U.S. patent application number 13/584213 was filed with the patent office on 2012-12-06 for method for producing sulfonamides.
This patent application is currently assigned to BASF SE. Invention is credited to Joachim Gebhardt, Michael Keil, Sandra Lohr, Guido Mayer, Axel Pleschke, Michael Rack, Thomas Schmidt, Jan Hendrik Wevers.
Application Number | 20120310010 13/584213 |
Document ID | / |
Family ID | 37697933 |
Filed Date | 2012-12-06 |
United States Patent
Application |
20120310010 |
Kind Code |
A1 |
Schmidt; Thomas ; et
al. |
December 6, 2012 |
Method for producing sulfonamides
Abstract
A process for preparing sulfonamides I ##STR00001## where the
variables are each as defined in the description, by reacting
m-nitrobenzoyl chlorides II with amino sulfones III, 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 chlorides II and B2 equivalents of base IV;
where B, B1 and B2 are each as defined in the description.
Inventors: |
Schmidt; Thomas; (Neustadt,
DE) ; Gebhardt; Joachim; (Wachenheim, DE) ;
Lohr; Sandra; (Ludwigshafen, DE) ; Keil; Michael;
(Friensheim, DE) ; Wevers; Jan Hendrik;
(Hohensuelzen, DE) ; Rack; Michael; (Eppelheim,
DE) ; Mayer; Guido; (Goennheim, DE) ;
Pleschke; Axel; (Mannheim, DE) |
Assignee: |
BASF SE
Ludwigshafen
DE
|
Family ID: |
37697933 |
Appl. No.: |
13/584213 |
Filed: |
August 13, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12095582 |
May 30, 2008 |
8263806 |
|
|
PCT/EP2006/068832 |
Nov 23, 2006 |
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13584213 |
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Current U.S.
Class: |
562/859 ;
562/862; 564/99 |
Current CPC
Class: |
C07C 303/40 20130101;
C07C 201/12 20130101; C07C 303/38 20130101; C07C 303/40 20130101;
C07C 303/38 20130101; C07C 205/58 20130101; C07C 311/51 20130101;
C07C 201/12 20130101; C07C 311/51 20130101 |
Class at
Publication: |
562/859 ;
562/862; 564/99 |
International
Class: |
C07C 303/40 20060101
C07C303/40; C07C 51/58 20060101 C07C051/58; C07C 51/60 20060101
C07C051/60 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 1, 2005 |
DE |
102005057681.8 |
Nov 7, 2006 |
EP |
06123569.3 |
Claims
1. A process for preparing a fluorinated m-nitrobenzoyl chloride of
formula IIA ##STR00031## wherein: R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are each hydrogen, halogen, cyano, nitro,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-alkoxy or C.sub.1-C.sub.6-haloalkoxy; wherein at
least one of the R.sup.1 to R.sup.4 radicals is fluorine, by
reacting a fluorinated m-nitrobenzoic acid of formula VIIA
##STR00032## wherein: R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
each hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy or
C.sub.1-C.sub.6-haloalkoxy; wherein at least one of the R.sup.1 to
R.sup.4 radicals is fluorine; with a chlorinating agent, wherein
the reaction takes place in the presence of catalytic amounts of a
phosphine derivative IX ##STR00033## wherein: R.sup.a, R.sup.b,
R.sup.c are each C.sub.1-C.sub.6-alkyl or phenyl, which may
optionally be substituted by C.sub.1-C.sub.4-alkyl; X is oxygen or
two single-bonded chlorine atoms; n is 0 or 1.
2. The process according to claim 1, wherein R.sup.1 is hydrogen;
R.sup.2 is hydrogen or halogen; R.sup.3 is hydrogen; and R.sup.4 is
hydrogen or halogen; wherein at least one of the R.sup.2 and
R.sup.4 radicals is fluorine.
3. The process according to claim 1, wherein the chlorinating agent
is selected from the group consisting of oxalyl chloride,
phosphorus trichloride, phosphorus pentachloride, thionyl chloride
and phosphoryl chloride (POCl.sub.3).
4. The process of claim 3, wherein the ratio of the chlorinating
agent to the fluorinated m-nitrobenzoic acid VIIA is 1.5 to 1.
5. The process of claim 4, wherein the phosphine derivative IX is
selected from the group consisting of triphenylphosphine,
triphenylphosphine oxide and tri(C.sub.1-C.sub.6-alkyl)phosphine
oxide.
6. The process of claim 1, wherein the reaction is effected
additionally in the presence of a Lewis acid.
7. The process of claim 6, wherein the Lewis acid is selected from
the group consisting of boric acid, tri-C.sub.1-C.sub.4-alkyl
borate and cyclic boric esters.
