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Патент USA US3078282

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United States Patent
3,978,270
C@
Patented Feb. 19, 1963
2
2
,
ethanol,'propanol or butanol in the presence of a catalyst;
such as hydrogen chloride. The reaction is performed
by employing a substantial molar excess of the alkanol
and heating the reaction mixture preferably at or about
the re?ux temperature. while gassing wtih a catalyst such
3,078,270,
DERIVATIVES 0F BENZOTHIADIAZINE
LI-DIOXIDE
Warren J. Close and Leo R. Swett, Waukegan, Ill., assign
ors to Abbott Laboratories, North Chicago, 111., a cor
as hydrogen chloride. Upon completion of the reaction,
the reactionniixture is cooled to precipitate the desired
poration of Illinois
No Drawing. Filed Aug. 14, 1959,'Ser. No. 833,682
11 Claims. (Cl. 260-243)
3 - carboalkoxy - 6-halo-2-alkyl-7-sulfamyl-3,4-djhydro
1,2,4-benzothiadiazine-l,l-tdioxide which is ?ltered o?
This invention relates to compounds cor-responding to 10 and, if desired, puri?ed by recrystallization from a suit
able -solvent;
the formula
Alternatively, the excess solvent may be
evaporated when the reaction is complete and the residue
recrystallized
to obtain the desired product.
X...
The ?nal step of the method is readily carried out by
15 adding anvexcess of_ ammonia or a lower alkylamine to
the product obtained in Step B. The reaction is prefer
ably carried out at‘ or about the boiling temperature of
and a method for their preparation. In the above
the amine. When the reaction is complete, the excess
formula, X represents chlorine, bromine or tri?uoro
ammonia or amine is evaporated and the residue recrys
methyl, R represents hydrogen or loweralkyl and R’ 20 tallized from water or aqueous alcohol to obtain the
NH
\GH-R’
l'\I-—R
\sé
represents COOH, COO-loweralkyl, CONH2, CONH
loweralkyl or CON (loweralkyl)2.
desired 3-alkylcarbamyl-6-halo-2-alkyl-7-sulfamyl-3,4-di
The term “lower
hydro-l,2,4;benzothiadiazine-1,l-dioxide as a crystalline
solid.
In an alternative method of preparation ,the com
alkyl” as employed throughout the speci?cation and
claims refers to the alkyl radicals containing from 1 to
4 carbon atoms, inclusive, whether branched or un 25 pounds having the formula
branched. These new compounds are crystalline solids
and are extremely useful as diuretic agents when admin
istered orally or by injection, in non-toxic amounts.
The compounds of the present invention can be pre
pared as illustrated by the following series of reactions: 30
A.
are readily prepared by adding one molecular proportion
NH:
of diazomethane dissolved in a suitable solvent such as
ether to one molecular proportion of a>3-carboxy-6-halo
7 - sulfamyl - 3,4-dihydro-l,2,4-benzothiadiazine-l,lldi
35 oxide dissolved in a suitable solvent such as methanol;
HaNOzS
SO:
Ne
$H-COOH
The reaction takes place smoothly at room temperature;
When the reaction is complete, the ‘solvents are evapo—
rated and the residue recrystallized from methanol or
other suitable solvents to obtain the desired product.v
40
The compounds of the present invention which corre
spond to the formula
N—R
SO:
may be prepared, if desired, by the reaction of one molec
ular proportion of a 3-carboxy-6-ha'lo-7-sulfamyl-3,4-di4
hydro-l,2,4-benzothiadiazine-l,l-dioxide with" two molec;
N5OH-OOOR’
HZNO IS
N--R
+
50 ular proportions of an alkylating agent such as diazo
methane in-the same manner as that described’when only
one molecular proportion of diazomethane isemployed.
/
The following examples illustrate the invention but
S02
55
are not to be construed as a limitation thereof.
3-Carb0xy-6-Chl0r0-7-Sulfamyl-3,4-Dihydro-I
EXAMPLE
,2,4
Bénzothiadiazine-I ,1 -Di0xide
In the above series of reactions, R, R" and R’” repre
sent hydrogen or loweralkyl, R’ represents loweralkyl 60
and X represents chlorine, bromine or tri?uoromethyl.
