Title of Invention

METHOD FOR PRODUCING SULFONAMIDES

Abstract The invention discloses a process for preparing sulfonamides I where the variables R1, R2, R3, R4, R5 and R6 are as defined in the specification; by reacting m-nitrobenzoyl chlorides II where the variables R1, R2, R3 and R4 are as defined in the specification: with amino sulfones III H2N-SO2NR5R6 III, where the variables R5 and R6 are as defined in the specification; under the influence of B equivalents of alkali metal or alkaline earth metal hydroxide as base, wherein, in step a), the amino sulfone III is reacted with B1 equivalents of alkali metal or alkaline earth metal hydroxide, and, in step b), the reaction mixture resulting from step a) is reacted with m-nitrobenzoyl chloride II and B2 equivalents of alkali metal or alkaline earth metal hydroxide; where B, B1 and B2 are as defined in the specification. The invention is also for production of corresponding aniline derivatives by reduction of sulfonamides so provided.
Full Text

Description
The present invention relates to a process for preparing sulfonamides I

where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-
haioalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
R5 and R6 are hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C7-cycloalkyl,
C3-C7-cycloalkenyl, C1-C6-alkoxy, phenyl or benzyl.
In the prior art, for example in WO 01/83459, a process is described for preparing
heterocyclyl-substituted phenylsulfamoylcarboxamides by the reaction of benzoic acid
derivatives with sulfamides in the presence if appropriate of a coupling reagent.
Moreover it is known for example from WO 04/39768 that N-aroylsulfonamides can be
prepared by the reaction of corresponding benzoic acid derivatives with sulfonic
diamides under the influence of base, by initially introducing sulfonic diamides and the
base and then adding the benzoic acid derivative.
It is thus an object of the present invention to provide a simple, economically viable and
implementabie process for preparing sulfonamides I, which firstly distinctly reduces
byproduct formation and simultaneously can achieve high ylelds and high purity of
product of value.
We have found that, surprisingly, this object is achieved by a process in which m-nitrobenzoyl chlorides II are reacted with amino sulfones III under the influence of 1.5 to 3 equivalents of base IV based on the amino sulfone III, which comprises, in
step a), reacting the amino sulfone III with 0.1 -1.3 equivalents of base IV, and, in step
b), reacting the reaction mixture resulting from step a) with m-nitrobenzoyl chlorides II
and the remaining portion of base IV.
Accordingly, the present invention relates to a process for preparing sulfonamides I

I,
where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl,
C1-C6-haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;

R5 and R6 are each hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkynyl,
C3-C7-cycloalkyl, C3-C7-cycloalkenyl, C1-C6-alkoxy, phenyl or
benzyl;
by reacting m-nitrobenzoyl chlorides II

where the variables R1, R2, R3 and R4 are each as defined above:
with amino sulfones III
H2N-SO2NR5R6 III,
where the variables R5 and R6 are each as defined above;
under the influence of B equivalents of base IV, wherein, in step a), the amino
sulfone III is reacted with B1 equivalents of base IV, and, in step b), the reaction
mixture resulting from step a) is reacted with m-nitrobenzoyl chloride !! and B2
equivalents of base IV;
where B is 1.5 - 3 equivalents of base IV with respect to the amino sulfone III;
B1 is a subportion of B and is in the range from 0.1-1.3 equivalents of
base IV with respect to the amino sulfone III; and
B2 is a subportion of B and is the difference between B and B1.
Depending on the substitution pattern, the sulfonamides I prepared by the process
according to the invention may comprise one or more centers of chirality and are then
present in the form of an enantiomeric or diastereomeric mixtures. The invention thus
provides a process for preparing either the pure enantiomers or diastereomers, or their
mixtures.

The organic molecular moieties specified for the substituents R1, to R6 and Ra, Rb and
Rc constitute collective terms for individual lists of the individual group members. All
hydrocarbon chains, i.e. all alkyl, haloalkyl, alkoxy and haloalkoxy moieties, may be
straight-chain or branched.
Unless stated otherwise, halogenated substituents preferably bear from one to five
identical or different halogen atoms. The term halogen in each case represents
fluorine, chlorine, bromine or iodine.
Examples of definitions include:
- C1-C4-alkyl: for example methyl, ethyl, n-propyl, 1-methylethyl, n-butyl,
1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl;
- C1-C6-alkyl: C1-C4-alkyl as specified above, and also, for example, n-pentyl,
1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,
n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,
3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl,
1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-
3-methylpropyl;
- C1-C4-ha!oalkyl: a C1-C4-alkyl radical as specified above which is partly or fully
substituted by fluorine, chlorine, bromine and/or iodine, i.e., for example,
chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-
fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-
trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-
fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-
difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloro-
propyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl,
2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1-(fluoromethyl)-2-fluoroethyl, 1-
(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-
chlorobutyl, 4-bromobutyl and nonafluorobutyl;
- C1-C6-haloalkyl: C1-C4-haloalkyl as specified above, and also, for example, 5-
fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, 6-
fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl and tridecafluorohexyl;
- C2-C6-alkenyl: for example ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-
butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-
2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-
methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-

methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-
tnethyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-
propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,
4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-
pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-
2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-
methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,
3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-
butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,
1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-
dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-
butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1 -butenyl, 1-ethyl-
2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1 -butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,
1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-
propenyl and 1-ethyl-2-methyl-2-propenyl;
C2-C6-alkynyl: for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-
butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-
methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-
dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-
hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,
2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-
pentynyl. 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-
dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-
butynyl, 1-ethyl-2-butynyl, 1 -ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-
2-propynyl;
C3-C6-cycloalkyl: for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl;
C3-C7-cycloalkenyl: for example 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl,
2-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 1,3-cyclopentadienyl,
1,4-cyclopentadienyl, 2,4-cyclopentadienyl, 1-cyclohexenyl, 2-cyclohexenyl,
3-cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 2,5-cyclohexadienyl;
1-cycloheptenyl, 3-cycloheptenyl, 4-cycloheptenyl, 3,5-cycloheptadienyl,
2,4-cycloheptadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl,
2,4,6-cycloheptatrienyl;
C1-C4-alkoxy: for example methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy,
1-methylpropoxy, 2-methylpropoxy and 1,1-dimethylethoxy;
C1-C6-alkoxy: C1-C4-alkoxy as specified above, and also, for example, pentoxy, 1-

methylbutoxy, 2-methylbutoxy, 3-methoxylbutoxy, 1,1-dimethylpropoxy, 1,2-di-
methylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-
methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,1,2-di-
methylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-
dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-tri-
methylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy;
- C1-C4-haloalkoxy: a C1-C4-alkoxy radical as specified above which is partly or fully
substituted by fluorine, chlorine, bromine and/or iodine, i.e., for example,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy,
bromodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromomethoxy, 2-
iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-
chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy,
pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2-chloropropoxy, 3-
chloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 2,2-difluoropropoxy, 2,3-
difluoropropoxy, 2,3-dichloropropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy,
2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 1-(fluoromethyl)-2-fluoroethoxy,
1-(chloromethyl)-2-chloroethoxy, 1-(bromomethyl)-2-bromoethoxy, 4-fluorobutoxy,
4-chlorobutoxy, 4-bromobutoxy and nonafluorobutoxy;
- C1-C6-haloalkoxy: C1-C4-haloalkoxy as specified above, and also, for example, 5-
fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy,
undecafluoropentoxy, 6-fluorohexoxy, 6-chlorohexoxy, 6-bromohexoxy, 6-
iodohexoxy and tridecafluorohexoxy.
In particularly preferred embodiments of the process according to the invention, the
variables R1, R2, R3, R4, R5 and R6 are each defined as follows, these definitions, alone
and also in combination with one another, constituting particular embodiments of the
process according to the invention:
Preference is given to the embodiment of the process according to the invention in
which
R1, is hydrogen, halogen or C1-C6-alkyl;
preferably hydrogen or halogen;
very preferably hydrogen, fluorine or chlorine;
more preferably hydrogen.
Equally preferred is the embodiment of the process according to the invention in which
R2 is hydrogen, halogen, cyano, C1-C6-alkyl or C1-C6-haloalkyl;
preferably hydrogen or halogen;
very preferably hydrogen, fluorine or chlorine;
more preferably hydrogen or fluorine;

exceptionally preferably hydrogen;
equally exceptionally preferably fluorine.
Equally preferred is the embodiment of the process according to the invention in which
R2 is hydrogen or halogen;
preferably halogen;
very preferably fluorine or chlorine;
more preferably fluorine.
Equally preferred is the embodiment of the process according to the invention in which
R3 is hydrogen, halogen or C1-C6-alkyl;
preferably hydrogen or halogen;
very preferably hydrogen, fluorine or chlorine;
more preferably hydrogen.
Equally preferred is the embodiment of the process according to the invention in which
R4 is hydrogen, halogen, cyano, C1-C6-alkyl or C1-C6-haloalkyl;
preferably hydrogen, halogen or cyano;
very preferably hydrogen, fluorine, chlorine or cyano;
more preferably hydrogen, chlorine or cyano;
exceptionally preferably hydrogen;
equally exceptionally preferably chlorine or cyano;
very exceptionally preferably chlorine.
Equally preferred is the embodiment of the process according to the invention in which
R4 is halogen or cyano;
preferably halogen;
very preferably fluorine or chlorine;
more preferably chlorine.
Equally preferred is the embodiment of the process according to the invention in which
R4 is hydrogen, halogen or cyano;
preferably hydrogen or halogen;
very preferably hydrogen, fluorine or chlorine;
more preferably hydrogen or chlorine.
Equally preferred is the embodiment of the process according to the invention in which
R5 and R6 independently
are each hydrogen, C1-C6-alkyl or C2-C6-alkenyl;
preferably hydrogen or C1-C6-alkyl;
very preferably C1-C6-alkyl;
more preferably C1-C4-alkyl.

Equally preferred is the embodiment of the process according to the invention in which
R5 is hydrogen or C1-C6-alkyl;
preferably hydrogen or C1-C4-alkyl;
very preferably C1-C4-alkyl;
more preferably methyl.
Equally preferred is the embodiment of the process according to the invention in which
R6 is hydrogen or C1-C6-alkyl;
preferably hydrogen or C1-C4-alkyl;
very preferably C1-C4-alkyl.
In a very preferred embodiment of the process according to the invention, the variables
R1, R2, R3 and R4are each as defined above, in particular the meanings indicated as
preferred, where at least one of the radicals R1, to R4is fluorine.
In a further very preferred embodiment of the process according to the invention, the
variables R1, R2, R3 and R4 are each defined as follows:
R1, is hydrogen;
R2 is hydrogen or halogen;
preferably halogen;
very preferably fluorine;
R3 is hydrogen; and
R4 is hydrogen,.chlorine or cyano;
preferably chlorine or cyano;
very preferably chlorine.
in a further very preferred embodiment of the process according to the invention, the
variables R1, R2, R3 and R4 are each defined as follows:
R1, is hydrogen;
R2 is hydrogen or halogen;
preferably halogen;
very preferably fluorine;
R3 is hydrogen; and
R4 is hydrogen or halogen;
preferably hydrogen or chlorine;
very preferably chlorine;
equally very preferably hydrogen.
In a further very preferred embodiment of the process according to the invention, the
variables R1, R2, R3 and R4 are each defined as follows:
R1, is hydrogen;