8. A process for preparing sulfonamides I ##STR00034## wherein:
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each hydrogen, halogen,
cyano, nitro, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-alkoxy or C.sub.1-C.sub.6-haloalkoxy; wherein at
least one of the radicals R.sup.1 to R.sup.4 is fluorine, R.sup.5
and R.sup.6 are each hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl,
C.sub.3-C.sub.7-cycloalkyl, C.sub.3-C.sub.7-cycloalkenyl,
C.sub.1-C.sub.6-alkoxy, phenyl or benzyl; wherein a fluorinated
m-nitrobenzoyl chloride IIA prepared according to claim 1 is
reacted with an amino sulfone III H.sub.2N--SO.sub.2NR.sup.5R.sup.6
III, wherein: R.sup.5 and Ware each hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl, C.sub.3-C.sub.7-cycloalkyl,
C.sub.3-C.sub.7-cycloalkenyl, C.sub.1-C.sub.6-alkoxy, phenyl or
benzyl.
9. The process according to claim 8, wherein R.sup.1 is hydrogen;
R.sup.2 is hydrogen or halogen; R.sup.3 is hydrogen; R.sup.4 is
hydrogen or halogen; wherein at least one of the R.sup.2 and
R.sup.4 radicals is fluorine; and R.sup.5 and R.sup.6 are each
C.sub.1-C.sub.6-alkyl.
10. A process for preparing a fluorinated m-nitrobenzoyl chloride
IIA ##STR00035## wherein: R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
each hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy or
C.sub.1-C.sub.6-haloalkoxy; wherein at least one of the radicals
R.sup.1 to R.sup.4 is fluorine, by hydrolyzing a fluorinated
m-nitrobenzotrichloride XA ##STR00036## wherein the variables
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each as defined above;
wherein the reaction takes places in the presence of a catalyst or
in a weakly acidic medium and at temperatures less than 80.degree.
C.
11. The process of claim 10, wherein the hydrolysis is carried out
solvent-free in the melt.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 12/095,582, filed May 30, 2008, which application is a National
Stage application of International Application No.
PCT/EP2006/068832 filed Nov. 23, 2006, the entire contents of which
is hereby incorporated herein by reference. This application also
claims the benefit under 35 U.S.C. .sctn.119 of German Patent
Application No. 10 2005 057 681.8, filed Dec. 1, 2005, and European
Patent Application No. 06123569.3, filed Nov. 7, 2006, the entire
contents of which is hereby incorporated herein by reference.
[0002] The present invention relates to a process for preparing
sulfonamides I
##STR00002##
where the variables are each defined as follows: [0003] R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are each hydrogen, halogen, cyano,
nitro, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-alkoxy or C.sub.1-C.sub.6-haloalkoxy; [0004]
R.sup.5 and R.sup.6 are hydrogen, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-alkenyl, C.sub.3-C.sub.6-alkynyl,
C.sub.3-C.sub.7-cycloalkyl, C.sub.3-C.sub.7-cycloalkenyl,
C.sub.1-C.sub.6-alkoxy, phenyl or benzyl.
[0005] 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.
[0006] 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.
[0007] It is thus an object of the present invention to provide a
simple, economically viable and implementable process for preparing
sulfonamides I, which firstly distinctly reduces byproduct
formation and simultaneously can achieve high yields and high
purity of product of value.
[0008] 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.
[0009] Accordingly, the present invention relates to a process for
preparing sulfonamides I
##STR00003## [0010] where the variables are each defined as
follows: [0011] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each
hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy or
C.sub.1-C.sub.6-haloalkoxy; [0012] R.sup.5 and R.sup.6 are each
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl, C.sub.3-C.sub.7-cycloalkyl,
C.sub.3-C.sub.7-cycloalkenyl, C.sub.1-C.sub.6-alkoxy, phenyl or
benzyl; by reacting m-nitrobenzoyl chlorides II
##STR00004##
[0012] where the variables R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are each as defined above: with amino sulfones III
H.sub.2N--SO.sub.2NR.sup.5R.sup.6 III,
where the variables R.sup.5 and R.sup.6 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 11 and B2 equivalents of base
IV; where [0013] B is 1.5-3 equivalents of base IV with respect to
the amino sulfone III; [0014] 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 [0015] B2 is a subportion of B and is the
difference between B and B1.
[0016] 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.
[0017] The organic molecular moieties specified for the
substituents R.sup.1 to R.sup.6 and R.sup.a, R.sup.b and R.sup.c
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.
[0018] 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.
