BENZODIOXOLE DERIVATIVES, PROCESSES FOR THE MANUFACTURE THEREOF AND CORRESPONDING PHARMACEUTICAL COMPOSITIONS

DERIVES DE BENZODIOXOLE, LEUR FABRICATION, ET PRODUITS PHARMACEUTIQUES A BASE DESDITS DERIVES

English Abstract

- 1 - Case 4-14161/+
Novel benzodioxole derivatives, processes for the
manufacture thereof and corresponding pharmaceutical
compositions.
Abstract
The invention relates to novel benzodioxole
derivatives of the general formula I
<IMG>
(I),
in which
R1 represents an unsubstituted or
substituted, aliphatic, aromatic or
heteroaromatic radical,
alk represents an alkylene, alkenylene
or alkylidene radical having a maximum of
5 carbon atoms,
n1 represents 0, 1 or 2
n2 represents 0 or 1,
R2, R3 and R4 each represents, independently of the
others, hydrogen, lower alkyl, lower

- 2 -
alkoxy or halogen, and
A represents the radical -0-R5, wherein R5
represents hydrogen or an unsubstituted
or substituted, aliphatic or araliphatic
hydrocarbon radical, or A represents the
radical
<IMG>
in which either R6 and R7 each
represents, independently of the other,
hydrogen or lower alkyl, or R6 and R7
are bonded to one another and, together
with the adjacent nitrogen atom,
represent optionally lower alkyl-
substituted tetra- to hexa-methylene-
imino, 4-morpholinyl or 1H-tetrazol-1-yl,
such as, for example, 5-methyl-6-
phenylsulphonyl-1,3-benzodioxole-2-
carboxylic acid.
The invention relates also to salts of compounds of the
general formula I in which A represents OR5 wherein R5
represents hydrogen, with bases, and to acid addition
salts of compounds of the general formula I in which
the radical R1 has a basic character and to processes
for the manufacture of the above compounds and the
salts thereof and to pharmaceutical compositions
containing them. These novel substances have diuretic
and supplementary uricosuric action and may be used,
preferably in the form of appropriate pharmaceutical
compositions, for the treatment of oedema and hyper-
tension.

Claims

- 76 -
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PRIVILEDGE OR PROPERTY IS CLAIMED ARE DEFINED AS FOLLOWS:
Claims
1. A process for the production of compounds of the general
formula I
<IMG> (I),
in which R1 represents an aliphatic hydrocarbon radical
that is unsubstituted or substituted by halogen having an
atomic number of up to 35, lower alkoxy or by lower alkyl-
thio and has, in total, that is to say including the sub-
stituents, a maximum of 12 carbon atoms, or represents a
mono- or bi-cyclic aryl radical that is unsubstituted or
substituted by lower alkyl, lower cycloalkyl, lower alkoxy,
lower alkylthio, lower alkylsulphonyl, trifluoromethyl,
hydroxy, lower alkanoyl, lower alkanoylamino, lower alkoxy-
carbonylamino and/or by lower alkylsulphonylamino, or a
moncyclic five-membered heterocyclic ring of aromatic
character having a maximum of two nitrogen atoms or one
nitrogen atom and/or one oxygen- or sulphur atom or a six-
membered heterocyclic ring of aromatic character with one
or two nitrogen atoms in the ring or a bicyclic radical
consisting of the above mentioned five-or six-membered
heterocyclic rings of aromatic character and a fuse benzene
ring, and
alk represents an alkylene, alkenylene or alkylidene radical
having a maximum of 5 carbon atoms, n1 represents 0,1 or 2

- 77 -
and n2 represents 0 or 1 and R2, R3 and R4 each represents, inde-
pendently of the others, hydrogen, lower alkyl, lower alkoxy or
halogen, and A represents the radical -O-R5, wherein R5 represents
hydrogen or an aliphatic or araliphatic hydrocarbon radical having,
in total, a maximum of 12 carbon atoms, that is unsubstituted or
substituted, in a position higher than the 1- or .alpha.-position, by
halogen having an atomic number of up to 35, hydroxy or by lower
alkoxy, or R5 represents a radical
<IMG>
in which either R6 or R7 each represents, independently of the
other hydrogen or lower alkyl, or R6 and R7 are bonded to one
another and, together with the adjacent nitrogen atom, represent
unsubstituted or lower alkyl-substituted tetra-to-hexa-methyl-
eneimino, 4-morpholinyl or 1H-tetrazol-1-yl, and salts of com-
pounds of the general formula I, characterised in that:-
a) a compound of the general formula II
<IMG> (II),

- 77a -
in which R1, alk, n1 , n2 , R2, R3 and R4 have the meanings given
above, or a salt thereof, is reacted with a compound of the
general formula III

- 78 -
<IMG> (III) ,
in which Hal represents halogen and A has the meaning given above
or with a salt of such a compound in which A represents OR5 wherein
R5 represents hydrogen, or
(b) in a compound of the general formula IV
<IMG> (IV),
in which Ab represents carboxy, lower alkoxycarbonyl or acetyl, and
R1, alk, n1, n2, R2, R3, R4 and A have the meanings given above
the radical Ab is replaced by hydrogen, or
(c) for the manufacture of a compound of the general formula I
in which A has the meaning given above with the exception of a
radical OR5 in which R5 represents hydrogen, and R1, alk, n2,
R2, R3 and R4 have the meanings given above and n1 represents 1
or 2, a compound of the general formula V

- 79 -
<IMG> (V),
is reacted with a compound of the general formula VI
R1-(alk)n2-S(O)n?-OH (VI),
or with an anhydride thereof, in which A1 has the meaning given
for A above with the exception of a radical OR5 in which R5
represents hydrogen, n? represents 1 or 2 and R2, R3 and R4, and
R1, alk and n2 have the meanings given above, or
d) for the manufacture of a compound in which n2 is 1 or R1 is
an aliphatic radical according to the definition and R1 or n2, as
the case may be, alk, n1, R2, R3, R4 and A have the meanings given
above a compound of the general formula VII
R1-(alk)n? - zd (VII),
in which zd represents a hydroxy group esterified by an inorganic
or organic acid, R1 has the meaning given above and n2 represents
1 or, if R2 is an aliphatic radical, may alternatively be 0, or
a compound of the general formula VIII
R1-(alk)n1-??N zdd? (VIII),
in which zdd ? represents a monovalent anion or the normal equiva-
lent of a polyvalent anion and R1 and n1 have the meanings given

- 80 -
above, is reacted with a salt of a compound of the general formula
IX
<IMG> (IX),
in which n1, R2, R3, R4 and A have the meanings given above or
e) a metal compound, optionally formed in situ, of the general
formula Xa or Xb
R1-(alk)n2-M1 (Xa) <IMG> (Xb)
in which M1 represents a monovalent metal ion and M2 represents a
divalent metal ion and R, alk and n2 have the meanings given above,
is reacted with a compound of the general formula XIa or XIb
<IMG> (XIa)

- 81 -
<IMG> (XIb)
in which Hal represents halogen and n1, R2, R3, R4 and A have the
meanings given above or
f) for the manufacture of a compound of the general formula I in
which A represents OR5 wherein R5 represents hydrogen, and R1, alk,
n1, n2, R2, R3 and R4 have the meanings given above, or a salt of
this compound: in a compound of the general formula XIII
<IMG> (XIII)
in which Af represents a group that can be converted into the
carboxy group and R1, alk, n1, n2, R2, R3 and R4 have the meanings
given above, the group Af is converted into the carboxy group in
free or salt form, or
g) for the manufacture of a compound of the general formula I in
which A has the meaning given above with the exception of a radical
OR5 in which R5 represents hydrogen, and R1, alk, n1, n2, R2 and
R3 have the meanings given above, a compound of the general
formula XIV

- 82 -
<IMG> (XIV),
in which Ag represents a carboxylic group, carboxylic acid halide
or anhydride, or a reactive ester thereof is reacted with a compound
of formula XV R5OH or ammonia or amines of the formula XVI <IMG>,
in which formulae R5, R6 and R7 have the meaning given under formu-
la I , and R1, alk, n1, n2, R2, R3 and R4 have the meanings given
above
h) if desired, a compound of the general formula I in which n1
represents 0 or 1 is oxidised to form the corresponding compound
in which n1 represents 1 or 2, or
i) if desired, a compound of the general formula I in which n1
represents 2 or 1 is reduced to form the corresponding compound in
which n1 represents 1 or 0, and/or, if desired, a compound of the
general formula I obtained in

- 83 -
the form of a racemate is separated into the optical
antipodes, and/or a resulting compound of the general
formula I in which A represents OR5 wherein R5
represents hydrogen is converted into a salt with a
base, or such a compound is feed from a resulting salt,
or a resulting compound of the general formula I having
basic character is converted into an acid addition salt,
or such a compound is freed from a resulting salt.

- 84 -
2. A process for the production of compounds of formula I
as claimed in claim 1, in which R1 represents phenyl,
thienyl, furyl or ar-benzothiazolyl, each of which is
unsubstituted or substituted a maximum of three times
by lower alkyl, lower alkoxy, halogen having an atomic
number of up to 35, lower alkanoyl and/or by lower
alkanoylamino, alk represents alkylene, alkylidene or
alkenylene having a maximum of 3 carbon atoms, R2
represents lower alkyl or halogen having an atomic number
of up to 35, R3 represents hydrogen, lower alkyl or
halogen having an atomic number of up to 35, R4
represents hydrogen and n1, n2 and A have the meanings
given in claim 1, and the salts of those compounds in
which R5 represents hydrogen with bases characterised
in that,
a) a compound of the general formula II
<IMG> (II),

- 85 -
in which R1, alk, n1, n2, R2, R3 and R4 have the
meanings given in claim I, or a salt thereof, is
reacted with a compound of the general formula III
<IMG> (III),
in which Hal represents halogen and A has the meaning
given in claim 1, or with a salt of such a compound in
which A represents OR5 wherein R5 represents
hydrogen, or
b) in a compound of the general formula IV
<IMG> (IV),
in which Ab represents carboxy, lower alkoxycarbonyl
or acetyl, and R1, alk, n1, n2, R2, R3, R4 and A
have the meanings given in claim 1, the radical Ab is
replaced by hydrogen, or

- 86 -
c) for the manufacture of a compound of the general
formula I in which A has the meaning given in claim 1
with the exception of a radical OR5 in which R5
represents hydrogen, and R1, alk, n2, R2, R3 and
R4 have the meanings given in claim 1 and n1
represents 1 or 2, a compound of the general formula V
<IMG> (V),
is reacted with a compound of the general formula VI
R1-(alk)n2-S(O)n?-OH (VI),
or with an anhydride thereof, in which A1 has the
meaning given for A in claim 1 with the exception of a
radical OR5 in which R5 represents hydrogen, n?
represents 1 or 2 and R2, R3 and R4, and R1, alk
and n2 have the meanings given in claim 1, or
d) for the manufacture of a compound in which n2
is 1 or R1 is an aliphatic radical according to the
definition and R1 or n2, as the case may be, alk, n1,
R2, R3, R4 and A have the meanings given in claim 1, a
compound of the general formula VII
R1-(alk)n? - zd (VII),

- 87 -
in which zd represents a hydroxy group esterified by an
organic or inorganic acid, R1 has the meaning given in
claim 1 and n2 represents 1 or, if R2 is an
aliphatic radical, may alternatively be 0, or a
compound of the general formula VIII
R1-(alk)n1-??N zdd? (VIII),
in which zdd? represents a monovalent anion or the
normal equivalent of a polyvalent anion and R1 and
n1 have the meanings given in claim 1, is reacted
with a salt of a compound of the general formula IX
<IMG> (IX),
in which n1, R2, R3, R4 and A have the meanings
given in claim 1 or
e) a metal compound, optionally formed in situ, of
the general formula Xa or Xb
R1-(alk)n2-M1 (Xa) <IMG> (Xb)

- 88 -
in which M1 represents a monovalent metal ion and M2
represents a divalent metal ion and R, alk and n2
have the meanings given in claim 1, is reacted with a
compound of the general formula XIa or XIb
<IMG> (XIa)
<IMG> (XIb)
in which Hal represents halogen and n1, R2, R3, R4
and A have the meanings given in claim 1, or
f) for the manufacture of a compound of the general
formula I in which A represents OR5 wherein R5 repre-
sents hydrogen, and R1, alk, n1, n2, R2, R3 and R4
have the meanings given in claim 1, or a salt of this
compound: in a compound of the general formual XIII
<IMG> (XIII)

_ 89 -
in which Af represents a group that can be converted
into the carboxy group and R1, alk, n1, n2, R2, R3
and R4 have the meanings given in claim 1, the group
Af is converted into the carboxy group in free or salt
form, or
g) for the manufacture of a compound of the general
formula I in which A has the meaning given in claim 1
with the exception of a radical OR5 in which R5
represents hydrogen, and R1, alk n1, n2, R2 and R3
have the meanings given in claim 1: in a compound of
the general formula XIV
<IMG> (XIV),
in which Ag represents a carboxylic group, carboxylic
acid halide, or anhydride, or a reactive ester thereof
and R1, alk, n1, n2, R2, R3 and R4 have the meanings
given in claim 1, the radical Ag is reacted with a
compound of formula XV: R5OH, or ammonia, or amines of
the formula XVI: HNR6R7, in which formulae R5, R6 and R7
have the meanings given in claim 1; and
h) if desired, a compound of the general formula I in
which n1 represents 0 or 1 is oxidised to form the
corresponding compound in which n1 represents 1 or
2, or

- 90 -
i) if desired, a compound of the general formula I in which
n1 represents 2 or 1 is reduced to form the corresponding
compound in which n1 represents 1 or 0, and/or, if
desired, a compound of the general formula I obtained in
the form of a racemate is separated into the optical
antipodes, and/or a resulting compound of the general
formula I in which A represents OR5 wherein R5
represents hydrogen is converted into a salt with a
base, or such a compound is freed from a resulting salt,
or a resulting compound of the general formula I having
basic character is converted into an acid addition salt,
or such a compound is freed from a resulting salt.
3 . A process for the production of compounds of formula I
as claimed in claim 1, in which R1 represents phenyl or
thienyl, each of which is unsubstituted or substituted a
maximum of three times by lower alkyl, lower alkoxy,
halogen having an atomic number of up to 35, lower
alkanoyl and/or by lower alkanoylamino, alk represents
methylene, n1 represents 2, n2 represents 0 or 1, R2
represents lower alkyl or halogen, R3 represents
hydrogen or lwoer alkyl, R4 represents hydrogen and A
represents OR5 wherein R5 represents hydrogen or lower
alkyl, and the pharmaceutically acceptable salts of
those compounds in which R5 represents hydrogen with
bases characterised in that,

- 91 -
a) a compound of the general formula II
<IMG> (II) ,
in which R1, alk, n1, n2, R2, R3 and R4 have the
meanings given in claim I, or a salt thereof, is
reacted with a compound of the general formula III
<IMG> (III) ,
in which Hal represents halogen and A has the meaning
given in claim 1, or with a salt of such a compound in
which A represents OR5 wherein R5 represents
hydrogen, or
b) in a compound of the general formula IV

- 92 -
<IMG> (IV),
in which Ab represents carboxy, lower alkoxycarbonyl
or acetyl, and R1, alk, n1, n2, R2, R3, R4 and A
have the meanings given in claim 1, the radical Ab is
replaced by hydrogen, or
c) for the manufacture of a compound of the general
formula I in which A has the meaning given in claim 1
with the exception of a radical OR5 in which R5
represents hydrogen, and R1, alk, n2, R2, R3 and
R4 have the meanings given in claim 1 and n1
represents 1 or 2, a compound of the general formula V
<IMG> (V),
is reacted with a compound of the general formula VI
R1-(alk)n2-S(O)n?-OH (VI),

-93 -
or with an anhydride thereof, in which A1 has the
meaning given for A in claim 1 with the exception of a
radical OR5 in which R5 represents hydrogen, n?
represents 1 or 2 and R2, R3 and R4, and R1, alk
and n2 have the meanings given in claim 1, or
d) for the manufacture of a compound in which n2
is 1 or R1 is an aliphatic radical according to the
definition and R1 or n2, as the case may be, alk, n1,
R2, R3, R4 and A have the meanings given in claim 1, a
compound of the general formula VII
R1-(alk)n? - zd (VII),
in which Z represents a hydroxy group esterified by an
organic or inorganic acid, R1 has the meaning give in
claim 1 and n2 represents 1 or, if R2 is an
aliphatic radical, may alternatively be 0, or a
compound of the general formula VIII
R1-(alk)n1-??N zdd? (VIII),
in which zdd? represents a monovalent anion or the
normal equivalent of a polyvalent anion and R1 and
n1 have the meanings given in claim 1, is reacted
with a salt of a compound of the general formula IX

- 94 -
<IMG> (IX),
in which n1, R2, R3, R4 and A have the meanings
given in claim 1 or
e) a metal compound, optionally formed in situ, of
the general formula Xa or Xb
R1-(alk)n2-M1 (Xa) <IMG> (Xb)
in which M1 represents a monovalent metal ion and M2
represents a divalent metal ion and R, alk and n2
have the meanings given in claim 1, is reacted with a
compound of the general formula XIa or XIb
<IMG> (XIa)

- 95 -
<IMG> (XIb)
in which Hal represents halogen and n1, R2, R3, R4
and A have the meanings given in claim 1, or
f) for the manufacture of a compound of the general
formula I in which A represents OR5 wherein R5 repre-
sents hydrogen, and R1, alk, n1, n2, R2, R3 and R4
have the meanings given in claim 1, or a salt of this
compound: in a compound of the general formual XIII
<IMG> (XIII)
in which Af represents a group that can be converted
into the carboxy group and R1, alk, n1, n2, R2, R3
and R4 have the meanings given in claim 1, the group
Af is converted into the carboxy group in free or salt
form, or
g) for the manufacture of a compound of the general
formula I in which A has the meaning given in claim 1
with the exception of a radical OR5 in which R5

- 96 -
represents hydrogen, and R1, alk, n1, n2, R2 and R3
have the meanings given in claim 1: in a compound of
the general formula XIV
<IMG> (XIV),
in which Ag represents a carboxylic group, carboxylic
acid halide, or anhydride, or a reactive ester thereof
and R1, alk, n1, n2, R2, R3 and R4 have the meanings
given in claim 1, the radical Ag is reacted with a
compound of formula XV: R5OH, or ammonia, or amines of
the formula XVI: HNR6R7, in which formulae R5, R6 and
R7 have the meanings given in claim 1; and
h) if desired, a compound of the general formula I in
which n1 represents 0 or 1 is oxidised to form the
corresponding compound in which n1 represents 1 or
2, or
i) if desired, a compound of the general formula I in
which n1 represents 2 or 1 is reduced to form the
corresponding compound in which n1 represents 1 or 0,
and/or, if desired, a compound of the general formula
I obtained in

- 97 -
the form of a racemate is separated into the optical
antipodes, and/or a resulting compound of the general
formula I in which A represents OR5 wherein R5
represents hydrogen is converted into a salt with a
base, or such a compound is freed from a resulting salt,
or a resulting compound of the general formula I having
basic character is converted into an acid addition salt,
or such a compound is freed from a resulting salt.
4. A process for the production of compounds of formula I
as claimed in claim 1, in which R1 represents phenyl
that is unsubstituted or substituted a maximum of three
times by lower alkyl, lower alkoxy and/or by halogen
having an atomic number of up to 35, alk represents
methylene, n1 represents 2, n2 represents 0 or 1, R2
represents lower alkyl or halogen, R3 represents
hydrogen or lower alkyl, R4 represents hydrogen and A
represents OR5 wherein R5 represents hydrogen or lower
alkyl, and the phenylsulphonyl radical is bonded in the
5- or 6-position, and the pharmaceutically acceptable
salts of those compounds in which R5 represents hydrogen
with bases characterised in that,
a) a compound of the general formula II
<IMG>
(II),