R2 is fluorine;
R3 is hydrogen; and
R4 is halogen;
preferably chlorine.
In a further very preferred embodiment of the process according to the invention, the
variables R1, R2, R3, R4 and R5 are each defined as follows:
R1, is hydrogen;
R2 is hydrogen or halogen;
preferably halogen;
very preferably fluorine;
R3 is hydrogen; and
R4 is hydrogen or halogen;
preferably hydrogen or chlorine;
very preferably chlorine;
equally very preferably hydrogen;
R5 and R6 are each hydrogen, C1-C6-alkyl or C2-C6-alkenyl;
preferably hydrogen or C1-C6-alkyl;
very preferably C1-C6-alkyl;
more preferably C1-C4-alkyl.
In a preferred embodiment of the process according to the invention, it is possible in
this way to prepare sulfonamides IA

where the variables are each as defined below:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl,
C1-C6-haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy; and
where at least one of the radicals R1, to R4 is fluorine, and
R5 and R6 are each hydrogen,C1-C6-alkyl,C3-C6-alknyl,C3-C6-alkynyl,C3-C7-
cycloalkyl, C3-C7-cycloalkenyl, C1-C6-alkoxy, phenyl or benzyl.
In a further preferred embodiment of the process according to the invention, it is
possible in this way to prepare sulfonamides I.a


where the variables R2, R3, R4, R5 and R6 are each as defined above, especially as
defined above with preference.
In a further preferred embodiment of the process according to the invention, it is
possible in this way to prepare sulfonamides l.b

where the variables R1, R3, R4, R5 and R6 are each as defined above, especially as
defined above with preference.
In a further preferred embodiment of the process according to the invention, it is
possible in this way to prepare sulfonamides l.c

where the variables R1, R2, R4, R5 and R6 are each as defined above, especially as
defined above with preference.
In a further preferred embodiment of the process according to the invention, it is
possible in this way to prepare sulfonamides l.d

where the variables R1, R2, R3, R5 and R6 are each as defined above, especially as
defined above with preference.
In a further preferred embodiment of the process according to the invention, it is
possible in this way to prepare sulfonamides l.e


where the variables R2, R4,R5 and R6 are each as defined above, especially as defined
above with preference, and where at least one of the R2 and R4 radicals is fluorine.
Outlined below are the preferred embodiments of the process according to the
invention, which, both considered on their own and considered in combination with one
another, constitute special embodiments of the process according to the invention.
The m-nitrobenzoyl chlorides II and with amino sulfones III can be reacted in equimolar
amounts with one another.
The molar amounts in which m-nitrobenzoyl chlorides II, preferably fluorinated
m-nitrobenzoyl chlorides IIA, and amino sulfones III are reacted with one another are
advantageously 1 : 0.9-1.8; preferably 1 : 0.9-1.5; very preferably 1 : 0.9-1.2; with
particular preference 1 : 0.95-1.2; with extraordinary preference 1 : 0.95-1.1 for the
ratio of II, preferably IIA, to III.
The reaction according to the invention of the m-nitrobenzoyl chlorides II with amino
sulfones III to give sulfonamides I proceeds typically at temperatures of from -30°C to
120oC, preferably from -10°C to 100°C, especially preferably from 0°C to 80°C, in an
inert organic solvent under the influence of 1.5-3 equivalents of a base IV with respect
to the amino sulfone III and, if appropriate, in the presence of a catalyst:
Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, heptane,
cyclohexane and mixtures of C5-C8-alkanes, aromatic hydrocarbons such as toluene,
o-, m- and p-xylene, haiogenated hydrocarbons such as methylene chloride,
chloroform, dichloroethane and chlorobenzene, ethers such as diethyl ether,
diisopropyl ether, tert-butyl methyl ether, dioxane, anisol and tetrahydrofuran, esters
such as ethyl acetate, propyl acetate, n-butyl acetate, methyl isobutyrate, isobutyl
acetate; and also dimethyl sulfoxide, dimethylformamide and dimethylacetamide; more
preferably aromatic hydrocarbons and haiogenated hydrocarbons.
It is also possible to use mixtures of the solvents mentioned, or mixtures of the solvents
mentioned with water.
The inventive reaction of the m-nitrobenzoyl chlorides II with amino sulfones III to
sulfonamides I takes place in the presence of a total of 1.5-3 equivalents of base IV
with respect to the amino sulfone III. These 1.5-3 equivalents of base IV represent the
total amount of base, "B", which is used in the process according to the invention.

In step a) of the process according to the invention the amino sulfone III is reacted with
0.1-1.3 equivalents of base with respect to the amino sulfone III. These
0.1-1.3 equivalents of base IV are a subportion of the aforementioned total amount of
base, B and are also referred to as amount of base "B1".
In step b) of the process according to the invention the reaction mixture resulting from
step a) is reacted with m-nitrobenzoyl chloride II and with the remaining amount of the
total amount of base, B, minus B1. The remaining amount of the total amount of base B
is also referred to as amount of base "B2".
Accordingly the relation between B, B1 and B2 is as follows: B1 + B2 = B.
Useful bases IV generally include inorganic compounds such as alkali metal and
alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide,
potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal
oxides such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali
metal and alkaline earth metal hydrides such as lithium hydride, sodium hydride,
potassium hydride and calcium hydride, alkali metal amides such as lithium amide,
sodium amide and potassium amide, alkali metal and alkaline earth metal carbonates
such as lithium carbonate, potassium carbonate and calcium carbonate, and alkali
metal hydrogencarbonates such as sodium hydrogencarbonate, alkali metal and
alkaline earth metal alkoxides such as sodium methoxide, sodium epoxide, potassium
ethoxide, potassium tert-butoxide, potassium tert-pentoxide and dimethoxymagnesium,
and also organic bases, for example tertiary amines such as trimethylamine,
triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted
pyridines such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic
amines, for example 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-
diazabicyc!o[4.3.0]non.-5-ene (DBN).
Particular preference is given to alkali metal and alkaline earth metal oxides and
tertiary amines.
Particular preference given to alkali metal and alkaline earth metal hydroxides,
extraordinary preference to alkali metal hydroxides.
1.5-3 equivalents of base IV (total amount of base B) are used, based on the amino
sulfone III.
Very preferably B is 1.8-2.5 equivalents based on the amino sulfone III.
Great preference is also given to 1.8-2.5 equivalents, based on the m-nitrobenzoyl
chlorides II, with particular preference on the fluorinated m-nitrobenzoyl chlorides HA


where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl,
C1-C6-haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
and at least one of the radicals R1, to R4 is fluorine.
In step a) of the process according to the invention the amino sulfone III is preferably
introduced initially in an inert solvent. Subsequently B1 equivalents of the base IV, i.e.,
0.1-1.3 equivalents, preferably 0.1-1 equivalent, very preferably 0.2-0.95 equivalent of
base IV are added. With particular advantage the base IV is added over a certain
period of time. Very preferably the B1 equivalents of the base IV are added
continuously, with very particular preference uniformly and continuously over a certain
period of time.
This time period of the addition of the B1 equivalents of base IV in step a) can be from
1 minute up to 20 hours. More generally this time period is 1 minute to 6 hours,
preferably 1 minute to 3 hours.
Alternatively, preferably in accordance with the variants described above, the amino
sulfone III can be added to the desired amount of base I, more particularly to the
amount of base B1 specified as being preferred.
In step b) of the process according to the invention, preferably, the m-nitrobenzoyl
chloride II, preferably the fluorinated m-nitrobenzoyl chioride iiA, preferably in dilution in
an inert solvent, and also the B2 equivalents of base IV are added to the reaction
mixture resulting from step a), preferably likewise in dilution in an inert solvent.
In step b), preferably, the addition of the m-nitrobenzoyl chloride II and also of the B2
equivalents of base IV take place simultaneously (i.e. parallel addition), very preferably
simultaneously over a certain period of time, with particular preference simultaneously
and continuously over a certain period of time, with very particular preference
simultaneously and uniformly and continuously over a certain period of time, to the
reaction mixture resulting from step a).
This time period for the addition of the m-nitrobenzoyl chloride II and also of the B2
equivalents of base IV in step b) can be from 1 minute up to 20 hours. More generally
this time period is 1 minute to 6 hours, preferably 1 minute to 3 hours.
Alternatively, preferably in accordance with the variants described above, the reaction
mixture resulting from step a) and also the amount of base B2 can be added
simultaneously, preferably offset over a certain period of time, to the m-nitrobenzoyl

chloride II, preferably in dilution in an inert solvent.
Furthermore, the m-nitrobenzoyl chloride II, preferably the fluorinated m-nitrobenzoyl
chloride IIA, can also be reacted in bulk, i.e., e.g., in the form of its melt, with the amino
sulfone III, in which case III is preferably dissolved in an inert solvent, the reaction
taking place under the influence of a base, preferably as described above.
In a further variant of the process according to the invention the reaction can also be
carried out in an aqueous multiphase system. This variant is preferred.
In another variant of the process according to the invention, the reaction can also be
carried out in an aqueous multiphase system with and without phase transfer catalyst
(PTC).
Preference is given to effecting the reaction in an aqueous multiphase system in the
presence of phase transfer catalysts.
Preference is given to effecting the reaction in an aqueous multiphase system in the
presence of phase transfer catalysts such as quaternary ammonium salts,
phosphonium salts, polyglycols and crown ethers.
Suitable quaternary ammonium salts comprise
tetra(C1-Ci8)alkylammonium fluorides, chlorides, bromides, iodides, hydrogensulfates,
hydroxides, perchlorates, borates, diborates or tetrafluoroborates, such as tetramethyl
ammonium fluoride tetrahydrate, tetramethylammonium chloride,
tetramethylammonium bromide, tetramethylammonium iodide, tetramethylammonium
hydroxide, methyltributylammonium chloride (e.g. ALIQUAT® 175),
methyltrioctylammonium chloride, methyltricaprylylammonium chloride (e.g. ALIQUAT®
336, ALIQUAT® HTA1), tetraethylammonium chloride, tetraethylammonium chloride
hydrate, tetraethylammonium bromide, tetraethylammonium hydroxide,
tetrabutylammonium fluoride, tetrabutylammonium fluoride trihydrate,
tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium
iodide, tetrabutylammonium hydrogensulfate, tetrabutylammonium hydroxide,
tetrabutylammonium perchlorate, tetrabutylammonium tetrafluoroborate,
tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium
hydroxide, tetrahexylammonium bromide, tetrahexylammonium iodide,
tetraoctylammonium bromide, cetyltrimethylammonium bromide,
dodecyltrimethylammonium bromide, dodecyltrimethylammonium chloride, C12-C14-
alkylthmethylammonium borate, C12-C14-alkyltrimethylammonium diborate;
N-phenyl(C1-C18)trialkylammonium fluorides, chlorides or bromides, such as
phenyltrimethylammonium chloride; N-benzyl(C1-C18)trialkylammonium fluorides,
chlorides or bromides, such as benzyltrimethylammonium chloride,

benzyltriethylammonium chloride, benzyltriethylammonium bromide,
benzyltributylammonium bromide;
pyridinium fluorides, chlorides or bromides, such as 1-C6tylpyridiniurn chloride
monohydrate, cetylpyridinium bromide.
Suitable phosphonium salts are, for example, tetraphenylphosphonium chloride or
bromide, benzyltriphenylphosphonium chloride, benzyltriphenylphosphonium bromide;
alkylphenylphosphonium chlorides, bromides, iodides, acetates, such as
methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide,
ethyltriphenylphosphonium iodide, ethyltriphenylphosphonium acetate,
butyltriphenylphosphonium chloride, butyltriphenylphosphonium bromide;
tetraalkyl(C1-C18)phosphonium chloride or bromide, such as tetrabutylphosphonium
bromide.
Suitable polyglycols and crown ethers are, for example, diethylene glycol dibutyl ether
("butyl diglyme"), 18-crown-6 and dibenzo-18-crown-6.
Preference is given to using tetra(C1-C18)alkylammonium hydrogensulfates and
tetra(C1-C18)alkylammonium chlorides, very preferably tetra(C1-C6)aikylammonium
hydrogensulfates and tetra(C1-C6)alkylammonium chlorides.
Very particular preference is given to using tetra(C1-C18)alkylammonium chlorides,
extraordinary preference to using tetra(C1-C6)alkylammonium chlorides.
Preference is likewise given to tetrabutylammonium fluoride, tetrabutylammonium
hydrogensulfate, methyltributylammonium chloride, tetrapropylammonium chloride,
tetrapropylammonium bromide, benzyltriphenylphosphonium chloride,
benzyltriphenylphosphonium bromide ordibenzo-18-crown-6.
In general, the phase transfer catalyst is used in an amount of up to 20 mol%,
preferably between 0.5 and 5 mol% and in particular between 0.3 and 2 mol%, based
on the m-nitrobenzoyl chlorides II, preferably the fluorinated m-nitrobenzoyl
chlorides If A.
Very particular preference is given to using 0.01-20 mol%, more preferably
0.05-5 mol%, most preferably 0.1-2 mol% of the phase transfer catalyst based on the
m-nitrobenzoyl chlorides II, preferably the fluorinated m-nitrobenzoyl chlorides MA.
The multiphase system comprises an aqueous phase and at least one organic liquid
phase. In addition, solid phases may also occur in the course of the reaction.
The aqueous phase is preferably a solution of alkali metal or alkaline earth metal
hydroxides or carbonates in water. With regard to suitable alkali metal or alkaline earth

