissolves. The re
sulting alcoholic solution is concentrated in vacuo to yield
at an elevated temperature employing at least two equiva
lents of chlorosulfonic acid; (b) treating the resulting
amino-ma,a-tri?uorotoluenedisulfonyl chloride deriva
the dipotassium salt of G-(tri?uoromethyl)-1,2,4-benzo
thiadiazine-7-sulfonamide 1,1-dioxide as a free ?owing
tives with aqueous ammonia to yield the corresponding
amino - a,a,a - tri?uorotoluenedisulfonamide
granular powder.
Similarly, using the equivalent quantity of sodium hy
derivatives,
which are also new intermediates of this invention; and
(c) cyclizing the amino-a,a,a-tri?uorotoluenedisulfonam
40
ide derivatives by treatment with formic acid at an elevat
ed temperature to yield the desired ?nal products in the
free acid form. These free acids can then, if desired, be
neutralized by treatment with alcoholic alkali metal hy
EXAMPLE 3
7-( Tri?uorom ethyl) -1 ,2,4-Benz0Zhiadiazine-5
droxide (e.g., potassium hydroxide and sodium hydrox 45
ide), whereby the alkali metal salts are formed.
Among the suitable starting materials for the process
of this invention may be mentioned Z-aminobenzotriflu
droxide instead of potassium hydroxide, the disodium salt
is obtained.
'
Sulfonamide 1,1-Di0xide
(a) Preparation of 4—amin0-oz,a,a-tri?u0r0-3,5-t0luene
sulf0namz'de.—-To 100 ml. of 99% chlorosulfonic acid at
room temperature is added slowly with stirring 20 g. of
4-aminobenzotri?uoride. ‘Heat is evolved and a clear
oride, 3-aminobenzotri?uoride, and 4-aminobenzotri?u
yellow solution is formed. To the solution is added dur
oride, which yield, respectively, the ?nd products: S-(tri 50 ing
one hour a total of 90 g. of sodium chloride. rIhe
?uoromethyl)-1,2,4-benzothiadiazine-7-sulfonamide 1,1
resulting mass is then heated by means of an oil bath to
dioxide; ?-(triiiuoromethyl)-1,2,4-benzothiadiazine-7-sul
180° (external temperature) and the temperature main
fonamide 1,1-dioxide; and 7-(tn'?uoromethyl)-1,2,4
tained at 180-185" for three hours. The reaction mixture
benzothiadiazine-S-sulfonamide 1,1-dioxide.
is then cooled and treated rapidly with a total of about
The following examples illustrate the invention (all 55 500
ml. of ice cold water. The hard granular mass dis
temperatures being in centigrade) :
integrates and yields a granular yellow-tan solid. This
EXAMPLE 1
6-( Tri?uoromethyl ) -1 ,2,4-B enzoth iadiaZine-7
Sulfonamide 1,1-Di0xz'de
(a) Preparation of 5-aminc-a,a,ot—tri?uor0-2,4-t0luene
sulf0namide.—'l"o 100 ml. of 99% chlorosulfonic acid at
room temperature is added dropwise 20 g. of m-amino
benzotri?uoride. Subsequently, this mixture is gradually
treated with a total of 90 g. of sodium chloride during a
period of one hour. The viscous mass resulting is then
heated by means of an oil bath to 180° and kept at this
solid is ?ltered and then stirred up with about 600 ml.
of ether. A clear yellow solution is formed. ‘This ether
60 solution is separated from any water, dried and concen
trated to about 50 ml. The resulting solution, which con
tains 4-arnino-a,a,a-tri?uoro-3,S-toluenedisulfonyl chlo
ride, is cooled in ice and treated slowly with 50 ml. of con
centrated aqueous ammonia. The mixture, which con
' sists of two phases, is gradually warmed on the steam bath
to about 90° and kept there for one hour. The product,
4 - amino - a,a,u-tri?uoro-3,S-toIuenedisulfonamide
sepa
rates and is ?ltered. The yield is about 12 g.