Step A of the method can'be conveniently carried out
by heating equimolar amounts of the sulfonamide and
glyoxylic acid (preferably an‘alkali metal salt of the acid)
01“
112N023
N5 on-o OOH
\ /NH
S02
Asu'spension of 22.8 grams (.081mole) ofi4lami'no-6
in water at or about the boiling temperature‘ and under 65 chlloro-1,3-benzenedisulfonamide in 300 ml.‘ of water was
re?ux until the reaction is complete. Upon cooling and
heated at the boiling temperature and’ under re?ux.
acidifying, the desired 3-carboxy-6-halo~7-sulfamyl-3,4
Thereafter, 8.8’ grams (.12_ mole) of glyoxylic acid-dis;
solved in one equivalent of 5% aqueous sodium hydrox
dihydro-1,2,4-benzothiadiazine-1,l-dioxide separates as a
ide was added portionwise with stirring and the result
crystalline solid which is removed vby ?ltration and re
70 ing mixture re?uxed for 1.5 hours. Upon" completion of
crystallized from water or alcohol.
the reaction, the reaction mixture was'coole'd and acidi
In step B of the method, the product obtained in Step
tied to precipitate‘ a- white solid. After recrystallization
A is esteri?ed with a lower alkanol'such as methanol,
3,078,270
Found:
of this solid from water, the desired 3-carboxy-6-chloro-7
sulfamyl - 3,4—dihydro-l,2,4-benzothiadiazine-1,1-dioxide
compound was obtained as a hydrate which melted at
EXAMPLE 5
125° C. with decomposition. Anal.--Calc’d. for
3-Carbamy [-6-Ch loro-Z-Methyl-7-Szzlfam yl-3,4-Dilz ydro
5
1 ,2,4-Benzotlziadiazine-l ,1 -Dioxide
C=25.4%; H=3.2%.
C8H8CIN3OGSZ
Found: C=25.4%,
'
H=3.2%.
EXAMPLE 2
N3 on~c~Nm
(Ii
01“
3-Carbamoethoxy-6-Chl0r0~7-Sulfamyl-3,4-Dihydr0
nmms
1,2,4-Benz0thiadiazine-I ,1 -Di0xide
/N—CH3
S 02
To 100 ml. of liquid ammonia at room temperature was
added 2.9 grams (.0078 mole) of the product prepared
in Example 3. The excess ammonia was thereafter evap
orated and 20 ml. of water added to the residue. The
white solid which precipitated was separated by ?ltration
To a solution of 1.71 grams (.005 mole) of 3-carboxy
‘ and found to melt at 245°—247° C. Upon analysis, the
nitrogen content of 15.8% was found to agree with the
6 - chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine
1,1-dioxide in 10 m1. of methanol was added portionwise
calculated value for 3-carbamyl-6-chloro-2-methyl-7-sul~
with stirring at room temperature, .21 gram (.005 mole) N 0 £amyl-3,4-dihydro-1,2,4-benzothiadiazine-l,l-dioxidc.
of diazomethane dissolved in 40 ml. of ether. The sol
EXAMPLE 6
vents were thereafter evaporated and the residue recrys
tallized from methanol to obtain the above-named prod
6~Chl0ro-3-(Dimethylcarbamyl)~2-Z'rdethyl-7-Sulfamyl
uct as a crystalline solid melting at 234°-236° C.
3,4-Dihydr0-1 ,2,4-Benzoth iadiazirze-J ,1 -Di0xia'e
Anal.—Calc’d. for C9H1UClN3O5S2: C=30.4%; H=2.8%.
Found: C=30.4%; H=3.0%.
>
EXAMPLE 3
3-Carbom ethoxy-6-Clzl0ro-2-Methyl-7-Sulfamyl-3,4
Dihydro-1,2,4-Benzothiadiazine-1,1-Dioxide
01"
H.NO2S
__
30
f‘?CH—'C—-OCH3
it’
\
famyl-3,4-dihydro-1,2,4-benzothiadiazine - 1,1 ~ dioxide to
100 ml. of dimethylamine at room temperature. The ex
cess amine was then evaporated and 25 ml. of water added
N-CH;
S02
This compound was prepared in the same manner as
to the residue. The desired product precipitated as a
white solid and after recrystallization from a methanol
water mixture melted at 265°-267° C. with decomposi
that described in Example 2 except that the amount of
diazomethane employed was doubled. The compound
H=3.9%.
ilOIl. Anal.—Calc’d.
Found: C=34.6%;
fOl' C11H15CH‘I4O5SQI
H=4.2%.
was found to melt at 224°—225° C. Anal.--Calc’d. for
CIOHHCINSOSSZ: C=32.5%;
C=32.6%; H=3.5%.