metal hydroxides or carbonates, reference is made to the above statements. Particular
preference is given to using alkali metal or alkaline earth metal hydroxides, especially
sodium hydroxide or potassium hydroxide.
Useful substances for the organic phase are preferably aliphatic, cycloaliphatic or
aromatic, optionally halogenated hydrocarbons, cyclic or open-chain ethers or mixtures
thereof, reference being made to the above statements with regard to the aliphatic,
cycloaliphatic or aromatic, optionally halogenated hydrocarbons, cyclic or open-chain
ethers.
If the organic phase used is a water-miscible solvent, the reaction can also be carried
out without a phase transfer catalyst.
In a preferred embodiment of the process according to the invention, the multiphase
system consists of aqueous sodium hydroxide or potassium hydroxide solution as the
aqueous phase and of toluene, chlorobenzene, dioxane, dichloroethane,
dichloromethane, tetrahydrofuran or methyltetrahydrofuran, or of mixtures of these
organic solvents as the organic phase.
In one particularly preferred embodiment of the process according to the invention the
multiphase system is composed of aqueous sodium or potassium hydroxide solution as
the aqueous phase and of unhalogenated or halogenated aromatic hydrocarbons such
as toluene, xylene or chlorobenzene, for example, extraordinarily preferably of
halogenated aromatic hydrocarbons such as chlorobenzene, for example, or of
mixtures of these organic solvents, as the organic phase.
When a multiphase system is used, it is possible, for example, to initially charge
m-nitrobenzoyl chloride II, preferably the fluorinated m-nitrobenzoyl chloride IIA, and
the phase transfer catalyst without additional solvent or in one of the aforementioned
organic solvents or solvent mixtures.
Thereafter, the aqueous solution of the base amount B2 and the reaction mixture
resulting from step a) are added either successively or simultaneously with mixing and
then the reaction is brought to completion within the desired temperature range.
When a multiphase system is used in step a) of the process according to the invention,
the amino sulfone III is preferably introduced in an inert solvent. Subsequently
B1 equivalents of base IV, i.e., 0.1-1.3 equivalents, preferably 0.1-1 equivalent, very
preferably 0.2-0.7 equivalent, of base IV are added, advantageously offset over a
certain period of time.
Subsequently, when using a multiphase system in step b), the phase transfer catalyst
will preferably first be added to the reaction mixture resulting from step a).

Subsequently the m-nitrobenzoyl chloride II and also the amount of base B2 will be
added. It is particularly preferred to add the m-nitrobenzoyl chloride II and also the
amount of base B2 in parallel, very preferably in parallel and offset over a certain
period of time, to the reaction mixture resulting from step a).
Alternatively, when using a multiphase system in step b) of the process according to
the invention, it is possible first to add the m-nitrobenzoyl chloride II and also the
amount of base B2 to the reaction mixture resulting from step a), and then to add the
phase transfer catalyst.
The reaction can be carried out at standard pressure, reduced pressure or under
elevated pressure, if appropriate under inert gas, continuously or batchwise.
The end of the reaction can easily be determined by the skilled worker by means of
routine methods.
The reaction mixture can be worked up by the methods customary for the purpose. In
general the solvent used is removed by customary methods, distillatively for example.
The crude product can then be taken up in a non-water-miscible organic solvent, any
impurities extracted with unacidified or acidified water, and the system can then be
dried and the solvent removed under reduced pressure. For further purification it is
possible to employ the typical methods such as crystallization, precipitation (for
example by addition of an apolar solvent such as pentane, cyclohexane, heptane or
toluene, or mixtures of said solvents) or chromatography.
When using a two-phase system it is usual to carry out extractive workup.
The end product can also be recovered by precipitation (e.g. by addition of an apolar
solvent such as pentane, cyclohexane, heptane or toluene, or mixtures of the stated
solvents).
in one preferred variant of the reaction in the process according to the invention, after
the ending of the reaction, in a step c) the reaction mixture is diluted by addition of
water and/or aqueous mineral acids, the pH of the aqueous phase being adjusted to
pH With particular preference the pH of the aqueous phase is adjusted to pH = 2-6.5, with
more particular preference to pH = 3-5.0.
Aqueous mineral acids suitable for this purpose are aqueous mineral acids known to
the skilled worker, such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric
acid, for example.
The reaction mixture can then be worked up by the methods customary therefor. In
general, the phases are separated and the solvent used will be removed by customary
processes, for example by distillation. For further purification, the customary processes
such as for example crystallization (for example also by addition of a nonpolar solvent

such as pentane, cyclohexane, heptane or toluene, or mixtures of the solvents
mentioned) can be employed.
When a biphasic system is used, workup will generally be effected by extraction.
In a further preferred variant of the reaction in the process according to the invention,
the dilute reaction mixture resulting from step c) is heated in a step d) and the phase
separation is carried out at this temperature. This version of the process according to
the invention is preferred primarily in those cases where step c) does not produce a
clear solution.
Preferably the dilute reaction mixture obtained in step c) is heated to a temperature a
short way beneath the boiling point and the phase separation is carried out at that
temperature. Subsequently the product of value can be recovered by typical methods,
such as removal of the solvent and, if appropriate, subsequent crystallization, for
example.
Furthermore, the organic phase resulting from step d) can be subjected if necessary
again to a step c) and, if appropriate, step d), it being possible for the repetition of
steps c) and d) to take place as often as desired, preferably once.
The amino sulfones III required for the preparation of the sulfonamides I are known in
the literature (Houben-Weyl, Methoden der organischen Chemie [Methods of organic
chemistry] Vol. E11, 1985, p. 1019; Hamprecht etal., Angew. Chem. 93, 151, 1981) or
can be prepared in accordance with the literature cited.
The m-nitrobenzoyl chlorides II required for the preparation of the sulfonamides I are
known from the literature and can be prepared, for example, by reacting m-nitrobenzoic
acids VII

where the variables are each defined as follows:
R1, R2, R3, R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl,
C1-C6-haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
with chlorinating agents.
The present invention accordingly further provides a process for preparing
sulfonamides I wherein the m-nitrobenzoyl chlorides II required for the purpose are
prepared from m-nitrobenzoic acids VII and chlorinating agents.

In particularly preferred embodiments of the process according to the invention the
variables R1, R2, R3 and R4 of the m-nitrobenzoyl chlorides II have the definitions stated
above in connection with the sulfonamides I, more particularly the definitions stated
there as being preferred, and, both considered alone and considered in combination
with one another, they represent particular embodiments of the process according to
the invention.
The preferred embodiments of the reaction of m-nitrobenzoic acids VII with chlorinating
agents are subject to the conditions stated below in connection with the reaction of
fluorinated m-nitrobenzoic acids VIIA with chlorinating agents in the presence of
catalytic amounts of a phosphine derivative IX, more particularly the embodiments
specified there as being preferred.
The prior art (for example WO 89/02891, WO 04/106324, WO 04/035545 and
US 6,251,829) describes in particular processes for preparing fluorinated benzoyl
chlorides from fluorinated benzoic acids. However, the problem of eliminating the
fluorine substituent occurs in the processes described in the prior art, in particular when
catalysts such as N,N-dimethylaminopyridine (DMAP) or nitrogen bases such as
pyridine, picoline or lutidine are used.
The fluoride released in turn has a damaging effect on the apparatus technology
("fluoride corrosion") and therefore entails correspondingly costly apparatus made of
higher-value materials. Moreover, the elimination of the fluoride leads to
contaminations or secondary components in the product of value.
However, when the process is carried out without catalyst, the ylelds are distinctly
lower or higher reaction temperatures are required.
It is thus a further object of the present invention to provide a simple, economically
viable and implementable process for preparing fluorinated m-nitrobenzoyl chlorides
IIA, which firstly distinctly reduces fluoride elimination and simultaneously can achieve
high ylelds and high purity of product of value.
We have found that, surprisingly, this object is achieved by a process in which
fluorinated m-nitrobenzoic acids VII are reacted with chlorinating agents, which
comprises effecting the reaction in the presence of catalytic amounts of a phosphine
derivative IX and, if appropriate, in the presence of a Lewis acid.
Accordingly, the present invention further relates to a process for preparing fluorinated
m-nitrobenzoyl chlorides IIA


where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl, C1-
C6-haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
where at least one of the R1, to R4 radicals is fluorine,
by reacting fluorinated m-nitrobenzoic acids VIIA

where the variables are each defined as follows:
R1, R2, R3, R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-
haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
where at least one of the R1, to R4 radicals is fluorine,
with chlorinating agents,
which comprises effecting the reaction in the presence of catalytic amounts of a
phosphine derivative IX

where the variables are each defined as follows:
Ra, Rb, Rc are each C1-C6-alkyl or phenyl, which may optionally be substituted
by C1-C4-alkyl;
X is oxygen or two single-bonded chlorine atoms;
n is 0 or 1.
The invention further relates to a process for preparing fluorinated sulfonamides IA (i.e.
sulfonamides I where at least one of the radicals R1, to R4 is fluorine) wherein the
fluorinated m-nitrobenzoyl chlorides IIA required for the purpose are prepared by the

process stated above from fluorinated m-nitrobenzoic acids VII.
Specified below are the preferred embodiments of the reaction of fluorinated
m-nitrobenzoic acids VIIA with chlorinating agents in the presence of catalytic
amounts of a phosphine derivative IX, with these embodiments, both considered alone
and considered in combination with one another, representing special embodiments of
the process according to the invention.
This process according to the invention for preparing fluorinated m-nitrobenzoyl
chlorides IIA comprises the reaction of fluorinated m-nitrobenzoic acids VIIA with
chlorinating agents in the presence of catalytic amounts of a phosphine
derivative IX:

where the variables are each as defined above in conjunction with the
preparation of fluorinated m-nitrobenzoyl chlorides IIA.
This reaction is effected typically at temperatures of from 20°C to 160°C, preferably
from 20°C to 120°C, especially preferably from 70°C to 120°C, in an inert organic
solvent.
The reaction pressure during the process according to the invention may, for example,
be in the range from 500 mbar to 10 bar. Preference is given to carrylng out the
reaction in the region of standard pressure, i.e: in the range from 0.9 to 1.2 bar.
The reaction time required for the reaction is generally in the range from 1 h to 24 h, in
particular in the range from 2 h to 8 h.
The process according to the invention can in principle be carried out in substance.
However, preference is given to carrylng out the process according to the invention in
an inert organic solvent.
In principle, all solvents which are capable of dissolving the fluorinated m-nitrobenzoic
acids VIIA, the chlorinating agent and the phosphine derivative III at least partly and
preferably fully under the reaction conditions are suitable.
Suitable solvents are, for example, aliphatic hydrocarbons such as pentane, hexane,

cyclohexane and mixtures of C5-C6 alkanes, aromatic hydrocarbons such as toluene, o-
, m- and p-xylene, halogenated hydrocarbons such as methylene chloride, chloroform
and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl
ether, dioxane, anisol and tetrahydrofuran, more preferably aromatic hydrocarbons or
halogenated hydrocarbons.
It is also possible to use mixtures of the solvents mentioned.
The chlorinating agents used are customary chlorinating agents such as oxalyl
chloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosphoryl
chloride (POCb). It is also possible to use gaseous or liquid phosgene, corresponding
dimers (trichloromethyl chloroformate, "diphosgene") or corresponding trimers
bis(trichloromethyl) carbonate, "triphosgene") (cf. R. Beckert et a!., Organikum, 22nd
edition 2004, p. 496-499).
Preferred chlorinating agents are oxalyl chloride, phosphorus trichloride,
phosphorus pentachloride, thionyl chloride and phosphoryl chloride (POCI3); thionyl
chloride is very preferred.
The fluorinated m-nitrobenzoic acids VIIA and the chlorinating agent are generally
reacted with one another in equimolar amounts. It may be advantageous to use the
chlorinating agent in an excess based on the m-nitrobenzbic acids VIIA. Preference
is given to using the chlorinating agent and the fluorinated m-nitrobenzoic acids
VIIA in a ratio of 2:1, more preferably 1.5:1.
The catalysts used are phosphine derivatives IX

where the variables are each defined as follows:
Ra, Rb, Rc are each C1-C6-aIkyl or phenyl, which may optionally be
substituted by C1-C4-alkyl;
X is oxygen or two'single-bonded chlorine atoms;
n is 0 or 1.
Preference is given to using triphenylphosphine, triphenylphosphine oxide (TPPO),
triphenyldichlorophosphine, tri(C1-C6-a[kyl)phosphine, tri(C1-C6-alkyl)phosphine oxide
and tri(C1-C6-alkyl)dichlorophosphine;
more preferably triphenylphosphine, triphenylphosphine oxide and tri(C1-C6-
aIkyl)phosphine oxide;
exceptionally preferably triphenylphosphine oxide.

