Note: Descriptions are shown in the official language in which they were submitted.
108~91
-
The present invention relates to a process for the pre-
paration of sulfamylbenzoic acids of the formula I
¦ .:
NH
X~
2 2 COOR
in which A represents lower alkyl, lower halogenated alkyl :
and lower cycloalkyl, X represents phenoxy which may be
substituted by lower alkyl, lower alkoxy, halogen, nitro and
amino, phenyl thio and N-methylpiperazino, and R means
hydrogen or an alkyl or cycloalkyl radical having up to
6 carbon atoms, which comprises nitrating derivatives of
sulfamoylbenzoic acids of the formula III
''.~ ~
' ',
.'
'
Y
~: ~ (III)
BNO2S COOR
'.
.
' ' ' ~ :
.
. E., -
~. 2
- .. .. . . ,, . , . ~ . .. :
: , -. ~ . - . . :
-. . : . :
~. .. ..
~ - . . , : , .
~08Zl~
in which Y means a halogen atom, R is defined as above and
B means a protective group of the formula
4 ~ ~ ~ 5
<
R6
in which R4, R5 and R6 mean identical or different alkyl groups
of low molecular weight, R4 meaning also possibly hydrogen and/
or two of the substituents R4, R5 and R6 being also possibly
connected with one another cyclically, and esterifying the com-
pounds obtained of formula IV
.
; 15
NO
(IV)
X~
: BNO2S COOR
:'
:, .
}~
~ ~ :
, -., ~. . .
: - .. .. : . : - : -
. ,- . . .:
:, . . . . ~ ' , ,' : : ' :
. .
- : . . ~ . .
1C~8~
if R means hydrcgen, and reac~ing the eompounds obtained of for-
mula IV, in which B and Y are defined as above,P~ however mea-
ning an alkyl or cycloalkyl radical, with compounds of the
formula XH, in which X is defined as above and reducing the
eompounds obtained of the formula V
~2
B~02.5~ COOR
in whieh R' means an alkyl or cyeloalkyl radieal having up
to 6 earbon atoms and B and X are defined as above and reae-
ting the eompounds obtained of the formula VI
1~'12
X ~ ~ (VI)
B~2S ~ ~ OOR'
' in whieh B,X and R' are defined as above with eompounds of
the formula VII
O
1 1 .
:~ A - C - 1 (VII)
. in whieh A is defined as above and L means a "leaving group"
or the radieal oR7 of an aetivated ester or an anhydride, R7
meaning also possibly ~ - A and reducing the compounds ob-
tained of the formula VIII
.' ,
, . .
- - ,' :, ' ' ,~,' -' . . : . :
, . ... , : :
. . .
.
,, , ~ , .
: . - .
38'Z191
C = o
1~1 .
- X 1 (VI~I)
B~2S ~ COO~ '
in which the radicals A,B,R' and X are defined as above by
boron hydride optionally in the presence of Lewis acids or by
complex boron hydrides in the presence of Lewis acids and hy-
drolyzing the compounds obtained of the formula IX,
A
CE~2
(IX)
N~I
B1~025~001~ '
in which A,B,X and R' are defined as above to obtain compounds
of the formuIa I, in which R means hydrogen and optionally
esterifying the acids obtained(in which R is H) in usual manner.
The sulfamylbenzoic acids of the formula I are pharma-
ceutical agents, especially valuable diuretics and saluretics.
A process for the preparation of these compounds is al-
ready known from German Offenlegungsschrift No. 2,345,229.
The process of the invention has especial advantages as
compared to the process of the former application and is more-
that
over surprising as it could not be expected~some reaction steps
can be performed smoothly.
-- 5 --
.. . . . : , . ,,, . :
,. . - : - . : .... : : : .. : .
. .
- - - ~ , , ' .
,, : . . .... :
.. . : , ... .
.
" 108Z~9l
Ha]o~enobenzoic acids of the formula II,for example, may
be nitrated surprisingly under mild conditions by incorporating
the protective group B into them, which proceeding is especialiy
important for their preparation on an industrial scale. ~-
The benzoic acids derivatives of the formula III used
according to the present invention may be obtained according
to various processes.
The reaction may be carried out in an especially simple
manner by using as starting compounds sulfamylbenzoic acids
derivatives of the formula II
h!OzS . Co~
- ~ ,. .
which are known in the literature, by varions condensation
processes, most of which are knwon in the literature.
The following references in the literature may be mentioned,
by way of example:
~ J. Org.Chem. 25 (1960), 352 - 356; Zh. Org. Khim 8 (1972), 286 -
` 291; Liebigs Ann. Chem. 750 (1971), 42; Zh. Org. Khim 6 (1970),
9, 1885; B. 94 (1961), 2731 - 2737; Ang. Ch. 78 (1966), 147 -
148; Ang. Ch. 80 (1968), 281 - 282;
Volume 97 (1964), 483 - 489; Volume 96 (1963), 802 - 812; J.
Org. Chem. 2 (1962), 4566 - 4570; Ang. Ch. 74 (1962), 781 -
782 and Doklady Akad. SSSR 145 (1962), 584.
The following derivatives, for example may be used accor-
ding to the invention as compounds of the formula III.
.
.
. . .
: . - . . , : , :
~' ' " , ' ' ' .
108219~
S C NO 5~ COCH
Compound
No. IR4 R5 R _
H CH3 CH3 C1
2 CH3 CH3 CH3 Cl
3 H C2H5 C2H5 C1
C4H9 CH3 CH3 Cl
, 5 H CH3 CH3 F
6 H CH3 CH3 Br
7 CH3 -CH2-CH2-CH2 CH2 C 2 C1
8 -CH2-CH2-CH2- CH3 C1
~' The compounds of the formula III are prepared according -
.
~, to the processes mentioned in the above references or in
analogous manner thereto. Instead of the aforesaid acids
,~ there may also be used the corresponding methyl and ethyl -
ester.
The nitration of the benzoic acid derivatives of the
formula III may be performed in different ways. The benzoic
acids derivatives, for example may be introduced into one of
the
,` . :
~ 7 ~
': '
. ` ~, .'':, ' .... ' ' ' '' . "'' '
- ,
1082191 1`
conventional nitration mixtures for the nitration of inert
aromatic agents ~cf. "Organikum", page 288, edition 1967).
The process may also be performed alternatively by dissolving
the benzoic acid derivatives of the formula III in oleum and
by controlling the nitration by adding dropwise nitric acid.
It is surprising that the benzoic acid derivatives of the
formula III, may be nitrated without altering other groups
in the molecule only by incorporating the protective group B
into the sulfamide radical.
The reaction temperature is in the range from about 55 to
130C, preferably in the range from 55 to 90C.
An advantageous method of carrying out the process of the
invention consists in firstly introducing a nitration acid
containing oleum and fuming nitric acid, in adding the sub-
stance and in heating the reaction mixture to a temperature
from about 60 to 80C.
The nitration may be observed by thin-layer chromatogra-
phy. The final products are isolated according to processes
- known in the literature, for example by pouring the reaction mixture onto ice and filtering off the precipitated crystals.
Suitable compounds for nitrating are acids or esters of
the formuIa III, in which Y,B and R are de~fined as above. When
nitrating esters of the formula III there are obtained, besides
the esters of the formula IV, acids of the formula IV(in which
R is H) in a small quantity.
The mixture may be separated in usual manner, for example
by treating it with aqueous sodium carbonate.
.
.
.
.
:.
- ~0B~l9l
The compcunds obtained of the formula IV, in which R
~eans hydrogen ~re then esterified in usual manner.
For esterifying the carboxyl group the carboxylic acid
is converted into its acid chloride, which chloride furnishes
S the corresponding esters of the formula IV when adding alcohols.