H=3.2%.
This compound was prepared by adding 7.12 grams
(.02 mole) of 3-carbomethoxy-6-chloro-2-methyl-7-sul
Found:
EXAMPLE 7
3-( n-Buz‘ylcarbamyl) -6-Chl0r0-2-Methyl-7-Sulfamyl
3,4-Dilzydr0-1,2,4-Benz0rhiadiazine-1,I-Dioxia'e
In an alternative method of preparation, 20 grams
(.053 mole) of 3—carb0xy-6-chloro-2-methyl-7-sulfamyl
3,4 - dihydro-l,2,4~benzothiadiazine-l,l-dioxide monohy
drate (M.P.=154° C.) was dissolved in 100 m1. of meth
anol to which was added 6 grams of acetone dimethyl
acetal and 2 ml. of concentrated hydrochloric acid.
Thereafter, two more G-gram portions of the acetal were
added at room temperature at one hour intervals.
The
This compound was prepared by the reaction of 1.0
resulting mixture was heated overnight at 50° C. The
gram (.0027 mole) of 3-carbomethoxy-6-chloro-2-methyl
solvents were then removed under reduced pressure and
the residue recrystallized from a methanol-water mixture
7 - sulfamyl - 3,4 - dihydro - 1,2,4 - benzothiadiazine - 1,1
dioxide with 10 ml. of n-butylamine in a manner similar
to obtain the desired 3-carbomethoxy-6-chloro~2-methyl-7
to that described in Example 6. The resulting product
sulfamyl - 3,4-dihydro—1,2,4-benzothiadiazine-1,1-dioxide
was a white solid which melted at 260° C.
which melted at 225° C.
EXAMPLE 4
EXAMPLE 8
6-Brom0-3-Carboxy-Z-Methyl-7-Sulfamyl-3,4-Dihydr0
3-Carb0xy-6-Chlore-2-Methyl-7-Sulfamyl-3,4-Dihydro
1,2,4-Benz0thiadiazine-1 ,1 -Di0xide
60
1,2,4-Benzothiadiazine-I,1-Dioxide
Neon-oo or:
Br‘
HzNOzS-
\
N_CH3
S02
Six grams (.02 mole) of 4-amino-6-chloro~3-(methyl
sulfamyl)-benzenesulfonamide were dissolved in 60 ml.
of water and the resulting solution heated at the boiling
temperature and under re?ux. A solution of 2.2 grams
(.03 mole) of glyoxylic acid in 10 ml. of water was then
added and the reaction mixture heated at the boiling tem
perature and under re?ux for one hour. The reaction
mixture was thereafter cooled to precipitate the desired
above-named product as a hydrate which was separated
by ?ltration. M.P.=156°-157° C. AnaL-Calc'd. for
A solution of 6.8 grams (.02 mole) of 4-amino-6
bromo - 3 - (methylsulfarnyl)-benzenesulfonamide in 100
ml. of boiling water was prepared and 3.0 grams (.04
mole) of glyoxylic acid added thereto. The resulting mix
ture was re?uxed for 90 minutes to complete the reaction.
The reaction mixture was then cooled and the desired
product which precipitated was separated by ?ltration.
It melted at 160°-162° C. with decomposition. Anal.-
Calc’d. for
Found:
C=25.7%;
CgH10BI‘N3O6S2'HgOI
H==3.2%.
3,078,270
6
E
_ This compound was prepared by adding .02 mole of
EXAMPLE 9
6 ~Br0m0-3 -Carbometh0xy-2-Mez‘hyl-7-Sulfamyl-3,4
3-carbomethoxy - 6 - chloro-2-methyl-7-sulfamyl-3,4-dihy
dro-l,2,4-benzothiadiazine-1,1~dioxide to 100 ml. of
Dihydro-I ,2,4-Benz0thiadiazine-J ,1 -Dioxide'
monomethylamine at room temperature.
The excess
amine was thereafter evaporated and the residue crystal
lized from a methanol~water mixture to obtain the desired.
product as a white, crystalline solid melting at 270°—271 °'
C. with decomposition. The product was further identi-‘
?ed by elemental analysis.