The phosphine derivative IX is used generally in amounts of from 0.01 to 5 mol%,
preferably from 0.1 to 1 mol%, more preferably from 0.1 to 0.5 mol%, based on the
amount of fluorinated m-nitrobenzoic acid VII used.
Moreover, the process according to the invention may additionally be carried out in the
presence of Lewis acids. The Lewis acids used are customary Lewis acids (cf., for
example, Lewis Acids in Organic Synthesis, ed. H. Yamamoto, Vol. 1 and 2, Weinheim
2000).
Suitable Lewis acids are in particular boron compounds such as
boron halides (e.g. BF3, BCI3, BF3 etherate), boric acid (H3BO3), boric anhydride, boric
esters (e.g. tri-C1-C4-aIkyl borate), borate (e.g. sodium borate/borax),
boronic acids (e.g. C1-C6-alkylboronic acids, arylboronic acids, especially
phenylboronic acid), C1-C4-alkyl boronates (e.g. C1-C6-alkyl C1-C4-alkyl boronates,
C1-C4-alkyl aryl boronates), cyclic boric esters (e.g. tris(C1-C4-alkoxy)boroxin, especially
trimethoxyboroxin, and triethanolamine borate).
Particular preference is given to boric acid, tri-C1-C4-alkyl borates or cyclic boric esters.
The Lewis acid is used generally in amounts of from 0.01 to 5 mol%, preferably from
0.1 to 1 mol%, based on the amount of m-nitrobenzoic acid II used.
The process can be carried out either continuously or discontinuously (batchwise or
semibatchwise).
In the process according to the invention, the reactants and reagents can in principle
be combined in any sequence, i.e. the reactants and the phosphine derivative IX and, if
appropriate, the Lewis acid may be introduced separately, simultaneously or
successively into the reaction vessel and reacted.
Advantageously, the fluorinated m-nitrobenzoic acid VIIA and the phosphine
derivative IX and, if appropriate, the Lewis acid are initially charged in an inert solvent
and the chlorinating agent is added with mixing, for example stirring.
However, it is also possible to initially charge the chlorinating agent together with
the phosphine derivative IX and, if appropriate, the Lewis acid, and then to add the
fluorinated m-nitrobenzoic acid VIIA, preferably dissolved in an inert solvent.
The reaction mixtures may be worked up in a customary manner, for example by
distilling off the solvent and removing the excess chlorinating reagent.
Some of the end products are obtained in the form of viscous oils which can be freed of
volatile fractions or purified under reduced pressure and at moderately elevated
temperature. When the intermediates and end products are obtained as solids, the
purification can also be effected by recrystallization or digestion.

Preference is given to not effecting any further purification after the reaction has ended.
The fluorinated m-nitrobenzoic acids IIA required for the preparation of the fluorinated
m-nitrobenzoyl chlorides VIIA are known in the literature or can be prepared by
nitrating the corresponding benzoic acids or by nitrating the corresponding methyl
benzoates and subsequently hydrolyzing (for example, R. Beckert et al., Organikum,
22nd edition 2004, p. 358-361).
The fluorinated m-nitrobenzoyl chlorides IIA obtainable by the process according to the
invention may be used as starting materials for the preparation of sulfonamides IA
which are themselves valuable intermediates for the synthesis of pharmacologically
active compounds or crop protection compositions.
The present invention therefore further provides a process for preparing sulfonamides
IA starting from fluorinated m-nitrobenzoyl chlorides IA.
Depending on the substitution pattern, the fluorinated m-nitrobenzoyl chlorides IIA may
comprise one or more centers of chirality and are then present in the form of an
enantiomeric or diastereomeric mixtures. The invention thus provides a process for
preparing either the pure enantiomers or diastereomers, or their mixtures.
The organic molecular moieties specified for the substituents R1, to R6 and Ra, Rb and
Rc constitute, according to the meanings indicated above, collective terms for individual
lists of the individual group members. All hydrocarbon chains, i.e. all alkyl, haloalkyl,
aikoxy and haloaikoxy moieties, may be straight-chain or branched.
Unless stated otherwise, halogenated substituents preferably bear from one to five
identical or different halogen atoms. The term halogen in each case represents
fluorine, chlorine, bromine or iodine.
!n conjunction with the fluorinated m-nitrobenzoyl chlorides IIA, the variables R1, R2, R3
and R4 are each as defined above, in particular the meanings indicated as being
preferred, where at least one of the R1, to R4 radicals in the combination of all four R1, to
R4 radicals is fluorine, these abovementioned definitions, alone and also in combination
with one another, constituting particular embodiments of the process according to the
invention.
Preference is given to the embodiment of the process according to the invention in
which
R1, is hydrogen, halogen or C1-C6-alkyl;
preferably hydrogen or halogen;
very preferably hydrogen, fluorine or chlorine;
more preferably hydrogen.

Equally preferred is the embodiment of the process according to the invention in which
R2 is hydrogen, halogen, cyano, C1-C6-alkyl or C1-C6-haloalkyl;
preferably hydrogen or halogen;
very preferably hydrogen, fluorine or chlorine;
more preferably hydrogen or fluorine;
exceptionally preferably hydrogen;
equally exceptionally preferably fluorine.
Also preferred is the embodiment of the process according to the invention in which
R2 is hydrogen or halogen;
preferably halogen;
very preferably fluorine or chlorine;
more preferably fluorine.
Equally preferred is the embodiment of the process according to the invention in which
R3 is hydrogen, halogen or C1-C6-alkyl;
preferably hydrogen or halogen;
very preferably hydrogen, fluorine or chlorine;
more preferably hydrogen.
Equally preferred is the embodiment of the process according to the invention in which
R4 is hydrogen, halogen, cyano, C1-C6-alkyl or C1-C6-haloalkyl;
preferably hydrogen, halogen or cyano;
very preferably hydrogen, fluorine, chlorine or cyano;
more preferably hydrogen, chlorine or cyano;
exceptionally preferably hydrogen;
equally exceptionally preferably chlorine or cyano;
very exceptionally preferably chlorine.
Also preferred is the embodiment of the process according to the invention in which
R4 is halogen or cyano;
preferably halogen;
very preferably fluorine or chlorine;
more preferably chlorine.
Also preferred is the embodiment of the process according to the invention in which
R4 is hydrogen, halogen or cyano;
preferably hydrogen or halogen;
very preferably hydrogen, fluorine or chlorine;
more preferably hydrogen or chlorine.

In a very preferred embodiment of the process according to the invention, the variables
R1, R2, R3 and R4 are each defined as follows:
R1, is hydrogen;
R2 is hydrogen or halogen;
preferably halogen;
very preferably fluorine;
R3 is hydrogen; and
R4 is hydrogen, chlorine or cyano;
preferably chlorine or cyano;
very preferably chlorine.
In a further very preferred embodiment of the process according to the invention, the
variables R1, R2, R3 and R4 are each defined as follows:
R1, is hydrogen;
R2 is hydrogen or halogen;
preferably halogen;
very preferably fluorine;
R3 is hydrogen; and
R4 is hydrogen or halogen;
preferably hydrogen or chlorine;
very preferably chlorine;
equally very preferably hydrogen.
In a further very preferred embodiment of the process according to the invention, the
variables R1, R2, R3 and R4 are each defined as follows:
R1, is hydrogen;
R2 is fluorine;
R3 is hydrogen; and
R4 is halogen;
preferably chlorine.
In an exceptionally preferred embodiment of the process according to the invention,
fluorinated m-nitrobenzoyl chlorides IIA.a (corresponds to formula IIA where R1, =
fluorine)
can be prepared, where R2, R3 and R4 are each as defined above, especially as
defined above with preference.

In a further exceptionally preferred embodiment of the process according to the
invention, fluorinated m-nitrobenzoyl chlorides IIA.b (corresponds to formula IIA where
R2 = fluorine)

can be prepared, where R1, R3 and R4 are each as defined above, especially as
defined above with preference.
In a further exceptionally preferred embodiment of the process according to the
invention, fluorinated m-nitrobenzoyl chlorides IIA.c (corresponds to formula IIA where
R3 = fluorine)
can be prepared, where R1, R2 and R4 are each as defined above, especially as
defined above with preference.
In a further exceptionally preferred embodiment of the process according to the
invention, fluorinated m-nitrobenzoyl chlorides IIA.d (corresponds to formula IIA where
R4 = fluorine)

can be prepared, where R1, R2 and R3 are each as defined above, especially as
defined above with preference.
In a further exceptionally preferred embodiment of the process according to the
invention, fluorinated m-nitrobenzoyl chlorides IIA.e (corresponds to formula IA where
R1 and R3=H)


can be prepared, where the variables R2 and R4 are each as defined above, especially
as defined above with preference, and where at least one of the R2 and R4 radicals is
fluorine.
In addition it is also possible to prepare m-nitrobenzoyl chlorides II by hydrolyzing the
corresponding benzotrichlorides X in the presence of a catalyst or in a weakly acidic
medium.

where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl,
C1-C6-haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy.
The present invention accordingly relates additionally to a process for preparing
sulfonamides I wherein the m-nitrobenzoyl chlorides II required for the purpose are
prepared by hydrolyzing benzotrichlorides X in the presence of a catalyst or in a weakly
acidic medium.
In particularly preferred embodiments of the process according to the invention the
variables R1, R2, R3 and R4 of the m-nitrobenzoyl chlorides II have the definitions
specified above in connection with the sulfonamides I,more particularly the definitions
specified there as being preferred, which, considered both alone and in combination
with one another, represent special embodiments of the process according to the
invention.
The preferred embodiments of the hydrolysis of corresponding benzotrichlorides X are
subject to the conditions specified below in connection with the hydrolysis of fluorinated
m-nitrobenzotrichlorides XA, more particularly the embodiments specified there as
being preferred.
In the prior art (e.g. O. Scherer et al., Liebigs Ann. Chem. 1964, 677, 83-95;
WO 06/090210) processes are described for preparing aromatic acid chlorides from the
corresponding benzoic acids. Under the reaction conditions described in the prior art,

however, the problem occurs of the elimination of fluorine substituents located on the
aromatic structure.
The fluoride released has the disadvantages such as those already outlined above in
connection with the preparation of benzoyl chlorides from the corresponding benzoic
acids.
Accordingly a further object of the present invention is to provide a process for
preparing fluorinated m-nitrobenzoyl chlorides IIA by hydrolysis of corresponding
fluorinated m-nitrobenzotrichlorides XA which significantly reduces the elimination of
fluoride, it being possible at the same time to obtain high ylelds and a high purity of the
product of value.
It has surprisingly been found that this object is achieved by means of a process
wherein fluorinated m-nitrobenzotrichlorides XA are hydroiyzed in the presence of a
catalyst or in a weakly acidic medium at temperatures less than 80°C.
The present invention accordingly further provides a process for preparing fluorinated
m-nitrobenzoyl chlorides IIA

where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-aikyl,
C1-C6-haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
where at least one of the radicals R1, to R4 is fluorine,
by hydrolyzing fluorinated m-nitrobenzotrichlorides XA

where the variables R1, R2, R3 and R4 are each as defined above,
wherein the reaction takes places in the presence of a catalyst or in a weakly
acidic medium and also at temperatures less than 80°C.