_ 98 _
in which R1, alk, n1, n2, R2, R3 and R4 have the
meanings given in claim I, or a salt thereof, is
reacted with a compound of the general formula III
<IMG> (III),
in which Hal represents halogen and A has the meaning
given in claim 1, or with a salt of such a compound in
which A represents OR5 wherein R5 represents
hydrogen, or
b) in a compound of the general formula IV
<IMG> (IV),
in which Ab represents carboxy, lower alkoxycarbonyl
or acetyl, and R1, alk, n1, n2, R2, R3, R4 and A
have the meanings given in claim 1, the radical Ab is
replaced by hydrogen, or

- 99 -
c) for the manufacture of a compound of the general
formula I in which A has the meaning given in claim 1
with the exception of a radical OR5 in which R5
represents hydrogen, and R1, alk, n2, R2, R3 and
R4 have the meanings given in claim 1 and n1
represents 1 or 2, a compound of the general formula V
<IMG> (V),
is reacted with a compound of the general formula VI
R1-(alk)n2-S(O)n?-OH (VI),
or with an anhydride thereof, in which A1 has the
meaning given for A in claim 1 with the exception of a
radical OR5 in which R5 represents hydrogen, n?
represents 1 or 2 and R2, R3 and R4, and R1, alk
and n2 have the meanings given in claim 1, or
d) for the manufacture of a compound in which n2
is 1 or R1 is an aliphatic radical according to the
definition and R1 or n2, as the case may be, alk, n1,
R2, R3, R4 and A have the meanings given in claim 1, a
compound of the general formula VII
R1-(alk)n? - zd (VII),

- 100 -
in which zd represents a hydroxy group esterified by an
organic or inorganic acid, R1 has the meaning given in
claim 1 and n2 represents 1 or, if R2 is an
aliphatic radical, may alternatively be 0, or a
compound of the general formula VIII
R1-(alk)n1-??N zdd? (VIII),
in which zdd? represents a monovalent anion or the
normal equivalent of a polyvalent anion and R1 and
n1 have the meanings given in claim 1, is reacted
with a salt of a compound of the general formula IX
<IMG> (IX),
in which n1, R2, R3, R4 and A have the meanings
given in claim 1 or
e) a metal compound, optionally formed in situ, of
the general formula Xa or Xb
R1-(alk)n2-M1 (Xa) <IMG> (Xb)

- 101 _
in which M1 represents a monovalent metal ion and M2
represents a divalent metal ion and R, alk and n2
have the meanings given in claim 1, is reacted with a
compound of the general formula XIa or XIb
<IMG> (XIa)
<IMG> (XIb)
in which Hal represents halogen and n1, R2, R3, R4
and A have the meanings given in claim 1, or
f) for the manufacture of a compound of the general
formula I in which A represents OR5 wherein R5 repre-
sents hydrogen, and R1, alk, n1, n2, R2, R3 and R4
have the meanings given in claim 1, or a salt of this
compound: in a compound of the general formual XIII
<IMG> (XIII)

- 102 -
in which Af represents a group that can be converted
into the carboxy group and R1, alk, n1, n2, R2, R3
and R4 have the meanings given in claim 1, the group
Af is converted into the carboxy group in free or salt
form, or
g) for the manufacture of a compound of the general
formula I in which A has the meaning given in claim 1
with the exception of a radical OR5 in which R5
represents hydrogen, and R1, alk, n1, n2, R2 and R3
have the meanings given in claim 1: in a compound of
the general formula XIV
<IMG> (XIV),
in which Ag represents a carboxylic group, carboxylic
acid halide, or anhydride, or a reactive ester thereof
and R1, alk, n1, n2, R2, R3 and R4 have the meanings
given in claim 1, the radical Ag is reacted with a
compound of formula XV: R5OH, or ammonia, or amines of
the formula XVI: NHR6R7, in which formulae R5, R6 and
R7 have the meanings given in claim 1; and
h) if desired, a compound of the general formula I in
which n1 represents 0 or 1 is oxidised to form the
corresponding compound in which n1 represents 1 or
2, or
i) if desired, a compound of the general formula I in
which n1 represents 2 or 1 is reduced to form the

- 103 -
corresponding compound in which n1 represents 1 or 0, and/or
if desired, a compound of the general formula I obtained in
the form of a racemate is separated into the optical
antipodes, and/or a resulting compound of the general
formula I in which A represents OR5 wherein R5
represents hydrogen is converted into a salt with a
base, or such a compound is freed from a resulting salt,
or a resulting compound of the general formula I having
basic character is converted into an acid addition salt,
or such a compound is freed from a resulting salt.
5. A process for the production of compounds of formula I
as claimed in claim 1 in which R1 represents phenyl that
is unsubstituted or substituted a maximum of three times
by methyl, methoxy and/or chlorine, alk represents
methylene, n1 represents 2, n2 represents 0 or 1, R2
represents methyl or chlorine, R3 and R4 represent
hydrogen, and A represents OR5 wherein R5 represents
hydrogen or lower alkyl, and the phenylsulphonyl radical
is bonded in the 5- or 6-position, and the pharma-
ceutically acceptable salts of those compounds in which
R5 represents hydrogen with bases, characterised in that,
a) a compound of the general formula II
<IMG> (II),

- 104 -
in which R1, alk, n1, n2, R2, R3 and R4 nave the
meanings given in claim I, or a salt thereof, is
reacted with a compound of the general formula III
<IMG>
(III),
in which Hal represents halogen and A has the meaning
given in claim 1, or with a salt of such a compound in
which A represents OR5 wherein R5 represents
hydrogen, or
b) in a compound of the general formula IV
<IMG>
(IV),
in which Ab represents carboxy, lower alkoxycarbonyl
or acetyl, and R1, alk, n1, n2, R2, R3, R4 and A
have the meanings given in claim 1, the radical Ab is
replaced by hydrogen, or
c) for the manufacture cf a compound of the general

- 105 -
formula I in which A has the meaning given in claim 1
with the exception of a radical OR5 in which R5
represents hydrogen, and R1, alk, n2, n2, R3 and
R4 have the meanings given in claim 1 and n1 .
represents 1 or 2, a compound of the general formula V
<IMG>
(V),
is reacted with a compound of the general formula VI
R1-(alk)n2-S(O)n?c-OH (VI),
or with an anhydride thereof, in which A1 has the
meaning given for A in claim 1 with the exception of a
radical OR5 in which R5 represents hydrogen, n1c
represents 1 or 2 and R2, R3 and R4, and R1, alk
and n2 have the meanings given in claim 1, or
d) for the manufacture of a compound in which n2
is 1 or R1 is an aliphatic radical according to the
definition and R1 or n2, as the case may be, alk, n1,
R2, R3, R4 and A have the meanings given in claim 1, a
compound of the general formula VII
R1-(alk)n?d-Zd (VII),

- 106 -
in which Zd represents a hydroxy group esterified by an
organic or inorganic acid, R1 has the meaning given in
claim 1 and n2 represents 1 or, if R2 is an
aliphatic radical, may alternatively be 0, or a
compound of the general formula VIII
R1-(alk)n1-??N Zdd? (VIII),
in which Zdd? represents a monovalent anion or the
normal equivalent of a polyvalent anion and R1 and
n1 have the meanings given in claim 1, is reacted
with a salt of a compound of the general formula IX
<IMG>
(IX),
in which n1, R2, R3, R4 and A have the meanings
given in claim 1 or
e) a metal compound, optionally formed in situ, of
the general formula Xa or Xb
R1-(alk)n2-M1 (Xa) <IMG> (Xb)

-107 -
in which M1 represents a monovalent metal ion and M2
represents a divalent metal ion and R, alk and n2
have the meanings given in claim 1, is reacted with a
compound of the general formula ?Ia or XIb
<IMG> (XIa)
<IMG> (XIb)
in which Hal represents halogen and n1, R2, R3, R4
and A have the meanings given in claim l, or
f) for the manufacture of a compound of the general
formula I in which A represents OR5 wherein R5 repre-
sents hydrogen, and R1, alk, n1, n2, R2, R3 and R4
have the meanings given in claim 1, or a salt of this
compound: in a compound of the general formual XIII
<IMG> (XIII)

- 108-
in which Af represents a group that car. be converted
into the carboxy group and R1, alk, n1, n2, R2, R3
and R4 have the meanings given in claim 1, the group
Af is converted into the carboxy group in free or salt
form, or
g) for the manufacture of a compound of the general
formula I in which A has the meaning given in claim 1
with the exception of a radical OR5 in which R5
represents hydrogen, and R1, alk, n1, n2, R2 and R3
have the meanings given in claim 1: in a compound of
the general formula XIV
<IMG> (XIV),
in which Ag represents a carboxylic group, carboxylic
acid halide, or anhydride, or a reactive ester thereof
and R1, alk, n1, n2, R2, R3 and R4 have the meanings
given in claim 1, the radical Ag is reacted with a
compound of formula XV: R5OH, or ammonia, or amines of
the formula XVI: HNR6R7, in which formulae R5, R6 and
R7 have the meanings given in claim 1; and
h) if desired, a compound of the general formula I in
which n1 represents 0 or 1 is oxidised to form the
corresponding compound in which n1 represents 1 or
2, or

- 109 -
i) if desired, a compound of the general formula I in which
n1 represents 2 or 1 is reduced to form the corresponding
compound in which n1 represents 1 or 0, and/or if
desired, a compound of the general formula I obtained in
the form of a racemate is separated into the optical
antipodes, and/or a resulting compound of the qeneral
formula I in which A represents OR5 wherein R5
represents hydrogen is converted into a salt with a
base, or such a compound is freed from a resulting salt,
or a resulting compound of the general formula I having
basic character is converted into an acid addition salt,
or such a compound is freed from a resulting salt.
6. Process according to claim 1 for the production of
5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic
acid, which comprises reacting 4-methyl-5-phenylsulfonyl-
1,3-benzenediol with dichloroacetic acid ethyl ester.
7. Process according to claim 1 for the production of
5-chloro-6-(2-chlorophenylsulfonyl)-1,3-benzodioxole-2-
carboxyclic acid, which comprises reacting 4-chloro-5-
(2-chlorophenylsulfonyl)-1,2-benzenediol with dichloro-
acetic acid ethyl ester.
8. Process according to claim 1 for the production of
5-(2-chlorophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-
carboxylic acid, which comprises reacting 4-(2-chloro-
phenylsulfonyl)-5-methyl-1,2-benzenediol with dibromo-
acetic acid.

- 110 -
9. Process according to claim 1 for the production of
5-chloro-6-(4-chlorophenylsulfonyl)-1,3-benzodioxole-2-
carboxylic acid, which comprises reacting 4-chloro-5-
(4-chlorophenylsulfonyl)-1,2-benzenediol with dibromo-
acetic acid.
10. Process according to claim 1 for the production of
5-(3-chlorophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-
carboxylic acid, which comprises reacting 4-(3-chloro-
phenylsulphonyl)-5-methyl-1,2-benzenediol with dibromo-
acetic acid.
11. Process according to claim 1 for the production of
5-chloro-6-(3-chlorophenylsulfonyl)-1,3-benzodioxole-2-
carboxylic acid, which comprises reacting 4-chloro-5(3-
chlorophenylsulfonyl)-1,2-benzenediol with dibromoacetic
acid.
12. Compounds of the formula I according to claim 1, in
which R1, alk, n1,n2' R2, R3 and R4 and A are as defined
in claim 1 or salts thereof with bases, whenever
prepared by a process as claimed in claim 1 or by an
obvious chemical equivalent thereof.
13. Compounds of formula I according to claim 2, in which
R1, alk, n1, n2,R2, R3,R4 and R5 are as defined in
claim 2 or salts thereof with bases, whenever prepared
by a process as claimed in claim 2 or by an obvious
chemical equivalent thereof.
14. Compounds of formula I according to claim 3, in which
R1, alk, n1, n2, R2, R3, R4 and A are as defined in
claim 3 or salts thereof with bases, whenever prepared

-111-
by a process as claimed in claim 3 or by an obvious
chemical equivalent thereof.
15. Compounds of formula I according to claim 4, in
which R1,alk,n1,n2, R2, R3, R4 and A are as defined
in claim 4 or salts thereof with bases, whenever
prepared by a process as claimed in claim 4 or by an
obvious ehemieal equivalent thereof.
16. Compounds of formula I aecording to claim 5, in
which R1, alk, n1, n2, R2, R3, R4 and A are as defined
in claim 5 or salts thereof with bases, whenever
prepared by a process as claimed in claim 5 or by an
obvious chemical equivalent thereof.
17. 5-Methyl-6-phenylsulfonyl-1,3-benzodioxole-2-
carboxylic acid, whenever prepared by a process as
claimed in claim 6 or by an obvious chemical equivalent
thereof.
18. 5-Chloro-6-(2-chloropenylsulfonyl)-1,3-benzodioxole-
2-carboxylic acid, whenever prepared by a process as
claimed in claim 7 or by an obvious chemical equivalent
thereof.

- 112 -
19. 5-(2-chlorophenylsulfonyl)-6-methyl-1,3-benzodioxole-
2-carboxylic acid, whenever prepared by a process as
claimed in claim 8 or by an obvious chemical equivalent
thereof.
20. 5-chloro-6-(4-chlorophenylsulfonyl)-1,3-benzodioxole-
2-carboxylic acid, whenever prepared by a process as
claimed in claim 9 or by an obvious chemical equivalent
thereof.
21. 5-(3-chlorophenylsulfonyl)-6-methyl-1,3-benzodioxole-
2-carboxylic acid, whenever prepared by a process as
claimed in claim 10 or by an obvious chemical equivalent
thereof.
22. 5-Chloro-6-(3-chlorophenylsulfonyl)-1,3-benzodioxole-
2-carboxylic acid, whenever prepared by a process as
claimed in claim 11 or by an obvious chemical equivalent
thereof.

Description

lZZ;~8~'~
Case 4-14161/+
Novel benzodioxole derivatives, processes for the
manufacture thereof and corresponding pharmaceutical
compositions.
_
The invention relates to novel benzodioxole
derivatives, processes for the manufacture thereof and
corresponding pharmaceutical compositions, and to the
use of these novel substances and compositions.
The novel compounds according to the invention
correspond to the general formula I
Rl-(alk)n2 ~ . R4
~ lil \ CO A (I),
R~- --0/
r~

1223~37~
in which
Rl represents an unsubstituted or
substituted, aliphatic, aromatic or
heteroaromatic radical,
alk represents an alkylene, alkenylene or
alkylidene radical having a maximum of 5
carbon atoms,
n represents 0, 1 or 2,
--1
n2 represents O or 1,
R2, R3 and R4 each represents, independently of the
others, hydrogen, lower alkyl, lower
alkoxy or halogen, and
A represents the radical -O-R5, wherein
R5 represents hydrogen or an unsubsti-
tuted or substituted aliphatic or
araliphatic hydrocarbon radical, or
represents the radical
-N
R7
in which either R6 and R7 each
represents, independently of the other,
hydrogen or lower alkyl, or R6 and R7
are bonded to one another and, together
with the ad~acent nitrogen atom,
represent optionally lower alkyl-
substituted tetra- to hexa-methyleneimino,
4-morpholinyl or lH-tetrazol-l-yl.
The novel compounds may be present in the form of
racemates or optical antipodes or, with the appropriate
meanings for the variables, alternatively in the form
of mixtures of racemates. The invention relates also
to salts of compounds of the general formula I in which

~ZZ387~
A represents OR5 wherein R5 represents hydrogen,
with bases, and to acid addition salts of compounds o~
the general formula I in which the radical Rl has a
basic character, and also to the manufacture of such
salts. Unless otherwise stated, hereinbefore and
hereinafter lower radicals or compounds are to be
understood as those having a maximum of 7, preferably a
maximum of 4, carbon atoms.
An aliphatic radical Rl is especially an
alkyl, alkenyl or alkynyl radical having a maximum of
12 carbon atoms, preferably lower alkyl, lower alkenyl
or lower alkynyl, such as octyl, nonyl, decyl, undecyl,
dodecyl, 2,2,4-trimethyl-1-pentenyl, l-octynyl or
pentyl, isopentyl, hexyl, heptyl, l-hexenyl, l-heptenyl
or, especially, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tert.-butylethenyl, l-methylethenyl,
2-propenyl, 2-butenyl, 2-methyl-2-propenyl, ethynyl or
l-propynyl.
An aromatic radical Rl is especially a 1- or 2-
naphthyl radical and above all a phenyl radical. A
heteroaromatic radical Rl is preferably a bicyclic
radical and especially a monocyclic radical. As a
corresponding monocyclic radical, Rl contains
especially two nitrogen atoms or, preferably, one
nitrogen atom and/or one oxygen or sulphur atom and is,
for example, a mono- or di-azacyclic, oxa- or
thia-cyclic or oxaza- or thiaza-cyclic radical having 5
ring members, for example lH-pyrrolyl, such as lH-
pyrrol-2-yl or -3-yl, lH-pyrazolyl, such as lH-pyrazol-
3-yl, -4-yl or -5-yl, lH-imidazolyl, such as lH-
imidazol-2-yl, -4-yl or -5-yl, furyl, such as 2- or 3-
furyl, thienyl, such as 2- or 3-thienyl, oxazolyl, such
as 2-oxazolyl, isoxazolyl, such as 3 or 5-isoxazolyl,
thiazolyl, such as 2- or 4-thiazolyl, or a mono- or di-
azacyclic radical having 6 ring members, for example,

lZZ387~
p~ridyl, such as 2-, 3- or 4-pyridyl, pyridazinyl, such
as 3-pyridazinyl, pyrimidinyl, such as 2-, 4- or 5-
pyrimidinyl, or 2-pyrazinyl. Corresponding bicyclic
radicals Rl comprise, for example, a 5-membered
hetero ring of aromatic character having two nitrogen
atoms or having one nitrogen atom and/or one oxygen or
sulphur atom as ring members and a fused-on benzene
ring, or a 6-membered hetero ring of aromatic character
having two or, especially, one nitrogen atom(s) as ring
member(s) and a fused-on benzene ring. Accordingly,
bicyclic heteroaryl is, for example, lH-indolyl, such
as lH-indol-2-yl, -3-yl, -4-yl, -5-yl or -6-yl, lH-
indazolyl, such as lH-indazol-3-yl, lH-benzimidazolyl,
such as lH-benzimidazol-2-yl, -4-yl, -5-yl or -6-yl,
benzofuranyl, such as 2-, 3-, 5- or 6-benzofuranyl,
benzo~b]thienyl, such as benzo[b]thien-2-yl, -3-yl,
-5-yl or -6-yl, benzoxazolyl, such as 2-, 4-, 5- or
6-benzoxazolyl, benzothiazolyl, such as 2-, 4-, 5- or
6-benzothiazolyl, or quinolinyl, such as 2-, 4-, 5- or
6-quinolinyl, isoquinolinyl, such as 1-, 3- or
4-isoquinolinyl, quinazolinyl, such as 2-, 4- or
6-quinazolinyl, quinoxalinyl, such as 2- or
6-quinoxalinyl, or phthalazinyl, such as 1- or
6-phthalazinyl.
As a substituted aliphatic radical, Rl is
substituted, for example, by halogen, such as bromine
or, especially, fluorine or chlorine, there being
mentioned especially polysubstitution at the same
carbon atom, that is to say geminal polysubstitution,
and substitution at a multiple bond, such as, for
example, in trichloromethyl, 2,2,2-trichloroethyl or
2-chloroethenyl. It is also possible for an aliphatic
radical Rl to be substituted, for example, by lower
alkoxy or lower alkylthio, such as, for example, by the
corresponding radicals mentioned below, and then Rl
..