Suitable alcohols for esterifiying are especially the low
molecular weight alcohols having from 1 to 6 carbon atoms, for
example methanol, ethanol, propanol, butanol, pentanol, iso-
propanol or hexanol or cyclohexanol and cyclopentanol.
The alcohols may be used in a stoichiometrical quantitiy,
but they are preferably used in a 5 to 20 fold molar excess.
Using them simulataneously as a solvent is moreover advantage-
ous .
; In the next step the compounds of the formula IV are con-
verted into compounds of the formula V, by reaction with com-
pounds of the formula XH optionally after having esterified
the carboxyl group.
It has now b~een found surprisingly that compounds of
- the formula IV, in which R means alkyl may be reacted with com-
pounds of the formula XH with good results under anhydrous con- ~ -
ditions.
Suitable compounds of the formula XH for example include
phenol, 4-methylphenol,3-methylphenol,2-methylphenol,4-chloro-
phenol,3-trifluoromethylphenol,3,5-dimethylphenol, 2,4-dimethyl-
phenol, 4-methoxyphenol, 3-methoxyphenol, 4-propylphenol, thio-
phe~ol and the thiophenols substituted in an analogous manner
as phenol, N-methylaniline, benzenesulfinic acid~ pyrrolidine,
, ..
_ g _
. .
~, .
.. .. .
.
:. .- :~, - . '
N~methylpiperazine, 5-methyl-2-mercapto-1,3,4-thiadiazole or
1-methyl-5-mercapto-1,2,3,4-tetrazole. Possibly present addi-
tional functionel groups in XH such as further OH groups, ~H2
or mercapto groups are blocked by conventional protective
groups, for example by acylation.
The reaction may be carried out without solvents, but is
performed preferably in a solvent. Organic solvents such as
ethers and tertiary carboxamides, especially diglymes, di-
methylformamide or hexamethylphosphoric acid trisamide (HMPT)
are especially appropriate.
The compounds X-H are used as such in the presence of
bases or in the form of their alkali metal or alkaline earth
metal salts. Suitable bases are alcoholates or alkali metal
amides.
Compounds of the formula HOR2 and HSR2,in which R2 is de-
fined as above are especially important. Especially important
are the thiophenol and phenol derivatives, ~ich may be sub-
stituted as mentioned above. -~
The thiophenol and phenol derivatives may be reacted in the
form of their anions. There may be mentioned especially the
alkali metal salts and particularly the sodium and potassium
salts.
The reaction may be carried out in the presence or in the
absence of a solvent. When operating without a solvent the
components are heated to a temperature from 100 to 200C, pre-
ferably from 140 to 180C. The products obtained may be isola-
ted in usual manner, for example by dis~olving the molten pro-
2~ ducts in a solvent and by precipitating subsequently by the
- 10 -
. . .
, , ' ~ , , -,
'
,
~' ' , . '~
1~8'~
addition of water or an organic nonsolvent.
Reacting ~ith phenolates or thiophenolates in solvents at
a temperature rrom 100 to 200C, preferably from 120 to 160C
is especially advantageous.
Suitable solvents are organic solvents, éspecially ter-
tiary carboxamides, polyethers or solvents having a high boiliny
point, for example HMPT, or tetramethylenesulfone. The esters
of the formula IV are reacted especially advantageously in ter-
tiary carboxamides, for example dimethylformamide or dimethyl-
acetamide. The reaction is terminated after 1 to 6 hours de-
pending on the chosen reaction temperature.
The final products of the formula V are isolated in usual
manner, for example by firstly filtering off the mineral salts
and by precipitating subsequently the reaction product by the
addition of a nonsolvent or by giving the reaction mixture into
water or onto ice and by isolating the precipitated reaction
product. 2
The compounds of the formula V, in which X means SOR or
SO2R2 are obtained from the compounds of the formula V, in
20 - which X is SR2, by oxidizing according to processes known in
the literature. The S oxides, for example, may be obtained by
oxidizing with peracetic acid in dimethylformamide at low tem- -
peratures, whereas the S dioxides are formed when adding an
excess of oxidant at higher temperatures.
The nitro group may be reduced into benzoic acid deri-
vatives of the formula V in various ways according to processes
known in the literature, for example by catalytic hydrogenation.
28 Raney nickel is preferably used as a catalyst. Conventio-
- 11 - -
'
: . ,' . .: . , ,. -.......... ~, . . . .
.. - . ,. , .. : , . . . . .
108'~91
nal noble metal catalysts such as palladium supported by car-
bon or platinum oxide may also be used.
The catalytic hydrogenation is performed in a way knwon
in the literature (cf.Organikum, pages 271 to 277, pages 507
to 510). The reaction is carried out in a solvent in the pre-
sence of a catalyst.
Suitable solvents are preferably organic solvents such as
methanol or ethanol, acetic acid ester, dioxane or other polar
solvents, especially amides such as dimethylformamide, di-
methylacetamide or H~PT.
Hydrogenation is performed at room temperature and under
atmospheric pressure or et elevated temperature and under pres-
sure above the atmospheric pressure, for example at 50C and
; under a pressure of 100 atmospheres, in an autoclave.
The 3-acylaminobenzoic acid derivatives of the formula
VIII may be obtained according to various processes. They may
be prepared, for example, by reacting in usual manner the
amino compounds VI with carboxylic acid derivatives capable
of forming amides, such as carboxylic acid anhydride or the
carboxylic halides. Leaving groups in the compounds of the for-
mula VII, for example may be halogen, trialkylammonium, pyri-
dinium or the group O CO-A. Preferred compounds of the formula
' VII, for example, are butyric acid chloride, butyric acid an-
hydride, cyclopropanecarboxylic acid chloride, cyclobutanecar-
boxylic acid chloride, benzoylchloride, benzoylpyridinium
chloride or ~ -chloropropionic acid chloride.
The reaction with the aforesaid compounds is performed
under the conditions of the Schotten-Baumann reaction. It may
be readlily observed by thin-layer chromatography, owing to
3 the fact that the compounds VI fluoresce at 366 m~ whereas the
compounds VIII do not fluoresce.
; Suitable reduction agents are various boron hydrides such
as diborane, optionally diborane in the presence of Lewis -
acids. They may be introduced into the reaction mixture, when
assuring protective measures, for example the use of nitrogen
as inert gas. A simpler method consists in dissolving the bo-
ron hydrides, for example diborane and in using the solution
.
- 12 -
,, , . .
. , .. , . . : . ,: . .- . :
- , . : ,
,
:.
108~91
obtaine~ for the reduction. Suitable solvents are especially
ethers such as tetrafurhne or diethylene glycol dimethyl ether.
When allowing to act complexe boron hydrides in the pre-
sence of Lewis acids there are even obtained higher yields.
The complexe boron hydrides used in the reduction method
are alkali metal boronates or alkaline earth metal boronates,
preferably sodium boron hydride.
Lewis acids appropriate for the present invention are
especially aluminium chloride, titanium tetrachloride and
boron trifluoride and its adducts such as boron trifluoride
etherate. When using the latter substance diborane may be
formed in situ during the reaction for example with sodium
boron hydride (cf. Fieser, Fieser: Reagent for Organic Syn-
thesis, John Wiley and Sons, Inc.,New York, volume 1, page
199)-
For attaining an especially high yield and especially
pure final products, the Lewis acids are preferably firstly
introduced with the compounds of the formula VIII and boron
or the complexe boron hydride are added thereafter.
The Lewis acid is preferably used in an excess and the
complexe boron hydride or the boron hydrides in at least
j stoichiometrical quantity calculated on the number of amide
groups to be reduced.
The reduction is performed in a solvent. Suitable sol-
vents are ethers such as tetrahydrofurane or diethylene glycol
~ dimethyl ether (diglyme). The solvent in which the reduction
is performed may be identical with that in which the boron
hydride is optionally dissolved, but it may also be a diffe-
rent one.