The present invention further provides a process for preparing fluorinated
sulfonamides IA, wherein the fluorinated m-nitrobenzoyl chlorides IIA required for the
purpose are prepared by the above-specified process from fluorinated
m-nitrobenzotrichlorides XA.
The variables R1, R2, R3 and R4 have the definitions stated beforehand in connection
with the fluorinated m-nitrobenzoyl chlorides IIA, more particularly the definitions stated
beforehand as being preferred, at least one of the radicals R1, to R4 in the combination
of all four radicals R1, to R4 being fluorine, and where these aforementioned definitions,
considered both alone and in combination with one another, represent special
embodiments of the process according to the invention.
The preferred embodiments of the hydrolysis of the fluorinated m-nitrobenzo-
trichlorides XAto fluorinated m-nitrobenzoyl chlorides IIA are outlined below, and,
considered both alone and in combination with one another, represent special
embodiments of the process according to the invention.
The hydrolysis of fluorinated m-nitrobenzotrichlorides XA to fluorinated m-nitrobenzoyl
chlorides IIA takes place at temperatures less than 80°C ( 29 and between 59°C and an acid and/or a catalyst.
Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane
and mixtures of C5-C8 alkanes, halogenated hydrocarbons such as methylene chloride
and chloroform, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether,
dioxane and tetrahydrofuran, ketones such as tert-butyl methyl ketone, and also
dimethylformarnide and dimethylacetamide, particular preference being given to
aliphatic hydrocarbons and halogenated hydrocarbons.
Mixtures of the stated solvents can also be used.
The reaction of the fluorinated m-nitrobenzotrichlorides XA to fluorinated
m-nitrobenzotrichlorides IIA can also be carried out solvent-free in the melt at
temperatures This version of the reaction regime is preferred.
It is preferred to add 1 equivalent of water to the reaction mixture, based on the
fluorinated m-nitrobenzotrichloride XA. Advantageously the water is added uniformly
over a certain period of time, e.g. over the course of 1 to 12 h, preferably over the
course of 2 to 6 h.

Acids used are inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric
acid, and also organic acids such as formic acid, acetic acid, propionic acid, oxalic
acid, toluenesulfonic acid, benzenesulfonic acid, camphor sulfonic acid, citric acid and
trifluoroacetic acid, with particular preference sulfuric acid, e.g. aqueous sulfuric acid,
or oleum.
The acids are used generally in an equimolar amount, but may also be used
catalytically.
Suitable catalysts are Lewis acids such as iron(lll) chloride, iron sulfate, cerium(lll)
chloride or copper(ll) chloride; iron(lll) chloride is particularly preferred. It is preferred to
use 0.003-0.1 equivalent, more preferably 0.003-0.001, very preferably 0.003-
0.006 equivalent of the catalyst in relation to the benzotrichloride X.
The reaction of the fluorinated m-nitrobenzotrichlorides XA to fluorinated
m-nitrobenzotrichlorides IIA can also be carried out only in the presence of a suitable
catalyst, without additional acid. This version of the reaction regime is preferred.
The reaction mixtures are worked up by customary methods known to the skilled
worker, such as by removing the solvent, for example. The catalyst can be removed by
extraction methods known to the skilled worker, as for example by dissolving the
reaction mixture in a suitable solvent, such as in aromatic hydrocarbons such as
toluene, o-, m- and p-xylene and chlorobenzene, preferably chlorobenzene, and then
carrylng out extraction with aqueous mineral acids such as hydrochloric acid or sulfuric
acid.
Alternatively the reaction mixture obtained can also be supplied in the form of its melt
directly to the next reaction stage, without further purification.
The fluorinated m-nitrobenzotrichlorides XA required for preparing the fluorinated
m-nitrobenzoyl chlorides IIA are known in the literature [e.g. WO 06/090210] or can be
prepared in accordance with the cited literature.
Furthermore, m-nitrobenzoyl chlorides II can also be prepared by the reaction of
corresponding benzotrichlorides X with m-nitrobenzoic acids VII in the presence of a
catalyst:


More particularly it is also possible to prepare fluorinated m-nitrobenzoyl chlorides IIA
by the reaction of fluorinated m-nitrobenzotrichlorides XA with fluorinated
m-nitrobenzoic acids VIIA in the presence of a catalyst:

The variables R1, R2, R3 and R4 have the definitions stated above in connection with
the m-nitrobenzoyl chlorides II, and/or the fluorinated m-nitrobenzoyl chlorides IIA,
more particularly the definitions stated above as being preferred, and these
aforementioned definitions, both considered alone and considered in combination with
one another, represent special embodiments of the process according to the invention.
The present invention accordingly further provides a process for preparing
sulfonamides I, more particularly fluorinated sulfonamides I A, wherein the
m-nitrobenzoyl chlorides II required for the purpose, more particularly the fluorinated
m-nitrobenzoyl chlorides IIA, are prepared by the aforementioned process from
benzotrichlorides X and m-nitrobenzoic acids VII, more particularly from
benzotrichlorides XA and fluorinated m-nitrobenzoic acids VIIA.
Described below are the preferred embodiments of the reaction of the
benzotrichlorides X and m-nitrobenzoic acids VII to form m-nitrobenzoyl chlorides II,
and these embodiments, considered both alone and in combination with one another,
represent special embodiments of the process according to the invention.
This reaction of the benzotrichlorides X with m-nitrobenzoic acids VII takes place
typically at temperatures of 70°C to 160°C, preferably 70°C to 120°C, with particular
preference 80°C to 110°C, if appropriate in an inert organic solvent in the presence of a
catalyst.
Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane

and mixtures of C5-C8 alkanes, halogenated hydrocarbons such as methylene chloride
and chloroform, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether,
dioxane and tetrahydrofuran, ketones such as tert-butyl methyl ketone, and also
dimethylformamide and dimethylacetamide; particular preference is given to aliphatic
hydrocarbons and halogenated hydrocarbons.
Mixtures of the stated solvents can be used as well.
The reaction of the benzotrichlorides X with m-nitrobenzoic acids VII to
m-nitrobenzotrichlorides II can also be carried out solventlessly in the melt at
temperatures of 70 to 120°C, preferably 80 to 110°C. This version of the reaction
regime is preferred.
Suitable catalysts are Lewis acids such as iron(lll) chloride, iron sulfate, cerium(lll)
chloride or copper(Il) chloride, for example, particular preference being given to iron(lll)
chloride.
It is preferred to use 0.003-0.1 equivalent, with particular preference 0.003-
0.001 equivalent, very preferably 0.003-0.006 equivalent of the catalyst in relation to
the benzotrichloride X.
The benzotrichlorides X and m-nitrobenzoic acids VI! are preferably reacted with, one
another in equimolar amounts.
The reaction mixtures are worked up by customary methods known to the skilled
worker, such as by removing the solvent, for example. The catalyst can be removed by
extraction methods known to the skilled worker, as for example by dissolving the
reaction mixture in a suitable solvent, such as in aromatic hydrocarbons such as
toluene, o-, m- and p-xylene and chiorobenzene, preferably chlorobenzene, and then
carrvjng out extraction with aqueous mineral acids such as hydrochloric acid or sulfuric
acid.
Alternatively the reaction mixture obtained can be supplied in the form of its melt
directly to the next reaction stage, without further purification.
The sulfonamides I and IA obtainable in accordance with the processes according to
the invention can be used as starting materials for the preparation of aniline
derivatives VI, which in turn are valuable intermediates for the synthesis of
pharmacologically active compounds or crop protection agents.
A further subject matter of the present invention, therefore, is the provision of a process
for preparing aniline derivatives VI by reducing sulfonamides I prepared beforehand by
the abovementioned processes according to the invention:


In connection with the aniline derivatives VI the variables R1, R2, R3, R4, R5 and R6
have the definitions stated above in connection with the sulfonamides I, more
particularly the definitions stated above as being preferred, and these aforementioned
definitions, considered both alone and in combination with one another, represent
special embodiments of the process according to the invention.
The reduction of the sulfonamides I to aniline derivatives VI is accomplished, for
exampie, using nascent hydrogen. For this purpose the nitro compound is reacted with
an acid in the presence of a base metal. Base metals are of course those which are
dissolved by a Bronsted acid with evolution of hydrogen. Metals of this kind generally
have a standard potential in the range from -0.1 to -1.0 V (in acidic aqueous solution at 15°C and 1 bar).
Examples of suitable metals are Zn, Fe and Sn, more particularly Fe. Acids
contemplated for this purpose include not only inorganic mineral acids, examples being
hydrochloric acid or dilute sulfuric acid, or mixtures of inorganic acid and one of the
aforementioned solvents, gaseous HCI in an ether or an alcohol or a mixture thereof,
for example, or organic carboxylic acids, appropriately acetic acid, propionic acid or
butyric acid.
The reaction conditions correspond substantially to the reaction conditions employed
for the reduction of aliphatic or aromatic nitro groups to aliphatic or aromatic amino
groups using nascent hydrogen (see, for example, H. Koopman, Rec. Trav. 80 (1961),
1075).
Depending on the nature of the metal and acid, the reaction temperature is situated
generally in the range from -20 to +120°C, preference being given, when using
alkanoic acids such as acetic acid, to using temperatures in the range from 50 to
100°C. The reaction time can be from a few minutes to several hours, e.g. about
20 minutes to 5 hours. Preferably the sulfonamide I for reduction is charged to the
reaction vessel and then the respective metal, preferably in finely divided form, more
particularly as a powder, is added to the reaction mixture with thorough mixing. The
addition takes place preferably over a period of 10 minutes to 2 hours. It is of course
also possible to introduce the metal and the acid initially and to add the sulfonamide I, if
appropriate together with an inert solvent. Frequently the reaction mixture is left to
afterreact at reaction temperature for a certain additional period, e.g. 10 minutes to

4 hours.
The reduction of I to VI is preferably conducted with iron powder in dilute acid. Suitable
acids are mineral acids such as hydrochloric acid or organic acids such as formic acid,
acetic acid, propionic acid, butyric acid. Preference is given to using acetic acid. The
amount of iron powder is preferably 2 to 5 mol, more particularly 2.5 to 4 mol, per mole
of the sulfonamide I. The amount of acid is generally not critical. Appropriately at least
an equimolar amount of acid is used, based on the sulfonamide I, in order that
reduction of the starting compound is as near complete as possible. The reaction can
be carried out continuously or discontinuously. The reaction temperatures are in that
case in the range from 50 to 100°C, preferably 65 to 75°C. In one embodiment, for
example, the iron powder is introduced initially in acetic acid and then the sulfonamide I
is introduced into the reaction vessel. The addition takes place preferably over the
course of 20 to 60 minutes with the constituents being mixed, by stirring for example.
After the end of the addition the reaction is allowed to continue for 0.5 to 2 hours more,
preferably about 1 hour, at reaction temperature. Alternatively the iron powder can also
be added with stirring to the mixture of the sulfonamide I in glacial acetic acid and the
reaction can be completed as described above.
The working-up for obtaining aniline derivative VI can take place by the methods that
are customary for that purpose. Generally speaking the solvent will first be removed, by
distillation, for example. For further purification it is possible to employ customary
techniques such as crystallization, chromatography, on silica gel for example, stirring
with a solvent, examples being aromatic hydrocarbons such as benzene, toluene,
xylene or aliphatic hydrocarbons such as petroleum ether, hexane, cyclohexane,
pentane, carboxylic esters such as ethyl acetate, etc, and mixtures thereof.
Also suitable as reducing agents, furthermore, are metal hydrides and semimetal
hydrides such as aluminum hydride and hydrides derived therefrom such as lithium
aluminum hydride, diisobutylaluminum hydride, boron hydrides such as diborane, and
boronates derived therefrom, such as sodium borohydride or lithium boronate. For this
purpose the sulfonamide I is contacted with the complex metal hydride in an inert
solvent at 10 to 65°C, advantageously 20 to 50°C. The reaction time is preferably 2 to
10 hours, and advantageously 3 to 6 hours. The reaction is preferably conducted in an
organic solvent that is inert toward the reducing agent. Suitable solvents include -
depending on the reducing agent selected - e.g. alcohols, examples being
C1-C4 alcohols such as methanol, ethanol, n-propanol, isopropanol or n-butanol, and
mixtures thereof with water, or ethers such as diisopropyl ether, methyl tert-butyl ether,
ethylene glycol dimethyl ether, dioxane or tetrahydrofuran.
In general 0.5 to 3, advantageously 0.75 to 2.5, mol of metal hydride, metal
hemihydride, boron hydride and/or boronate is used per mole of sulfonamide I. The

process follows the procedure described in Organikum, VEB Deutscher Verlag der
Wissenschaften, Berlin 1976, 15th edition, pp. 612-616.
A further suitable reducing agent for the conversion of the sulfonamide I into the aniline
derivative VI is hydrogen in the presence of catalytic amounts of a transition metal
catalyst, more particularly with transition metals from transition group 8. This reduction
of the sulfonamides I to aniline derivatives VI with hydrogen is preferred.
Outlined below are the preferred embodiments of this reduction, which, considered
both alone and in combination with one another, represent special embodiments of the
process according to the invention.
The reaction takes place typically at temperatures of 0°C to 100°C, preferably at 10°C
to 50°C, either solventlessly or in an inert solvent (cf. e.g. Tepko et al., J. Org. Chem.
1980,45,4992).
Depending on the solubility of the substrate for hydrogenation, suitable solvents are
aliphatic hydrocarbons such as pentane, hexane, cyclohexane and mixtures of
C5-C8 alkanes;
aromatic hydrocarbons such as toluene, o-, m- and p-xylene;
halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene;
ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole
and tetrahydrofuran;
carboxylic esters such as ethyl acetate;
nitriles such as acetonitrile and propionitrile;
ketones such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl
ketone;
alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-
butanol:
and also dimethyl sulfoxide, dimethylformamide and dimethylacetamide,
carboxylic acids such as acetic acid, or aqueous solutions of organic acids such as
acetic acid and water,
with particular preference alcohols such as methanol, ethanol, n-propanol, isopropanol,
n-butanol and tert-butanol; aromatic hydrocarbons such as toluene, O-, m- and p-xylene
and also chlorobenzene.
It is also possible to use mixtures of the stated solvents. In addition it is also possible to
operate without solvent.
Preferred transition metal catalysts comprise a transition metal from the group Ni, Pd,
Pt, Ru, Rh and Ir. Particular preference is given to palladium, platinum, ruthenium and
iridium.