[0019] Examples of definitions include: [0020]
C.sub.1-C.sub.4-alkyl: for example methyl, ethyl, n-propyl,
1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and
1,1-dimethylethyl; [0021] C.sub.1-C.sub.6-alkyl:
C.sub.1-C.sub.4-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; [0022] C.sub.1-C.sub.4-haloalkyl: a
C.sub.1-C.sub.4-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-dichloropropyl, 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; [0023] C.sub.1-C.sub.6-haloalkyl:
C.sub.1-C.sub.4-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; [0024]
C.sub.2-C.sub.6-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-methyl-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; [0025] C.sub.2-C.sub.6-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; [0026] C.sub.3-C.sub.8-cycloalkyl: for
example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl; [0027] C.sub.3-C.sub.7-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; [0028]
C.sub.1-C.sub.4-alkoxy: for example methoxy, ethoxy, propoxy,
1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy and
1,1-dimethylethoxy; [0029] C.sub.1-C.sub.6-alkoxy:
C.sub.1-C.sub.4-alkoxy as specified above, and also, for example,
pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methoxylbutoxy,
1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy,
1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy,
3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,
1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,
2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy,
2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy,
1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy; [0030]
C.sub.1-C.sub.4-haloalkoxy: a C.sub.1-C.sub.4-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;
[0031] C.sub.1-C.sub.6-haloalkoxy: C.sub.1-C.sub.4-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.
[0032] In particularly preferred embodiments of the process
according to the invention, the variables R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 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:
[0033] Preference is given to the embodiment of the process
according to the invention in which
[0034] R.sup.1 is hydrogen, halogen or C.sub.1-C.sub.6-alkyl;
[0035] preferably hydrogen or halogen; [0036] very preferably
hydrogen, fluorine or chlorine; [0037] more preferably
hydrogen.
[0038] Equally preferred is the embodiment of the process according
to the invention in which
[0039] R.sup.2 is hydrogen, halogen, cyano, C.sub.1-C.sub.6-alkyl
or C.sub.1-C.sub.6-haloalkyl; [0040] preferably hydrogen or
halogen; [0041] very preferably hydrogen, fluorine or chlorine;
[0042] more preferably hydrogen or fluorine; [0043] exceptionally
preferably hydrogen; [0044] equally exceptionally preferably
fluorine.
[0045] Equally preferred is the embodiment of the process according
to the invention in which
[0046] R.sup.2 is hydrogen or halogen; [0047] preferably halogen;
[0048] very preferably fluorine or chlorine; [0049] more preferably
fluorine.
[0050] Equally preferred is the embodiment of the process according
to the invention in which
[0051] R.sup.3 is hydrogen, halogen or C.sub.1-C.sub.6-alkyl;
[0052] preferably hydrogen or halogen; [0053] very preferably
hydrogen, fluorine or chlorine; [0054] more preferably
hydrogen.
[0055] Equally preferred is the embodiment of the process according
to the invention in which
[0056] R.sup.4 is hydrogen, halogen, cyano, C.sub.1-C.sub.6-alkyl
or C.sub.1-C.sub.6-haloalkyl; [0057] preferably hydrogen, halogen
or cyano; [0058] very preferably hydrogen, fluorine, chlorine or
cyano; [0059] more preferably hydrogen, chlorine or cyano; [0060]
exceptionally preferably hydrogen; [0061] equally exceptionally
preferably chlorine or cyano; [0062] very exceptionally preferably
chlorine.
[0063] Equally preferred is the embodiment of the process according
to the invention in which
[0064] R.sup.4 is halogen or cyano; [0065] preferably halogen;
[0066] very preferably fluorine or chlorine; [0067] more preferably
chlorine.
[0068] Equally preferred is the embodiment of the process according
to the invention in which
[0069] R.sup.4 is hydrogen, halogen or cyano; [0070] preferably
hydrogen or halogen; [0071] very preferably hydrogen, fluorine or
chlorine; [0072] more preferably hydrogen or chlorine.
[0073] Equally preferred is the embodiment of the process according
to the invention in which
[0074] R.sup.5 and R.sup.6 independently [0075] are each hydrogen,
C.sub.1-C.sub.6-alkyl or C.sub.2-C.sub.6-alkenyl; [0076] preferably
hydrogen or C.sub.1-C.sub.6-alkyl; [0077] very preferably
C.sub.1-C.sub.6-alkyl; [0078] more preferably
C.sub.1-C.sub.4-alkyl.
[0079] Equally preferred is the embodiment of the process according
to the invention in which
[0080] R.sup.5 is hydrogen or C.sub.1-C.sub.6-alkyl; [0081]
preferably hydrogen or C.sub.1-C.sub.4-alkyl; [0082] very
preferably C.sub.1-C.sub.4-alkyl; [0083] more preferably
methyl.
[0084] Equally preferred is the embodiment of the process according
to the invention in which
[0085] R.sup.6 is hydrogen or C.sub.1-C.sub.6-alkyl; [0086]
preferably hydrogen or C.sub.1-C.sub.4-alkyl; [0087] very
preferably C.sub.1-C.sub.4-alkyl.
[0088] In a very preferred embodiment of the process according to
the invention, the variables R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are each as defined above, in particular the meanings indicated as
preferred, where at least one of the radicals R.sup.1 to R.sup.4 is
fluorine.