3 The reduction can be performed in a wide temperature range.
It may be carried out at low temperature, for example of about
- 10C, at room temperature or at a slightly increased tempe-
rature. The time of reduction depends on the reaction com-
ponent used and on the chosen temperature.
A preferred method of carrying out the process of the in-
vention consists in firstly introducing the benzoic acid
derivatives o the formula VII into an inert solvent together
- 13 -
; - , . , . , . . ......................... . . -- - .
.
::
1~8~1gl
with the Lewis acids and in adding a solu~ion of boron hydride
or the complexe boron hydride, optionally of a suspension of
the complexe boron hydride in the same or in a different sol-
vent at 0C and stirring for a short period. The cornplexe boron
hydride may also be directly added in a solid state. For acce-
le~ating th^ ~c-ctio.. l~ ..ay a'so bc opGlatêd Gptiv--aliy a~ a
higher temperature or when h~ving terminated the addition of
the reducing agent, the reaction mixture may be heated for
about 1 hour up to 50C.
Another method consists in firstly introducing the sub-
stance to be reduced together with the complexe boron hydride
and in adding the Lewis acid at a temperature from about -10C
to room temperature. A suitable complexe boron hydride is
especially the sodium boron hydride. The course of the reaction
may be observed by the thin-layer chromatography, by the fact
that there appears an intensive blue fluorescence (in the range
of 366 nm) of the compounds formed of the formula IX. Double
bonds optionally in group A may be reduced simultaneously in
the reduction according to the invention.
The final prouct may be isolated in various ways. In a
preferred method the solution of the reaction product is
liberated of possibly present reducing agent by adding water
and small quantities of an acid and the benzoic acid esters
obtained are precipitated subsequently by adding a nonsolvent.
When using diethyleneglycol dimethyl ether water is especially
suitable as nonsolvent. The benzoic acid esters of the formula
IX formed crystallize nearly quantitatively.
The 5-sulfamylbenzoic acids of the formula I (in which R
is H) according to the invention may be obtained~ alkaline hydro-
3 lysis of the compounds of the formula IX, by heating the latter
compounds for several hours in sodium hydroxide solution or
potassium hydroxide solution on the vapor bath. Thereby the
; ester is saponified and the protective group B and moreover
possibly present further protective groups are split off.
The 5-sulfamylbenzoic acids of the formula I (in which R
is ~) may also be directly obtained by partly concentrating the
reaction mixture after having de~troyed the excess of reducing
- 14 -
- : -: . " : -:: ' ' ' ' ' '
,
,
108Zl91
agent, adding a base and heating for a certain period. As
base there may be used, for exa~le, sodium hydroxide solu-
tion. The 5-sulfamylbenzoic acids of the formula I may be
directly isolated thereby in the form of their salts. The
free acids are obtained by slightly acidifying.
It is also possible to introduce the protective group
B into compounds of the formulae IV,V,VI or VIII, in which
B means in this case 2 hydrogen atoms, in a later reaction
step for obtaining compounds of the formula IX, in which R'
may also be replaced by R.
; For esterifying the corresponding esters of the formula
I, in which R means an alkyl radical, the acids are ester-
ified in usual manner, for example in the above-mentioned
; manner.
The free carboxylic acids may be converted into their
pharmaceutically compatible salts by reacting them with the
corresponding bases such as alkali metal, alkaline earth
metal or aluminium hydroxides or carbonates.
An important number of highly efficient pharmaceutical
agents, especially diuretics and saluretics may be prepared
according to the process of the invention, some of which -:
will be mentioned hereafter:
3-cyclopro ~ methylamino-4-(4'-chlorophenoxy)-5-sulfamyl-
~5 benzoic acid, - -
3-cyclopropylmethylamino-4-(4'-methylphenoxy)-5-sulfamyl-
benzoic acid,
3-cyclopropylmethylamino-4-(4'-ethylaminophenoxy)-5-sulfamyl-
benzoic acid,
~ - 15 -
Y~ .
- , : . - : . . .
.
.
1082~91
3-cyclopropylmethylamino-4-(4'-aminophenoxy)-5-sulfamyl-
benzoic acid,
3-cyclopropylmethylamino-4-(4'-methoxyphenoxy)-5-sulfamyl-
benzoic acid,
3-cyclopropylmethylamino-4-(4'-hydroxyphenoxy)-5-sulfamyl-
ben~oic acid,
3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-sulfamyl-
benzoic acid,
.
- 15(a) -
~ .
:
- ~08'hl91
3-cyclopropylmethylamino-4 (2',4'-dimethylphenoxy)--5-sulfamyl-
benzoicacid,
3-cyclopropylme-chylamino-4-(3',4'-dimethylphenoxy)-5-sulfamyl~
benzoicacid,
3-cyclopropylmethylamino-4-(3'-tri.fluorophenoxy)-5-sulfamyl-
hen.zoi cacid ~
3-cyclopropylmethylamino-4-phenylthio-5-sulfamylbenzoicacid,
3-cyclobutylmethylamino-4-phenoxy-5-sulfamylbenzoicacid,
3-cyclobutylmethylamino-4-phenylthio-5-sulfamylbenzoicacid,
3-benzylam.ino-4-phenoxy-5-sulfamylbenzoicacid,
3-benzylamino-4-(4'-chlorophenoxy)-5-sulfonylbenzoicacid,
3-benzylamino-4-(4'-methylphenoxy)-5-sulfamylbenzoicacid,
3-benzylamino-4-phenylthio-5-sulfamylbenzoicacid,
3-phenylethylamino-4-phenoxy-5-sulfamylbenzoicacid,
3-phenylethylamino-4-(4'-chlorophenoxy)-5-sulfamylbenzoicacid,
3-phenylethylamino-4-(4'-methylphenoxy)-5-sulfamylbenzoicacid,
3-phenylethylamino-4-(4'-methoxyphenoxy)-5-sulfamylbenzoicacid,
. .
3-Phenylethylamino-4-(4'-ethylaminophenoxy)-5-sulfamylbenzoic
acid,
3-phenylethylamino-4-(4'-aminophenoxy)-5-sulfamylbenzoicacid,
3-phenylethylamino-4-(2',4'-dimethylphenoxy)-5-sulfamylbenzoic-
acid,
3-phenylethylamino-4-phenylthio-5-sulfamylbenzoicacid,
3-furfurylamino-4-phenoxy-5-sulfamylbenzoicacid,
3-furfurylamino-4-phenylthio-5-sulfamylbenzoicacid,
3-thenylamino-4-phenoxy-5-sulfamylbenzoicacid,
3-thenylamino-4-(4'-methylphenoxy)-5-sulfamylbenzoicacid,
3-thenylamino-4-phenylthio-5-sulfamylbenzoicacid,
: 3
The following examples illustrate the invention.
E X A M P L E 1:
. . . . .. .. . .. .. ..
3-n-Butylamino-4-phenoxy-5-sulfamylbenzoic acid
a~ 4-Chloro-5-N,N-dimethylaminomethyleneaminosulfonyl-
benzoic acid
Thionyl chloride was added dropwise to a solution of
- 16 -
'
. . :
.