The transition metal catalysts can be used as they are or in supported form. Preference
is given to using supported catalysts. Examples of supports are activated carbon,
alumina, ZrO2, TiO2, SiO2, carbonates and the like, preferably activated carbon.
It is also possible to use transition metal catalysts doped with various transition group
elements, e.g. copper, iron, nickel or vanadium, in various proportions.
The transition metals can also be used in the form of activated metals such as Raney
nickel or in the form of compounds.
Furthermore, the transition metals can also be used in the form of compounds. Suitable
transition metal compounds are, for example, palladium oxide and platinum oxide. Also
suitable are noble metal sulfides such as platinum sulfide (cf. Houben-Weyl, Methoden
der organischen Chemie, vol. IV/iC, pp. 520-526).
The catalysts are used generally in an amount of 0.005 to 10 mol% (calculated as
metal), preferably 0.001 to 10 moI%, more preferably 0.0055 to 2 mol%, with particular
preference 0.005 to 0.5 mol%, based in each case on the sulfonamide I for reduction.
The reduction can be carried out under standard hydrogen pressure or under elevated
hydrogen pressure, with for example a hydrogen pressure of 0.01 to 50 bar, preferably
0.1 to 40 bar, with particular preference from 1 to 20 bar, with especial preference 1 to
16 bar.
If appropriate the nitro compounds of the formula II are purified prior to the
hydrogenation by means of extractive stirring with activated carbon or recrystallization
from an organic solvent by addition of a second solvent, e.g. acetone/water.
In the case of chlorinated sulfonamides I the hydrogenation is carried out - depending
on the sensitivity of the substituent - preferably at 20 to 170°C, with particular
preference at 20 to 140°C, with great preference at 20 to 80°C.
In the case of sulfonamides I having reactive halogen substituents it is further advisable
to carry out hydrogenation in neutral solution, where appropriate with oniy slightly
elevated pressure, with small amounts of nickel, palladium, platinum, ruthenium,
rhodium or else iridium catalysts. Noble metal sulfides such as platinum sulfide are also
suitable.
The reaction mixture is worked up after the catalyst has been separated off by known
methods. Generally speaking, first the solvent is removed, by distillation for example.
For further purification it is possible to employ typical techniques such as extraction,
crystallization, chromatography (on silica gel, for example) or stirring with a solvent

(aromatic hydrocarbons, for example, such as benzene, toluene or xylene, or aliphatic
hydrocarbons, for example, such as petroleum ether, hexane, cyclohexane, pentane,
carboxylic esters such as ethyl acetate, etc, and mixtures thereof).
The reduction of the sulfonamides I to aniline derivatives VI can also take place with
sodium sulfide, advantageously in aqueous ammoniacal solution, in the presence of
ammonium chloride. The reaction temperature is generally between 40 to 90°C,
preferably between 60 to 80°C. It is judicious to use 3 to 4 mol of sodium sulfide
per mole of sulfonamide I.
The examples which follow serve to further illustrate the invention:
1. Preparation of the fluorinated m-nitrobenzoyl chlorides IIA
The ylelds of fluorinated m-nitrobenzoyl chloride IIA were, unless stated otherwise,
determined by means of quantitative HPLC:
Sample preparation:
First, the fluorinated m-nitrobenzoyl chlorides IIA formed as the product were converted
to the corresponding methyl esters. To this end, the samples of the fluorinated m-
nitrobenzoyl chlorides IIA to be determined were weighed into a 100 ml standard flask
which was made up to 100 ml with methanol. The mixture was left to stir at room
temperature for a further 10 min.
Chromatographic conditions:
Column: symmetry C18 5 µm 250 x 4.6 mm from Waters®
Wavelength: 222 nm
Eluent: gradient of A (0.1% by volume of H3PO4 in H2O) and B (0.1% by volume of
H3PO4 in CH3CN); 10 min 70% B, then B rising from 70% to 100% within
15 min, then, back to 35% within 2 min, then 7 min 35% B.
Flow rate: 1 ml/min
Pressure: approx. 150 bar
Calibration:
The calibration was effected with external standard (corresponding methyl
nitrobenzoate). To establish the standard, a total of 5 samples of the pure substances
were weighed in the following concentrations (precision +/- 0.1 mg): approx. 0.1 g/l,
approx. 0.2 g/l, approx. 0.3 g/l, approx. 0.4 g/l, approx. 0.5 g/l.
With the aid of a suitable PC program, a calibration line was established. For the
substances detailed above, this was a linear function. Standard deviation, correlation
coefficient and straight-line equation were calculated.
For each of the components, their concentration can thus be determined based on the

particular external standard.
The fluoride values were determined by means of the following test method:
1 - 2 ml of the sample were extracted with 50 ml of demineralized water. After the
aqueous phase had been removed, depending on the concentration expected, an
aliquot part thereof was used for the measurement.
The measurement was effected in a buffer solution (TISAB) at pH 5.26 by means of an
ion-selective electrode (measurement concentration > 1 mg/l of fluoride; detection limit
The error limit is +/- 0.002 g/l.
The following units were used:
Ion-sensitive fluoride electrode e.g. Metrohm 6.0502.150
Reference electrode e.g. Metrohm 6.0733.100
Ion meter e.g. Radiometer PHM 250
Example 1.1: 4-fluoro-5-nitrobenzoyl chloride (with TPPO)

18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid and 0.1 g (0.00036 mol) of
triphenylphosphine oxide (TPPO) were initially charged in chlorobenzene and the
suspension was heated at 95°C with stirring. Subsequently, 16.8 g (0.14 mol) of thionyl
chloride were added within 10 min. The reaction mixture was stirred at 105-110°C for a
further 2 h.
Subsequently, the reaction mixture was allowed to cool to room temperature and the
fluoride content of the solution was determined, which was 0.01 g/l.
Subsequently, the solvent and excess thionyl chloride were removed by distillation.
After addition of chlorobenzene, 40.8 g (98% of theory; determined by means of
19F-NMR with internal standard) of the title product were obtained as a solution in
chlorobenzene.
The following examples 1.2 to 1.9 were carried out analogously to example 1.1.
Example 1.2: 2-chloro-4-fluoro-5-nitrobenzoyl chloride (with TPPO)


22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid
16.8 g (0.14 mol) of thionyl chloride
0.1 g (0.00036 mol) of triphenyl phosphine oxide
yleld*: 46.5 g (> 99% of theory) of the title compound as a solution in chlorobenzene
Fluoride value: 0.01 g/l
Example 1.3: 4-fluoro-5-nitrobenzoyl chloride (without catalyst)
18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid
16.8 g (0.14 mol) of thionyl chloride
yleld*: 47.3 g (86% of theory) of the title compound as a solution in chlorobenzene
Fluoride value: 0.26 g/l
Example 1.4: 2-chloro-4-fluoro-5-nitrobenzoyl chloride (without catalyst)
22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid
16.8 g (0.14 mol) of thionyl chloride
yleld: 47.0 g (95% of theory) of the title compound as a solution in chlorobenzene
Fluoride value: 0.02 g/l
Example 1.5: 4-fluoro-5-nitrobenzoyl chloride (with DMAP)
18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid
16.8 g (0.14 mol) of thionyl chloride
0.1 g (0.0008 mol) of 4-dimethylaminopyridine
yleld*: 40.8 g (96% of theory) of the title compound as a solution in chlorobenzene
Fluoride value: 0.03 g/l
Example 1.6: 2-chloro-4-fluoro-5-nitrobenzoyl chloride (with DMAP)
22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid
16.8 g (0.14 mol) of thionyl chloride
0.1 g (0.0008 mol) of 4-dimethylaminopyridine
yleld: 46.8 g (97% of theory) of the title compound as a solution in chlorobenzene
Fluoride value: 0.05 g/l
Example 1.7: 4-fluoro-5-nitrobenzoyl chloride (with DMF)
18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid
16.8 g (0.14 mol) of thionyl chloride
0.1 g (0.0014 mol) of dimethylformamide
yleld*: 40.8 g (98% of theory) of the title compound as a solution in chlorobenzene
Fluoride value: 0.02 g/l
Example 1.8: 4-fluoro-5-nitrobenzoyl chloride (with pyridine)
18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid
16.8 g (0.14 mol) of thionyl chloride

0.1 g (0.0013 mol) of pyridine
yleld*: 40.8 g (96% of theory] of the title compound as a solution in chlorobenzene
Fluoride value: 0.03 g/l
Example 1.9: 2-chloro-4-fluoro-5-nitrobenzoyl chloride (with pyridine)
22.3 g (0.1 mol) 2-chloro-4-fluoro-5-nitrobenzoic acid
16.8 g (0.14 mol) of thionyl chloride
0.1 g (0.0013 mol) of pyridine
yleld: 46.8 g (98% of the title compound as a solution in chlorobenzene
Fluoride value: 0.13 g/l
These experiments show that the process according to the invention distinctly reduces
the fluoride elimination:
When the process is carried out according to known reaction conditions without
catalyst or with catalysts such as DMAP, DMF or pyridine, there is elimination of
fluoride which leads to a fluoride concentration of from 0.02 to 0.26 g/l, whereas the
fluoride concentration when the reaction takes place under the inventive conditions is
only 0.01 g/l.
Example 1.10
A mixture of 475 g (1.6 mol) of 2-chloro-4-fluoro-5-nitrobenzotrichloride and 1.5 g
(9.1 mmol) of iron chloride was introduced and melted by heating to 75°C. Over the
course of 2 h 29.2 g (1.6 mol) of water were metered in beneath the surface. In the
course of the metered addition hydrogen chloride was produced, and was taken off via
a suitable off-gas system. During the reaction the internal temperature rose slightly.
After the end of the metered addition the system was stirred at 75°C for 3 h. Residues
of hydrogen chloride were driven off by introduction of nitrogen. The warm melt was
transferred with stirring to a vessel containing 367 g of chlorobenzene which had been
conditioned at 10°C. After cooling to approximately 20°C, this organic phase was
extracted once with 300 g of 32% aqueous hydrochloric acid. Phase separation gave
732.0 g of a solution of 50.5% by weight (97% of theory) of 2-chloro-4-fluoro-5-
nitrobenzoyl chloride in chlorobenzene. The free fluoride content of the organic phase
was less than 0.01 g/1000 g ( * In these examples, the yleld was determined by means of 19F-NMR with internal standard.