[0089] In a further very preferred embodiment of the process
according to the invention, the variables R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are each defined as follows:
[0090] R.sup.1 is hydrogen;
[0091] R.sup.2 is hydrogen or halogen; [0092] preferably halogen;
[0093] very preferably fluorine;
[0094] R.sup.3 is hydrogen; and
[0095] R.sup.4 is hydrogen, chlorine or cyano; [0096] preferably
chlorine or cyano; [0097] very preferably chlorine.
[0098] In a further very preferred embodiment of the process
according to the invention, the variables R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are each defined as follows:
[0099] R.sup.1 is hydrogen;
[0100] R.sup.2 is hydrogen or halogen; [0101] preferably halogen;
[0102] very preferably fluorine;
[0103] R.sup.3 is hydrogen; and
[0104] R.sup.4 is hydrogen or halogen; [0105] preferably hydrogen
or chlorine; [0106] very preferably chlorine; [0107] equally very
preferably hydrogen.
[0108] In a further very preferred embodiment of the process
according to the invention, the variables R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are each defined as follows:
[0109] R.sup.1 is hydrogen;
[0110] R.sup.2 is fluorine;
[0111] R.sup.3 is hydrogen; and
[0112] R.sup.4 is halogen; [0113] preferably chlorine.
[0114] In a further very preferred embodiment of the process
according to the invention, the variables R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each defined as follows:
[0115] R.sup.1 is hydrogen;
[0116] R.sup.2 is hydrogen or halogen; [0117] preferably halogen;
[0118] very preferably fluorine;
[0119] R.sup.3 is hydrogen; and
[0120] R.sup.4 is hydrogen or halogen; [0121] preferably hydrogen
or chlorine; [0122] very preferably chlorine; [0123] equally very
preferably hydrogen;
[0124] R.sup.5 and R.sup.6 are each hydrogen, C.sub.1-C.sub.6-alkyl
or C.sub.2-C.sub.6-alkenyl; [0125] preferably hydrogen or
C.sub.1-C.sub.6-alkyl; [0126] very preferably
C.sub.1-C.sub.6-alkyl; [0127] more preferably
C.sub.1-C.sub.4-alkyl.
[0128] In a preferred embodiment of the process according to the
invention, it is possible in this way to prepare sulfonamides
IA
##STR00005##
where the variables are each as defined below: [0129] R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are each hydrogen, halogen, cyano,
nitro, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-alkoxy or C.sub.1-C.sub.6-haloalkoxy; and [0130]
where at least one of the radicals R.sup.1 to R.sup.4 is fluorine,
and [0131] R.sup.5 and R.sup.6 are each hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl,
C.sub.3-C.sub.6-alkynyl, C.sub.3-C.sub.7-cycloalkyl,
C.sub.3-C.sub.7-cycloalkenyl, C.sub.1-C.sub.6-alkoxy, phenyl or
benzyl.
[0132] In a further preferred embodiment of the process according
to the invention, it is possible in this way to prepare
sulfonamides I.a
##STR00006##
where the variables R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
are each as defined above, especially as defined above with
preference.
[0133] In a further preferred embodiment of the process according
to the invention, it is possible in this way to prepare
sulfonamides I.b
##STR00007##
where the variables R.sup.1, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
are each as defined above, especially as defined above with
preference.
[0134] In a further preferred embodiment of the process according
to the invention, it is possible in this way to prepare
sulfonamides I.c
##STR00008##
where the variables R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6
are each as defined above, especially as defined above with
preference.
[0135] In a further preferred embodiment of the process according
to the invention, it is possible in this way to prepare
sulfonamides I.d
##STR00009##
where the variables R.sup.1, R.sup.2, R.sup.3, R.sup.5 and R.sup.6
are each as defined above, especially as defined above with
preference.
[0136] In a further preferred embodiment of the process according
to the invention, it is possible in this way to prepare
sulfonamides I.e
##STR00010##
where the variables R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are each
as defined above, especially as defined above with preference, and
where at least one of the R.sup.2 and R.sup.4 radicals is
fluorine.
[0137] 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.
[0138] The m-nitrobenzoyl chlorides II and with amino sulfones III
can be reacted in equimolar amounts with one another.
[0139] 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.
[0140] 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.degree. C. to 120.degree. C., preferably from -10.degree. C. to
100.degree. C., especially preferably from 0.degree. C. to
80.degree. 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:
[0141] Suitable solvents are aliphatic hydrocarbons such as
pentane, hexane, heptane, cyclohexane and mixtures of
C.sub.5-C.sub.8-alkanes, aromatic hydrocarbons such as toluene, o-,
m- and p-xylene, halogenated 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
halogenated hydrocarbons.
[0142] It is also possible to use mixtures of the solvents
mentioned, or mixtures of the solvents mentioned with water.
[0143] 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.
[0144] 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".
[0145] 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".
[0146] Accordingly the relation between B, B1 and B2 is as follows:
B1+B2=B.