23874
may represent, for example, methoxyethyl, ethoxyethyl
or methylthioethyl. As a substituted aromatic or
heteroaromatic radical, Rl is substituted one or
mor~ times, preferably a maximum o~ three times, ~or
example by halogen, such as bromine, iodine or,
especially, fluorine or chlorine; by lower alkyl, such
as, for example, ethyl, propyl, isopropyl, butyl,
isobutyl, tert.-butyl or, especially, methyl; by lower
cycloalkyl, such as cyclopentyl or, especially,
cyclohexyl; by lower alkoxy, lower alkylthio or lower
alkylsulphonyl, such as ethoxy, propoxy, isopropoxy,
butoxy or isobutoxy, or ethylthio, isopropylthio or
butylthio, or ethylsulphonyl, especially methoxy,
methylthio and methylsulphonyl; and/or by
trifluoromethyl, hydroxy, lower alkanoyl, lower
alkanoylamino, lower alkoxycarbonylamino or lower
alkylsulphonylamino, such as, for example, formyl,
acetyl, propionyl, butyryl or isobutyryl, or formamido,
acetamido, propionamido, butyramido or isobutyramido,
or methoxycarbonylamino or ethoxycarbonylamino, or
methanesulphonamido or ethanesulphonamido; or by lower
alkoxycarbonyl, carbamoyl, mono- or di-lower
alkylcarbamoyl, sulphamoyl or mono- or di-lower
alkylsulphamoyl, such as, for example, methoxy- or
ethoxy-carbonyl, methyl-, ethyl- or isopropyl-
carbamoyl, dimethyl- or diethyl-carbamoyl, methyl- or
ethyl-sulphamoyl or dimethylsulphamoyl.
An alkylene, alkenylene or alkylidene radical alk
may be straight-chain or branched and is, for example,
1,1- or 2,2- or 1,2-dimethylethylene, l-ethylethylene,
tetramethylene or l-propylethylene, or 3,3-dimethyl-
propenylene, or l-methylpropylidene, 2-methyl-
propylidene, butylidene or l-ethylpropylidene, but
especially a radical containing a maximum of 3 carbon
atoms, such as ethylene, propylene, trimethylene, or

~Z2387'1
ethenylene, propenylene or l-methylethenylene, or
ethylidene, propylidene, or l-methylethylidene, and,
especially, methylene.
R2, R3 and R4 are, as lower alkyl, for example
ethyl, propyl, isopropyl, butyl, isobutyl or tert.-
butyl and, especially, methyl; as lower alkoxy, for
example ethoxy, propoxy, isopropoxy, butoxy, isobutoxy
and, especially, methoxy and, as halogen, bromine,
iodine, especially fluorine or, more especially,
chlorine.
In a radical A, R5 as an unsubstituted or
substituted, aliphatic or araliphatic hydrocarbon
radical is, for example, alkyl having a maximum of 12
carbon atoms, especially lower alkyl, also 2- or 3-lower
alkenyl, or 2-lower alkynyl, lower alkoxy-lower alkyl,
halogenated lower alkyl, such as geminal polyhalo-lower
alkyl, or, for example, phenyl-lower alkyl or cinnamyl
in which the phenyl radical may be substituted, for
example in the same manner as a phenyl radical Rl.
Alkyl R5 is, for example, propyl, isopropyl, butyl,
isobutyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,
octyl, nonyl, decyl, dodecyl and, especially, methyl or
ethyl; lower alkenyl R5 is, for example, allyl, l- or
2-methallyl, 2-butenyl or 3-butenyl; lower alkynyl is,
for example, 2-propynyl; lower alkoxy-lower alkyl is
especially 2- or 3-lower alkoxy-lower alkyl, such as,
for example, 2-methoxy-, 2-ethoxy-, 2-isopropoxy- or
2-butoxy-ethyl, 2- or 3-methoxypropyl, 2- or 3-
ethoxypropyl, also 3- or 4-methoxybutyl or 3- or 4-
ethoxybutyl, and halogenated lower alkyl is especially
geminally polyhalogenated lower alkyl, that is to say
lower alkyl polyhalogenated at the same carbon atom,
such as 2,2,2-trifluoro- or 2,2,2-trichloro-ethyl.
Phenyl-lower alkyl R5 is, for example, benzyl,

lZ23874
-- 7
2-phenylethyl, 2- or 3-phenylpropyl or 2-, 3- or 4-
phenylbutyl.
As lower alkyl, R6 and R7 may bel ~or example,
the radicals already mentioned as corresponding
representatives of R5 andl as optionally lower alkyl-
substituted tetra- to hexa-methyleneimino, R6 and
R7 together represent, for example, 2- or 3-methyl-1-
pyrrolidinyll 2l5-, 3l3- or 3l4-dimethyl-1-pyrrolidinyl,
l-piperidinyl, 2-, 3- or 4-methyl-1-piperidinyl, 2,6-
or 4,4-dimethyl-1-piperidinyl or hexahydro-1~5-
azepin-l-yl.
Salts of the novel compounds are especially salts
cf compounds of the general formula I in which A
represents hydroxy, that is to say R5 represents
hydrogen, with bases, especially pharmaceutically
acceptable salts of such compounds with bases. As such
salts with bases there come into consideration, for
example, alkali metal or alkaline earth metal salts,
such as sodium, potassium, calcium or magnesium salts,
and also ammonium salts with ammonia or organic amines,
such as mono- or di-lower alkylamines, for example
methylamine, ethylamine, dimethylamine or diethylamine,
or with optionally lower alkylated mono- or
di-(hydroxyalkyl)-amines or with tri-(hydroxyalkyl)-
amines, for example 2-aminoethanol, 2-(diethylamino)-
ethanol, 2,2'-iminodiethanol, N-methyl-2,2'-
iminodiethanol or 2,2',2''-nitrilotriethanol.
As acid addition salts, especially
pharmaceutically acceptable acid addition salts, of
compounds of the general fo-rmula I in which Rl is of
basic character there come into consideration, for
example, those with suitable inorganic acids, such as
hydrohalic acidsl for example hydrochloric acid or
hydrobromic acid, and also nitric acid, sulphuric acid
or phosphoric acid, or with suitable organic acids,

122~l~7~
-- 8
such as carboxylic acids, for example acetic acid,
propionic acid, glycolic acid, succinic aci~, maleic
acid, hydroxymaleic acid, methylmaleic acid, fumaric
acid, malic acid, tartaric acid, citric acid, benzoic
acid, cinnamic acid, mandelic acid, ~alicylic acid,
4-aminosalicylic acid, 2-phenoxybenzoic acid,
2-acetoxybenzoic acid, embonic acid, nicotinic acid or
isonicotinic acid, or organic sulphonic acids, such as
lower alkanesulphonic acids optionally containing
hydroxy, for example methanesulphonic acid,
ethanesulphonic acid, 2-hydroxyethanesulphonic acid or
ethane-1,2-disulphonic acid, or arylsulphonic acids,
for example benzenesulphonic acid, 4-methylbenzene-
sulphonic acid or naphthalene-2-sulphonic acid, or
other acidic substances, such as ascorbic acid.
The novel compounds of the general formula I and
their salts exhibit valuable pharmacological
properties. They have, in particular, a diuretic and
sodium-diuretic action, in rats in a dosage range of
from 1 to 300 mg/kg per os and in dogs in doses of
from 1 to 20 mg/kg and above per os, which may be
ascertained by collecting the urine over a period of
3 hours after administration (rats) and hourly over a
period of 5 hours after administration (dogs) and
determining the volume of urine and of sodium,
potassium and chlorine ions. In this case the
excretion of potassium is increased to a lesser extent
than is the excretion of sodium; the good tolerability
should also be emphasised.
For example, the administration to rats of lOmg/kg
per os of 5-methyl-6-phenylsulphonyl-1,3-benzodioxole-
2-carboxylic acid (6 animals per dose), in comparison
with untreated control animals, increases the excretion
of sodium ions by a factor of 3.6, of potassium ions by

lZ23l37~
g
a factor of 1.1 and of chlorine ions by a factor of
2.6. In dogs, Eor example the administration of
20 mg/kg ~ os o~ 5-methyl-6-phenylsulphonyl-~,3-
benzodioxole-2-carboxylic acid (4 animals per dose)
increases the average excretion per minute measured
during the first 5 hours after administration of the
active ingredient in comparison with the average
excretion per minute during the hour before
administration, with regard to sodium ions by a factor
of 13.3, with regard to potassium ions by a factor of
only 1.5, with regard to chlorine ions by a factor of
10.4 and with regard to the volume of urine by a factor
of 3.2. In rats and dogs, the increase in the
excretion of potassium ions brought about by the
carboxylic acid mentioned is thus very slight compared
with the increase in the excretion of sodium ions and
chlorine ions.
Furthermore, the compounds of the general formula I
exhibit uricosuric activity, as can be seen, for
example from experiments on Cebus apes (Cebus appella).
In these experiments the test animals, under
pentobarbital narcosis, are given, by intravenous
infusion, polyfructosane in Ringer solution and the
test substance in the form of an aqueous solution is
injected intravenously in doses of increasing size.
Urine is collected for three 10 minute periods before
the first administration of test substance and then
after each dose of test substance, and arterial blood
is removed before the first collection period and after
the last collection period. The uric acid and
polyfructosane clearance is calculated from their
plasma and urine concentration and finally the
fractional excretion of uric acid FEUR is determined
as a quotient of the uric acid clearance and glomerular
filtration rate. In this test, compounds of the

1~23874
I 0
general formula I, such as, for example, 5-methyl-6-
phenylsulphonyl-1,3-benzodioxole-2-carboxylic acid,
exhibit activity in a dosage range of from 1 to 10
mg/kg i.v. Accordingly, the compounds of the general
formula I and their pharmaceutically acceptable salts
can be used as potassium~protecting diuretics having
supplementary uricosuric action, for example for the
treatment of oedema and hypertension.
The invention relates preferably to compounds of
the general formula I in which Rl represents an
aliphatic hydrocarbon radical that is unsubstituted or
substituted by halogen having an atomic number of up to
35, lower alkoxy or lower alkylthio and has, in total,
that is to say including the substituents, a maximum of
12 carbon atoms, or represents a mono- or bi-cyclic
aryl radical that is unsubstituted or substituted by
lower alkyl, lower cycloalkyl, lower alkoxy, lower
alkylthio, lower alkylsulphonyl, trifluoromethyl,
hydroxy, lower alkanoyl, lower alkanoylamino, lower
alkoxycarbonylamino and/or by lower
alkylsulphonylamino, or a corresponding heteroaryl
radical having a maximum of two nitrogen atoms, or one
oxygen or sulphur atom and optionally one nitrogen atom,
as hetero ring members, alk, nl, n2, R2, R3 and R4
have the meanings given under formula I and R5
represents hydrogen or an aliphatic or araliphatic
hydrocarbon radical having, in total, a maximum of 12
carbon atoms, that is unsubstituted or substituted, in
a position higher than the 1- or a-pOsitiOn, by halogen
having an atomic number of up to 35, hydroxy or by
lower alkoxy, or R5 represents a radical

lZZ3137~
in which R6 and R7 have the meanings given under
formula I, and salts of those compounds in which R5
represents hydrogen with bases.
The invention relates especially to compounds of
the general formula I in which Rl represents phenyl~
thienyl, furyl or ar-benzothiazolyl, each of which is
unsubstituted or substituted a maximum of three times
by lower alkyl, lower alkoxy, halogen having an atomic
number of up to 35, lower alkanoyl and/or by lower
alkanoylamino, alk represents alkylene, alkylidene or
alkenylene having a maximum of 3 carbon ato~st R2
represents lower alkyl or halogen having an atomic
number of up to 35, R3 represents hydrogen, lower
alkyl or halogen having an atomic number of up to 35,
R4 represents hydrogen and nl, n2 and A have
the meanings given under formula I, but nl represents
especially 2, n2 represents especially O and A
represents especially OR5 wnerein R5 represents
hydrogen or lower alkyl, and salts of those compounds
in which R5 represents hydrogen with bases.
The invention relates more especially to compounds
of the general formula I in which Rl represents
phenyl or thienyl, each of which is unsubstituted or
substituted a maximum of three times by lower alkyl,
lower alkoxy, halogen having an atomic number of up to
35, lower alkanoyl and/or by lower alkanoylamino, alk
represents methylene, nl represents 2, n2 represents
0 or 1, R2 represents lower alkyl, especially methyl,
or halogen, especially fluorine or chlorine, R3
represents hydrogen or lower alkyl, especially methyl,
R4 represents hydrogen and A represents OR5 wherein
R5 represents hydrogen or lower alkyl, and the
pharmaceutically acceptable salts of those compounds in
which R5 represents hydrogen with bases.
The invention relates more especially to compounds

::~ZZ38'7':~
of the general form~la I in which Rl represents
phenyl that is unsubstituted or substituted a maximum
o~ three times by lower al~yl, lower alkoxy and/or by
halogen having an atomic number of up to 35, alk
represents methylene, nl represents 2, n2 represents
0 or 1, R2 represents lower alkyl, especially methyl,
or halogen, especially fluorine or chlorine, R3
represents hydrogen or lower alkyl, especially methyl,
R4 represents hydrogen and A represents OR5 wherein
R5 represents hydrogen or lower alkyl, and the
phenylsulphonyl radical is bonded in the 5-- or
6-position, and the pharmaceutically acceptable salts
of those compounds in which R5 represents hydrogen
with bases.
The invention relates above all to compounds of
the general formula I in which Rl represents phenyl
substituted a maximum of three times by lower alkyl,
especially methyl, lower alkoxy, especially methoxy,
and/or halogen, especially chlorine, but is especially
unsubstituted phenyl, lk represents methylene, nl
represents 2, n2 represents 1 or, especially 0, R2
represents lower alkyl, especially methyl, or halogen,
especially chlorine, R3 and R4 represent hydrogen, and
A represents OR5 wherein R5 represents hydrogen or
lower alkyl, and the phenylsulphonyl radical is bonded
in the 5- or 6-position, and the pharmaceutically
acceptable salts of those compounds in which R5
represents hydrogen with bases, such as the 5-methyl-6-
phenylsulphonyl-1,3-benzodioxole-2-carboxylic acid
already mentioned above, and the pharmaceutically
acceptable salts thereof with bases.
The novel compounds of the general formula I and
salts of those compounds in which A represents OR5
wherein R5 is hydrogen, or that have a basic character,
are manufactured in a manner known ~ se, by

31 374
a) reacting a compound of the general formula II
Rl (alk)n2 S(O)nl R4
. ~ / OH
(II),
`./ OH
R2
in which Rl, alk, nl, n2~ R2~ R3 and R4 have the
meanings given under formula I, or a salt thereof, with
a compound of the general formula III
Hal
CH-CO-A
Hal (III),
in which Hal represents halogen and A has the meaning
given under formula I, or with a salt of such a
compound in which A represents OR5 wherein R5 represents
hydrogen, or
b) in a compound of the general formula IV
Rl-~ alk)n2-s(o)nl
\ / 4
\ / Ab (IV),
. ~ ~ o / CO-A
R2
in which Ab represents carboxy, lower alkoxycarbonyl

iZZ387~
- 14 -
or acetyl, and Rl, alk, nl, n2, R2, R3, 4
have the meanings given under formula I, replacing the
radical Ab by hydrogen, or
c) for the manufacture of a compound of the general
formula I in which A has the meaning given under formula
I with the exception of a radical OR5 in which R5
represents hydrogen, and Rl, alk, n2, R3 and R4
have the meanings given under formula I and nl
represents 1 or 2, reacting a compound of the general
formula V
R4
R3 1 1! CH-CO-A
~./ ~O (V),
R2
with a compound of the general formula VI
Rl-(alk)n2-S(O)nl-OH (VI),
or with an anhydride thereof, in which Al has the
meaning given for A under formula I with the exception
of a radical OR5 in which R5 represents hydrogen,
nlC represents 1 or 2 and R2, R3 and R4 and Rl, alk
and n2 have the meanings given under formula I, or
d) for the manufacture of a compound in which n2
is 1 or Rl is an aliphatic radical according to the

~2Z3874
definition, and Rl or n2, as the case ~ay be, alk, nl,
R2, R3, R4 and A have the meanings given under formula I,
reacting a compound of the general formula VIII
Rl~(alk)n2 _ z (VII~
in whi.ch zd represents a reactively esterified
hydroxy group, especially halogen having an atomic
number of at least 17, Rl has the meaning given under
formula I and, n2 represents 1 or, if R2 is an
aliphatic radical, may alternatively be 0, or reacting
a compound of the general formula VIII
Rl~(alk)nl-~ N zdd~ (VIII)
in which zdd9 represents a monovalent anion or the
normal equivalent of a polyvalent anion and Rl and
n have the meanings given under formula I, with a
_1
salt of a compound of the general formula IX
H-~S(O)nll R
\ ~ 4
~.~/o\
3 ! i! , CH-co-A
/~ . ~ --O
2 (IX)
in which nl, R2, R3, R4 and A have the meanings given
under formula I, or

l~Z3~37~
- 16 -
e) reacting a metal compound, optionally formed in
s _ , of the general formula xa or Xb_
Rl-~alk)n2
R -(alk)n2-Ml (Xa) M2 (Xb)
Rl-(alk)n2
in which Ml represents a monovalent metal ion and
M2 represents a divalent metal ion, and R, alk
and -2 have the meanings given under formula I,
with a compound of the general formula XIa or XIb
Hal-S ~nl R4
~ ./\
3 !~ 1! CH-CO-A (XIa)
~ ,~ ~O
R2
A OC CH \ , ~t 3 ~ ¦j CH-CO-A
R2 (XIb)
in which Hal represents halogen and nl, R2, R3,
R4 and A have the meanings given under formula I, or
f) for the manufacture of a compound of the general
formula I in which A represents OR5 wherein R5
represents hydrogen, and Rl, alk, nl, n2, R2, R3
and R4 have the meanings given under formula I, or a

3874
salt of this compound: in a compound of the general
formula XIII
Rl (alk~n2 S(O) 1 R
~ j/\
~ ./ O (XIII),
in which Af represents a group that can he converted
into the carboxy group and Rl, alk, nl, n2, R2, R3
and R4 have the meanings given under formula I,
converting the group Af into the carboxy group in
free or salt form, or
g) for the manufacture of a compound of the general
formula I in which A has the meaning given under
formula I with the exception of a radical OR5 in
which R5 represents hydrogen, and Rl, alk, nl, n2, R2
and R3 have the meanings given under formula I: in
a compound of the general formula XIV
(alk~n2-s(o)nl R4
~/\ g
R2 ¦ li CH-A (XIV),
o
R3
in which A9 represents a radical that can be
converted into a radical -CO-Al in which Al has the

lZ23~37
-- 18 ~
meaning given for A under formula I with the exception
of a radical OR5 in which R5 represents hydrogen,
and Rl, alk~ nl~ n2~ R2, R3 and R4 have the meanings
given under formula I, converting the radical Ag into
the radical -CO-Al, and
h) if desired, oxidising a compcund of the general
formula I in which nl represents 0 or 1 to form the
corresponding compound in which nl represents 1 or 2, or
i) if desired, reducing a compound of the general
formula I in which nl represents 2 or 1 to form the
corresponding compound in which nl represents 1 or 0,
and/or, if desired, converting a resulting compound of
the general formula I in a different manner known per
se into a different compound of the general formula I,
and/or separating a compound of the general formula I
obtained in the form of a racemate into the optical
antipodes, and/or converting a resulting compound of
the general formula I in which A represents OR5
wherein R5 represents hydrogen into a salt with a
base or freeing such a compound from a resulting salt,
or converting a resulting compound of the general
formula I having basic character into an acid addition
salt or freeing such a compound from a resulting salt.
In the starting materials of the general formula
III, Hal is preferably chlorine or bromine, but may
also be fluorine or iodine, it also being possible for
two different halogen atoms to be present. The
reactions according to process a) are preferably
carried out in organic solvents that are inert under
the reaction conditions, for example ethereal
solvents, such as, for example, dibutyl ether, 1,2-
dimethoxyethane, diethyleneglycol dimethyl ether,
tetrahydrofuran or dioxan; alcoholic solvents, such as,
for example, methanol, ethanol, isopropanol, butanol,
2-methoxyethanol or 2-ethoxyethanol; or amide-type
. .