Example 1.11
A mixture of 296 g (1 mol) of 2-chloro-4-fluoro-5-nitrobenzotrichloride and 0.95 g
(5.7 mmol) of iron chloride was introduced and melted by heating to 70°C. Over the
course of 2 h 18.1 g (1 mol) of water were metered in beneath the surface. During the
metered addition hydrogen chloride was formed, and was taken off via a suitable off-
gas system. During the reaction there was a slight increase in the internal temperature.
Toward the end of the metered addition a precipitate was formed which, at the end of
the subsequent stirring time, had dissolved again. After the end of the metered
addition, stirring was continued at 75°C for 3 h. Residues of hydrogen chloride were
driven off by introduction of nitrogen. The warm melt was cooled and solidified. This
gave 235 g of 2-chloro-4-fluoro-5-nitrobenzoyl chloride with a purity of 97.5% (96% of
theory).
Example 1.12
In the same way as example 1.11, 296 g (1 mol) of 2-chloro-4-fluoro-5-nitrobenzo-
trichloride, 0.95 g (5.7 mmol) of iron chloride and 18.2 g (1 mol) of water were reacted
at 80°C. This gave 238 g of 2-chloro-4-fluoro-5-nitrobenzoyl chloride with a purity of
97% (97% of theory).
Example 1.13
In the same way as in example 1.11, 296 g (1 mol) of 2-chloro-4-fluoro-5-nitrobenzo-
trichloride, 0.5 g (3 mmol) of iron chloride and 18.2 g (1 mol) of water were reacted at
120°C. After the end of the metered addition of the water, stirring was continued for
30 minutes at 120-125°C. The system was subsequently cooled to 60°C. Residues of
hydrogen chloride were driven off by introduction of nitrogen. The warm melt was
cooled and solidified. This gave 236 g of 2-chloro-4-fluoro-5-nitrobenzoyl chloride with
a purity of 95% (95% of theory). The free fluoride content was 0.110 g/1000 g
(110 ppm).
Example 1.14
A mixture of 148 g (0.5 mol) of 2-chloro-4-fluoro-5-nitrobenzotrichloride and 0.5 g
(3 mmol) of iron chloride was introduced and melted by heating to 85°C. Over the
course of 1 h 111 g (1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid in solid form were
added. During the metered addition hydrogen chloride was formed, and was taken off
via a suitable off-gas system. During the metered addition a precipitate formed. The
temperature was raised to 120°C and the mixture was stirred for 2 h. In the course of
this stirring period the precipitate dissolved again. Residues of hydrogen chloride were
driven off by introduction of nitrogen. The warm melt was cooled and solidified. This
gave 2-chloro-4-fluoro-5-nitrobenzoyl chloride with a purity of 95% (94% of theory).
2. Preparation of the sulfonamides I

Example 2.1: N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N',N'-diethylsulfonamide
A mixture of 8.22 g (27.0 mmol) of N,N-diethylsulfamoylamide, 5.40 g (53.0 mmol) of
triethylamine and 170 mg of lutidine were admixed in 40 g of chlorobenzene at 70°C
with 12.4 g (25.0 mol) of 2-chloro-4-fluoro-3-nitrobenzoyl chloride in 12 g of
chlorobenzene. The reaction mixture was subsequently stirred at 70°C for 2 h. The
mixture was acidified by means of addition of cone, hydrochloric acid, cooled to 0°C
and stirred for 1 h.
The solid was filtered off and washed once with HCI solution. 6.7 g (73% of theory) of
the title compound were obtained.
1H NMR (500 MHz, CDCI3) 5 = 9.30 ppm (br. s., NH), 8.45 (d, Ar-H), 7.45 (d, Ar-H),
3.5 [q, CH2CH3], 1.30 (t, CH2CH3).
Example 2.2: N-(4-fluoro-3-nitrobenzoyl)-N'-i-propyl-N'-methylsulfonamide
8.22 g (54.0 mol) of N-methyl-N-(1-methylethyl)sulfamoylamide, 36.0 mg (0.30 mmol)
of dimethylaminopyridine (DMAP), 11.0 g (0.107 mmol) of triethylamine were admixed
in 30 ml of toluene at 70°C with 10.2 g (49.1 mmol) of 4-fluoro-3-nitrobenzoyl chloride
in 30 ml of toluene. The suspension was subsequently stirred at RT for 2 h. The
mixture was acidified by means of addition of cone, hydrochloric acid and stirred for
1 h. The solid was filtered off, washed once with 1N HCI solution and recrystallized
from chlorobenzene. A final filtration and drylng under reduced pressure gave rise to
14.3 g (87% of theory) of the title compound as yellowish crystals having a melting
point of 164-165°C.
1H NMR (500 MHz, C1-DMSO) 5 = 12.3 ppm (br. s., NH), 8.85 (d, Ar-H), 8.40-8.45 (m,
Ar-H), 7.75 (t, Ar-H), 4.25 [sept., CH(CH3)2], 2.95 (s, CH3), 1.15 ppm [d, CH(CH3)2].
Example 2.3: N-(4-fluoro-3-nitrobenzoyl)-N'-i-propyl-N'-methylsulfonamide
A solution of 4.10 g (27.0 mmol) of N-methyl-N-(1-methylethyl)sulfamoylamide in 50 g
of dioxane was admixed at 25°C with 4.30 g (50% in water) of NaOH. During this
addition, a solution of 5.32 g (25.0 mmol) of 4-fluoro-3-nitrobenzoyl chloride and 20 g of
dioxane was added dropwise. The reaction mixture was subsequently stirred at 25°C
for 12 h. The mixture was diluted by means of addition of 140 g of water and acidified
with cone, hydrochloric acid, cooled to 0°C and stirred for 1 h. The solid was filtered off
and washed once with HCI solution. 7.6 g (86% of theory) of the title compound having
an m.p. of 164-165°C were obtained.
Example 2.4: N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N'-i-propyl-N'-methylsulfonamide
A solution of 41.1 g (0.27 mol) of N-methyl-N-(1-methylethyl)sulfamoylamide and
2.41 g (3.00 mmol) of tetrabutylammonium chloride in 500 g of tetrahydrofuran was

admixed at 25°C with 41.0 g (50% in water) of NaOH. During this addition, a solution of
59.7 g (0.25 mdl) of 2-chloro-4-fluoro-3-nitrobenzoyl chloride and 65 g of
tetrahydrofuran was added dropwise. The reaction mixture was subsequently stirred at
25°C for 2 ft and acidified by means of addition of cone, hydrochloric acid. This was
followed by extraction with dichloromethane. The combined organic phases were dried
over magnesium sulfate and the solvent was removed under reduced pressure. 67 g
(76% of theory) of the title product having an m.p. of 125-127°C were obtained.
1H NMR (400 MHz, CDCI3) 5 = 9.1 ppm (s, NH), 8.4 (d, Ar-H), 7.45 (d, Ar-H), 4.25
(sept, /Pr-H), 2.95 (s, Me), 1.25 (d, Pr-H).
Example 2.5: N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N'-i-propyl-N'-methylsulfonamide
A solution of 41.1 g (0.27 mol) of N-methyl-N-(1-methylethyl)sulfamoylamide and
0.75 g (1.25 mmol) of tributylmethylammonium chloride in 630 g of chlorobenzene was
admixed at 20°C with 41.0 g (50% in water) of NaOH. During this addition, a solution of
59.7 g (0.25 mol) of 2-chloro-4-fluoro-3-nitrobenzoyl chloride and 65 g of
chlorobenzene was added dropwise. The biphasic reaction mixture was subsequently
stirred at 20°C for 1 h and then acidified by means of addition of cone, hydrochloric
acid. Finally, the mixture was cooled to 0°C, and the precipitated solid was filtered off
and washed with 1N HCI solution. 72.5 g (82% of theory) of the title compound were
obtained.
1H NMR (400 MHz, CDCI3) 8 = 9.1 ppm (s, NH), 8.4 (d, Ar-H), 7.45 (d, Ar-H), 4.25
(sept., Pr-H), 2.95 (s, Me), 1.25 (d, Pr-H).
Example 2.6:
A solution of 41.1 g (0.27 mol) of N-methyl-N-(1-methylethyl)sulfamoylarnide and
0.75 g (12.0 mmol) of tributylmethylammonium chloride in 633 g of chlorobenzene was
admixed at 20°C with 41.0 g (50% in water) of NaOH over the course of 60 min. The
addition of a solution of 59.7 g (0.25 mol) of 2~chloro-4-fluoro-3-nitrobenzoyl chloride
and 62 g of chlorobenzene took place 15 min after the beginning of addition of the
base, over the course of 45 min. The reaction mixture was subsequently stirred at 20°C
for 1 h and diluted by addition of 430 g of water. The aqueous phase was acidified to a
pH of 1 using concentrated hydrochloric acid, and 320 g of cyclohexane were added.
The mixture obtained was cooled to 0°C. The precipitate was isolated by filtration and
dried at 70°C under reduced pressure. This gave 80.1 g (88% of theory) of N-(2-chloro-
4-fluoro-3-nitrobenzoyl)-N'-isopropyl-N'-methylsulfamide in a purity of 96%. The solid
contained 2.2% of 2-chloro-4-fluoro-3-nitrobenzoic acid (determination via quantitative
HPLC: column: Symmetry C18 5 µm 250 x 4.6 mm from Waters®; wavelength:
222 nm, 205 nm; eluent: gradient of A (0.1% by volume H3PO4 in H2O) and B (0.1% by
volume H3PO4 in CH3CN); flow rate: 1 ml/min; pressure: about 150 bar).
Example 2.7:

A solution of 43.1 g (0.277 mol) of N-methyl-N-(1-methylethyl)sulfamoylatnide and
0.77 g (12.0 mmol) of tributylmethylammonium chloride in 640 g of chlorobenzene was
admixed over the course of 60 min at 20°C with 43.7 g (50% in water) of NaOH. After
the base had been added for 15 minutes, a parallel addition commenced of 64.0 g
(0.26 mol) of 2-chloro-4-fluoro-3-nitrobenzoyl chloride in 67 g of chlorobenzene. This
addition took place over the course of 45 min. The reaction mixture was subsequently
stirred at 20°C for 1 h and diluted by addition of 424 g of water and 138 g of isohexane.
The aqueous phase was acidified to a pH of 5.5 using concentrated hydrochloric acid
and then separated off at 68°C. The organic phase was extracted a second time with
addition of 430 g of water and 60 g of isohexane, and the phases were separated at
68°C. The resulting organic phase was admixed with a further 280 g of isohexane and
then cooled to 0°C. Filtration, washing with water and drylng under reduced pressure at
70°C gave 82.4 g (87% of theory, purity 96.5%) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-
N'-isopropyl-N'-methylsulfamide.
Example 2.8:
A solution of 43.1 g (0.277 mol) of N-methyl-N-(1~methylethyl)sulfamoylarnide and
0.77 g (12.0 mmol) of tributylmethylammonium chloride in 637 g of chlorobenzene was
admixed over the course of 60 min at 20°C with 43.7 g (50% in water) of NaOH. After
the base had been added for 15 minutes, a parallel addition commenced of 65.0 g
(0.26 mol) of 2-chloro-4-fluoro-3-nitrobenzoyl chloride in 70 g of chlorobenzene. This
addition took place over the course of 45 min. The reaction mixture was subsequently
stirred at 20°C for 1 h and diluted by addition of 424 g of water and 138 g of isohexane.
The aqueous phase was acidified to a pH of 4.5 using concentrated hydrochloric acid
and then separated off at 68°C. The organic phase was extracted a second time with
addition of 430 g of water and 60 g of isohexane, and the phases were separated at
68°C. The resulting organic phase was admixed with a further 280 g of isohexane and
then cooled to 0°C. Filtration, washing with water and drylng under reduced pressure at
70°C gave 82.1 g (87% of theory, purity 97%) of N-(2-ch!oro-4-fluoro-3-nitrobenzoyl)-
N'~isopropyl=N'=methylsu!famide. !n the solid, HPLC analysis found no contamination
with 2-chloro-4-fluoro-3-nitrobenzoic acid.
Example 2.9:
A solution of 8.22 g (54.0 mmol) of N-methyl-N-(1-methylethyl)sulfamoylarnide in 25 g
of water and 6.48 g (162.4 mmol) of NaOH was admixed with 1.74 g (5.40 mmol) of
tetrabutylammonium bromide (TBAB) and 10 g of chlorobenzene. Subsequently, at
25°C, a solution of 10.49 g (48.6 mmol) of 4-fluoro-3-nitrobenzoyl chloride and 25 g of
chlorobenzene was added dropwise over 40 min. The two-phase reaction mixture was
subsequently stirred at 25°C for 3 h. Following phase separation, the organic phase
was dried over magnesium sulfate and the solvent was removed under reduced
pressure. This gave 4.56 g (46.2%) of N-(4-fluoro-3-nitrobenzoyl)-N'-isopropyl-N'-
methylsulfamide having an m.p. of 164-165°C.