- ~8~
58.9 g (0.25 mole) of 4-chloro-5-sulfamoylbenzoic acid in
183 g (2.5 moles) of dimethylformamide (DMF) at -10C. The
solution was then allowed to heat to room temperature,
stirred for 2 hours and poured on ice. The precipiate was
filtered and washed ~ith water until it was neutral. 4-
Chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic
acid was obtained in a very high yield in the form of
crystals having a melting point from 266 to 267C.
b) 3-Nitro-4-chloro-S-N,N-dime,hylaminomethyleneaminosul-
_nylbenzoic acid
42 ml of fuming nitric acid were added dropwise to 60
ml of 20~ oleum while cooling with ice, thereafter 34.9g
(0.12 mole) of 4-chloro-5-N,N-dimethylaminomethyleneamino-
sulfonylbenzoic acid was slowly introduced. After stirring
at 75C for 8 hours the solution was cooled to room tempe-
rature, poured on ice and the precipitate was washed with
water until it was neutral. 3-Nitro-4-chloro-5-N,N-di-
methylaminomethyleneaminosulfonylbenzoic acid was obtained
in the form of crystals having a melting point from 274
to 276C.
c) 3-Nltro-4-chloro-5-N,N-dimethylaminomethyleneaminosul-
fonylbenzoic acid methyl ester
50.4 g (0.15 mole) of 3-nitro-4-chloro-5-N,N-dimethyl- -
aminomethyleneaminosulfonylbenzoic acid were refluxed in
a solution of 150 ml of thionyl chloride containing 5 drops
of DMF, for 1 hour. After having drawn off the excess of
thionyl chloride in vacuo the solid acid chloride was
suspended in 200 ml of methanol. The suspension was re-
- 17 -
.
. :
.
."' ~ - ' :: - .' ' ' ' '.' ~ :
` ~0i 32~91
fluxed for hal an hour, cooled, filtered and washed with
cold metnanol.
3--Nitro-4-chloro-5-N,N~dimethylaminomethyleneaminosul-
,were obtained
fonylbenzoic acid methyl ester crystal~ having a melting
point from ~ b8 to i69nO. A second crystal modification ~ :
having a melting point of 155C may also occur.
d) 3-Nitro-4-phenoxy-5-N,N--dimethylaminomethyleneaminosul-
fonylbenzoic acid methyl ester
A solution of 105 g (0.3 mole) of 3-nitro-4-chloro-5-
N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester and 47.5 g (0.36 mole) of potassium phenolate in
600 ml of DMF were refluxed for two hour hours. After
cooling and filtering off the potassium chloride the solu-
tion was given onto ice/water and stirred for 1 hour. The
precipitate was filtered, washed with water and dried.
, After having dissolved the crude product in 900 ml of
~ acetone the solution was cleared up with carbon, concen-
: i
trated to a volume of 500 ml and diluted with 1 l of
methanol. The precipitate was filtered at 10C after having
been stirred for 1 hour and washed with cold methanol.
3-Nitro-4-phenoxy-5-N,N-dimethylaminomethyleneamino-
` sulfonylbenzoic acid methyl ester was obtained in the form
of crystals having a melting point of from 191 to 193C.
e) 3-Amino-4-phenoxy-5-N,N-dimethylaminomethyleneamino-
sul~onylbenzoic acid methyl ester
61 g (0.15 mole) of 3-nitro-4-phenoxy-5-N,N-dimethyl-
aminomethyleneaminosulfonylbenzoic acid methyl ester were
hydrogenated in dimethylformamide with Raney Nickel at
, .
, - 18 -
:-' -,.
. , ~ . , .
, ; ~
- 1~82~1
at
for 8 hour~ room temperature and under atmospheric pres-
sure. After having filtered off the catalyst the solution
of DMF was given onto ice.
3-Amino-4-phenoxy-5-N,N-dimethylaminomethylenesulfony]-
benzoic acid methyl ester was obtained in the form of
crystals having a melting point from 255 to 256C
f) 3-n-Butyrylamino-4-phenoxy-5-N,N-dimethylaminomethy]ene-
aminosulfonylbenzoic acid methyl ester
10 g of 3-amino-4-phenoxy-5-N,N-dimethylaminomethylene-
aminosulfonylbenzoic acid methyl ester were heated to the
boil together with 2.6 ml of pyridine in 100 ml of ab-
solute dioxane. A solution of 5.3 g of butyric acid chloride
-- in 50 ml of absolute acetone was slowly added thereto drop-
wise. The reaction was terminated after 1.5 to 2 hours.
The solution was concentrated, the remaining oil was ab-
sorbed by a small quantity of methanol and the mixture
was introduced dropwise into cold ice water while vigo-
rously stirring. The 3-n-Butyrylamino-4-phenoxy-5-N,N-
dimethylaminomethyleneaminosulfonylhenzoic acid methyl
ester precipitated and was filtered with suction.
Recrystallization from CH30H/H20, melting point from 177
to 178C
g) 3-n-Butylamino-4-phenoxy-5-N,N-dimethylaminomethylene-
.. . . . . . . . . . . .
aminosulfonylbenzoic acid methyl ester
10 g of the butyryl compound prepared sub f) were sus-
pended in 100 ml of absolute diglyme, 6 ml of BF3 etherate
were added and a solution of 1.4 g of NaBH4 in 50 ml of
absolute diglyme was added dropwise. The reaction mixture
,
-.- , .. , - ' ~ :
.. . : . . .. :
' - - : -: :- .
': . -- ' '- ' ' ~ . , ,', ' ~ . . .
,, :
,: ~ ' ' : :
., , : -: : -' :
. ' ~ Z~9iL
was stirred for about 1 hour and the excess OL reducing
agent was destroyed by adding a small quantity of water
(foaming!) Then the reaction product was filtered and the
product was precipitated by adding 200 ml of water at low
iemperatures.
The 3-Butylamino-4 phenoxy-5-N,N-dimethylaminomethylene-
aminosulfonylbenzoic acid methyl ester formed~impurified
by about5~ of 3-n-butylamino-4-phenoxy-5-sulfamylbenzoic
acid methyl ester was recrystallized from CH30H.
Melting point from 111 to 112C.
h) 3-n-Butyl-4-phenoxy-5-sulfamylbenzoic acid
The crude product obtained sub g) was refluxed with ~n
NaOH until the solution was clear. Then the product ob-
tained was allowed to cool and the 3-n-butylamino-4-
phenoxy-5-sulfamylber.zoic ~cid precipitated with 2n HCl.
Recrystallization from ethanol/water; melting point from
` 234 to 235C.
E X A M P L E 2:
a) 3-(3'-Chloropropionylamino)-4-phenoxy-5-N,N-dimethyl-
aminomethyleneaminosulfonylbenzoic acid methyl ester
10 g of 3-amino-4-phenoxy-5-N,N-dimethylaminomethylene-
aminosulfonylbenzoic acid methyl ester were heated to the
oil with 3.6 ml of pyridine in 100 ml of absolute dioxane.
A solution of 7 g of ~ -chloropropionic acid chloride in
2~ 50 ml of absolute acetone was added dropwise. After 4
hours the solution was concentrated, absorbed by a small
quantity of CH30H and introduced dropwise while stirring
into ice water. The 3-(3'-Chloropropionylamino)-4-phenoxy-
- 20 -
: ~
., ~.
, . . .
- ~08~
5-N,N~dinlethylaminomethyleneaminosulfonylbenzoic acid
methyl ester precipitated in this way was recrystallized
from CH3OH/H2O; melting point 190C.
b) 3-(3'-Chloropropylamino)-4-phenoxy-5-N,N-dimethylamino-
methyleneaminosulfon5~1benzoic acid methyl ester
The process was performed as described in Example 1g).
The product was recrystallized from CH30H. Melting point
from 150 to 151C.
E ~ A M P L E 3.