12~3~37~
-- 19 --
solvents, such as, for example, dimethylformamide or
N,N,N',N',N'',N''-hexamethylphosphoric acid triamide;
or in hydrocarbons, such as, for example, petroleum
ether, cyclohexane, benzene or toluene. Reactions with
free compounds of the general formula II and also with
free haloacetic acids of the general formula III are
preferably carried out in the presence of basic
substances. As such basic substances there may be
used, for example, organic or inorganic derivatives of
alkali metals or alkaline earth metals: as organic
derivatives, there may used, for example, alkali metal
or alkaline earth metal alkoxides, such as sodium or
lithium methoxide, ethoxide, n-butoxide or
tert.-butoxide, or barium methoxide, and as inorganic
derivatives, for example, corresponding hydroxides,
such as sodium, potassium or calcium hydroxide, or
carbonates, such as, for example, sodium or potassium
carbonate. In particular carbonates may be used in
relatively large excess, for example up to 5-fold
excess. When using carbonates, also other organic
solvents, such as lower alkanones, for example acetone
or 2-butanone, may come into consideration as being
sufficiently inert.
Suitable salts of compounds of the general formula
II and of the dihaloacetic acids which may be used
falling within the scope of the general formula III
are, for example, corresponding alkali metal salts or
alkaline earth metal salts. The reaction temperatures
are, for example, between room temperature and
approximately 150C and preferably between
approximately 70 and 120C.
Some of the starting materials of .he general
formulae II and III are known and others may be
manufactured analogously to the known compounds. Thus,

3874
- 20 -
for example, starting materials of the general formula
II may be manufactured by firstly condensing
1,2-dimethoxybenzene, which can be substituted in a
manner corresponding to the definition for R2, R3
and R4, with an anhydride of a sulphonic acid of the
general formula VI in polyphosphoric acid at elevated
temperature, for example at approximately from 100 to
110C, to form the corresponding sulphone, or with an
acyl halide derived from such a sulphonic acid or from
a corresponding sulphonic acid, according to the
Friedel-Crafts method, for example by means of
aluminium chloride in 1,2-dichloroethane at room
temperature, to form the corresponding sulphone or
corresponding sulphoxide, and cleaving the two methoxy
groups in this sulphone or sulphoxide in a manner known
per se, for example by heating with pyridine
hydrochloride or with 48 % hydrobromic acid in acetic
acid. If starting materials of the formula II are
required in which alk represents a lower alkylidene
radical, but especially a l-lower alkylalkylidene
radical, such as the l-methylethylidene radical, it is
possible, after the Friedel-Crafts condensation and
before the cleaving of the methoxy groups, to introduce
into a sulphone compound in which alk represents
methylene or lower alkylidene, one or preferably two
lower alkyl radicals, or one lower alkyl radical,
respectively, especially methyl, by reaction with a
lower alkyl halide, such as methyl iodide, for example
in a two-phase system comprising a concentrated aqueous
solution of tetrabutylammonium hydroxide or bromide and
an inert organic solvent, for example methylene
chloride. A process which results directly in
dihydroxysulphones of the general formula II and is r
therefore, especially advantageous is the reaction of
sulphinic acids falling within the scope of the general

i2Z31~
- 21 -
formula VI, in the form of sodium salts, with 1,2-
benzenediols optionaily substituted in a manner
corresponding to the definition for R2, R3 and R4
in the presence of potassium hexacyanoferrate(III) and
sodium acetate in water.
Starting materials of the general formula II in
which nl is O can be manufactured, for example,
analogously to process d).
To carry out process b), for example a starting
material of the general formula IV in which Ab
represents carboxy and A, Rl, R2, R3 and R4 have the
meanings given under formula I is heated in the
presence or absence of a catalyst, for example copper
powder, and/or of a solvent or diluent, such as, for
example, o-dichlorobenzene or 1,2,3,4-tetra-
hydronaphthalene, until at least an approximately
equimolar amount of carbon dioxide has been liberated.
Starting materials of the general formula IV in which
Ab represents carboxy and A represents OR5 wherein
R5 represents hydrogen are manufactured, for example,
by hydrolysis of corresponding compounds in which A is
OR5 wherein R5 represents lower alkyl, and the
substituent in the corresponding position to Ab is
lower alkoxy or cyano, in acidic or alkaline medium,
for example by heating with a strong mineral acid in an
aqueous or aqueous-organic, for example aqueous-lower
alkanolic, medium, or with at least twice the molar
amount of an alkali metal hydroxide, especially sodium
or potassium hydroxide, for example in a lower alkanol,
such as methanol, ethanol, ispropanol or n-butanol, or
in a lower alkanediol or monoalkyl ether thereof, for
example ethyleneglycol, 2-methoxyethanol or 2-
ethoxyethanol, water optionally bein~ added to the
mentioned solvents in a volume ratio of solvent to
water of approximately from 10:1 to 1:2. It is also

lZZ387~
- 22 -
possible to use water as the reaction medium or, for
example, a mixture of water and water-soluble9 ethereal
solvents, such as dioxan or tetrahydrofuran.
If the hydrolysis is effected in a water-
containing mineral acid, the decarboxylation accordin~
to the process may be carried out sub~equently, that is
to say, in the same medium and operation.
Starting materials of the general formula IV in
which Ab represents carboxy and A represents a
radical corresponding to the definition given under
formula I with the exception of a radical OR5 in
which R5 represents hydrogen, can be manufactured,
for example, by partial hydrolysis in alkaline medium
from corresponding compounds having lower
alkoxycarbonyl as the radical Ab using an
approximately equimolar amount of an alkali metal
hydroxide instead of at least twice the molar amount.
Another possibility for the manufacture of such
starting materials of the general formual IV consists
in the hydrogenolysis of corresponding compounds which
contain benzyloxycarbonyl in the Ab position.
The dealkoxycarbonylation or deacetylation of
corresponding starting materials of the general formula
IV, that is to say, those in which Ab represents
lower alkoxycarbonyl or acetyl and A represents a
radical according to the definition with the exception
of a radical OR5 in which R5 represents hydrogen,
is effected, for example, by reaction with an
approximately equimolar amount of an alkali metal-lower
alkoxide in an anhydrous lower alkanol, and if A
represents a radical OR5 in which R5 represents
lower alkyl, it is preferable to select the same lower
alkanol, for example methanol, ethanol or n-butanol,
both as component of the starting ester and of the
lower alkoxide and as reaction medium. It is also

874
- 23 -
possible, however, to carry out a transesterification
by using as reaction medium a relatively high-boiling
alkanol that is not the same as the lower alkanol
present as the ester component and distilling off a
portion thereof simultaneously with the reaction
according to the definition, or to allow Eor only a
partial transesterification if the ester of the general
formula I formed as a reaction product is not to be
used directly as active ingredient but is to be
hydrolysed to form the corresponding acid. Instead of
a lower alkanol it is also possible to use as a
reaction medium, for example, an inert organic solvent,
such as, for example, benzene or toluene. The reaction
according to the definition is carried out at room
temperature or at elevated temperature, for example at
the boiling temperature of the reaction medium used.
If required, the resulting ester of the general formula
I may, as already mentioned in connection with the
transesterification, be hydrolysed to form the
corresponding acid in the same operation if water is
added to the reaction medium.
The starting materials of the general formula IV
in which Ab represents lower alkoxycarbonyl or
acetyl, and the above-mentioned precursors for
compounds of the general formula IV containing carboxy
as radical Ab that contain lower alkoxycarbonyl or
cyano in the Ab position, can be manufactured
analogously to process a) by reacting compounds of the
general formula II in the presence of a base with
geminal dihalo compounds that differ from those of the
general formula III by the presence of lower
alkoxycarbonyl, acetyl or cyano in place of the
hydrogen atom located adjacent to two halogen atoms.
According to process c), for example free
sulphonic acids of the general formula VI in

~ZZ3137~
- 2~ -
polyphosphoric acid or pyrophosphoric acid can be
condensed with compounds of the general formula V at
elevated temperature, for example at from approximately
80 to approximately 120C, especially at from
approximately 100 to 110C. It is also possible to
condense anhydrides of compounds of the general formula
VI, for example the halides thereof, such as chlorides
or bromides, also, for example, symmetrical anhydrides
thereof, with compounds of the general formula V in the
presence of customary Friedel-Crafts condensation
agents, such as aluminium chloride or tin(IV) chloride,
also, for example, zinc chloride, and also, for
example, in concentrated sulphuric acid, phosphoric
acid, polyphosphoric acid or pyrophosphoric acid. The
above-mentioned acids are preferably used when there is
used as starting material a symmetrical anhydride of a
sulphonic acid of the general formula VI. When
condensation agents are used, the reactions are
preferably carried out in a solvent~ As such solvents
there may be used, for example, halogenated
hydrocarbons, such as 1,2-dichloroethane, carbon
tetrachloride, methylene chloride or o-dichlorobenzene,
and also, for example, aliphatic or cycloaliphatic
hydrocarbons, such as heptane or cyclohexane,
nitrohydrocarbons, such as nitromethane,
nitrocyclohexane or nitrobenzene, and also, under mild
conditions, carbon disulphide. The reaction
temperature is between approximately -20C and +80C,
preferably between approximately 0 and room
temperature.
The starting materials of the general formula V
may, for their part, be manufactured analogously to
process a) from 1,2-benzenediol, optionally substituted
in a manner corresponding to the definition for R2, R3
and R4, such as, for example, 4-methyl-1,2-benzenediol

~223874
- 25 -
with dihaloacetic acids or functional derivatives
thereof corresponding to the general formula III. Some
of the sulphonic OL sulphinic acids of the general
formula IV and functional derivatives of compounds of
the general formula VI required as second reactant are
known and others may be manufactured analogously to the
known acids and derivatives.
Reactions of compounds of the general formula VII,
such as, for example, optionally substituted alkyl,
alkenyl or alkynyl halides or aralkyl, especially
benzyl, halides with salts, especially alkali metal
salts, for èxample sodium or potassium salts, of
compounds of the general formula IX are carried out,
for example, in water or in an aqueous-organic or
organic medium, for example in a lower alkanol, such as
methanol or ethanol, preferably at elevated
temperature, that is to say, for example, at from
approximately 70 to approximately 160, especially at
approximately from 80 to 100, or at the boiling
temperature of the medium or in a closed vessel at a
temperature above that temperature. The salt of the
compound of the general formula VII can also be formed
in situ by adding alkali metal hydroxides or alkali
metal salts of weak acids, for example sodium acetate.
The diazonium salts of the general formula VIII
are manufactured in customary manner from the
corresponding primary amines in which nl is preferably
0 and Rl is an aromatic radical, for example in
aqueous solution by treatment with hydrochloric acid
and sodium nitrite, and are reacted while heating and
with the addition of sodium hydroxide solution with
salts of compounds of the general formula IX optionally
formed in situ. Starting materials of the general
formulae VII and VIII are known or can be manufactured
analogously to the known compounds. Starting materials

~23874
- 26 -
of the general formula IX are obtained, for example, ~y
reaction of corresponding sulphur-free benzodioxole
derivatives of the general formula v with
chlorosulphonic acid to form corresponding chloro-
sulphonyl compounds and by reduction which is known
per se to form corresponding sulphinic acids, for
example with sodium sulphite, or to form mercaptans,
for example with zinc dust and concentrated
hydrochloric acid in diethyl ether or an ethereal
solvent.
In the process according to e), there are used as
starting materials of the general formula Xa, for
example, butyllithium, phenyllithium or
4-methoxyphenyllithium, see, for example, A. Schonberg
_ al., Chem. Ber. 66, 237-244 (1933), or alternatively
corresponding Grignard compounds, and as starting
material of the general formula Xb, for example,
diphenylcadmium, bis-(4-chlorophenyl)-cadmium or
bis-(4-methoxyphenyl)-cadmium, see, for example,
H.R. Henze et al., J. Chem. Soc. 1957, 1410-1413,
or diphenyl mercury, and in both cases the process is
carried out, for example, in absolute diethyl ether or
a different ethereal solvent. Sulphochlorides of the
general formula XIa have already been mentioned as
precursors for compounds of the general formula IX, as
have the corresponding sulphinic acids and mercaptans
which can be obtained therefrom by reduction. From the
former, sulphinyl chlorides of the general formula
XIa are obtained, for example, with thionyl chloride,
and from the latter disulphides of the general formula
XIb are obtained by oxidation which is known
se.
In the manufacture of compounds of the general
formula I in whlch A represents the radical OR5 wherein

:~2Z31374
-- 27 --
R5 represents hydrogen, according to process f) the
conversion of a group Af into the carboxy group can
be effected in a manner known per _, especially by
hydrolysis in an alkaline or acidic medium, it being
possible in the former case to obtain a salt also
directly. Starting materials for the hydrolysis are in
the first instance those compounds of the general
formula I in which A is not a radical OR5 in which R5
represents hydrogen, especially such compounds which
can readily be hydrolysed, such as, for example, the
lower alkyl esters, but also other functional
derivatives of the carboxylic acids desired as end
products, such as, for example, nitriles and imido
esters, especially imido-lower alkyl esters, of
carboxylic acids falling within the scope of the
general formula I. The hydrolysis is effected, for
example, in lower alkanolic or aqueous-lower alkanolic
alkali hydroxide solutions at from room temperature to
approximately 100C or the boiling temperature of the
reaction medium. Lower alkyl esters, such as methyl or
ethyl esters, and other readily cleavable esters of the
carboxylic acids falling within the scope of the
general formula I can be hydrolysed under even milder
conditions, for example in the presence of potassium or
sodium carbonate at room temperature or, if necessary,
at a slightly elevated temperature, for example 40C,
in an aqueous-organic medium, for example by adding
water to the reaction mixture obtained in the reaction
according to a) in a water-miscible solvent, such as,
for example, 1,2-dimethoxyethane. From the initially
obtained alkali metal salt solutions of the carboxylic
acids falling within the scope of the general formula
I, it is possible either to obtain the corresponding

1~3874
- 28 -
pure alkali salt directly by concentration and filtra-
tion or concentration by evaporation and recrystallisa-
tion, or to free the carboxylic acid first of all and
then to purify it, for example by recrystallisation
and, if desired, convert it into a salt again with a
suitable inorganic or organic base. Functional
derivatives of the carboxylic acids falling within the
scope of the general formula I may also be converted
into the free carboxy]ic acid of the general formula I
in an acidic medium, for example by heating in
sulphuric acid diluted with water, for example 60-70 %
sulphuric acid, or in lower alkanolic-aqueous
hydrochloric acid.
The required functional derivatives of carboxylic
acids that fall within the scope of the general formula
I are manufactured, for example, according to one of
the processes mentioned above, and other functional
derivatives, such as, for example, nitriles, are
manufactured analogously to these processes.
Starting materials of the general formula XIV are,
according to the nature of the radical Ag they
contain, for example carboxylic acids, carboxylic acid
halides or anhydrides, especially mixed anhydrides, and
also activated esters, for example cyanomethyl esters,
and also lower alkyl esters, that can be reacted,
optionally in the presence of condensation agents, with
hydroxy compounds of the general formula XV
R5 - OH (XV)
or ammonia or amines of the general formula XVI
/R6
H~ (XVI)
R7

lZZ387~
- 29 -
in which formulae R5 and R6 and R7 have the meanings
given under formula Il or are salts, especially alkali
metal or alkaline earth metal saltsl of free carboxylic
acids, that can be reacted with reactive esters of
hydroxy compounds of the general formula xVr such as
halides, or organic sulphonic acid esters, for example
lower alkanesulphonic or arenesulphonic acid esters,
such as methanesulphonic or _-toluenesulphonic acid
esters, or alternatively with carbamic acid halides,
especially chlorides, derived from amines of the
general formula XVI in which the radicals R6 and R7 are
other than hydrogen; and also, for example, the imido
esters, especially imido-lower alkyl esters, or
nitriles, that can be hydrolysed to form esters,
especially lower alkyl esters, and to form
unsubstituted amides, respectively. Free carboxylic
acids can be reacted, for example, also with
diazo-lower alkanes to form lower alkyl esters, or with
isocyanates that are derived from primary amines
falling within the scope of the general formula XVI, to
form N-mono-substituted amides.
The reactions of free carboxylic acids with
hydroxy compounds of the general formula XV are
effected advantageously in the presence of an acidic
water-removing catalyst, such as a protonic acid, for
example in the presence of hydrochloric or hydrobromic
acid, sulphuric acid, phosphoric acid or boric acid,
benzenesulphonic or toluenesulphonic acid, or a Lewis
acid, for example boron trifluoride etherate, in an
excess of the hydroxy compound used and/or in an inert
solvent, for example in a hydrocarbon of the benzene
series, such as benzene or toluene, a halogenated
hydrocarbon, such as chloroform, methylene chloride or
chlorobenzene, or in a ethereal solvent, such as
tetrahydrofuran, if necessary with removal by

~ZZ387~
- 30 -
distillation, for example azeotropic distillation, ~f
the water freed in the reaction. It is also possible
to carry out the reactions in the presence of other
water-binding condensation agents, for example in the
presence of carbodiimides substituted by hydrocarbon
radicals, such as N,N'-diethyl-, N,N'-dicyclohexyl- or
N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide, in
inert organic solvents, for example those mentioned
above. Halides and mixed anhydrides are reacted, for
example, in the presence of acid-binding agents, for
example organic, especially tertiary, nitrogen hases,
such as, for example, triethylamine, ethyl
diisopropylamine or pyridine, or alternatively
inorganic bases, for example alkali metal or alkaline
earth metal hydroxides or carbonates, such as sodium,
potassium or calcium hydroxide or carbonate, in inert
organic solvents, for example those mentioned above,
and, if necessary, while heating. The reactions of
reactive esters of carboxylic acids of the general
formula I, for example the cyanomethyl esters, with
hydroxy compounds of the general formula XV are carried
out, for example, in a solvent that is inert towards
the reactants, for example in a hydrocarbon, such as
toluene or xylene, an ethereal solvent, such as
tetrahydrofuran or dioxan, or alternatively, at
moderate temperatures, in an ester, such as ethyl
acetate, in a temperature range of from approximately
0C to approximately 120C, preferably at from room
temperature to approximately 60C. For the
transesterification of lower alkyl esters of carboxylic
acids of the general formula I it is preferable to use
hydroxy compounds of the general formula XV having a
boiling point clearly above that of the esterified
lower alkanol and to carry out the reaction, for
example, in an excess of the hydroxy compound and~or in
.

i~23~37
-- 31 --
an inert organic solvent that preferably also has a
boiling point clearly higher than that of the lower
alkanol, preferably in the presence of a catalyst, for
example an alkali metal-lower alkoxide, such as sodium
or potassium methoxide or ethoxide, at elevated
temperature and, preferably, while distilling off the
lower alkanol that is liberated. The hydrolysis of
imido esters, especially of imido-lower alkyl esters,
of carboxylic acids of the general formula I is
effected, for example, by means of a water-containing
mineral acid, such as hydrochloric or sulphuric acid;
and imido ester hydrochlorides obtained, for example,
by the addition of hydrogen chloride to nitriles and
reaction with anhydrous hydroxy compounds of the
general formula XV, especially lower alkanols, can,
after the addition of water, be hydrolysed directly to
form the corresponding esters, or, for example, the
corresponding ester of the general formula I can also
be obtained from a mixture of nitrile, hydroxy compound
and sulphuric acid having a suitable water content,
without isolating the imido ester formed in situ.
The reaction of free carboxylic acids of the
general formula I with compounds of the general formula
XVI is effected, for example, in the presence of the
above-mentioned water-binding agents and in the
above-mentioned inert organic solvents, but it is also
possible to convert the ammonium salts formed first of
all from the free carboxylic acids and the compounds of
the general formula XVI into amides of the general
formula I by heating, optionally in a suitable organic
solvent having a medium or high boiling point, such as,
for example, xylene, chlorobenzene or
1,2,3,4-tetrahydronaphthalene, and removal by
distillation, optionally azeotropic distillation, of
the water liberated in the reaction.