[0147] 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-diazabicyclo[4.3.0]non-5-ene (DBN).
[0148] Particular preference is given to alkali metal and alkaline
earth metal oxides and tertiary amines.
[0149] Particular preference given to alkali metal and alkaline
earth metal hydroxides, extraordinary preference to alkali metal
hydroxides.
[0150] 1.5-3 equivalents of base IV (total amount of base B) are
used, based on the amino sulfone III.
[0151] Very preferably B is 1.8-2.5 equivalents based on the amino
sulfone III.
[0152] 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 IIA
##STR00011## [0153] where the variables are each defined as
follows: [0154] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each
hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy or
C.sub.1-C.sub.6-haloalkoxy; [0155] and at least one of the radicals
R.sup.1 to R.sup.4 is fluorine.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] In step b) of the process according to the invention,
preferably, the m-nitrobenzoyl chloride II, preferably the
fluorinated m-nitrobenzoyl chloride 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).
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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.
[0164] 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).
[0165] Preference is given to effecting the reaction in an aqueous
multiphase system in the presence of phase transfer catalysts.
[0166] 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.
[0167] Suitable quaternary ammonium salts comprise
tetra(C.sub.1-C.sub.18)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.RTM. 175), methyltrioctylammonium chloride,
methyltricaprylylammonium chloride (e.g. ALIQUAT.RTM. 336,
ALIQUAT.RTM. 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,
C.sub.12-C.sub.14-alkyltrimethylammonium borate,
C.sub.12-C.sub.14-alkyltrimethylammonium diborate;
N-phenyl(C.sub.1-C.sub.18)trialkylammonium fluorides, chlorides or
bromides, such as phenyltrimethylammonium chloride;
N-benzyl(C.sub.1-C.sub.18)trialkylammonium fluorides, chlorides or
bromides, such as benzyltrimethylammonium chloride,
benzyltriethylammonium chloride, benzyltriethylammonium bromide,
benzyltributylammonium bromide; pyridinium fluorides, chlorides or
bromides, such as 1-cetylpyridinium chloride monohydrate,
cetylpyridinium bromide.
[0168] 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(C.sub.1-C.sub.18)phosphonium chloride or
bromide, such as tetrabutylphosphonium bromide.
[0169] Suitable polyglycols and crown ethers are, for example,
diethylene glycol dibutyl ether ("butyl diglyme"), 18-crown-6 and
dibenzo-18-crown-6.
[0170] Preference is given to using
tetra(C.sub.1-C.sub.18)alkylammonium hydrogensulfates and
tetra(C.sub.1-C.sub.18)alkylammonium chlorides, very preferably
tetra(C.sub.1-C.sub.6)alkylammonium hydrogensulfates and
tetra(C.sub.1-C.sub.6)alkylammonium chlorides.
[0171] Very particular preference is given to using
tetra(C.sub.1-C.sub.18)alkylammonium chlorides, extraordinary
preference to using tetra(C.sub.1-C.sub.6)alkylammonium
chlorides.
[0172] Preference is likewise given to tetrabutylammonium fluoride,
tetrabutylammonium hydrogensulfate, methyltributylammonium
chloride, tetrapropylammonium chloride, tetrapropylammonium
bromide, benzyltriphenylphosphonium chloride,
benzyltriphenylphosphonium bromide or dibenzo-18-crown-6.
[0173] 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
IIA.
[0174] 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 IIA.
[0175] 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.
[0176] 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.
[0177] If the organic phase used is a water-miscible solvent, the
reaction can also be carried out without a phase transfer
catalyst.
[0178] 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.
[0179] 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.
[0180] 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.
[0181] 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.
[0182] 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.
[0183] 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).
[0184] 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.
[0185] The reaction can be carried out at standard pressure,
reduced pressure or under elevated pressure, if appropriate under
inert gas, continuously or batchwise.
[0186] The end of the reaction can easily be determined by the
skilled worker by means of routine methods.
[0187] 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.
[0188] 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.
[0189] When using a two-phase system it is usual to carry out
extractive workup.
[0190] 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).
[0191] 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 .ltoreq.7.
[0192] 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.
[0193] 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.
[0194] 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.
[0195] When a biphasic system is used, workup will generally be
effected by extraction.
[0196] 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.
[0197] 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.
[0198] 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.
[0199] 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 et al., Angew. Chem. 93, 151, 1981) or can
be prepared in accordance with the literature cited.
[0200] 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
##STR00012##
where the variables are each defined as follows: [0201] R.sup.1,
R.sup.2, R.sup.3, R.sup.4 are each hydrogen, halogen, cyano, nitro,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-alkoxy or C.sub.1-C.sub.6-haloalkoxy; with
chlorinating agents VIII.
[0202] 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 VIII.
[0203] In particularly preferred embodiments of the process
according to the invention the variables R.sup.1, R.sup.2, R.sup.3
and R.sup.4 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.