3-Cyclopropylmethylamino-4-phenoxy-5-sulfamylben-zol- -
- acid
a) 3-Cyclopropanecarboxamido-4-phenoxy-5-N,N-dimethylamino-
methyleneaminosulfonylbenzoic acid methyl ester
9.2 ml (0.1 mole) of cyclopropanecarboxylic acid
chloride in 100 ml of absolute acetone were added dropwise
to a boiling solution of 19 g (0.05 mole) of 3-amino-4-
phenoxy-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic
acid methyl ester in 100 ml absolute dioxane and 5 ml of
pyridine. After having heated for 2 and a half hours while
refluxing the reaction product was cooled, filtered with
carbon and the solution was concentrated at the rotation
-:
evaporator. The solid residue was carefully washed with
acetone and dried thereafter. Melting point from 220 to
- 222C.
b) 3-Cyclopropylmethylamino-4-phenoxy-5-N,N-dimethylamino-
méthyleneaminosulfonylbenzoic acid methyl ester
23 g (0.052 mole) of 3-cyclopropanecarboxamido-4-phenoxy-
5-N,N-dimethylamonomethyleneaminosulfonylbenzoic acid
- 21 -
:
.-, ,, , ,, - :, ~.. . . : . - ..
- - .. . -, . . . .
. . . : - . -: . :: .: ... .
. - :. . - . . :,: -:
.
91
methyl ester were suspended in a solution of 250 ml of ab-
solute diglyme and 15 ml of BF3 e-therate. A solution of
3.5 g of NaBH4 in 200 ml of absolute diglyme was added
dropwise at room temperature while rapidly stirring, the
mixture obtained was stirred for 3 hours at room tempe-
rature, the excess of sodium boron hydride was decomposed
with 20 ml of water and the solution was poured on ice.
After standing over night at low temperatures the solu-
tion was filtered by suction, dried and recrystallized
from glacial acetic acid. Crystals having a melting point
from 150 to 152C.
c) 3-Cyclopropylmethylamino-4-phenoxy-5-sulfamylbenzoic
- acid
The product obtained sub b) was refluxed with 2n NaOH
until the solution was clear. Then it was allowed to cool
and 3-cyclopropylmethylamino-4-phenoxy-5-sulfamylbenzoic
acid was precipitated with 2n HCl.
', Recrystallization from glacial acetic acid. Melting point
from 234C.
E X A M P L E 4:
3-Cyclopropylmethylamino-4-(4'-methylphenoxy)-5-sulfamyl-
benzoic acid
a) 3-Nitro-~-(4'-methylphenoxy)-5-N,N-dimethylamino-
methyleneaminosuifonylbenzoic acid methyl ester
.. ... . _ .. . _ . _ _
A solution of 105 g (0.3 mole) of 3-nitro-4-chloro-5-
N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester and 53 g (0.36 mole) of potassium 4-methylpheno],ate
in 600 ml of DMF was refluxed for 3 hours. After cooling
- 22 -
- ... .', , ' ' ..... ~ - ~ '
,
Z3,91
and filtering off the potassium chloride the solution was
poured on ice/water and stirred for 1 hour. The pre-
cipitate was filtered, washed with water and dried.
After having dissolved the crude product in 900 ml of
acetone, the solution obtained was cleared with carbon,
concentrated to a volume of 500 ml and diluted with 1 l
of methanol. The precipitate was filtered after having
been stirred for 1 hour at 10C and washed with cold
methanol. 3-Nitro-4-(4-methylphenoxy)-5-N,N-dimethylamino-
methyleneaminosulfonylbenzoic acid methyl ester was ob-
tained in the form of crystals having a melting point from
196 to 198C.
-- b) 3-amino-4(4'-methylphenoxy)-5-N!N-dimethylaminomethylene-
aminosulfonylbenzoic acid methyl ester
A solution of 80 g of 3-nitro-4-(4'-methylphenoxy)-5-
N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester in 400 ml of DMF was hydrogenated for 8 hours at
40C and,under 50 atmospheres with about 10 g of Raney
nickel. After filtration of the catalyst the DMF solution
was poured on ice. The precipitate was filtered by suction,
dried and recrystallized from methanol. 3-Amino-4-(4'-
methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-
benzoic acid methyl ester was obtained, in the form of
~ ~ .
crystals having a melting point of from 168 to 169C.
c) 3-Cyclopropanecarboxamido-4-(4'-methylphenoxy)-5-N,N-
.
` -dimethylaminomethyienéaminosuifonylbenzoic acid methyl
.. ..
ester -
To a boiling solution of 49 g of 3-amino-4-(4'-methyl-
- 23 - -
~ . ' ' ,:
- .. . . . ...
.
:' ':
. , '' : ~ , :
1082191
phenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic
acid methyl ester in 250 ml of absolute dioxane and 12.5 ml
of pyridine a solution of 26.1 g of cyclopropanecarboxylic
acid chloride in 250 ml of absolute dioxane was added drop-
wise. The solution was concentrated and recrystallizedfrom acetone or methanol. 3-Cyclopropanecarboxamido-4-(4'-
methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-
benzoic acid methyl ester was obtained in the form of
crystals having a melting point from 201 to 203C.
d) 3-Cyclopropylmethylamino-4-(4'-methylphenoxy)-5-N,N-
; dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester
65 g of 3-cyclopropanecarboxamino-4-(4'-methylphenoxy)-
5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester were suspended in 600 ml of absolute diglyme 40 ml of
BF3 etherate were added and a solution of 9.5 g of NaBH4
in 500 ml of absolute diglyme was added dropwise at a temp-
erature from 0 to 5C. The reaction solution was stirred
for 4 hours at 0C and for 2 hours at room temperature, the
20 excess of reducing agent was destroyed by the addition of
water and the product obtained was precipitated by further
; adding 3 liters of ice water. The 3-Cyclopropylmethylamino-
4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneamino-
sulfonylbenzoic methyl ester formed impurified by about 5%
25 of 3-cyclopropylmethylamino-4-(4'-methylphenoxy)-5-sulfamoyl-
benzoic acid methyl ester was recrystallized from methanol.
Melting point from 158 to 159C.
e) 3-Cyclopropylmethylamino-4-(4-methylphenoxY)-5-sulfa-
- 24 -
. ~ ., : . : : . .
~08Zl~l :
moylbenzoic acidThe product obtained sub d) was refluxed with 2n NaOH
until a clear solution was obtained. The product obtained
was allowed cool and 3-cyclopropylmethylamino-4-(4-methyl-
phenoxy)-5-sulfamoylbenzoic acid was precipitated with 2n
of HCl. Recrystallization from glacial acetic acid. Melting
point from 230 to 232C.
E X A M P L E 5:
3-Cyclopropylmethylamino-4-(4'-fluorophenoxy)-5-sulfa-
moylbenzoic acid
a) 3-Nitro-4-(4'-fluorophenoxy)-5-N,N-dimethylamino-
methyleneaminosulfonylbenzoic acid methyl ester
A solution of 210 g (0.6 mole) of 3-nitro-4-chloro-5-
N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl
15 ester and 120 g of sodium-4-fluorophenolate in 800 ml of
absolutè DMF was stirred for 3 to 4 hours at a temperature
from 120 to 130C. The cold solution was slowly added
dropwise while vigorously stirring in 4 to 5 liters of ice
; water. The precipitated product was filtered by suction,
carefully washed with water, digested with acetone at ele-
vated temperatures and recrystallized from glycol mono-
methyl ether. Melting point from 224 to 225C.
b) 3-Amino-4-(4'-fluorophenoxy)-5-N,N-dimethylamino-
` ' methyleneaminosulfonylbenzoic acid methyl ester
140 g of the nitro compound (18a) were dissolved in
Dl~ and hydrogenated with Raney nickel for 8 hours at 50C,
- under a pressure of 50 atmospheres. The Raney nickel was
separated by suction-filtering and the solution obtained
- 25 -
,
'. ' .~
', , '' . ' : - : , -. . ~ ' '
- ~ , ' : -,
.:, ~ -
1~8~Z1'~1
was introduced dr~pwise in to ice water. The precipitated
substance was separated and washed with CH30H and with
ether subsequently. The practically pure subtance could be
recrystallized from glycol monomethyl ether. White crystals
of a melting point from 234 to 236C.
c) 3-Cyclopropanecarboxamido-4-(4'-fluorophenoxy)-5-N,N-
dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester
~ 9.2 ml (0.1 mole) of cyclopropanecarboxylic acid in 100
ml of absolute acetone were added dropwise to a boiling solu-
tion of 20 g (0.05 mole) of 3-amino-4-(4'-fluorophenoxy)-5-
N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester in 100 ml of absolute dioxane. After having refluxed
for half an hour the reaction mixture was cooled to 0C.