lZ23~374
- 32 -
As reactive functional derivatives of carboxylic
acids of the general formula I for the reaction with
compounds of the general formula XVI and as associated
condensation agents and solvents there come into
consideration substantially the same derivatives,
condensation agents and solvents as those indicated
above for reactions with hydroxy compounds of the
general formula XV, except that as acid-binding agent
and optionally as the only reaction medium, it is
possible to use instead of other bases, that is to say
tertiary organic bases, alternatively an excess of the
compound of the general formula XVI to be reacted. The
partial hydrolysis of the corresponding nitriles,
mentioned as a further possibility for forming
N-unsubstituted amides, may be carried out, for
example, by means of water-containing mineral acids,
such as hydrochloric acid or dilute sulphuric acid, at
room temperature or at moderately elevated temperature.
The free carboxylic acids of the general formula I
required as starting materials for process g) can be
manufactured especially according to process a) or b),
and the reactive functional derivatives thereof can
be manufactured, for example, from the free carboxylic
acids, in a manner known ~ se.
The oxidation according to h) is effected, for
example, by means of hydrogen peroxide in an organic or
organic-aqueous solvent that is inert with respect to
the hydrogen peroxide, such as acetic acid optionally
containing water, for example in the mixture resulting
from glacial acetic acid and aqueous hydrogen peroxide
solution, at moderately elevated temperatures between
approximately 60 and 100C, especially at
approximately from 80 to 90C and, if a sulphonyl
compound corresponding to nl = 2 is to be obtained
as oxidation product, with more than twice the molar

l'~Z3874
- 33 -
amount of hydrogen peroxide. The oxidation of
corresponding thio compounds to form sulphonyl
compounds corresponding to nl = 0 or 1 is carried
out, for example, either according to the above process
in a temperature range of approximately from 20 to
60C with, if necessary, an amount of hydrogen
peroxide that is merely approximately equimolar, or~
for example, especially using alkali metal periodate,
especially sodium or potassium periodate, such as
sodium meta-periodate, in organic-aqueous medium, for
example lower-alkanolic aqueous medium, especially
ethanolic-aqueous medium, at reduced temperature, for
example at from OC to room temperature.
According to process i), for example compounds of
the general formula I in which nl is 1 can be reduced
to form corresponding compounds in which nl is 0 by
means of triphenylphosphine in boiling carbon
tetrachloride.
Resulting salt-forming compounds of the formula I
can be converted into salts in a manner known ~ se;
for example, those with hydroxy as radical A may be
converted with corresponding bases, such as, for
example, alkali metal hydroxides, into salts with
bases, or those having a basic character may be
converted into their acid addition salts. Preferably
pharmaceutically acceptable salts are manufactured.
Resulting salts can be converted into the free
compounds in a manner known per se, for example by
treatment with an acidic reagent, such as a mineral
acid, or with a base, for example an alkali metal
hydroxide solution, such as sodium hydroxide solution.
The compounds, and their salts, can also be
obtained in the form of their hydrates, or their
crystals may include the solvent used for crystallisa-
tion.
;

8~4
- 34 -
As a result of the close relationship between the
novel compounds of the general formula I in which A
represents hydroxy in free form and in the form of
their salts with bases, and between those compounds in
which the radical Rl has basic character in free form
and in the form of acid addition salts, hereinbefore
and hereinafter the free compounds and their salts
shall be understood to mean optionally also the corres-
ponding salts and free compounds, respectively, where
appropriate with regard to meaning and purpose.
Depending upon the number of centres of asymmetry
and upon the starting materials and procedures chosen,
the novel compounds may be obtained in the form of
racemates or mixtures of racemates (mixtures of
diastereoisomers) or, where desired, also in the form
of pure antipodes.
Resulting mixtures of racemates may be separated
into the pure racemates or diastereoisomers in known
manner, on the basis of the physicochemical differences
between the constituents, for example by chromatography
and/or fractional crystallisation. Resulting racemates
may also be separated into the optical antipodes
according to known methods, for example by recrystal-
lisation from an optically active solvent, with the aid
of micro-organisms or by reaction of an acidic end
product of the general formula I with an optically
active base that forms salts with the racemic acid, or
by reaction of a basic end product of the general
formula I with an optically active acid, and separating
the salts obtained in this manner, for example on the
basis of differing solubility, into the diastereo-
isomers, from which the antipodes may be freed by the
action of suitable agents. Advantageously the more
active of the two antipodes is isolated.

~Z~38~7'~
The invention relates also to those embodiments of
the process according to which a compound obtainable as
an intermediate at any stage of the process is used as
starting material and the remaining steps are carried
out, or a starting material is used in the form of a
salt and/or racemate or antipode, or, especially, is
formed under the reaction conditions.
The starting materials used in the processes of
the present invention are preferably those which result
in the compounds described at the beginning as being
especially valuable. The present invention relates
also to novel starting materials and to processes for
their manufacture.
The invention relates also to pharmaceutical
preparations that contain compounds of the general
formula I as active ingredients, and to processes for
their manufacture.
The pharmaceutical preparations according to the
invention are for enteral, such as oral or rectal, and
for parenteral, administration to warm-blooded animals.
The dosage of the active ingredient, which may be
administered alone or together with a customary carrier
or adjunct, depends upon the species of warm-blooded
animal, age and individual condition and upon the
method of administration. The daily doses are between
0.15 and 20 mg/kg for mammals, the daily dose for a
mammal weighing approximately 70 kg preferably being
between 10 and 600 mg, especially between 25 and
300 mg, depending on individual condition and age.
Appropriate oral dosage unit forms, for example
dragées, tablets or capsules, contain preferably from 5
to 150 mg, especially from 10 to 100 mg, of an active
ingredient according to the invention, that is to say,
a compound of the general formula I or a pharma-
ceutically acceptable salt of a compound of the

lZi~387~
- 36 -
general formula I that is capable of salt formation,
together with pharmaceutical carriers.
The pharmaceutical preparations of the present
invention are manufactured in a manner known per se,
for example by means of conventional mixing,
granulating, confectioning, dissolving or lyophilising
processes. For example, pharmaceutical preparations
for oral use can be obtained by combining the active
ingredient with solid carriers, optionally granulating
a resulting mixture and processing the mixture or
granulate, if desired or necessary after the addition
of suitable adjuncts, to form tablets or dragée cores.
Suitable carriers are especially fillers, such as
sugar, for example lactose, saccharose, mannitol or
sorbitol, cellulose preparations and/or calcium
phosphates, for example tricalcium phosphate or calcium
biphosphate, also binders, such as starch pastes using,
for example, maize, wheat, rice or potato starch,
gelatine, tragacanth, methylcellulose and/or polyvinyl-
pyrrolidone, and/or, if desired, disintegrators, such
as the above-mentioned starches, also carboxymethyl
starch, crosslinked polyvinylpyrrolidone, agar, alginic
acid or a salt thereof, such as sodium alginate.
Adjuncts are especially flow-regulating agents and
lubricants, for example silica, talc, stearic acid or
salts thereof, such as magnesium stearate or calcium
stearate, and/or polyethylene glycol. Dragée cores are
provided with suitable coatings that are optionally
resistant to gastric juices, there being used, inter
alia, concentrated sugar solutions which may contain
gum arabic, talc, polyvinylpyrrolidone, polyethylene
glycol and/or titanium dioxide, lacquer solutions in
suitable organic solvents or mixtures of solvents or,
for the production of coatings that are resistant to
gastric juices, solutions of suitable cellulose

~Z3874
preparations, such as acetylcellulose phthalate or
hydroxypropylmethylcellulose phthalate. Dyes or
pigments can be added to the tablets or dragée
coatings, for example for identification purposes or to
indicate different doses of active ingredient.
Further pharmaceutical preparations for oral
administration are dry-fill capsules consisting of
gelatine and also soft sealed capsules consisting of
gelatine and a plasticiser, such as glycerine or
sorbitol. The dry-fill capsules may contain the active
ingredient in the form of a granulate, for example in
admi%ture with fillers, such as lactose, binders, such
as starches, and/or glidants, such as talc or magnesium
stearate, and optionally stabilisers. In soft
capsules, the active ingredient is preferably dissolved
or suspended in suitable liquids, such as fatty oils,
paraffin oil or liquid polyethylene glycols, it being
possible also to add stabilisers.
As rectally administrable pharmaceutical
preparations there come into consideration, for
example, suppositories which consist of a combination
of the active ingredient with a suppository base.
Suitable suppository bases are, for example, natural or
synthetic triglycerides, paraffin hydrocarbons,
polyethylene glycols and higher alkanols. It is also
possible to use gelatine rectal capsules which contain
a combination of the active ingredient with a base
material; as base materials there come into con-
sideration, for example, liquid triglycerides,
polyethylene glycols and paraffin hydrocarbons.
Especially suitable for parenteral administration
are aqueous solutions of an active ingredient in water-
soluble form, for example a water-soluble salt, also
suspensions of the active ingredient, such as
corresponding oily injection suspensions, there being
~.. .

1;~238~4
- 38 -
used suitable lipophilic solvents or vehicles, such as
fatty oils, for example sesame oil, or synthetic fatty
acid esters, for example ethyl oleate or triglycerides,
or aqueous injection suspensions that contain
substances which increase the viscosity, for example
sodium carboxymethylcellulose, sorbitol and/or dextran,
and, optionally, stabilisers.
The invention relates also to the use of the novel
compounds of the formula I and the pharmaceutically
acceptable salts thereof as pharmacologically active
compounds, especially as diuretics having supplementary
uricosuric action, preferably in the form of pharma-
ceutical preparations, in a method for the prophylactic
and/or therapeutic treatment of the human or animal
body, especially for the treatment of oedema and/or
hypertension.
The following Examples illustrate the invention
described above but are not intended to limit its scope
in any way. Temperatures are given in degrees
Centigrade.

87
- 39 -
Example 1:
27~7 g (200 mmol) of anhydrous potassium carbonate
are added to a suspension of 10.6 g (40 mmol) of 4-
methyl-5-phenylsulphonyl-1~2-benzenediol in 65 ml of
cold 1~2-dimethoxyethane While stirring ~igorously,
a solution of 7 ~5 g (50 mmol) of dichloroacetic acid
ethyl ester in 5 ml of 1,2-dimethoxyethane is added
dropwise thereto in the course of 30 minutes. The
mixture is stirred for a further hour at room temp-
erature and is then boiled under reflux for 3 hours
while stirring. It is then cooled to 30 , water is
added~ and the whole is stirred for 30 minutes and
adjusted to pH 1-2 with hydrochloric acid. Some of
the 1,2-dimethoxyethane is removed in a rotary e~ap-
orator and the solution remaining is e~tracted three
times with ethyl acetate. The combined ethyl acetate
solutions are washed with water~ and then with satur-
ated sodium chloride solution~ dried over sodium sul-
phate~ treated with activated carbon and concentrated
by evaporation. The resulting yellow-green oil is
crystallised from ethyl acetate/hexane. The sand-
coloured crystals are dissolved in ethyl acetate and
treated again with activated carbon. The sol~-ent is
removed in a rotary evaporator. The yellow oil remain-
ing is crystallised from methylene chloride at 0~
yielding 5-methyl-6-phenylsulphonyl-1,3-benzodioxole-
2-carboxylic acid having a melting point of 169-171 .
The starting material can be produced as follows:
a) A solution of 50 g (152 mmol) of potassium hexa-
cyanoferrate (III) and 95 g of sodium acetate trihydrate
in 200 ml of water is added dropwise in the course of
30 minutes~ at room temperature under nitrogen~ to a
solution of 16.4 g (100 mmol) of the sodium salt of
benzenesulphinic acid and 13.6 g (110 mmol) of 4-
methyl-1,2-benzenediol in 150 ml of water. After

3~374
-- 40 _
stirring for 1 1/2 hours, the reaction mixture is
acidified and repeatedly extracted ~ith ethyl acetate.
The combined organic phases are washed with water and
saturated sodium chloride solution~ dried ov~r sodium
sulphate and concentrated by evaporation. The residue
is recrystallised rom et~er/hexane, yielding 4-msthyl-
5-phenylsulphonyl-1,2-benzenediol having a melting
point of 145-149.
Example 2
.
A mixture of 20 8 g (100 mmol) of 5-methyl-1~3-
benzodioxole-2-carboxylic acid ethyl ester, 18.2 g
(105 mmol) of the sodium salt of benzenesulphonic acid~
200 g of polyphosphoric acid and 85 ml of methanesulphonic
acid is stirred vigorou~ly for 4 days at 25 under
nitrogen, 500 ml of ice-water are then added to the
reaction mixture while cooling with ice~ and the whole
i5 extracted four times with ether. The combined
organic phase~ are washed first with water~ then with
a saturated sodium chloride solution~ dried over sodium
sulphate and concentrated to dryness by evaporation
The 5-methyl-6-phenyl~ulphonyl-1~3-benzodioxole-2-
carboxylic acid ethyl ester remaining is purified by
column chromatography over silica gel using as eluant
ethyl acetate/hexane in a ratio of 1:1. The fractions
containing uniform substance are combined and concen-
trated by evaporation. The yellow oily residue crys-
tallises on standing. It is stirred for two hours at
0 with ether~ filtered~ washed with cold ether and
dried. The ester~ crystallising into bright yellow
needles~ melts at 89-90.
8.6 g (24.7 mmol) of 5-methyl-6-phenylsulphonyl-
1~3-benzodioxole-2-carboxylic acid ethyl ester are
suspended in 37 ml of methanol. 37 ml of lN sodium
hydroxide solution are then slowly added at room temp-
erature~ the starting material soon dissol~ingc After
one hour the reaction mixture is cooled~ concentrated
, ,~

l;ZZ387
-- 41 --
hydrochloric acid is added and the whole is extracted
three times with ethyl acetate The combined organic
phases are washed with water and then with a saturated
sodium chloride solution, dried over sodium sulphate
and concentrated by evaporation 50 ml of methylene
chloride are added to the yellow oil remaining~ and
the l~hole is stirred until crystallisation occurs
The filtered crystals are recrystallised from a small
amount of 1,2-dichloroethane, yielding 5-methyl-6-
phenylsulphonyl-1,3-benzodioxole-2-carboxylic acid in
the form of white crystals having a melting point of
169-171,
The 5-methyl-1,3-benzodioxole-2-carboxylic acid
ethyl ester used as starting material can be produced,
for example~ in accordance with one of the two processes
described below:
a) A solution of 38.7 g (0.3 mol) of dichloroacetic
acid~ 12 g (0 3 mol) of sodium hydroxide, 40 ml of water
and o,6 g of Aliquat is stirred under nitrogen and heated
to 95, At this temperature~ there is added dropwise
thereto~ in the course of 2~ houre in a uniform manner~
a solution of 24.8 g (0.2 mol) of 4-methyl-1,2-benzene-
diol (homopyrocatechol)~ 100 ml of water and 20 g (0.5
mol) of sodium hydroxide~ which has been produced
beforehand under nitrogen, The whole is further stirred
for 1~ hours at 95 and then cooled to room temperature,
The reaction mixture is acidified to pH 8 with hydro-
chloric acid and washed twice with ether. The aqueous
phase is then adjusted to pH 1-2 with concentrated
hydrochloric acid and extracted with ether. The com-
bined ether solutions are washed with water and saturated
sodium chloride solution~ dried over sodium sulphate
and concentrated completely by evaporation in a rotary
evaporator.

iZZ3~374
-- 42 --
The crude 5-methyl-1~3-benzodioxole-2-carboxylic
acid obtained as residue in a) is dissolved in 400 ml of
anhydrous ethanol and b~iled for 2 hours with 0.5 ml of
concentrated hydrochloric acid. The solution is concen-
trated to a large extent and the resulting crude ester is
dissolved in ether or methylene chloride. The solution is
washed with saturated sodium bicarbonate solution, water
and saturated sodium chloride solution~ dried over sod-
ium sulphate and concentrated to dryness by evaporation
The crude product remaining, which is in the form of
a brown oil~ is distilled under a water jet vacuum~
the 5-methyl-1~3-benzodioxole-2-carboxylic acid ethyl
ester pàssing over at 105-108/5 mbar,
b) A solution of 6.2 g (50 mmol) of 4-methyl-1,2-
benzenediol in 20 ml of dimethylformamide is added to
a suspension of 34,6 g (250 mmol) of anhydrous potassium
carbonate in 150 ml of dimethylformamide, After 5
minutes~ there is added thereto~ in the course of 15
minutes~ a solution of 12 g (55 mmol) of dibromoacetic
acid in 25 ml of dimethylformamide, and the whole is
heated at 80 for 4 hours Water is then added to the
reaction mixture and the whole is acidified and repeat-
edly extracted with ethyl acetate. The combined extracts
are washed with water and with saturated sodium chloride
solution~ dried over magnesium sulphate and concentrated
by evaporation The residue is esterified in the manner
described in a) with ethanol in the presence of a small
amount of concentrated hydrochloric acid.
Example 3:
In a manner analogous to that described in ~xample
1~ a mixture of 27.1 g (196 mmol) of potassium carb-
onate~ 12.5 g (39.16 mmol) of 4-chloro-5-(2-chloro-
phenylsulphonyl)-1~2-benzenediol and 6.76 g (43.08 mmol)
of dichloroacetic acid ethyl ester in 200 ml of 1,2-
dimethoxyethane is boiled under reflux for 15 hours,

387~
The solid material~ which has settled on the wall~ is
scratched away, a further 27 1 g (196 mmol) of potassium
carbonate and 6.76 g (43.o8 mmol) of dichloroacetic acid
ethyl ester are added and the whole ~s boiled under
reflux for a further 8 hours The rcaction mixture
is poured onto ice/water~ acidified and extracted with
ethyl acetats, ~fter concentration by e~aporation~
the 5-chloro-6-(2-chlorophenylsulphonyl)-1,3-benzodioxole~
2-carboxylic acid remaining, which is in the form of
a brown oil~ is brought to crystallisation in aceto-
nitrile and recrystallised once more from acetonitrile~
resulting in white crystals having a melting point of
226-227,
The required 4-chloro-5-(2-chlorophenylsulphonyl)-
1~2-benzenediol is produced as follows:
a) 24.6 g (170 mmol) of 4-chloro-1~2-benzenediol
are added while stirring~ under nitrogen, to a solution
of Z8 8 g (163 mmol) of 2-chlorobenzenesulphinic acid
(obtained by the reduction of 2-chlorobenzenesulphonyl
chloride with sodium sulphite) in 163 ml of 1N sodium
hydroxide solution. In the course of 40 minutes there
is added dropwise thereto~ at room temperature, a sol-
ution of 82 g (240 mmol) of potassium hexacyanoferrate
(III) and 150 g of sodium acetate trihydrate in 300 ml
of water. The solution becomes turbid and an oil forms
which~ after stirring for 2 hours~ crystall~ses. The
reaction mixture is extracted three times with ethyl
acetate. The organic phases are washed with water and
saturated sodium chloride solution~ dried and concentrated
by evaporation. The crude brown crystals are dissolved
in warm isopropanol and treated with activated carbon
The solution is filtered~ concentrated to 200 ml~ added
dropwise to 800 ml of ice-cold water and stirred for
2 hours while cooling with ice. The white suspension
is filtered with suction~ and the filtration r~due is

iZZ3
-- 4~ --
washed with water and driedt yielding 4-chloro-5-(2-
chlorophenylsulphonyl)-1,2-benzenedi~l in the form of
white crystals having a melting point of 226-229 .
~xample 4:
A suspension of 12 0 g (43.1 mmol) of 4-methyl-
5-(4-methylphenylsulphonyl)-1~2-benzenediol and 30 g
(216 mmol) of freshly calcined potassium carbonate in
200 ml of dry 1,2~dimethoxyethane is stirred for 5 min-
utes, under nitrogen, using a high-speed stirrerO In
the course of this the temperature rises to 75 Then,
while stirring moderately (propeller stirrer), there
i5 added dropwise thereto~ in the course of one hour,
a solution of 6,77 g (43,1 mmol) of dichloroacetic acid
ethyl ester in 50 ml of dry 1~2-dimethoxyethane and the
mixture is then boiled under reflux for 15 hours, It
iB subsequently poured onto an ice/water mixture and
adjusted to pH 1-2 with concentrated hydrochloric acid.
Some of the 1~2-dimethoxyethane is evaporated off in
a rotary evaporator and the solution remaining is extracted
with ethyl acatate. The combined organic phases are
washed with water and saturated sodium chloride solution~
dried over sodium sulphate and concentrated by evapor-
ation in a rotary evaporator The resulting black oil
is dissolved in ethanol~ 0,5 g of p-toluenesulphonic
acid i9 added~ and the whole is boiled under reflux
in a vessel provided with a Soxhlet attachment that is
filled with molecular sieve The ethanolic solution is
then concentrated completely by evaporation and chromato-
graphed over silica gel (solvent sthyl acetate/hexane
in a ratio of 1:1 ) . The uniform fractions containing
the desired substance are combined and concentrated by
evaporation, In this manner 5-methyl-6-(~-methylphenyl-
sulphonyl)-1~3~benzodioxole-2-carboxylic acid ethyl
ester is obtained in the form of a yellow oil~ which
can be hydrolysed directly,