[0204] The preferred embodiments of the reaction of m-nitrobenzoic
acids VII with chlorinating agents VIII are subject to the
conditions stated below in connection with the reaction of
fluorinated m-nitrobenzoic acids VIIA with chlorinating agents VIII
in the presence of catalytic amounts of a phosphine derivative IX,
more particularly the embodiments specified there as being
preferred.
[0205] The prior art (for example WO 89/02891, WO 04/106324, WO
04/035545 and U.S. Pat. No. 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.
[0206] 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.
[0207] However, when the process is carried out without catalyst,
the yields are distinctly lower or higher reaction temperatures are
required.
[0208] 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 yields and high purity of product of value.
[0209] We have found that, surprisingly, this object is achieved by
a process in which fluorinated m-nitrobenzoic acids VII are reacted
with chlorinating agents VIII, 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.
[0210] Accordingly, the present invention further relates to a
process for preparing fluorinated m-nitrobenzoyl chlorides IIA
##STR00013## [0211] where the variables are each defined as
follows: [0212] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each
hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy or
C.sub.1-C.sub.6-haloalkoxy; [0213] where at least one of the
R.sup.1 to R.sup.4 radicals is fluorine, by reacting fluorinated
m-nitrobenzoic acids VIIA
[0213] ##STR00014## [0214] where the variables are each defined as
follows: [0215] R.sup.1, R.sup.2, R.sup.3, R.sup.4 are each
hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy or
C.sub.1-C.sub.6-haloalkoxy; [0216] where at least one of the
R.sup.1 to R.sup.4 radicals is fluorine, with chlorinating agents
VIII, which comprises effecting the reaction in the presence of
catalytic amounts of a phosphine derivative IX
[0216] ##STR00015## [0217] where the variables are each defined as
follows: [0218] R.sup.a, R.sup.b, R.sup.c are each
C.sub.1-C.sub.6-alkyl or phenyl, which may optionally be
substituted by C.sub.1-C.sub.4-alkyl; [0219] X is oxygen or two
single-bonded chlorine atoms; [0220] n is 0 or 1.
[0221] The invention further relates to a process for preparing
fluorinated sulfonamides IA (i.e. sulfonamides I where at least one
of the radicals R.sup.1 to R.sup.4 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.
[0222] Specified below are the preferred embodiments of the
reaction of fluorinated m-nitrobenzoic acids VIIA with chlorinating
agents VIII 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.
[0223] 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 VIII
in the presence of catalytic amounts of a phosphine derivative
IX:
##STR00016## [0224] where the variables are each as defined above
in conjunction with the preparation of fluorinated m-nitrobenzoyl
chlorides IIA.
[0225] This reaction is effected typically at temperatures of from
20.degree. C. to 160.degree. C., preferably from 20.degree. C. to
120.degree. C., especially preferably from 70.degree. C. to
120.degree. C., in an inert organic solvent.
[0226] 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 carrying out the reaction in the region
of standard pressure, i.e. in the range from 0.9 to 1.2 bar.
[0227] 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.
[0228] The process according to the invention can in principle be
carried out in substance. However, preference is given to carrying
out the process according to the invention in an inert organic
solvent.
[0229] 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.
[0230] Suitable solvents are, for example, aliphatic hydrocarbons
such as pentane, hexane, cyclohexane and mixtures of
C.sub.5-C.sub.8 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.
[0231] It is also possible to use mixtures of the solvents
mentioned.
[0232] The chlorinating agents VIII used are customary chlorinating
agents such as oxalyl chloride, phosphorus trichloride, phosphorus
pentachloride, thionyl chloride, phosphoryl chloride (POCl.sub.3).
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 al., Organikum, 22nd edition
2004, p. 496-499).
[0233] Preferred chlorinating agents VIII are oxalyl chloride,
phosphorus trichloride, phosphorus pentachloride, thionyl chloride
and phosphoryl chloride (POCl.sub.3); thionyl chloride is very
preferred.
[0234] The fluorinated m-nitrobenzoic acids VIIA and the
chlorinating agent VIII are generally reacted with one another in
equimolar amounts. It may be advantageous to use the chlorinating
agent VIII in an excess based on the m-nitrobenzoic acids VIIA.
Preference is given to using the chlorinating agent VIII and the
fluorinated m-nitrobenzoic acids VIIA in a ratio of 2:1, more
preferably 1.5:1.
[0235] The catalysts used are phosphine derivatives IX
##STR00017## [0236] where the variables are each defined as
follows: [0237] R.sup.a, R.sup.b, R.sup.c are each
C.sub.1-C.sub.6-alkyl or phenyl, which may optionally be
substituted by C.sub.1-C.sub.4-alkyl; [0238] X is oxygen or two
single-bonded chlorine atoms; [0239] n is 0 or 1.