To a solution of 2.1 grams (.005 mole) of the product
EXAMPLE 14
obtained in Example 8 in 10 ml. of methanol was added
By
the
reaction
of
4-amino-6-chloro—3-(isopropyl-sul
a solution of .21 gram (.005 mole) of diazomethane in
famyD-benzenesulfonamide (M.P.=15S°—l57° C.) with
40 ml. of ether. The addition was carried out with stir
gly'oxylic acid as described in Example 4, the desired 3
ring at room temperature. Upon completion of the reac
tion, the solvents were evaporated to obtain the desired 15 rcarboxy-6-chloro-2-isopropyl-7-sulfamyl - 3,4 - dihydro‘
1,2,4~benzothiadiazine-1,1-dioxide is obtained.
product as a residue which melted at 224°—228° C.
An?l.—-C3.1C’d. for C1QH12BIN3O§S21
2.9%. Found: C=29.0%; H=3.0%.
EXAMPLE l0
3-Carboxy-7-SuZfamyl-6-Tri?uoromr‘thyl-3,4-Dihydror
1 ,2,4-Benzothiadiazine-1 ,1 -Di0xia'e
Further
reaction with excess methanol as described in the alterna
H:
tive method employed in Example 3 results in the forma
tion of 3-carbomethoxy-6-chloro-2-isopropyl-7-sulfamyl
20
3,4#dihydro-1,2,4-benzothiadiazine-l,l-dioxide.
In a manner similar to that described in the foregoing;
examples, other derivatives of 7-sulfamyl-3,4-dihydro~_
'1,2,4-benzothiadiazine-1,l-dioxide can be prepared of
which the following are representative:
3-carboxy-6-chloro-2-n-butyl derivative by the reaction
25
of 4-amino-6-chloro-3~(n-butylsulfamyl) - benzenesulfon
amide with glyoxylic acid. Further reaction of this deriv~
ative with methanol, ethanol, n-propyl alcohol or tert.
To a- re?uxing solution of 1.0 gram (.003 mole) of
butyl alcohol in the presence of hydrogen chloride results
4-amino-6-tri?uorornethyl-l,3-benzenedisulfonamide in 15
30 in the formation of the 3-carbomethoxy-6-chloro-2-n
ml. of water was added a solution of 0.33 gram (.0045
butyl;' 3-carbethoxy-6—chloro-2-n-butyl; 3-carbo-n-pro
mole) of glyoxylic acid in 10 ml. of water. Following
poxy-6~chloro-2-n-butyl and 3-carbo-tert.~butoxy-6-chloro
the addition, the reaction mixture was re?uxed for 1.5
Z-n-butyl derivatives, respectively. Subsequent reaction of
hours. Upon cooling, the desired product precipitated
any of these 3~carboalkoxy-6-chloro-2-n-butyl derivatives
with ammonia, monomethylamine, dimethylamine, mono
and was separated by ?ltration. IvI.P.=220° C. with de
composition.
ethylamine, diethylamine, monopropylamine, dipropyl
EXAMPLE 11
amine, monobutylamine or dibutylamine will produce the
3-Carb0xy-6—Chl0r0-2-Ethyl-7-Sulfamyl-3,4-Dihydr0
3-carbarnyl - 6 - chloro-2-n-butyl;
3-methylcarbamyl-6
chloro-Z-n-butyl; 3-dimethylcarbamyl~6-chloro-2-n-butyl;
1 ,2,4-Benz0thiadiazine-1 ,1 -Di0xide
40
3-ethylcarbamyl-6-chloro-2-n-butyl; S-diethylcarbamyl-G
chloro-Z-n-butyl; 3~propylcarbamyl-6-chloro-2~n-butyl; 3F
dipropylcarbamyl-6-chloro-2~n-butyl; 3-butylcarbamyl46i
chloro-Z-n-butyl and 3-di'butylcarbamyl-6'chloro-2-n-buty1
derivatives of 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadi
azine-Ll-dioxide, respectively.
This compound was prepared in the same manner as
3-carboxy-6-bromo-2-ethyl derivative by the reaction of
that described in Example 4 by the reaction of 4-amino—
4-arnino-6-bromo-3—(ethylsulfamyl) - benzenesulfonamide
6¢chloro~3-(ethylsulfamyl) - benzenesulfonamide (ll/LR:
with glyoxylic acid. Further reaction of this derivative
with methanol, ethanol, isopropyl alcohol or sec. butyl
alcohol in the presence of hydrogen chloride results in the
formation of the 3-carbomethoxy~6-bromo~2-ethyl; 3'
152°~154° C.) and glyoxylic acid. The monohydrate was
a white solid which melted at 190°—191° C. with decom
position. Upon analysis, the product was found to con
tain 30.98% C; 3.92% H and 11.07% N compared to the
theoretical values of 30.96% C; 3.63% H and 10.83% N.