~3~374
-- 45 --
A solution of 10 g of 4-methyl-5-(4-methylphe~yl-
sulphonyl)-1~3-benzodioxole-2~carboxylic acid ethyl
ester in 30 ml of rnethanol is cooled to 5. 41.3 ml
of 1N sodium hydroxide solution are added thereto
under nitrogen~ while stirring, the temperature rising
to 30 . The mixture is cooled to 20 and stirred at
room temp~rature for 30 minutes. Ice-water is then added,
the whole is filtered, and the filtrate is adjusted
to pH 1-2 with concentrated hydrochloric acid and ex-
tracted three times with ethyl acetate. The combined
ethyl acetate phases are washed with water and with a
saturated sodium chloride solution, dried over sodium
sulphate and concentrated completely by evaporation
The residue is crystallised from acetonitrile. The
crystallisate is stirred with cold ether~ then filtered
and dried The resulting 5-methyl-6-(4-methylphenyl-
sulphonyl)-1,3-benzodioxole-2-carboxylic acid melts
at 162-165
The required 4-methyl-5-(4-methylphenylsulphonyl)-
1,2-benzenediol is produced as follows:
a) Under nitrogen~ a mixture of 500 g of polyphosphoric
acid and 47.6 g (250 mmol) of ~-toluenesulphonic acid
monohydrate is heated to 100 and then added to 41.9 g
(275 mmol) of 1~2-dimethoxy-4-methylbenæene (4-methyl-
veratrole) The reddish suspension is stirred at 105
for 30 minutes, cooled to 80~ 1500 ml of water are
added and the whole is cooled to room temperature.
The reaction mixture is extracted with ethyl acetate.
The organic phase is washed with water~ dried~ treated
with activated carbon and concentrated by e~aporation.
The resulting solid substance is recrystallised from
toluene, but can also be further reacted directly. The
1~2-dimethoxy-4-methyl-5-(4-methylphenylsulphonyl)-
benzene is obtained from toluene in the form of white
crystals having a melting point of 133-134.5 .

~Z~3879
-- 46 --
b) 326 g of anhydrous pyridine hydrochloride are
heated to 180 1~7hile stirring9 33 g (113 m~ol) of
1,2--dimethoxy--4-methyl--5--(phenylsulphonyl~_benzene
are rapidly added The reaction mixture is heated
at 190 for a further 1~ minutes and stirred at this
temperature for one hour The hot reaction mixture
is poured onto an ice/water mixture and extracted
three times with ether The ether phases are combined,
washed with water and saturated sodium chloride solu~
tion~ dried over sodium sulphate and concentrated by
e~aporation in a rotary e~aporator In this manner~
dark-brown crystals are obtained, which are crystallised
from ether/hexane 1,2-Dimethoxy-4-methyl-~-(phenyl-
sulphonyl)-benzene having a melting point of 162-163
is thus obtained in the form of sand-coloured crystals
These crystals are used further without additional
purification.
Example 5:
In a manner analogous to that described in Example
4~ using 25 0 g (83.7 mmol) of 4-(4-chlorophenylsulphonyl)-
5-methyl-1~2-benzenediol~ 13.2 g (83 7 mmol) of dichloro-
acetic acid ethyl ester~ 57 g (418 mmol) of potassium
carbonate and 220 ml of 1~2-dimethoxyethane~ with sub-
sequent hydrolysis with sodium hydroxide solution in
methanol~ the desired 5-(4-chlorophenylsulphonyl)-6-
methyl-1~3-benzodioxole-2-carboxylic acid is obtained
in the form of white crystals having a melting point of
169-171 (from 1,2-dichloroethane).
The required 4-(4-chlorophenylsulphonyl)-5-methyl-
1~2-benzenediol is produced as follows:
a) 27.9 g (224.6 mmol) of 4-methyl-1,2-benzenediol
are added while stirring~ under nitrogen~ to a solution
of 35.0 g (198.2 mmol) of 4-chlorobenzenesulphinic acid

~Z23874
-- 47 --
(obtained by reduction of 4-chlorobenzenesulphonyl
chloride with sodium sulphite) in 198~2 ml of aqueous
lN sodium hydroxide solution. There is added drop-
wise thereto at room temperature~ in the course of
40 minutes, a solution of 109 g (330,3 mmol) of pot-
assium hexacyanoferrate (III) and 198.2 g of sodium
acetate trihydrate in 400 ml of water. After stirring
for 1 2 hours~ the reaction mixture is acidified and
extracted with ethyl acetate. The combined organic
phases are washed with water and saturated sodium
chloride ~olution~ dried over sodium sulphate and
concentrated by evaporation, The solid residue is
recrystallised from 1~2-dichloroethane. The 4-(4-
chlorophenyl~ulphonyl)-5-methyl-1~2-benzenediol so
obtained melts at 184-186,
Example 6-
In a manner analogous to that described in
Example 4,there i8 obtained by condensation of 25.0 g
(72,2 mmol) o~ 4-(4-cyclohexylphenylsulphonyl)-5-methyl-
1~2-benzenediol with 11.3 g (72.7 mmol) of dichloro-
acetic acid ethyl ester and 50 g (361 mmol) of potassium
carbonate in 190 ml of 1~2-dimethoxyethane and sub-
sequent hydrolysis with sodium hydroxide solution in
methanol~ 5-(4-cyclohexylphenylsulphonyl)-6-methyl-
1,3-benzodioxole-2-carboxylic acid in the form of white
crystals having a melting point o~ 159-161.5 (from
ethyl acetate/hexane).
The 4-(4-cyclohexylphenylsulphonyl)-5-methyl-
1~2-benzenediol used as starting material is obtained
from 28.2 g (226.7 mmol) of 4-methyl-1~2-benzenediol
and 44.9 g (200 mmol) of 4-cyclohexylbenzenesulphinic
acid (produced by reduction of the corresponding
sulphonyl chloride with sodium q-lphite) by oxidative
condensation in a manner analogous to that described
in ~xample 5a).

~ZZ;~874
- 48 _
Example 7:
~ suspension of 34,6 g (250 mmol) of freshly
calcined potassium carbonate in 150 ml of dimethyl-
formamide is stirred first with a hig~-speed stirrer
for 5 minutes and then with a Ilormal stirrer. ~ sol-
ution of 16,07 g (50 mmol) of 4-(3-acetamidophenyl-
sulphonyl)-5-methyl-1~2-benzenediol in 50 ml of di-
methylformamide is then added, After 5 minutes,
a solution of 11.98 g (55 mmol) of dibromoacetic acid
in 25 ml of dimethylformamide is added in the course
of 15 minutes and this r~action mixture is heated
for 4 hours at 80, Water is then added and the
whole is acidified with hydrochloric acid and fil-
tered with suction, The filtrate is repeatedly ex-
tracted with ethyl acetate, The solid substance is
dissolved in the combined organic phases and the sol-
ution is washed with water and saturated sodium chloride
solution~ dried over magnesium sulphate and concentrated
at 60 until crystallisation begins, 5-(3-acetamido-
phenylsulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic
acid is recrystallised from ethyl acetate, m,p, 186-
188,
The required 4-(3-acetamidophenylsulphonyl)-5-
methyl-1~2-benzenediol is obtained in a manner analogous
to that described in Example 3a) from 29,7 g (150 mmol)
of 3-acetamidobenzenesulphinic acid and 21,1 g (170 mmol)
of 4-methyl-1,2-benzenediol by oxidative coupling;
m,p, 220-2Z2 (from isopropanol/water),
Example 8:
In a manner analogous to that described in Example
4~ the desired ~-(4-fluorophenylsulphonyl)-6-methyl-
1~3-benzodioxole-2-carboxylic acid is obtained in the
form of white crystals having a melting point of
157-t58,5 (from 1~2-dichloroethane) by condensation

~ZZ387
-- 49 --
of 19 0 g (67,3 mmol) of 4-(4-fluorophenylsulphonyl)-
5-methyl-1~2-benzenediol with 10. 6 g ( 67. 3 mmol ) of
dichloroacetic acid ethyl ester and 46.5 g (336,5 mmol)
of potassium carbonate in 200 ml of 1~2-dimethoxyethane
and subsequent hydrolysis with sodium hydroxide solution
in methanol.
The required 4-(4-fluorophenylsulphonyl)-5-methyl-
1,2-benzenediol is obtained in the form of yellow crys-
tals having a melting point of 175-177 (from acetonitrile)
in a manner analogous to that described in Example 5a)
by oxidative condensation of 31.6 g (197 mmol) of p-
fluorobenzenesulphinic acid (produced either by reduction
of the corresponding sulphonyl chloride with sodium
sulphite or by Friedel-Crafts reaction of fluorobenzene
and carbon disulphide) with 38,7 g (312 mmol) of 4-
methyl-1~2-benzenediol
Example 9:
A suspension of 72.8 g (526 mmol) of freshly
calcined potassium carbonate in 300 ml of 1~2-dimethoxy-
ethane is stirred under nitrogen for 10 minutes using
a high-speed stirrer and then~ ~hile stirring normally~
37.0 g (105.3 mmol) of 4-(3-acetamido-4-methoxyphenyl-
sulphonyl)-5-methyl-1~2-benzenediol~ 16.5 g (105.3 mmol)
of dichloroacetic acid ethyl ester and 3 g of tetrabutyl-
ammonium bromide are added. The mixture is boiled under
reflux~ 300 ml of acetone are added~ the whole is boiled
under reflux for 3 more hours, a ~urther 60 g of potassium
carbonate and 16.5 g of dichloroacetic acid ethyl ester
are added~ and the whole is boiled under reflux for 9
more hours, The reaction mixture is poured into water
and acidified to pM 1-2 with hydrochloric acid. Some
of the solvent is evaporated off in vacuo and the aqueous
phase remaining is extracted with ethyl acetate. The
combined organic phases are washed with water and satur-
ated sodium chloride solution~ dried over sodium sulphate
and concentrated by evaporation in a rotary evaporator.

iZ~:387
-- 50 --
The residue is recrystallised four times from aceto-
nitrile~ yielding 5-(3-acetamido-4-methoxyphenylsul-
phonyl)-6-me$hyl-1,3-benzodioxole-2-carboxylic acid in
the form of white crystals having a melting point of
230 (sintering at 150)
The required 4-(3-acetamido-4-methoxyphenylsul-
phonyl)-5-methyl-1,2-benzenediol is obtained in a manner
analogous to that described in ~xample 5a) from 34 4 g
(150 mmol) of 3-acetamido-4-methoxybenzenesulphinic acid
and 211 g (170 mmol) of 4-methyl-1~2-benzenediol in the
form of crystals ha~ing a melting point of 230-232
(from isopropanol),
ExamPle 1 0:
In a manner analogous to that described in Example
4~ 30,0 g (111 mmol) of 4-methyl-5-(2-thienylsulphonyl)_
1~2-benzenediol, 17.4 g ( 111 mmol) of dichloroacetic acid
ethyl ester and 76,7 g (555 mmol) of potassium carbonate
in 300 ml of 1~2-dimethoxyethane are boiled under reflux
After 18 hours~ the reaction mixture is poured into water,
stirred ~or one hour at room temperature and then adjusted
to pH 1-2 by means of hydrochloric acid. Some of the 1,2-
dimethoxyethane is distilled off in vacuo and the mixture
remaining is extracted with ethyl acetate, The combined
organic phases are washed with water and saturated sodium
chloride solution, dried over sodium sulphate and concen-
trated by evaporation in a rotary evaporator. The result-
ing dark-red oil is chromatographed over silica gel
As eluant~ a mixture of chloroform/methanol/concentrated
ammonia in a ratio of 40:10:1 is used until elution of
the starting diol~ then an analogous mixture in a ratio
of 12:5:1 is used, The uniform fractions are combined
and concentrated almost completely by evaporation.
Ice/water is added to the residue and the pH is adjusted
to 1-2 with concentrated hydrochloric acid. The acidic
solution is extracted with ethyl acetate. The combined

~L2Z3~74
organic phases are washed, dried and concentrated by
evaporation The residue is boiled in diisopropyl ether
and the black sludge formed is removed by decanting.
The clear solution is concentrated to a large extent
and the substance which has crystallised out is filtered
off with suction. The crystals are recrystallised from
1~2-dichloroethane~ yielding 5-methyl-6-(2-thienylsul_
phonyl)-1~3-benzodioxole-2-carboxylic acid in the form
of white crystals having a melting point of 162 5-164.5
a) The 4-methyl-5-~(2-thienylsulphonyl)-1,2-benzene-
diol required as starting material is obtained in a manner
analogous to that described in Example 5a) from 90 g
(600 mmol) of 2-thiophenesulphinic acid (obtained by
reduction o f 2-thiophenesulphonyl chloride with sodium
sulphite) and 84.5 g (681 mmol) of 4-methyl-1~2-benzene-
diolin the form of yellowi~h crystals having a melting
point of 161-163,5 (from ethyl acetate).
Fxample 11:
In a manner analogous to that described in Example
4~ 21,3 g (64 mmol) of 4-(2,5-dichlorophenylsulphonyl)-
5-methyl-1~2-benzenediol, 10.0 g (64 mmol) of dichloro-
acetic acid ethyl ester and 44.2 g (320 mmol) of potass-
ium carbonate in 160 ml of 1~2-dimethoxyethane are boiled
under reflux, After 18 hours~ the reaction mixture is
filtered and the solid filtration residue is washed twice
with 1~2-dimethoxyethane. ~4 g of fresh potassium
carbonate and 10 g of dichloroacetic acid ethyl ester
are added to the combined organic solutions and the whole
is stirred for 5 minutes using a high-speed stirrer and
boiled~ while stirring normally~ for a further 17 hours.
Working up is carried out in a manner analogous to that
described in ~xample 10. After dr~ing carefully~ 5-
(2~5-dichlorophenylsulphonyl)-6-methyl-1~3-benzodioxole-
2-carboxylic acid is obtained in the form of white crystals
having a melting point of 155-157 (from diisopropyl ether).

23~37
_ 52 --
a) The 4-(2,5-dichlorobenzenesulphonyl)-5-methyl-
1~2-benzenediol used as starting material is obtained
in the form of sand-coloured crystals having a melting
point of 209.5-212 (from acetonitrile) from 40 g (189.5
mmol) of 2,5-dichlorobenzenes~lphinic acid (produced
by reduction of 2~5-dichlorobenzenesulphochloride with
sodium sulphite) and 26.7 g (215 mmol) of 4-methyl-1~2-
benzenediol in a manner analogous to that described in
Example 5a).
Example 12:
23 g (77 mmol) of 4-(2-chlorophenylsulphonyl)-
5-methyl-1~2-benzenediol are added to a finely partic-
ulate suspension of 50 9 g (385 mmol) of freshly calcined
potassium carbonate in 180 ml of dry dimethylformamide
and there is added dropwise thereto~ in the course of
15 minutes~ a solution of 8 50 g (39 mmol) of dibromo-
acetic acid in 80 ml of dim0thylformamide, The mixture
i8 then stirred for 15 hours at 80 , Subsequently~
the reaction mixture is poured onto ice and adjusted to
pH 1-2 with concentrated hydrochloric acid The aqueous
phase is extracted once more with ethyl acetate. The
combined organic phases are washed with water and sat-
urated sodium chloride solution~dried with sodium sul-
phate and concentrated by evaporation. The resulting
brown oil is ~tirred with 150 ml of ethyl acetate at 0
until crystallisation occurs. The crude 5-(2-chloro-
phenylsulphonyl)-6-methyl-1~3-benzodioxole-2-carboxylic
acid so obtained is recrystallised twice from aceto-
nitrile~ resulting in the form of sand-coloured crystals
having a melting point of 211-213.5.
a) The 4-(2-chlorophenylsulphonyl)-5-methyl-1,2-
benzenediol is obtained in the form of white crystals
having a melting point of 225-229 (from ethyl acetate)
in a manner analogous to that described in Example 5a)
from 26.5 g (150 mmol) of 2-chlorobenzenesulphinic acid
and 21.1 g (170 mmol) of 4-methyl-1~2-benzenediol.