[0240] Preference is given to using triphenylphosphine,
triphenylphosphine oxide (TPPO), triphenyldichlorophosphine,
tri(C.sub.1-C.sub.6-alkyl)phosphine,
tri(C.sub.1-C.sub.6-alkyl)phosphine oxide and
tri(C.sub.1-C.sub.6-alkyl)dichlorophosphine;
more preferably triphenylphosphine, triphenylphosphine oxide and
tri(C.sub.1-C.sub.6-alkyl)phosphine oxide; exceptionally preferably
triphenylphosphine oxide.
[0241] 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.
[0242] 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).
[0243] Suitable Lewis acids are in particular boron compounds such
as boron halides (e.g. BF.sub.3, BCl.sub.3, BF.sub.3 etherate),
boric acid (H.sub.3BO.sub.3), boric anhydride, boric esters (e.g.
tri-C.sub.1-C.sub.4-alkyl borate), borate (e.g. sodium
borate/borax), boronic acids (e.g. C.sub.1-C.sub.6-alkylboronic
acids, arylboronic acids, especially phenylboronic acid),
C.sub.1-C.sub.4-alkyl boronates (e.g. C.sub.1-C.sub.6-alkyl
C.sub.1-C.sub.4-alkyl boronates, C.sub.1-C.sub.4-alkyl aryl
boronates), cyclic boric esters (e.g.
tris(C.sub.1-C.sub.4-alkoxy)boroxin, especially trimethoxyboroxin,
and triethanolamine borate).
[0244] Particular preference is given to boric acid,
tri-C.sub.1-C.sub.4-alkyl borates or cyclic boric esters.
[0245] 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.
[0246] The process can be carried out either continuously or
discontinuously (batchwise or semibatchwise).
[0247] 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.
[0248] 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
VIII is added with mixing, for example stirring. However, it is
also possible to initially charge the chlorinating agent VIII
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.
[0249] 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.
[0250] Preference is given to not effecting any further
purification after the reaction has ended.
[0251] 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).
[0252] 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.
[0253] The present invention therefore further provides a process
for preparing sulfonamides IA starting from fluorinated
m-nitrobenzoyl chlorides IA.
[0254] 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.
[0255] The organic molecular moieties specified for the
substituents R.sup.1 to R.sup.6 and R.sup.a, R.sup.b and R.sup.c
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, alkoxy and
haloalkoxy moieties, may be straight-chain or branched.
[0256] 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.
[0257] In conjunction with the fluorinated m-nitrobenzoyl chlorides
IIA, the variables R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each
as defined above, in particular the meanings indicated as being
preferred, where at least one of the R.sup.1 to R.sup.4 radicals in
the combination of all four R.sup.1 to R.sup.4 radicals is
fluorine, these abovementioned definitions, alone and also in
combination with one another, constituting particular embodiments
of the process according to the invention.
[0258] Preference is given to the embodiment of the process
according to the invention in which
[0259] R.sup.1 is hydrogen, halogen or C.sub.1-C.sub.6-alkyl;
[0260] preferably hydrogen or halogen; [0261] very preferably
hydrogen, fluorine or chlorine; [0262] more preferably
hydrogen.
[0263] Equally preferred is the embodiment of the process according
to the invention in which
[0264] R.sup.2 is hydrogen, halogen, cyano, C.sub.1-C.sub.6-alkyl
or C.sub.1-C.sub.6-haloalkyl; [0265] preferably hydrogen or
halogen; [0266] very preferably hydrogen, fluorine or chlorine;
[0267] more preferably hydrogen or fluorine; [0268] exceptionally
preferably hydrogen; [0269] equally exceptionally preferably
fluorine.
[0270] Also preferred is the embodiment of the process according to
the invention in which
[0271] R.sup.2 is hydrogen or halogen; [0272] preferably halogen;
[0273] very preferably fluorine or chlorine; [0274] more preferably
fluorine.
[0275] Equally preferred is the embodiment of the process according
to the invention in which
[0276] R.sup.3 is hydrogen, halogen or C.sub.1-C.sub.6-alkyl;
[0277] preferably hydrogen or halogen; [0278] very preferably
hydrogen, fluorine or chlorine; [0279] more preferably
hydrogen.
[0280] Equally preferred is the embodiment of the process according
to the invention in which
[0281] R.sup.4 is hydrogen, halogen, cyano, C.sub.1-C.sub.6-alkyl
or C.sub.1-C.sub.6-haloalkyl; [0282] preferably hydrogen, halogen
or cyano; [0283] very preferably hydrogen, fluorine, chlorine or
cyano; [0284] more preferably hydrogen, chlorine or cyano; [0285]
exceptionally preferably hydrogen; [0286] equally exceptionally
preferably chlorine or cyano; [0287] very exceptionally preferably
chlorine.
[0288] Also preferred is the embodiment of the process according to
the invention in which
[0289] R.sup.4 is halogen or cyano; [0290] preferably halogen;
[0291] very preferably fluorine or chlorine; [0292] more preferably
chlorine.