EXAMPLE 12
carbethoxy-6-bromo-2-cthyl; 3-carbo-isopropoxy-6~bromo
2-ethyl and 3-carbo-sec.-butoxy-6-bromo-2-ethyl deriva
tives, respectively. Subsequent reaction of any of these 3_
carboalkoxy-6-brorno-2-ethyl derivatives with ammonia,
monomethylamine, dimethylamine, monoethylamine, di
3-Carb0methoxy-6-Chloroh2-Ethyl-7-Sulfamyl-3,4-Dihy
droJ ,2 ,4 -B enzoth iadiazine-J ,1 -Di0xide
et-hylamine, monopropylamine, dipropylamine, mono
butylamine or di‘butylamine will produce the 3-carbamyl_
NH
6-bromo-2-ethyl; 3-methylcarbamyl-6-bromo-2-ethyl; 3j
dimethylcarbamyl-6ebromo-2-ethyl; 3 - ethylcarbamyl-6
bromo-2—ethyl; 3-diethylcarbarnyl-6-bromo-2-ethyl; 3~
propylcarbamyl-6-brorno-2-ethyl; 3 - dipropylcarbamyl-6~
This compound was prepared by the reaction of the
compound prepared in Example 11 with excess methanol.
The procedure was identical to that described in the al
ternative method employed in Example 3. The product
O) 5
brorno-Z-ethyl; 3-butylcarbamyl-6~brorno-2-ethyl- and. 3'
dibutylcarba-myl-6ebromo-2-ethyl derivatives of 7-sul
famyl-3,4-dihydro-l,2,4-benzothiadiazine-1,l-dioxide, re
spectively.
3-carboxy-6-tri?uorornethyl-Z-methyl derivative by the
was a crystalline solid which melted at 222°~224° C.
EXAMPLE 13
reaction of 4-amino - 6 - tri?uoromethyl-3-(methylsulfa
6-Ch loro-Z-M ethyl-3- (M ethy lcarbamyl ) -7-S ulfamyl-S ,4
reaction of this derivative with methanol, ethanol, pro~
panol or isobutanol in the presence of hydrogen chloride
results in the formation of the 3-carbornethoxy-6-tri~
myD-benzenesulfonamide with glyoxylic acid. Further
?uoromethyl-2-methyl; 3~carbethoxy-6-tri?uoromethyl-2
methyl; 3-carbopropoxy-6-tri?uoromethyl-2-methyl and
S02
75
3-carbo-iscbutoxy-6-tri?uoromethyl-2methyl derivatives,
3,078,270
8
respectively. Subsequent reaction of any of these S-carQ
In Step C of the method, a mixture of a 2-alkyl-3
b0alkoxy-6-trilluoromethyl-Z-methyl derivatives with am
keto-6-halo-7-sulfamyl - 3,4 - dihydro - 1,2,4 - benzothiadi
monia, monomethylamine, dimethylarnine, monoethyl
amine, diethylarnine, monopropylamine, dipropylamine,
azine-l,1-di0xide and an aqueous alkali metal hydroxide
solution, preferably sodium hydroxide, is heated at the
boiling temperature and under re?ux for a period of time
monobutylamine or dibutylamine will produce the 3-car-»
bamyl-6-tri?uoromethyl-2-methyl; 3-methylcarbamyl-6-tri
to complete the reaction. After treatment with charcoal,
the reaction mixture is ?ltered and the ?ltrate acidi?ed
?uoromethyl-Z-methyl; 3-dimethylcarbamyl - 6 - tri?uoro'
methyl - 2 ~ methyl; 3-ethylcarbarnyl~6-tri?uoromethyl-2~
methyl; 3-diethylcarbamyl - 6 - tri?uoromethyl-Z-methyl;'
3-propylcarbamyl-G-tri?uoromethyl-Z-methyl; 3~dipropyl~
to obtain the desired 2-alkylsulfamyl-4-sulfamyl-5-halo
aniline as a White solid which is separated and dried.