1~3~il7'1
-- 53 --
Example 1~:
In a manner analogous to that described in Example
12, 5-(3-acetamido-4-chlorophenylsulphonyl)-6-methyl-1,3-
benzodioxole-2-carboxylic acid is obtained by condensation
of 22.0 g (61.8 mmol) of 4-(3-acetamido-4-chlorophenyl-
sulphonyl)-5-methyl-1,2-benzenediol with 16.25 g (74.18
mmol) of dibromoacetic acid and 42.7 g (309 mmol) of pot-
assium carbonate in 225 ml of dimethylformamide; ~ p. 198-200.
Working up is carried out likewise in a manner anal-
ogous to that described in ~xample 12, by chromatographing
the dark-red oil obtained as crude product over a silica
gel funnel (chloroform/methanol/concentrated ammonia 40:10:1).
The uniform fractions are extracted with e~thyl acet-
ate~ and the substance remaining after concentration by
evaporation of the extract is recrystallised from acetonit-
rile~ yielding the end product in the form of sand-coloured
crystals having a melting point of 198-200 (sinters ~om 120 ).
The 4-(3-acetamido-4-chlorophenYlsulphonyl)-5-
methyl-1~2-benzenediol used as starting material is
produced as follows:
a) 66 g (297.8 mmol) of 4-chloro-3-nitrobenzenesulphinic
acid (produced by reduction of 4-chloro-3-nitrobenzenesul-
phonyl chloride with sodium sulphite) are condensed with
41,g5 g (337,9 mmol) of 4-methyl-1~2-benzenediol in a
manner analogous to that described in Example 4, yielding
4-(4-chloro-3-nitrophenylsulphonyl)-5-methyl-1~2-benzene-
diol in the form of crystals having a melting point of
196-197 (from ethyl acetate/hexane).
b) 47 5 g (138.2 mmol) of the product obtained accord-
ing to a) are catalytically hydrogenated with hydrogen in
the presence of Raney nickel to form 4-(3-amino-4-chloro-
phenylsulphonyl)-5-methyl-1~2-benzenediol, The latter is
crystallised from 1~2-dichloroethane in the form of sand-
coloured crystals having a melting point of 191-193 .
c) 40 g (112.42 mmol) of the amine obtained according
to b) are acetylated with 11.48 g (112.42 mmol) of acetic

1~3874
-- 54 --
anhydride in 240 ml of glaci~l acetic acid to ~orm the
desired 4-(3-acetamido-4-chlorophenylsulphonyl)-5-methyl-
1,2-benzenediol, which is obtained from acetonitrile
in the form of white crystals having a melting point
of 224-226 5.
xample 1L~:
21 ~ g (70 3 mmol) of 4-chloro-5-(4-mathylphenyl-
sulphonyl)-1~2-benzenediol and 48 6 g (approximately
350 mmol) of anhydrous pulverised potassium carbonate
are suspensed in 160 ml of dimethylformamide at room
temperature under inert gas. A solution of 16 8 g
(77,L~ mmol) of dibromoacetic acid in 80 ml of dimethyl-
formamide is then added dropwise thereto at room temp-
erature~ while stirring~ inthe course of 15 minutes,
The reaction mixture is then heated for 15 hours at
while stirring. -For working up, the reaction mix-
ture is poured onto an ice/water mixture and acidified
with concentrated hydrochloric acid to pH 2 The crude
product is extracted with ethyl acetate and the solvent
is evaporated off The crude acid remaining is dissolved
in 100 ml of methanol~ and 0 5 ml of concentrated hydro-
chloric acid is added. After standing for 5 hours at
room temperature~ crystallisation commences, The crystal
suspension is cooled in an ice bath for 18 hours, then
the crystals are filtered off and washed with ice-cold
methanol They are then suspended in 60 ml of methanol~
and 35 ml of 2N sodium hydroxide solution are added at
room temperature~ a solution being formed. After being
left to stand for one hour~ the solution is poured out
onto an ice/water mixture and acidified with 6N hydro-
chloric acid. The 5-chloro-6-(~-methylphenylsulphonyl)-
1~3-benzodioxole-2-carboxylic acid precipitates and is
extracted with ethyl acetate. The residue of the extract~
obtained by concentration by evaporation~ is recrystallised
from acetonitrile~ and in this manner the above substance

~2~3~374
is obtained in the form of sand-coloured crystals having
a melting point of 181-183 5
The aromatic starting material is produced as
follows:
a) In a manner analogous to that described in Example
5a)~ ~-toluenesulphinic acid is oxidatively condensed
with 4-chloro-1~2-benzenediol On recrystallisation
from 1,2-dichloroethane, 4-chloro-(4-methylphenyl~lphonyl)-
1~2-benzenediol is obtained in the form of colourless
crystals having a melting point of 162-164.
~xample 15:
42.~ g (approximately 0.13 mol) o~ 4-bromo-5-(phen-
ylsulphonyl)-1~2-benzenediol and 90,0 g (approximately
o.65 mol) of anhydrous pulverised potassium carbonate
are stirred in 300 ml of dimethylformamide under inert
gas protection, At room temperature~ half of a solution
of 57,0 g (approximately o,z6 mol) of dibromoacetic acid
in 100 ml of dimethylformamide is added, The reaction
mixture is stirred for 8 hours at 95~ then the remainder
of the dibromoacetic acid solution is added and the
whole is stirred for a further 8 hours at 95 Sub-
sequently~ the dimethylformamide is distilled off at
reduced pressure~ the residue is dissolved in water~
the solution is adjusted to pH 1-2 with concentrated
hydrochloric acid and extraction is carried out with
ethyl acetate. The ethyl acetate solution is washed
with water~ dried over sodium sulphate and concentrated
by evaporation, The residue is dissolved in 150 ml
of methanol,and 0,3 ml of concentrated hydrochloric acid
is added. After being left to stan~ overnight at room
temperature~ the solution is concentrated by evaporation
and the residue is chromatographed on a column of silica
gel with the eluant mixture ethyl acetate/hexane 1:2,
The uniform fractions are combined and concentrated by
evaporation, 50 ml of 2N sodium hydroxide solution are

lZ2387
-- 56 --
added to the residue obtained by concentration by evap-
oration, and the whole is stirred at room temperature
with a magnetic stirrer until a solution has formed
This solution is adjusted to pH 1-2 with concentrated
hydrochloric acid and the precipitated acid is repeat-
edly extracted with ethyl acetate. The combined ethyl
acetate solutions are washed with water9 dried with
sodium sulphate, filtered and concentrated by evapor-
ation~ resulting in 5-bromo-6-(phenylsulphonyl)-1,3-
benzodioxole-2-carboxylic acid in the form of a white
crystalline crust, Recrystallisation from ethyl
acetate/hexane yields the above substance in the form
of colourless crystals having a melting point of 219-
222 (decomposition).
The aromatic starting material is obtained in
tha following manner:
a) 48.o g of 4-bromo-1~2-benzenediol ~cf W, Ros~mund,
Ber. 62~ 1262 and so forth (1923)] are oxidatively con-
densed with 33.4 g of the sodium salt of benzenesulphinic
acid in a manner analogous to that described in Example
5a), Crystallisation from 1,2-dichloroethane yields
4-bromo-5-(phenylsulphonyl)-1,2-benzenediol in the form
of colourless crystals having a melting point of 166-168.
Example 16:
25.0 g (approximately 85 mmol) of 4-(4-methoxy-
phenylsulphonyl)-5-methyl-1~2-benzenediol are reacted
in 200 ml of dimethylformamide~ using 60 g of potassium
carbonate~with 20.4 g (93.5 mmol) of dibromoacetic acid
in 100 ml of dimethylformamide~ in a manner entirely
analogous to that described in Example ~4, The resulting
crude acid is dissolved in ethyl acetate~ and a solution
of 5.8 g of the sodium salt of hexanoic acid in methanol
is added, The resulting crystals are filtered off and
dried, In this manner the sodium salt of 5-(4-methoxy-

387
- 57 -
phenylsulphonyl)-6-methyl-1,3-benzodioxol~-2-carboxylic
acid is obtained in the form of colourless crystals
having a melting point of above 220 (d0composition)
The aromatic starting material is obtained as
~ollows:
a) 37 5 g of 4-methoxybenzenesulphinic acid (obtained~
for example, by reduction of 4-methoxybenzenesulphonyl
chloride with sodium sulphite) are condensed oxidatively
with 30.7 g of 4-methyl-1,2-benzenediol in a manner
analogous to that described in Example 5a) and, after
crystallisation from 1~2-dichloroethane~ 4-(4-methoxy-
phenylsulphonyl)-5-methyl-1~2-benzenediol is obtained
in the form of colourless crystals having a melting point
of 1L~5-147-5 .
ExamPle 17:
15 0 g (0 05 mol) of 4-(2,4-difluorobenzenesulph-
onyl)-5-methyl-1~2-benzenediol and 34 6 g (0.25 mol) of
potassium carbonate are suspended at room temperature
under nitrogen protection in 100 ml of dimethylformamide
In the course of 10 minutes~ a solution of 11.9 g (approx-
imately 0 055 mol) of dibromoacetic acid in 30 ml of
dimethylformamide is added dropwise and the reaction
mixture is then heated at 90 for 5~ hours while stirring.
The reaction mixture is poured into 1500 ml of water and
adjusted to p~ 1-2 with concentrated hydrochloric acid.
The crude acid is extracted with ethyl acetate, and the
ethyl acetate solution is washed with water~ dried over
sodium sulphate~ filtered and concentrated by evapor-
ation, 50 ml of 1N sodium hydroxide solution are added
to the residue obtained by concentration by evaporation~
and the resulting solution is concentrated by evaporation
in a rotary evaporator until the sodium salt befi ns to
crystallise out By the addition of isopropanol and heat-
ing to reflux a solution is obtained again~ activated

1,.~Z387'~
-- 58 --
carbon is added and the ~lole is filtered. On cooling
the filtrate~ the sodium salt of 5-(2,4-difluorophenyl-
sulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid
is precipitated in the form of colourless needles
~fter filtration and drying9 the salt melts at a
temperature of above 200, after sintering from 160.
The starting material is produced as follows:
a) By Meerwein reaction using 2~4-difluoroaniline
as starting matsrial, 2,4-difluorobenzenesulphonyl
chloride, b.p : ~7/5 mbar, is obtained
b) By reduction of 2,4-difluorobenzenesulphonyl chlor-
ide with sodium sulphite~ 2,4-difluorobenzenesulphinic
acid is obtained
c) In a manner analogous to that described in Example
5a)~ there is obtained by oxidative condensation of
23 5 g of 2,4-difluorobenzenesulphinic acid with 18.5 g
of 4-methyl-1,2-benzenediol~ after recrystallisation
from 1~2-dichloroethane~ 4-(2~4-difluorobenzenesulph-
onyl)-5-methyl-1~2-benzenediol having a melting point
of 158-162,
Example 18:
In a manner analogous to that described in Example
1, 18~3 g of 4-(3-chloro-4-fluorophenylsulphonyl)-5-
methyl-1,2-benzenediol is reacted in the presenc0 of
39 9 g of potassium carbonate with 10.0 g of dichloro-
acetic acid ethyl ester in 150 ml of dimethoxyethane.
There is obtained~ after analogous working up and re-
crystallisation from acetonitrile~ 5-(3-chloro-4-fluoro-
phenylsulphonyl)-6-methyl-1~3-benzodioxole-2-carboxylic
acid in the form of colourless crystals having a melting
point of 188.5-190.5,
The aromatic starting material is produced as
follows:
a) The 3-chloro-4-fluorobenzenesulphochloride used

lZ;Z3~74
-- 59 --
in Example 18b~ b p 90-95 / 5 mbar) is obtained according
to processes known in the literature, for example by
Meerwein reaction from 3-chloro-4-fluoroaniline.
b) By reduction of 3-chloro-4-fluorobenzenesulpho-
chloride with sodium sulphite~ 3-chloro-~-fluorobenzene-
sulphinic acid having a melting point of 66-68 is ob-
tained
c) There is obtained in a manner analogous to that
described in Example 5a)~ by oxidative condensation of
3-chloro-4-fluorobenzenesulphinic acid with 4-methyl-
1~2-benzenediol~ the 4-t3-chloro-4-fluorophenylsulphonyl)-
5-methyl-1~2-benzenediol used in the above Example 18
having a melting point of 166-167.5 in the form of
colourless crystals.
Example 19:
In a manner analogous to that described in Example
17~ 14 g (42.8 mmol) of 5-(4-chloro-2,5-dimethylphenyl-
sulphonyl)-4-methyl-1~2-benzenediol and 10.3 g of dibromo-
acetic acid are reacted in the presence of 29,6 g of
potassium carbonate in 150 ml of dimethylformamide ar.d~
after working up~ salt formation with sodium hydroxide
solution and recrystallisation from isopropanol/water~
there is obtained the sodium salt of 5-(4-chloro-2~5-
dimethylphenylsulphonyl)-6-methyl-1~3-benzodioxole-2-
carboxylic acid in the form of colourless crystals having
a melting point of >180 (decomposition).
The 5-(4-chloro-2~5-dimethylphenylsulphonyl~-4-
methyl-1~2-benzenediol used as starting material is
obtained by oxidative condensation of 4-chloro-2~5-
dimethylbenzenesulphonic acid (in turn obtained by red-
uction of 4-chloro-2,5-dimethylbenzenesulphochloride
with sodium sulphite) ~ith 4-methyl-1~2-benzenediol in
a manner analogous to that described in Example 5a) and
crystallisation from ethyl acetate~ in the form of

lZZ38~74
-- 60 --
yellowlsh cryst~ls having a melting point of 193-196.
(sintering from 143),
Example 20-
.
31.2 g (0.1 mol~ of 5-(4-chloro-2,5 dimethyl-
phenylsulphonyl)-4-methyl-1~2-benzenediol and 55 g
(0 4 mol) of potassium carbonate are suspended in 150 ml
of dimethylformamide under an inert gas, ~t room temp-
erature 17,3 g (0.11 mol) of dichloroacetic acid ethyl
ester are added and the mixture is then heated at 80
for 10 hours For working up, the dimethylformamide
is distilled off in vacuo and the residue is dissolved
in water, The solution is acidified to pH 1-2 with
concentrated hydrochloric acid and the precipitated crude
acid is repeatedly extracted with ethyl acetate. The
combined ethyl acetate solutions are concentrated by
evaporation and the residue is dissolved at elevated
temperature in the equivalent amount of 2N sodium hydr-
oxide solution. On cooling~ the sodium salt of 5-(4-
chloro-2~5-dimethylphenylsulphonyl)-6-methyl-1~3-benzo-
dioxole-2-carboxylic acid precipitates. ~fter cooling~
it is filtered off and recrystallised from isopropanol
in the manner described in Example 19.
ExamPle 21:
In a manner analogous to that described in Example
17~ 25 g (71,7 mmol) of 4-(2~4-dichloro-5-methylphenyl-
sulphonyl)-5-methyl-1,2-benzenediol are reacted with
17.14 g (78.7 mmol) of dibromoacetic acid in the pres-
ence of 49 5 g of potassium carbona-te in 250 ml of
dimethylformamide After working up~ salt formation
and recrystallisation in a manner analogous to that
described in Example 17~ the sodium salt of 5-(2~4-
dichloro_5_methylphenylsulphonyl)-6-methyl-1~3-benzo-
dioxole_2_carboxylic acid is obtained in the form of
colourless crystals having a melting point of 200

~23874
(decomposition),
a) The 4~/2,4-dichloro-5-methylphenylsulphonyl)-
5-methyl-1,2-benzenediol used above is obtained by
oxidative condensation of 294-dichloro-5-methylbenzene-
sulphinic acid (obtained from 2,4-dichloro-5-methylbenz-
enesulphochloride by reduction with Na-sulphite) with
4-methyl-1~2-benzenediol in a manner analogous to that
described in Example 5a); m,p, 203,5-206 (decomposition9
from acetonitrile),
Example 22:
In a manner analogous to that described in Example
15~ 60,0 g of 4-(4-bromophenylsulphonyl)-5-methyl-1~2-
benzenediol are reacted in the presence of 120 g of
potassium carbonate in 300 ml of dimethylformamide with
a solution of 76.2 g of dibromoacetic acid in 100 ml of
dimethylformamide, After working up and chromatographic
purification in a manner analogous to that described in
Example 15 and crystallisation from 1~2-dichloroethane~
5-(4-bromophenylsulphonyl)-6-methyl-1~3-benzodioxole-
2-carboxylic acid is obtained in the form of sand-coloured
crystals having a melting point of 170-172,5,
a) The 4-(4-bromophenylsulphonyl)-5-methyl-1~2-
benzenediol used in the above Example is obtained by
oxidative condensation of 76,o g of ~-bromobenzenesul-
phinic acid (obtained from ~-bromobenzenesulphochloride
by reduction with sodium sulphite) with 53,0 g of 4-methyl-
1,2-benzenediol in a manner analogous to that described
in Example 5a), in the form of colourless crystals
having a melting point of 190-191.5 (~rom chloroform),
Example 23:
39,6 g (approximately 0.105 mol) o~ 4-[(2-tert.-
butyl-6_benzothiazolyl)-sulphonyl]-5-methyl-1~2-benzene-
diol and 72.3 g (0,523 mol) of potassium carbonate are

i2'23874
-- 62 _
stirred in 300 ml of dimethylformamide at room temp-
erature under inert gas protection. In the course of
20 minutes there is added dropwise thereto half of
a solution of 45 6 g (0.209 mol) of dibromoacetic
acid in 100 ml of dimethylformamide The reaction
mixture is subsequently stirred for 21 hours at 100
and~ during this time~ the remainder of the dibromo-
acetic acid solution is added in small portions. For
working up, the dimethylformamide is distilled off in
a rotary evaporator under a water jet vacuum, The
residue is dissolved in water and adjusted to pH 1-2
with concentrated hydrochloric acid. The precipitated
acid is extracted three times with ethyl acetate. The
combined ethyl acetate solutions are washed once with
water~ dried over sodium sulphate~ filtered and con-
centrated by evaporation. The residue is dissolved
in 500 ml of ethanol, and after the addition of 0.5 ml
of ~oncentrated hydrochloric acid the solution is left
to stand at room temperature for 10 days. During this
time~ the ethyl ester of 5-methyl-6-[(2-tert.-butyl-
6-benzothiazolyl)-sulphonyl]-1~3-benzodioxole-2-car-
boxylic acid is precipitated in the form of colourless
crystals. The cryst~ suspension is cooled to 0 and
the crystals are filtered off. 90 ml of 2N sodium
hydroxide solution are added to the crystals~ still
moist with ethanol~ and the mixture is stirred for 2
hours at room temperature, a solution being formed.
This is acidified with concentrated hydrochloric acid
and the precipitated acid is extracted three times with
ethyl acetate. The athyl acetate solutions are washed
with water~ dried over sodium sulphate9 filtered and
concentrated by evaporation in ~acuo to dryness. The
residue is recrystallised from ethyl acetate~ yielding
5-methyl-6-~(2-tert.-butyl-6-benzothiazolyl)-sulphonyl]-
1,3-benzodioxole-2-carboxylic acid in the form of
colourlegs crystals ha~ing a melting point of 247

~Z'2387'~
-- 6~ --
(decomposition), after sintering from 203.
The starting material is produced as follows:
a) 2-Tert,-butyl-6-benzothiazolesulphochloride is
obtained by the kno1~ Meerwein reaction, using as starting
material 6-amino-2-tert,-butylbenzothiazole,
b) By reduction of 2-tert,-butyl-6-benzothiazole-
sulphochloride, 2-tert.-butylbenzothiaz~2-sulphinic
acid~ which melts at a temperature of above 150 , is
obtained,
c) 4-~ethyl-5-[(2-tert,-butyl-6-benzothiazolyl)-
sulphonyl]-1~2-benzenediol having a melting point of
185 (decomposition) is obtained in a manner analogous
to that described in Example 5a) with subsequent chrom-
atography,
Exam~le 24:
In a manner analogous to that described in Example
15~ corresponding amounts of 4-chloro-5-phenylsulphonyl-
1,2-benzenediol and dibromoacetic acid in dimethylform-
amide are reacted in the presence of potassium carbonate,
After working up, purification and recrystallisation in
a manner analogous to that described in Example 15~ 5-
chloro-6-phenylsulphonyl-1,3-benzodioxole-2-carboxylic
acid ha~ing a melting point of 183-185 is obtained.
a) The 4-chloro-5-phenylsulphonyl-1,2-benzenediol
used in the above Example is obtained by reaction of
benzenesulphinic acid with 4-chloro-1,2-benzenediol
in a manner analogous to that described in Example 5a);
m,p, 161-165.
Example 25:
In a manner analogous to that described in Example
15~ there is obtained by reaction of corresponding amounts
o~ 4-chloro-5-(4-chlorophenylsulphonyl)-1~2-benzenediol
and dibromoacetic acid in dimethylformamide in the presence

l'~Z3~374
-- 64
of potassiu~ carbonate and by analogous working up~
purification and recrystallisation, 5-chloro-6-~4-
chlorophenylsulphonyl)-1,3-benzodioxole-2-carboxylic
acid having a melting point of 194-196.
a) The 4-chloro-5-(4-chlorophenylsulphonyl~ 2-
benzenediol used in the above Example is obtained by
reaction of 4-chlorobenzenesulphinic acid and 4-chloro-
1~2-benzenediol in a manner analogous to that described
in Example 5a); m p 165-176
Example 26:
In a manner analogous to that described in Example
14~ 20 1 g of 4-(4-acetylphenylsulphonyl)-5-methyl-1,2-
benzenediol and 28,3 g of dibromoacetic acid are reacted
in 130 ml of dimethylformamide in the presence of 45 g
of potassium carbonate, After analogous working up and
purification~ 5-(4-acetylphenylsulphonyl)-6-methyl-1~3-
benzodioxole-2-carboxylic acid having a melting point of
107-110 is obtained
The aromatic starting material is produced as
follow~:
a) By the reduction of 4-acetylbenzenesulphonyl chlor-
ide with sodium sulphite~ 4-acetylbenzenesulphinic acid
is obtained.
b) By oxidative condensation of 4-acetylbenzene-
sulphinic acid with 4-methyl-1~2-benzenediol~ 4-(4-acetyl-
phenylsulphonyl)-5-methyl-1~2-benzenediol having a melting
point of 184-188 is obtained.
Example 27:
10.0 g (0 0359 mol) of 4-phenylsulphonyl-5-ethyl-
1~2-benzenediol and 31.5 g (0.288 mol) of potassium carb-
onate are placed in 100 ml of dimethylformamide at room
temperature under inert gas protection~ and ~.0 g (0.0413
mol)of dibromoacetic acid are added. The reaction mixture