3-Cyclopropanecarboxamido-4-(4'-fluorophenoxy)-5-N,N-di-
methylaminomethyleneaminosulfonylbenzoic acid methyl ester
~ precipiated in the form of crystals;it was filtered by
- suction, firstly with a small quantity of cold acetone,thereafter with cold water, washed and dried. Melting
~ point from 201 to 202C.
d) 3-Cyclopropylmethylamino-4-(4~-fluorophenoxy)-5-N~N-
dimethylaminomet_yleneaminosulfonylbenzoic acid methyl
ester
The example was carried out as 3b with recrystallization
from methanol. Melting polnt from 165 to 166C.
e) 3-Cyclopropylmethylamino-4-(4~-fluorophenoxy)-5-sulfa
moylbenzoic acid
-
The product obtained sub d) was refluxed with 2n NaOH
-,`
- 26 -
- ~ : -: - . - - - ~ . .
:' - .~ ~:; '' ' . '
'
1C~8~
until a clear solution was obtained. The ~olution formed
was allowed to cool, cleare~ with carbon and 3-cyclopropyl-
methylamino-4-(4'-fluorophenoxy)-5-sulfamoylbenzoic acid
was precipitated with 2n HCl.
Recrystallization from methanol. Melting point from 228 to
229C.
E X A M P L E 6:
moylbenzoic acid
a) 3-Nitro-4-(4'-chlorophenoxy)-5-N,N-dimethylam _omethylene
aminosulfonylbenzoic acid methyl ester
A solution of 164 g of 3-nitro-4-chloro-5-N,N-dimethyl-
aminomethylenesulfonylbenzoic acid methyl ester and 117 g
of potassium-p-chlorophenolate in 800 ml of freshly distil-
led DMF was refluxed for 2 to 3 hours. The reaction mixture
was introduced dropwise while vigorously stirring into the
4-fold quantity of ice/H2O. The product precipitating there-
-;
by was separated and boiled out with CH30H/acetone. Melting
point from 227 to 228C.
b~ 3-Amino-4-(4'-chlorophenoxy)-5-N,N-dimethylaminomethylene-
aminosulfonylbenzoic acid methyl ester
130 g of the nitro compound t20a) were hydrogenated in
1 liter of DMF with Raney nickel for 9 hours under a pres-
sure of 50 atmospheres, at a temperature of 50C. The so-
lution was concentrated after Raney nickel had been filtered
by suction and the residue was boiled out with CH30H.
White substance having a melting point from 207 to 208C.
c) 3-Cyclopropanecarboxamido-4-(4'-chlorophenoxy)-5-N,N-
- 27 -
-- : ~ : -
.
.: . , . : . : ,,
. ~
' . .` '' ~ : - , : . .
~08~
-
dimet_ylamLnomethyleneaminosulfonylbenzoic acicl methyl
ester
The reaction was performed in an analogous manner to
Example 5c). Melting point from 195 to 196C.
d) 3-Cyclopropylmethylamino-4-(4'-chlorophenoxy)-5-N,N-
dimethy]aminomethyleneaminosulfonylbenzoic acid m~ yl-
ester
The reaction was carried out in an analogous manner to
Example 3b), with recrystallization from methanol. Melting
point from 186 to 187C.
e) 3-Cyclopropylmethylamino-4-(4'-chlorophenoxy)-5-sul~a-
moylbenzoic acid
The Example was carried out in an analogous manner to
Example 5e), with recrystallization from methanol. Melting
point from 247 to 248C.
E X A M P L E 7:
3-Cyclopropylmethylamino-4-(4'-benzyloxyphenoxy)_-5-sulfa-
moylbenzoic acid
; a) 3-Nitro-4-(4'-benzyloxyphenoxy)-5-N,N-dimethylamono-
methyleneaminosulfonylbenzoic acid methyl ester
87.5 g (0.25 mole) of 3-nitro-4-chloro-5-N,N-dimethyl-
- aminomethyleneaminosulfonylbenzoic acid methyl ester were
dissolved in S00 ml of anhydrous dimethylformamide and 77.5 g
(0.25 mole) of sodium-4-benzyloxyphenolate were added. The
reaction mixture was refluxed for 3 to 4 hours while stir-
ring vigorously. After cGoling, the turbid solution was
introduced dropwise into 3 liters of ice/water. The pre-
cipitating yellow product was filtered by suctionrcarefully
- 28 -
.:
, .. . . .
.
: ,, . : .
91
washed with water and recrystallized from methanol. 94 g
of 3~nitro-4-(4'--benzyloxyphenoxy)-5-N,N-dimethylamino-
methylaminosulfonylbenzoic acid methyl ester were obtained
as yellow crystals having a melting point of 132C.
b) 3-Amino-4-(4'-benzyloxyphenoxy)-5-N,N-dimethylamino-
methyleneaminosulfonylbenzoic acid methyl ester
94 g of 3-nitro-4-(4'-benzyloxyphenyloxy)-5-dimethyl-
aminomethyleneaminosulfonylbenzoic acid methyl esters were
dissolved in 1.5 liters of dimethylformamide and hydroge-
nated with Raney nickel at room temperature and under
atmospheric pressure for a period from 6 to 7 hours. The
product obtained was filtered and the clear solution thus
formed was introduced dropwise into ice/water. The pre-
cipitated 3-amino-4-(4'-benzyloxyphenoxy)-5-N,N-dimethyl-
aminomethyleneaminosulfonylbenzoic acid methyl ester was
recrystallized from methanol. About 70 g were obtained
in the form of white crystals having a melting point of
170C.
c) Cyclopropanecarboxamido-4-(4'-benzyloxyphenoxy)-5-N,N-
dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester
- 5.5 ml of cyclopropanecarboxylic acid chloride in 50 mlof absolute acetone were added dropwise to a boiling solu-
tion of 14.5 g (0.03 mole) of 3-amino-4-(4'-benzyloxy-
phenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic-
acid methyl ester in 150 ml of absolute dioxane and 3 ml
of pyridine. After refluxing for 6 hours the mixture ob-
tained was cooled to 0C. 3-Cyclopropanecarboxamido-4-(4'-
- 29 -
108'~
benzyloxyphenoxy)-5-M,N-dimethylaminomothvleneaminosulfonyL-
benzoic acid methyl ester precipitated, which was filtered
by suction and washed with acetone and ether. Melting point
from 210 to 211C.
d) 3-Cyclopropylmethylamino-4-(4'-benzyloxyphenoxy)-5-
sulfamoylbenzoic acid
5.6 g of the product obtained sub c) were suspended in
a solution of 50 ml of absolute diglyme and 4 ml of ~F3
etherate. A solution of 1 g of NaBH4 in 50 ml of absolute
diglyme was added dropwise while rapidly stirring. The
reaction mixture was stirred for 2 hours at a temperature
of 20C, cooled and given on ice. The crude product was
filtered and refluxed with 2n NaOH for 1 hour. Thereafter
- is was cooled, and precipitated with carbon and 3-cyclo-
propylmethylamino-4-(4'-benzylphenoxy)-5-sulfamoylbenzoic
acid with 2n HCl. Recrystallization from glacial acetic
acid. Melting point from 235 to 236 C.