temperature for two hours. During this time the reaction
(b) Preparation of 7-(tri?uor0methyl) -l,2,4-benzothia
mixture becomes solid and stirring is discontinued. The 70 diazine-S-sulfonamide 1,1 -di0xide.—l2 g. of 4-amino
mixture is then cooled by an ice bath and when cool, the
a,a,a-tri?uoro-3,S-toluenedisulfonamide and 300 ml. of
reaction mixture is rapidly diluted with 500 ml.- of ice
98—100% formic acid are re?uxed for two hours and the
3,040,042
3
4
mixture concentrated to dryness in vacuo. The residual
7. A process for preparing a compound of claim 1
which comprises interacting a compound of the formula
solid is recrystallized from boling water to give 7-(tri?u
oromethyl)<1,2,4-benzothiadiazine-S-sulfonamide
1,1-di
it“
oxide as colorless needles, M.'P. about 300°.
EXAMPLE 4
CF41
with formic acid at an elevated temperature.
By substituting Z-aminobenzotri?uoride for the 4
8. The process of claim 7 wherein 5-aml.DO-Ot,OL,Ot-U'l
aminobenzotri?uoride in the procedure of step a in EX 10
?uoro-Z-toluenedisulfonamide is the reactant.
ample 3 and then following the procedures of steps ‘a
9. The process of claim 1 wherein 4-arnino-a,ot,a-tri
and b of the example, there is obtained ?rst Z-amino
?uoro-3,5-toluenedisulfonamide is the reactant.
a,o¢,a-tri?uoro-3,S-toluenedisulfonyl chloride; then, 2
10. The process of claim 7 wherein 2-amino-a,a,u-tri
amino-a,a,a-tri?uoro-3,S-toluenedisulfonamide; and ?nal 15
?uoro-3,S-toluenedisulfonamide is the reactant.
ly, 5—(tri?uoromethyl) - l,2,4-benzothiadiazine?pulfon
11. A process for preparing a compound of claim 6
which comprises interacting a compound of the formula
amide 1,1-dioxide, which forms as colorless needles, M.P.
above 300°, when recrystallized from boiling water.
The invention may be variously otherwise embodied
within the scope of the appended claims.
20
What is claimed is :_
1. A compound selected from the group consisting of
benzothiadiazines of the formula
CFg
—SOaCl
SOzOl
S02
25 with aqueous ammonia.
12. A process for preparing a compound of claim 5
which comprises interacting a compound selected from the
group consisting of Z-aminobenzotri?uoride, 3-amino
benzotri?uoride, and 4-aminobenzotri?uoride with at least
and alkali metal salts thereof.
2. 6 - (tr-i?uoromethyl) - 1,2,4 - benzothiadiazine - 7 -
30
sulfonarnide 1,1-dioxide.
two equivalents of ‘chlorosulfonic acid in the presence of
an alkali metal chloride.
13. 5-tri?uoromethyl-2,4-disulfarnyl-aniline.
3. 5 — (tri?uoromethyl) - 1,2,4 - benzot-hiadiazine - 7 -
14. 5 - amino - a,u,a - tri?uoro - 2,4 - toluenedisulfonyl
sul-fonarnide 1,1-dioxide.
chloride.
4. 7 - (tn'?uoromethyl) - 1,2,4 - benzot-hiadiazine - 5 -
>
35
sulfonamide l,1.-dioxide.
References Cited in the ?le of this patent
5. A compound of the formula
_ UNITED STATES PATENTS
2,809,194
40
Novello __________ _,____ Oct. 8, 1957
OTHER REFERENCES
"Craig et al.: J. Org. Chem, vol. 22,. pages 709-711,
6. A_ compound of the formula
NH:
June 1957.
UNITED STATES PATENT OFFICE
CERTIFICATE OF CORRECTION
Patent No. 3,040,042
2%‘
June 19, 1962
Harry Louis Yale et a1.
5 in the above numbered pat
It is hereby certified that error appear
ent should read as
ent requiring correction and that the said Letters Pet
corrected below.
Column 4,
line 11, for "-2-" read —-
—2,4-
.
Signed and sealed this 23rd day of October I962.
:SEAL)
Attest:
ERNEST W. SWIDER
Attesting Officer
DAVID L. LADD
Commissioner of Patents
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