3~37'~
-- 65 --
is maintained at ~n internal temperature of approximately
for 14 hours while stirring, Subsequently~ the
dimethylformamide is distilled off in a rotary evaporator
under a water jet ~acuum9 and the residue is taken up
in water, The pH is adjusted to 1-2 with concentrated
HCl, the crude acid is extracted with ethyl acetate~
and the ext~act is dried with sodium sulphate, filtered
and concentrated to dryness by evaporation in a rotary
evaporator, The residue is dissolved in 100 ml of abso-
lute ethanol~ 0~2 ml of concentrated HCl are added and
the whole is boiled at reflux for two hours, It is
then concentrated to dryness by evaporation~ the residue
is taken up in ethyl acetate and washed in a separating
funnel once with saturated sodium bicarbonate solution
and twice with water, The ethyl acetate phase is dried
over sodium sulphate~ filtered and concentrated by evap-
oration, 20 ml of 2N NaOH are added to the residue and
the whole is heated on a warm water bath until a yellowish
solution has formed, The solution is cooled, adjusted
to pH 1-2 with concentrated HCl, and the purified 5-
phenylsulphonyl-6-ethyl-1,3-benzodioxole-2-carboxylic
acid is extracted with ethyl acetate, ~ne extract sol-
ution i~ dried over sodium sulphate and filtered, 50 ml
of toluene are added and the ethyl acetate is evaporated
off in a rotary evaporator, The acid is precipitated
in the form of colourless crystals having a melting point
of 143-145 ,
a) The 4-phenylsulphonyl-5-ethyl-1~2-benzenediol
used in the above Example is obtained by oxidative coupling
of benzenesulphinic acid with 4-ethyl-1~2-benzenediol
in a manner analogous to that described in Example 1a);
m.p. 1~0-182.
Example 28:
27.5 g ~0,097 mol) of 4-(2-methylphenylsulphonyl)-

1;~;23~37
-- 66 --
5-methyl-1,2-benzenediol~ 62.1 g (0 45 mol) of potassium
carbonate and 32.7 g (0 14~ mol) of dibromoacetic acid
(97C/o strength) are reacted in 300 ml of dimethylformamide
under an inert gas atmosphere in a manner analogous to
that described in Ex~mple 27, ~fter working up~ purific-
ation by way of the ethyl ester and hydrolysis, in a
manner entirely analogous to that described in Example 27,
5-(2-methylphenylsulphonyl)-6-methyl-1~3-benzodioxole-
2-carboxylic acid is obtained in the form of colourless
crystals having a melting point of 178-180 (from toluene)
The 4-(2-methylphenylsulphonyl)-5-methyl-1,2-
benzenediol used above is produced as follows:
a) 33.2 g tO 108 mol) of 1~2-dimethoxy-4-(2-methyl-
phenylsulphonyl)-5-methylbenzene and 70 g (o.6 mol) of
pyridine hydrochloride are heated together in a bath of
200 for 2~ hours to form a melt, The melt is poured
onto ice~ 20 ml of concentrated HCl are added ~ld extrac-
tion with ethyl acetate is then carried out The extract
solution is washed twice with water, dried with sodium
sulphate~ filtered and concentrated in a rotary evapor-
ator, When a volume of approximately 100 ml has been
reached~ the product begins to crystallise out The
whole is cooled for ~ hour in an ice bath~ filtered, and
the resulting beige crystals of 4-t2-methylphenylsul-
phonyl)-5-methyl-1~2-benzenediol having a melting point
of 221-223 are dried
The starting material used in Example 28a) is
obtained in the following manner:
b) 50 g f phosphorus pentoxide are covered~ by pouring~
with 400 ml of methanesulphonic acid and the whole is
stirred at 60 until a clear solution has formed, 30.4 g
to.2 mol) of 1,2-dimethoxy-4-methylbenzene and 43 g (0.2
mol) of 2-methylbenzenesulphonic acid (80 % strength) are
~hen added~ and the internal temperature is increased to

i;~'23~37
-- 67 --
~o for 30 minutes, The mi~ture is poured onto 4 litres
of ice-water and extracted with ethyl acetate~ The
extract solution is washed twice with water~ dried over
sodium sulphate, filtered and concentrated by evapor-
ation in a rotary evaporator. The oil remaining crys-
tallises immediately. It is triturated with di~hyl ether
and filtered off, In this manner colourless crystals of
1~2-dimethoxy-4-(2-methylphenylsulphonyl)- 5 - m ethylbenzene
having a melting point o~ 126-128 are obtained,
xample 29:
24,5 g (0,088 mol) of 4-(3-methylphenylsulphonyl)-
1~2-benæenediol~ 60,7 g (0,44 mol) of potassium carbonate
and 29,6 g (0,132 mol) of dibromoacetic acid (97 % strength)
are reacted in 300 ml of dimethylformamide in a manner
analogous to that described in Example 27, After working
up~ purification by way of the ethyl ester and hydrolysis
in a manner analogous to that described in Example 27
colourless crystals of 5-(3-methylphenylsulphonyl)-6-
methyl-1~3-benzodioxole-2-carboxylic acid having a melting
point of 155-157 are obtained from toluene/ethyl acetate,
a) The 4-(3-methylphenylsulphonyl)-1~ 2-benzenediol
used above is produced in a manner analogous to that
described in Example 28a) by ether cleaving of 1,2-
dimethoxy-4-(3-methylphenylsulphonyl)-5-methylbenzene
by means of pyridine/hydrochloride; m,p, 172-174 (from
toluene/ethyl acetate),
b) The above 1,2-dimethoxy-4-(3-methylphenylsulphonyl)-
5-mathylbenzene is obtained by reacting 3-methylbenzene-
sulphonic acid with 1,2-dimethoxy-4-methylbenzene in a
manner analogous to that dascribed in Example 28b);
m,p, 135-140 (from ether),
Example_30:
13,1 g (o,0438 mol) of 4-(3-chlorophenylsulphonyl)-
5-methyl-1~2-benzenediol~ 30,0 g (0,217 mol) of potassium
carbonate and 14,7 g (o,o65 mol) of dibromoacetic acid

1~387~
( 97 % strength) are stirred in 150 ml of dimethylform-
amide for 5 hours at an internal temperature of 80
under an inert gas atmosphere. ~fter working up~ pur-
ification by way of the ~hyl ester Qnd hydrolysis in
a manner analogous to that described in Example 27~
colourless crystals of 5-(3-chlorophenylsulphonyl)-6-
methyl-1,3-benzodioxole-2-carboxylic acid having a
melting point of 172-174 (from toluene/ethyl acetate)
are obtained,
a) The 4-(3-chlorophenylsulphonyl)-5-methyl-1,2-ben-
zenediol used abo~e is obtained in a manner analogous
to that described in Example 28a) by ether cleaving
from 1~2-dimethoxy~4-(3-chlorophenylsulphonyl)-5-methyl-
benzene by means of pyridine hydrochloride; m p. 185-
187 (from toluene/ethyl acetate).
b) The 1~2-dimethoxy-4-(3-chlorophenylsulphonyl)-
5-methylbenzene used in Example 30a) is obtained in
a manner analogous to that described in ~xample 28b)
by condensation of 3-chlorobenzenesulphonic acid with
1,2-dimethoxy-4-methylbenzene in phosphorus pentoxide/
methanesulphonic acid while heating for one hour at 80;
m.p. 151-152 (from toluene).
Example 31:
9.2 g (0.029 mol) of 4-chloro-5-(3-chlorophenyl-
sulphonyl)-1,2-benzenediol~ 18.0 g (0.13 mol) of potassium
carbonate and 9.5 g (o.042 mol) of dibromoacetic acid
(97 /0 strength) are reacted in 70 ml of dimethylformamide
in a manner analogous to that described in ~xample 27.
After working up and esterifying in a manner analogous
to that described in Example 27, the crude ester is
chromatographed o~er 200 g of silica gel with the sol~ent
mixture hexane/ethyl acetate (9~ and the uniform frac-
tions are combined, concentrated by evaporation and
then hydrolysed with 2N NaOH. After liberation and

~Z~2~874
-- 69 --
isolation of the 5-chloro-6-(3-chlorophenylsulphonyl)-
1~3-benzodioxole-2-carboxylic acid, this is recrys-
tallised from toluene/ethyl acetate; m p 182-18L~ .
The 4-chloro-5-(3-chlorophenylsulphonyl)-1,2-
benzenediol used above can be produced in the follo~ng
manners:
a) By oxidative coupling of 3-chlorobenzenesulphinic
acid with 4-chloro-1~2-benzenediol in a manner analogous
to that described in Example 3a) there is obtained~ after
crystallisation from toluene/ethyl acetate, 4-chloro-5-
(3-chlorophenylsulphonyl)-1,2-benzenediol having a
melting point of 192-194.
b) 4-chloro-5-(3-chlorophenylsulphonyl)-1~2-benzene-
diol is also obtained by ether cleaving 1, 2-dimethoxy-
4-chloro-5-(3-chlorophenylsulphonyl)-benzene by means of
pyridine hydrochloride in a manner analogous to that
described in Example 28a),
c) The 1~2-dimethoxy-4-chloro-5-(3-chlorophenyl-
sulphonyl)-benzene used in ~xample 31b) is obtained by
reacting 3-chlorobenzenesulphonic acid with 1,2-dimeth-
oxy-4-chlorobsnzene in a manner analogous to that des-
cribed in Example 28b); m p, 154-156.
xample 32:
19.7 g (o,065 mol) of 4-chloro-5-(4-fluorophenyl_
sulphonyl)-1~2-benzenediol~ 40,1 g to~29 mol) of pot-
assium carbonate and 23.6 g (0.108 mol) of dibromoacetic
acid ~7 ~ strength) are stirred in 160 ml of dimethyl-
formamide for 20 hours at 80 under an inert gas atmos-
phere. The dimethylformamide is evaporated off in a
rotary evaporator under a water jet vacuum and the res-
idue is taken up in water. The pH is adjusted to 1-2
with concentrated HCl~ then extraction is carried out

1223~374
_ 70 --
~ith ethyl acetate The extract solution is concen-
trated by evaporation and the residue is dissolved in
250 ml of absolute ethanol ~fter the addition of
0,2 ml of concentrated HCl~ the whole is boiled at
reflux for 2 hours and then concentrated to dryness
by evaporation. The resinous residue is chromatographed
over 400 g o~ silica gel with a solvent mixture of
chloroform/hexane/ethyl acetate (1:1:1). The uniform
fractions are collected and concentrated by evaporation,
100 ml of 2N NaOH are added to the resulting ethyl
ester of 5-chloro-6-(4-fluorophenylsulphonyl)-1~3-benzo-
dioxole-2-carboxylic acid and the whole is stirred
for one hour at 80 At elevated temperature, activated
carbon is added to the resulting yellow solution and
filtration is carried out, On cooling~ the sodium salt
o~ 5-chloro-6-(4-fluorophenylsulphonyl)-1~3-benzodioxole-
2-carboxylic acid crystallises into fine colourless
flakes; m.p 216-220 (decomposition).
a) The 4-chloro-5-(4-fluorophenylsulphonyl)-1,2-
benzenediol used above is obtained in a manner analogous
to that describad in Example 3a) by oxidative coupling
of 4-chloro-1,2-benzenediol with 4-fluorobenzenesulphinic
acid; m p 180-182 (from ethyl acetate/toluene).
xample 33:
18.1 g (0 05 mol) of 4-chloro-5-(4-bromophenyl-
sulphonyl)-1~2-benzenediol~ 31,0 g (o,244 mol) of pot-
assium carbonate and 18.4 g (0 083 mol) of dibromoacetic
acid (97,~ strength) are reacted in 120 ml of dimethyl~
formamide in a manner analogous to that described in
Example 27. After working up~ purification by way of
the ethyl ester and hydrolysis entirely analogously to
Example 27~ 5.8 g of 5-chloro-6-(4-bromophenylsulphonyl)-
1~3-benzodioxole-2-carkoxylic acid having a melting point
Of 193-196 (from toluene) are obtained.

i22~87
- 71 _
a) The 4-chloro-5-(4-bromophenylsulphonyl)-1~2-
benzenediol used above is obtained by oxidative coupling
of 4-bromobenzenesulphinic acid with 4-chloro-1,2-
benzenediol in a manner analogous to that described in
Example 3a); m p. 183-187.
Example 34-
.
12 3 g (0 037 mol~ of 5-phenylsulphinyl-6-methyl-
1~3-benzodioxole-2-carboxylic acid ethyl ester are
heated with 20 ml of 2N NaOH for 2 hour at 60-70
The mixture is cooled~ ad~justed to p~I 1-2 with 2~ HCl
and extracted with ethyl acetate. The extract solution
is washed with water~ dried over sodium sulphate~ fil-
tered and concentrated by e~aporation, The crystalline
residue of 10 g is dissolved at elevated temperature
with 300 ml of ethyl acetate and 50 ml of acetone,
activated carbon is added and the whole is filtered.
The filtrate is concentrated to 100 ml in a rotary
evaporator, Beige~oloured crystals of 5-phenylsulphinyl-
6-methyl-1~3-benzodioxole~2-carboxylic acid having a
melting point of from 170 (decomposition) are thereby
precipitated,
The ethyl ester used above is produced in the
following manner:
a) 20,8 g (0.1 mol) of 5-methyl-1~3-benzodioxole-2-
carboxylic acid ethyl ester (Example 2b) and 19,2 g
(0.125 mol) of phenylsulphinic acid chloride are dissolved
in 200 ml of 1,2-dichloroethane and cooled to 5 using
an ice-bath. 13.3 g (0.1 mol) of aluminium chloride
are introduced in the course of approximately 15 min-
utes at from 5-10 while stirring The mixture is
stirred for a further hour in the ice-bath and is then
poured out onto ice-water, The resulting emulsion is
diluted with 200 ml of dichloroethane and filtered
across a layer of a filter aid (for example Hyflo),
The filtrate is introduced into a separating funnel and
the layers are separated, The organic phase is dried

lZ2~374
-- 72 --
over sodium sul~hate, filtered and concentrated to
dryness by evaporation ~ ligrht brown honey-like
product, 5-phenylsulphinyl-6-methyl-1,3-benzodioxole-
2-carboxylic acid ethyl ester, is obtained
250 ml of absolute ethanol and 0.2 ml of con-
centrated HCl are added to 24.4 g (0 G65 mol) of 5-chloro-
6_(4-chlorophenylsulphonyl)-1,3-benzodioxole-2-carbox-
ylic acid (obtained according to Example 25) and the
whole is boiled at reflux for 2 hour 100 ml of ethanol
are distilled off and there crystallises from the remain-
ing solution~ on cooling~ 5-chloro-6-(~-chlorophenyl-
sulphonyl)-1~3-benzodioxole-2-carboxylic acid ethyl
ester in the form of coarse colourless crystals; m.p.
122-123
Example 36:
3.88 g (o,oo6g mol) of 5-chloro-6-(4-chlorophenyl-
sulphonyl)-1~3-benzodioxole-2-carboxylic acid ethyl ester
are dissolved in 20 ml of dimethylformamide and are
added to 0.71 g (0.012 mol) of guanidine at room temp-
erature The mixture i9 stirred for 2 hours at room
temperature~ then poured out onto 200 ml of water ~fter
stirring for ~ hour, a crystalline suspension has formed
This is filtered~ washed with water~ and the crude prod-
uct is dried in a vacuum drying chamber at 30-40 . The
crude product is then digested with 25 ml of ethyl
acetate~ partial dissolution and recrystallisation
occurring. The whole is cooled for ~ hour in an ice-
bath, filtered and dried~ yielding~ in the form of beige
crystals~ 5-chloro-6-(4-chlorophenylsulphonyl)-1,3-
benzodioxole-2-carboxylic acid guanidide having a melt-
ing point of from 215 (decomposition),
Example 37:
4.03 mol of 5-chloro-6-(4-chlorophenylsulphonyl)-

~;~23874
1~3-benzodioxole-2-carbo~lic acid ethyl ester are
dissolved at room temperature in 50 ml of dichloro-
methan0. While stirring vigorously~ 50 ml of a con-
centrated aqueous ammonia solution are added, and
stirring is continued for 18 hours. A thick crystalline
suspension is formed from the initial emulsion. This
suspension is then adjusted by 6N HCl to pH 2-3 at room
temperature~ filtered and subsequently washed ~ith
water ~fter drying~ colourless crystals of 5-chloro-
6-(4-chlorophenylsulphonyl)-1,3-benzodioxole-2-carbox-
ylic acid amide having a melting point of 240-242
are obtained,
Example 38:
34.8 g (0 1 mol) of 5~phenylsulphonyl-6-methyl-
1,3-benzodioxole-2-carboxylic acid ethyl ester (from
Example 2) are dissolved in 350 ml of dioxan (absolute)
and treated in a pressure autoclave with approximately
20 g of ammonia gas. The reaction mixture is heated
for 10 hours at 80 in the autoclave~ ths pressure is
released~ and the solution is concentrated to dryness
by evaporation under reduced pressure. The residue is
recrystallised from 120 ml of ethanol~ yielding colour-
less crystals of 5-phenylsulphonyl-6-methyl-1,3-benzo-
dioxole-2-carboxylic acid amide having a melting point
cf 138-141.
Example 39:
Tablets containing 50 mg of 5-methyl-6-phenyl-
sulphonyl-1~3-benzodioxole-2-carbox~lic acid can be
manufactured~ for example~ in the following composition:

lZ23874
Composition per tablet
5-methyl-6-phenylsulphonyl-1,3-
benzodioxole-2-carboxylic acid 50 mg
lactose 50 mg
wheat starch 73 mg
colloidal silica 13 mg
talc 12 mg
magnesium stearate 2 mg
200 mg
Manufacture
The active ingredient is mixed with lactose~ a
portion of the wheat starch and with colloidal silica
and the mixture is forced through a sieve. A further
portion of the wheat starch is made into a pas'e on a
water bath with 5 times the amount of water~ and the
powder mixture is kneaded with this paste until a
slightly plastic mass i8 formed. The mass is forced
through a sieve having a mesh width of approximately
3 mm~ dried~ and the dry granulate is forced through
a sieve again. The remainder of the wheat starch~ the
talc and the magnesium stearate are then admixed. The
resulting mixture is pressed to form tablets each of
250 mg with(a)breaking notch (es)
Example 40:
To produce 1000 capsules each containing 50 mg
of active ingredient~ 50.0 g of 5-methyl-6-phenylsulph-
onyl-1~3-benzodioxole-2;carboxylic acid are mixed with
223.0 g of lactose~ the mixture is uniformly moistened
with an aqueous solution of 2.0 g of gelatin and gran-
ulated by means of a suitable sieve (for example sieve
III according to Ph Helv V ). The granulate is mixed

3874
with 10,0 g of ~ied corn starch and 15,0 g of talc and
filled uniformly into 1000 hard gelatin capsules~ size 1,
It is possible to use instead of 5-methyl-6-
phenylsulphonyl-1,3-benzodioxole-2-carboxylic acid in
~xamples 39 and 40, a different compound of the general
formula I or a pharmaceutically acceptable salt of a
compound of the general formula I capable of salt form-
ation~ for example one of the compounds described in
Examples 3 to 38,or a pharmaceutically acceptable salt
of such a compound,