E X A M P L E 8:
3- Cyclopropylmethylamino-4-(4'-hydroxyphenoxy)-5-sulfamoyl-
benzoic acid
2 g of 3-cyclopropylmethylamino-4-(4'-benzyloxyphenoxy)-
5-sulfamoylbenzoic acid were suspended in 50 ml of H20,
dissolved with 5 ml of 2n NaOH and hydrogenated with ~aney
nickel at 50C, under a hydrogen (H2)pressure of 50 atmos-
pheres for 4 hours. After having filtered off the catalyst
3-cyclopropylmethylamino-4-(4'-hydroxyphenoxy)-5-sulfamoyl-
benzoic acid was precipitated with 2n HCl. The precipitate
was filtered off with suction, carefully washed with water
- 30 -
-. . : - ,
- :, : .
: ...... -, , - ~ , ~
~ . - .. ... . . . .
108Z~
and dried. Melting point from 265 to 266C.
E X A M P L E 9:
3-Cyclopropylmethylamin~-4-~4'-nitrophenoxy)-5-sulfa-
moylbenzoic acid
a) 3-Cyclopropanecarboxamido-4-(4'-nitrophenoxy)-5-N,N-
dimethylaminomethyleneaminosul~onylbenzoic acid methy
ester
5 g of 3-cyclopropanecarboxamido-4-phenoxy-5-N,N-di-
methylaminomethyleneaminosulfonylbenzoic acid methyl ester
1~ were given portionswise into 30 ml of fuming nitric acid
at a temperature from -10 to -20C. The mixture was stir-
red for 10 minutes and the solution was poured on ice. 3-
Cyclopropanecarboxamido-4-(4'-nitrophenoxy)-5-N,N-dimethyl-
-- aminomethyleneaminosulfonylbenzoic acid methyl ester pre-
cipitated as crystals; it was filtered by suction and
thoroughly washed with water. Melting point from 215 to
216C.
b) 3-Cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-N,N-
dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester
22 g (0.045 mole) of 3-cyclopropanecarboxamido-4-(4'-
nitrophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-
benzoic acid methyl ester were suspended in a solution of
; - 150 ml of absolute diglyme and 12.8 ml of BF3 etherate and
heated to a temperature from 55 to 50C. A solution of 3 g
of NaBH4 in 100 ml of absolute diglyme was added at said
temperature while rapidly stirring. After having stirred
for 1 hour at 50C the solution was cooled to 0C, the ex-
.'
~:
.
- . . . :, '. ' -, : ., . . .~... - . .- :
, , . - : . - . . - :
. . :. , . . - - . : . - .
.
.. . . .
~8~ ~91
cess of NaBH~ was decomposed with a small quantiiy of water
~nA the product remaining was placed on ice. 3.Cyclopropyl-
methylamino-4-~4'-nitrophenoxy)-5-dimethylaminomethylene-
aminosulfonylbenzoic acid methyl ester crystalliæed, it was
filtered with suction washed with water, dried and boiled
out with methanol. Melting point from 233 to 235C.
.
c3 3-Cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-sulfamoyl-
benzoic acid
17 g of 3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-
N,N-dimethylaminomethyleneaminosl~lfonylbenzoic acid methyl
ester were suspended in 400 ml of 1 n NaOH and stirred for
3 hours at 95C. The solution was allowed to cool and 3-
cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-sulfamoyl-
benzoic acid was precipitated with concentrated HCl (pl~
Recrystallization from methanol after concentration of the
solution. Melting point of 230C (decomposition).
E X A MP__E 10:
' .
benzoic acid
3 g (0.074 mole) of 3-cyclopropylmethylamino-4-(4'-nitro-
- phenoxy)-5-sulfamoylbenzoic acid were hydrogenated in 50 ml
of methanol with 10% of Pd/C at 20C under a hydrogen pres-
sure of 10 atmospheres for 8 hours. After having filtered
off the catalyst the methanolic solution was concentrated
and 3-cyclopropylmethylamino-4-(4'-aminophenoxy)-5-sulfa-
moylbenzoic acid was precipitated with ether. Melting point
t7~C (decomposition).
E X A MP L E i-1-
- 32 -
- ~ .: ',:
- : - . ,
, , , ,'~ ' '
.
1082~91
~= methylamino~ phenylthio-5~sulfamoylben~oic
.
acid
a) 3-Nitro-4-phenylthio-5-N,N-dimethylaminomethyleneam no-
sulfonylbenzoic acid methyl ester
A solution of 210 g ~0.6 mole) of 3-nitro-4-chloro-5-
N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester and 108 g (0.66 mole) of potassium thiophenolate in
800 ml of DMF was refluxed for 2.5 hours. The solution was
poured on ice, the precipitate was filtered with suction,
washed with water, dried and recrystallized from acetone.
3-Nitro-4-phenylthio-5-N,N-dimethylaminomethyleneamino-
sulfonylbenzoic acid methyl ester was obtained as crystals
having a melting point from 205 to 207C.
b) 3-Amino-4-phenylthio-5-N,N-dimethylaminomethyleneamino-
sulfonylbenzoic acid methyl ester
110 g (0.26 mole) of 3-nitro-4-phenylthio-5-N,N-di-
methylaminomethyleneaminosulfonylbenzoic acid methyl ester
were hydrogenated for 8 hours in 400 ml of DMF with Raney
nickel at 50C and under a pressure of 100 atmospheres.
After filtration of the catalyst the DMF solution was poured
on ice. The precipitate was filtered with suction, washed
with water~dried and recrystallized from acetone. 3-Amino-
4-phenylthio-5-N,N-dimethylaminomethyleneaminosulfonylben-
zoic acid methyl ester was obtained as crystals having a
meltlng point from 214 to 215C.
c) 3 Cyclopropanecarboxamido-4-phenylthio-5-N~N-dimeth
.. .. .. . . .. .. .. .. .. ..
aminomethyleneaminosulfonylbenzoic acid methyl ester
To a boiling solution of 22 g ~0.056 mole) of 3-amino-
- 33 -
.: '
.: .
, ~
. ' : ' ~, '. ' . . '
: ', , ", ,.. ".. ; . . , ~ .
; . . . . - . . :
~08~191
4-phenylthio-~-N.N-dimethylaminomethyleneaminosulfonylben-
zoic acid methyl ester in 125 ml of absolute dioxane and
5.8 ml (0.11 mole) of pyridine there were added dropwise
6.1 g (0.067 mole) of cyclopropanecarboxylic acid chloride
in 125 ml of abso]ute acetone. After having refluxed for
2 hours, the mixture obtained was cooled, filtered with
carbon and concentrated at the rotation evaporator. The
residue was suspended in acetone and filtered. The crude
product was recrystallized from DMF/methanol.
3-Cyclopropanecarboxamido-4-phenylthio-5-N,N-dimethyl-
aminomethyleneaminosulfonylbenzoic acid methyl ester was
obtained, the crystals of which had a melting point from
245 to 247C
- d) 3-Cyclopropylmethylamino-4-phenylthio-5-sulfamoylbenæoic
acid
14.4 g (0.031 mole) of 3-cyclopropanecarboxamido-4-phenyl-
thio-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid
methyl ester were suspended in a solution of 55 ml of ab-
solute diglyme and 8.1 ml of BF3 etherate. A solution of
2.36 g ~0.062 mole) of NaBH4 in 55 ml of absolute diglyme
was added dropwise at room temperature while rapidly stir-
ring, the solution obtained was stirred for 5 hours at a
~ temperature from 20 to 30 C and poured on ice. The crude
- product was filtered and recrystallized from methanol.
8.8 g of the reduced compound were refluxed with 70 ml of
2n NaOH until a clear solution was formed. Thereafter the
solution was cooled and 3-cyclopropylmethylamino-4-phenyl-
- thio-5-sulfamoylbenzoic acid was precipitated with 2n HC1.
! ' 34 -
:
- i : ~ , , ~
.. .