What we desire to particularly point out and distinctly
'10
carbamyl-6-tri?uoromethyl-Z-methyl; 3-butylcarbamyl-6—
claim as our invention is:
tri?uoromethyl - 2 ~ methyl and 3-dibutylcarbamyl-6~tri
1. 3-carbomethoxy-6-chlore-2-methyl-7-sulfamyl~3,4-di
hydro-1,2,4-benzothiadiazine-1, l-dioxide.
2. 3-carboxy-6»chloro-2-methyI-7-sulfamyl-3,4-dihydro
?uoromethyl~2-methyl derivatives of 7-sulfamyl-3,4-di
hydro-1,2,4~benzothiadiazine-1,l-dioxide, respectively.
l,2,4-benzothiadiazine-1,l-dioxide.
The sulfonamide compounds employed as one of the
starting materials in the present invention can be pre~
pared as shown in the following series of reactions where
in X is chlorine, bromine or tri?uoromethyl and R is a
lower-alltyl radical containing from 1 to 4 carbon atoms, _
3. B-carbamyl-é-chloro - 2 - methyl-7-sulfamyl-3,4-dihy
dro-1,2,4-benzothiadiazine-1,1-dioxide.
4. 6-chloro-3- ( dimethylcarb amyl) -2-methyl-7-sulfamyl~
3,4-dihydro-l,2,4-benzothiadiazine-l,l-dioxide.
5. 6-bromo-3-carboxy-2-methyl-7-sulfamyl-3,4-dihydro
1,2,4-benzothiadiazine-1, l-dioxidc.
6. 6-bromo-3-carbomethoxy~2~methyl-7-sulfamyl-3,4-di~
hydro-l,2,4-benzothiadiazine-1,l-dioxide.
7. 3-carboxy-7-sulfamyl-6-tri?uorornethyl - 3,4~dihydro
25
1,2,4-benzothiadiazine-1,1-dioxide.
8. 3-carbomethoxy-6-chloro-2-ethyl-7 - sulfamy1-3,4-di
hydro-1,2,4-benzothiadiazine-1,l-dioxide.
9. 6-chloro-2-methyl-3-(methylcarbamyl)-7 - sulfamyl
3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide.
30
10. Compounds selected from the group consisting
of .(a) a compound corresponding to the formula
35
Step A of the method can be carried out conveniently
by heating a mixture of two molecular proportions of
X_
mNons-
\(|JH-—llI|I-—O-—R’
N‘R 0
S02
and (b) a compound corresponding to the formula
urea and one molecular proportion of a 5-halo-2,4-di
sulfamylaniline at a temperature of about 180° C. for a 40
/N5
/R'
tH—t~N\
period of about one hour. Upon completion of the
HgNOzS\ / LR 0
R"
reaction, water is added to the reaction mixture which
is thereafter heated to effect solution. The aqueous solu
S02
tion is then treated with charcoal and ?ltered. The
wherein X is a member selected from the group con
?ltrate is acidi?ed to precipitate the desired 3-keto-6-halo 45 sisting of chlorine, bromine and tri?uoromethyl, and R,
7-sulfamyl - 3,4 ~ dihydro - 1,2,4 - benzothiadiazine-Ll-di
oxide as a crystalline solid which is separated by ?ltration
and dried.
Step B of the method is carried out by adding one
molecular proportion of an alkali metal hydride, prefer
ably sodium hydride, to a solution of one molecular pro
portion of a 3-keto-6-halo-7-sulfamyl-3,4-dihydro-1,2,4
benzothiadiazine-1,1-dioxide in dry dimethylformamide.
The mixture is stirred and heated to about 70° C. to effect
solution. One molecular proportion of an alkyl iodide
dissolved in dimethylformamide is thereafter added drop
wise and stirring is continued for about two hours at 70°
C. When the reaction is complete, the reaction mixture
is poured into water and cooled below room temperature
R’ and R" are members selected from the group con
sisting of hydrogen and lower alkyl.
'11. A compound of the formula
F36
HrNOgS~
NeoH-o 0 o R
\ /NH
SO:
wherein R is a member selected from the group con
sisting of hydrogen and lower alkyl.
References Cited in the ?le of this patent
Freeman et al.: Iour. Org. Chem,, volume 16 (1951),
to precipitate the desired 2-alkyl-3-keto-6-halo-7-sulfa~ 60 page 821.
Wagner et al.: Synthetic Organic Chemistry, pages
myl-3,4-dihydro - 1,2,4 - benzothiadiazine-l,l-dioxide as a
480-481 and 568-569 (1953).
crystalline solid which is separated by ?ltration and dried.
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