Example 2.10:
A solution of 10.5 g (69.0 mmol) of N-methyl-N-(1-methylethyl)sulfamoylamide,
190.0 mg (0.80 mmol) of tributylmethylammonium chloride in 160 g of chlorobenzene,
and 0.86 g of water was admixed with 10.9 g (137.0 mmol, 50%) of NaOH.
Subsequently at 20°C a solution of 15.8 g (66.0 mmol) of 2-chloro-4-fluoro-3-
nitrobenzoyl chloride and 16 g of chlorobenzene was added dropwise in 65 min. The
two-phase reaction mixture was subsequently stirred overnight at 20°C. The reaction
mixture was diluted with 106 g of water and acidified to a pH of 1 with sulfuric acid
(98% strength). Following phase separation, the organic phase was cooled to 0°C and
filtered. The resulting solid was washed on the filter with dilute sulfuric acid (pH 1) and
finally dried at 70°C under reduced pressure. This gave 9.3 g (37.3% of theory) of
N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N'-isopropyl-N'-methylsulfamide. Additionally an
organic phase was obtained that contained 6.08 g (24.4% of theory) of N-(2-chloro-4-
fluoro-3-nitrobenzoyl)-N'-isopropyl-N'-methylsulfamide and also 3.29 g (22.5% of
theory) of 2-chloro-4-fluoro-3-nitrobenzoic acid (determination by quantitative HPLC in
the same way as in ex. 2.3).
3. Preparation of the aniline derivatives VI
Example 3.1; N-(N-(4-Fluoro-3-aminobenzoyl)-N'-isopropyl-N'-methylsulfamide
89.0 g (0.28 mol) of N-(4-fluoro-3-nitrobenzoyl)-N'-isopropyl-N'-methylsulfamide in
methanol were admixed with 5.9 g (10 mol%) of Pd/C and hydrogenated with 2-5 bar of
hydrogen with stirring at 25-30°C- After 12 h the solution was depressurized, the
reaction mixture was filtered and the solvent was removed by distillation. This gave
80.0 g (98%) of the title compound in the form of a beige solid (m.p.: 148-150°C).
In addition to the implementation described above, table 1 lists further experiments
carried out in the same way as the above process:



Example 3.2: N-(N-(2-Chloro-4-fluoro-3-aminobenzoyl)-N'-isopropyl-N'-methylsulfamide
8.00 g (23.0 mmol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N'-isopropyl-N'-
methylsulfamide in 33 g of toluene and 8 g of methanol were admixed with 190 rng
(0.055 mol%) of 3% Pt/C and hydrogenated with 5 bar of hydrogen with stirring at
70°C. After 12 h the solution was depressurized, the reaction mixture was filtered and
the solvent was removed by distillation. This gave 4.7 g (64%) of the title compound in
the form of a solid (m.p.: 147-149°C).
Example 3.3: N-(N-(2-Chloro-4-fluoro-3-aminobenzoyl)-N'-isopropyl-N'-methylsulfamide
8.00 g (0.023 mol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N'-isopropyl-N'-
methylsulfamide and 70 mg (6 mol%) of ammonium chloride in 33 g of toluene and 8 g

of methanol were admixed with 0.19 g (0.15 mol%) of 10% Pd/C and hydrogenated
with 5 bar of hydrogen with stirring at 70°C. After 10 h the solution was depressurized,
the reaction mixture was filtered and the solvent was removed by distillation. This gave
6.4 g (89%) of the title compound in the form of a solid (m.p.: 147-149°C).
Example 3.4: N-(N-(2-Chloro-4-fluoro-3-aminobenzoyl)-N'-isopropyl-N'-methylsulfamide
182.4 g (0.500 mol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N'-isopropyl-N'-
methylsulfamide in 391 g of methanol were admixed with 1.33 g (0.005 mol%) of 1%
Pt-2%V/C and hydrogenated with 5 bar of hydrogen with stirring at 60°C. After 6 h the
solution was depressurized, the reaction mixture was filtered and the solvent was
removed by distillation. This gave 157.1 g (97%) of the title compound in the form of a
solid (m.p.: 147-149°C).
Example 3.5: N-(N-(2-Chloro-4-fluoro-3-aminobenzoyl)-N'-isopropyl-N'-methylsulfamide
8.00 g (0.023 mol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N'-isopropyl-N'-
methylsulfamide in 75 g of toluene and 8 g of methanol were admixed with 0.24 g
(0.05 mol%) of 2.4% Pt/2.4% Pd/C and hydrogenated with 5 bar of hydrogen with
stirring at 70°C. After 11 h the solution was depressurized, the reaction mixture was
filtered and the solvent was removed by distillation. This gave 6.48 g (90%) of the title
compound in the form of a solid (m.p.: 147-149°C).

We claim :
1. A process for preparing sulfonamides I

where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-
haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
R5 and R6 are each C1-C6-alkyl;
by reacting m-nitrobenzoyl chlorides II

where the variables R1, R2, R3 and R4 are each as defined above:
with amino sulfones III
H2N-SO2NR5R6 Ml,
where the variables R5 and R6 are each as defined above;
under the influence of B equivalents of alkali metal or alkaline earth metal hydroxide as base, wherein, in step a), the amino sulfone III is reacted with B1 equivalents of alkali metal or
alkaline earth metal hydroxide, and, in step b), the reaction mixture resulting from step a) is
reacted with m-nitrobenzoyl chloride II and B2 equivalents of alkali metal or alkaline earth metal
hydroxide;
where B is 1.5 - 3 equivalents of alkali metal or alkaline earth metal hydroxide with respect to
the amino sulfone III;
B1 is a subportion of B and is in the range from 0.1 -1.3 equivalents of alkali metal or
alkaline earth metal hydroxide with respect to the amino sulfone III; and
B2 is a subportion of B and is the difference between B and B1.
2. The process for preparing sulfonamides I as claimed in claim 1, wherein B is 1.8 - 2.5
equivalents of alkali metal or alkaline earth metal hydroxide with respect to the amino
sulfone III.
3. The process for preparing sulfonamides I as claimed in claim 1 or 2, wherein, in step a),
the amino sulfone is introduced as an initial charge in an inert solvent and then B1
equivalents of alkali metal or alkaline earth metal hydroxide are added.
4. The process for preparing sulfonamides I as claimed in any one of claims 1 to 3, wherein
B1 is 0.1 -1 equivalent of alkali metal or alkaline earth metal hydroxide with respect to
the amino sulfone III.

5. The process for preparing sulfonamides I as claimed in any one of claims 1 to 4, wherein,
in step b), the m-nitrobenzoyl chloride II and the B2 equivalents of alkali metal or alkaline
earth metal hydroxde are added simultaneously to the reaction mixture resulting from
step a).
6. The process for preparing sulfonamides I as claimed in any one of claims 1 to 5, wherein
the reaction is carried out in an aqueous multiphase system.
7. The process for preparing sulfonamides I as claimed in any one of claims 1 to 6, wherein
the m-nitrobenzoyl chlorides II are prepared by
reacting m-nitrobenzoic acids VII

where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl,
C1-C6-haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
with chlorinating agents, such as herein described; or by
hydroiyzing corresponding benzotrichlorides X

where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-
haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
in the presence of a catalyst or in a weakly acidic medium; or by
- reacting corresponding benzotrichlorides X with m-nitrobenzoic acids VII in the
presence of a catalyst.
8. The process for preparing sulfonamides I as claimed in any one of claims 1 to 6, wherein
the m-nitrobenzoyl chlorides II are prepared by reacting m-nitrobenzoic acids VII

where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-
haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
with chlorinating agents, such as herein described.
9. The process for preparing sulfonamides I as claimed in any one of claims 1 to 6, wherein
the m-nitrobenzoyl chlorides II are prepared by hydroiyzing corresponding
benzotrichlorides X


where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-
haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
in the presence of a catalyst or in a weakly acidic medium.
10. The process for preparing sulfonamides I as claimed in any one of claims 1 to 6, wherein
the m-nitrobenzoyl chlorides II are prepared by reacting corresponding benzotrichlorides

where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-
haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
with m-nitrobenzoic acids VII

where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-
haloalkyl, C1-C6-alkoxy or C1-C6-haloalkoxy;
in the presence of a catalyst.
11. A process for preparing sulfonamides I as claimed in any one of claims 1 to 10, wherein at
least one of the radicals R1, to R4 is fluorine.
12. A process for preparing sulfonamides I as claimed in any one of claims 1 to 11, wherein
R1, is hydrogen;
R2 is hydrogen or halogen;
R3 is hydrogen; and
R4 is hydrogen or halogen;
where at least one of the R2 and R4 radicals is fluorine.
13. The process as claimed in claim 8 wherein at least one of the radicals R1, to R4 is fluorine;
and wherein the reaction takes place in the presence of catalytic amounts of a phosphine
derivative IX


where the variables are each defined as follows:
Ra, Rb, Rc are each C1-C6-alkyl or phenyl, which may optionally be substituted by
C1-C4-alkyl;
X is oxygen or two single-bonded chlorine atoms;
n is 0 or 1.
14. The process as claimed in claim 13, wherein
R1, is hydrogen;
R2 is hydrogen or halogen;
R3 is hydrogen; and
R4 is hydrogen or halogen;
where at least one of the R2 and R4 radicals is fluorine.
15. The process as claimed in claim 13 or 14, wherein the chlorinating agent is selected from
the group of oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl
chloride and phosphoryl chloride (POCl3).
16. The process as claimed in any of claims 13 to 15, wherein the ratio of chlorinating agent
to fluorinated m-nitrobenzoic acids II is 1.5 to 1.
17. The process as claimed in any of claims 13 to 16, wherein the phosphine derivatives IX
are selected from the group of triphenylphosphine, triphenylphosphine oxide and tri(C1-
C6-alkyl)phosphine oxide.
18. The process as claimed in any of claims 13 to 17, wherein the reaction is effected
additionally in the presence of a Lewis acid.
19. The process as claimed in any of claims 13 to 18, wherein the Lewis acid is selected from
the group of boric acid, tri-C1-C4-alkyl borate or cyclic boric esters.
20. A process for preparing aniline derivatives VI

where the variables are each defined as follows:
R1, R2, R3 and R4 are each hydrogen, halogen, cyano, nitro, C1-C6-alkyl, C1-C6-haloalkyl,
C1-C6-alkoxy or C1-C6-haloalkoxy;
R5 and R6 are each C1-C6-alkyl;
by reducing sulfonamides I, prepared by a process as claimed in any one of claims 1 to
10.
21. The process as claimed in claim 20, wherein the reduction is carried out with hydrogen in
the presence of catalytic amounts of a transition metal catalyst.



ABSTRACT


METHOD FOR PRODUCING SULFONAMIDES
The invention discloses a process for preparing sulfonamides I

where the variables R1, R2, R3, R4, R5 and R6 are as defined in the specification; by
reacting m-nitrobenzoyl chlorides II

where the variables R1, R2, R3 and R4 are as defined in the specification: with amino
sulfones III
H2N-SO2NR5R6 III,
where the variables R5 and R6 are as defined in the specification;
under the influence of B equivalents of alkali metal or alkaline earth metal hydroxide as
base, wherein, in step a), the amino sulfone III is reacted with B1 equivalents of alkali
metal or alkaline earth metal hydroxide, and, in step b), the reaction mixture resulting from
step a) is reacted with m-nitrobenzoyl chloride II and B2 equivalents of alkali metal or
alkaline earth metal hydroxide;
where B, B1 and B2 are as defined in the specification.
The invention is also for production of corresponding aniline derivatives by reduction of
sulfonamides so provided.

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Patent Number 256537
Indian Patent Application Number 2462/KOLNP/2008
PG Journal Number 27/2013
Publication Date 05-Jul-2013
Grant Date 28-Jun-2013
Date of Filing 18-Jun-2008
Name of Patentee BASF SE
Applicant Address 67056 LUDWIGSHAFEN
Inventors:
# Inventor's Name Inventor's Address
1 RACK MICHAEL HILDASTR. 11/1, 69214 EPPELHEIM
2 MAYER GUIDO PAUL-MUNCH-WEG 7, 67161 GONNHEIM
3 SCHMIDT THOMAS PFARRGASSE 8, 67433 NEUSTADT
4 WEVERS JAN HENDRIK GARTENSTR. 11, 67591 HOHEN-SULZEN
5 LOHR SANDRA BENCKISER STR. 30, 67059 LUDWIGSHAFEN
6 PLESCHKE AXEL GRALSSTRASSE 8, 68199 MANNHEIM
7 KEIL MICHAEL FONTANESTR. 4, 67251 FREINSHEIM
8 GEBHARDT JOACHIM PEGAUER STR. 51, 67157 WACHENHEIM
PCT International Classification Number C07C 303/38
PCT International Application Number PCT/EP2006/068832
PCT International Filing date 2006-11-23
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 102005057681.8 2005-12-01 Germany
2 06123569.3 2006-11-07 Germany