.:: , . .: - -
:
10~
By recrystallization from methanol/water (3:1) there were
obtained crystals having a melting point from 214 to 215C.
.
E X A ~IP I, E 12:
3-Cyclobutylamino-4-phenylthio-5-sulfamoylbenzoic acid
a) 3-Cyclobutanecarboxam~ L~ ,N-dimethyl-
aminomethyleneaminosulfonylbenzoic acid methyl ester
To a boiling solution of 23.6 g (0.06 mole) of 3-amino-
4-phenylthio-5-N,N-dimethylaminomethyleneaminosulfonyl-
benzoic acid methyl ester in 150 ml of absolute dioxane
and 7.5ml of pyridine there were added dropwise 12.7 ml
(0.12 mole) of cyclobutanecarboxylic acid chloride in 150
- ml of absolute acetone. After refluxing for 1 hour, the
reaction mixture was concentrated at the ~otation eva-
porator and the residue was suspended in 500 ml of ace-
tone, filtered and washed with acetone.
3-Cyclobutanecarboxamido-4-phenylthio-5-N,N-dimethyl-
aminomethyleneaminosulfonylbenzoic acid was obtained. Mel-
.J' ting point from 231 to 232C.
b) 3-Cyclobutylmethylamino-4-ph_nylthio-5-N,N-dimethylamino-
.
methyleneaminosulfonylbenzoic acid methyl ester
i
28 g (0.062 mole) of 3-cyclobutanecarboxamido-4-phenyl-
thio-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid
methyl ester were suspended in a solution of 280 ml of
absolute diglyme and 16.5 ml of BF3 etherate. A solution
of 5.5 g of NaBH4 in 250 ml of diglyme was added dropwise
while rapidly stirring, the reaction mixture was stirred
for half an hour at a temperature from 40 to 50C, cooled,
the excess of NaBH4 was decomposed with a small quantity
,
....
.
.- . - . . ... . . .
,
.
. , ~ ,
,, , . : .
3Z~9l
of wate~ and the solution was poured on ice. After having
allo~ed the solution to stand over night the precipitate
was filtered with suction, dried and recrystallized from
methanol/water.
3-cyciobutyirnethylamino-4-phenylthio-5-N~N-dimethyl-
aminomethyleneaminosulfonylbenzoic acid methyl ester was
obtained, the crystals of which had a melting point from
193 to 195C.
c) 3-Cyclobutylamino-4-phenylthio-5-sulfamoylbenzoic acid
5 g of 3-cyclobuLylmethylamino-4-phenylthio-5-N,N-di-
methylaminomethyleneaminosulfonylbenzoic acid methyl ester
were suspended in 100 ml of 1n NaOH and hydrolyzed for 1.5
hours at a temperature from 95 to 100C. Then the hydro-
lysate was cleared up with active carbon, cooled and slightly
acidified with concentrated HCl (pH of 2).
3-Cyclobutylmethylamino-4-phenylthio-5-sulfamoylbenzoic
acid precipitated, was washed with water, dried and re-
crystallized from glacial acetlc acid.
Crystals having a melting point from 227 to 228C.
E X A M P L E 13:
3-Cyclopropylamino-4-N-methylpiperazino-5-sulfam
benzoic acid (salt of HCl)
:
a) 3-Nitro-4-N-methylpiperazino-5-N,N-dimethylaminomethylene-
aminosulfonylbenzoic acid methyl ester
34.g g (0.1 mole) of 3-nitro-4-chloro-5-N,N-dimethyl~
aminomethyleneaminosulfonylbenzoic acid methyl ester, 11 g
= 12.22 ml (0.11 mole) of N-methylpiperazine, 11,1 g= 15.2
ml (0.11 mole) of triethylamine in 150 ml of DMF were heated
- 36 -
. , - , - : . :
. . . .
- . . , . :
-: ~ . - , , : ,', - .' . . : :
,, . . , ~ - : : . : .
., , . : -- ~: :
~0~2191
for 2.5 hours at a temperature of 85C. After cooling, the
product obtained was poured in about 1 liter of ice water,
the precipitate was filtered with suction,washed with water,
dried and recrystallized from acetic acid ester. 3-Nitro-
4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosul-
fonylbenzoic acid methyl-ester was obtained, the crystals
; of which had a melting point from 181 to 182C.
b) 3-Amino-4=methylplperazino-5-N,N-dimethylaminomethylene-
aminosulfonylbenzoic acid methyl ester
82.6 g (0.2 mole) of 3-nitro-4-N-methylpiperazino-5-
N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester were hydrogenated in 750 ml of DMF with Raney nickel
at a temperature of 50C under a pressure of 100 atmos-
pheres for 12 hours. After having filtered off the catalyst
the DMF solution was given on ice.
After recrystallization from methanol 3-amino-4-N-
methylpiperazino-5-N~N-dimethylaminomethyleneaminosulfonyl-
benzoic acid methyl ester was obtained as crystals having a
melting point from 208 to 209C.
c) 3-Cyclopropan~carboxamido-4-N-methylpiperazino-5-N,N-
dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester
.
The example was carried out as Example 3a) wiLh re-
crystallization from water. Melting point from 155 to
157C.
d) 3-Cyclopropylmethylamino-4-N-methylpiperazino-5-N,N-
dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester
16 g (0.035 mole) of 3-cyclopropanecarboxamido-4-N-
- 37 -
., .: ~ ~ . . .
': ~' -' ' ~', ' :
~ . '
1082191
methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonyl-
benzoic acid methyl ester were suspended in a solution of
100 ml of absolute diglyme and 18.5 ml of BF3 etherate. A
solution of 2.7 g of NaBH4 in 100 ml of absolute diglyme
was added dropwise at room temperature while rapidly stir-
ring, the mixture obtained was stirred for 3 hours at 55C,
cooled, the excess of NaBH4 was decomposed with a small
quantity of water and the solution was poured on ice. The
crude product was filtered and recrystallized from methanol.
3-Cyclopropylmethylamino--4-N-methylpiperazino-5-N,N-
dimethylaminomethyleneaminosulfonylbenzoic acid methyl
ester was obtained, the crystals of which had a melting
point of 194C.
e) 3-Cyclopropylmethylamino-4-N-methylpiperazino-5-sulfa-
moylbenzoic acid (salt of HCl)
5 g of 3-cyclopropylmethylamino-4-N-methylpiperazino-
5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid
methyl ester were refluxed for 2 hours in 40 ml of 2n NaOH.
The product obtained was allowed to cool, cleared up with
20 carbon and 3-cyclopropylmethylamino-4-N-methylpiperazino-
5-sulfamoylbenzoic acid was precipitated with concentrated
hydrochloric acid (pH of 3). The mother liquor was de-
canted and the residue was separated by stirring with ace-
tone. Melting point 280C (decomposition).
25 E X A M P L E 14:
.
3-Nitro-4-chloro-N,N-dimethylaminomethyleneaminosulfonyl-
benzoic acid
42 ml of fuming nitric acid was added dropwise to 60 ml of
- 20~ oleum while cooling with ice. The solution was
- 38 -
. . - - ~ -:
. . . - : - , , : ~ .
.
,
: . . -- -
.. . . .
1~8,5~9~
heated to 90C and 34.9 g (0.12 mole) of 4-chloro-5-N,N~
dimethylaminomethyleneaminosulfonylbenzoic acid were added
slowly. In this process the temperature raise to 100C.
After having stirred for 3 hours at 90C, the product ob-
tained was cooled to room temperature, poured on ice, and
the precipitate was washed until it was neutral. 3~Nitro-
4-chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic
acid was obtained in the form of crystals having a mel-
ting point from 274 to 276C.
_ 39 _
. - , .: , ~
; '- '' ~ ' ' ~ :
.