[0293] Also preferred is the embodiment of the process according to
the invention in which
[0294] R.sup.4 is hydrogen, halogen or cyano; [0295] preferably
hydrogen or halogen; [0296] very preferably hydrogen, fluorine or
chlorine; [0297] more preferably hydrogen or chlorine.
[0298] In a very preferred embodiment of the process according to
the invention, the variables R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are each defined as follows:
[0299] R.sup.1 is hydrogen;
[0300] R.sup.2 is hydrogen or halogen; [0301] preferably halogen;
[0302] very preferably fluorine;
[0303] R.sup.3 is hydrogen; and
[0304] R.sup.4 is hydrogen, chlorine or cyano; [0305] preferably
chlorine or cyano; [0306] very preferably chlorine.
[0307] In a further very preferred embodiment of the process
according to the invention, the variables R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are each defined as follows:
[0308] R.sup.1 is hydrogen;
[0309] R.sup.2 is hydrogen or halogen; [0310] preferably halogen;
[0311] very preferably fluorine;
[0312] R.sup.3 is hydrogen; and
[0313] R.sup.4 is hydrogen or halogen; [0314] preferably hydrogen
or chlorine; [0315] very preferably chlorine; [0316] equally very
preferably hydrogen.
[0317] In a further very preferred embodiment of the process
according to the invention, the variables R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are each defined as follows:
[0318] R.sup.1 is hydrogen;
[0319] R.sup.2 is fluorine;
[0320] R.sup.3 is hydrogen; and
[0321] R.sup.4 is halogen; [0322] preferably chlorine.
[0323] In an exceptionally preferred embodiment of the process
according to the invention, fluorinated m-nitrobenzoyl chlorides
IIA.a (corresponds to formula IIA where R.sup.1=fluorine)
##STR00018##
can be prepared, where R.sup.2, R.sup.3 and R.sup.4 are each as
defined above, especially as defined above with preference.
[0324] In a further exceptionally preferred embodiment of the
process according to the invention, fluorinated m-nitrobenzoyl
chlorides IIA.b (corresponds to formula IIA where
R.sup.2=fluorine)
##STR00019##
can be prepared, where R.sup.1, R.sup.3 and R.sup.4 are each as
defined above, especially as defined above with preference.
[0325] In a further exceptionally preferred embodiment of the
process according to the invention, fluorinated m-nitrobenzoyl
chlorides IIA.c (corresponds to formula IIA where
R.sup.3=fluorine)
##STR00020##
can be prepared, where R.sup.1, R.sup.2 and R.sup.4 are each as
defined above, especially as defined above with preference.
[0326] In a further exceptionally preferred embodiment of the
process according to the invention, fluorinated m-nitrobenzoyl
chlorides IIA.d (corresponds to formula IIA where
R.sup.4=fluorine)
##STR00021##
can be prepared, where R.sup.1, R.sup.2 and R.sup.3 are each as
defined above, especially as defined above with preference.
[0327] In a further exceptionally preferred embodiment of the
process according to the invention, fluorinated m-nitrobenzoyl
chlorides IIA.e (corresponds to formula IA where R.sup.1 and
R.sup.3.dbd.H)
##STR00022##
can be prepared, where the variables R.sup.2 and R.sup.4 are each
as defined above, especially as defined above with preference, and
where at least one of the R.sup.2 and R.sup.4 radicals is
fluorine.
[0328] 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.
##STR00023## [0329] where the variables are each defined as
follows: [0330] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each
hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy or
C.sub.1-C.sub.6-haloalkoxy.
[0331] 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.
[0332] In particularly preferred embodiments of the process
according to the invention the variables R.sup.1, R.sup.2, R.sup.3
and R.sup.4 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.
[0333] 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.
[0334] 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.
[0335] 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.
[0336] 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 yields and a high purity of the product of value.
[0337] It has surprisingly been found that this object is achieved
by means of a process wherein fluorinated m-nitrobenzotrichlorides
XA are hydrolyzed in the presence of a catalyst or in a weakly
acidic medium at temperatures less than 80.degree. C.
[0338] The present invention accordingly further provides a process
for preparing fluorinated m-nitrobenzoyl chlorides IIA
##STR00024## [0339] where the variables are each defined as
follows: [0340] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each
hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy or
C.sub.1-C.sub.6-haloalkoxy; [0341] where at least one of the
radicals R.sup.1 to R.sup.4 is fluorine, by hydrolyzing fluorinated
m-nitrobenzotrichlorides XA
[0341] ##STR00025## [0342] where the variables R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are each as defined above, [0343] wherein the
reaction takes places in the presence of a catalyst or in a weakly
acidic medium and also at temperatures less than 80.degree. C.
[0344] 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.
[0345] The variables R.sup.1, R.sup.2, R.sup.3 and R.sup.4 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
R.sup.1 to R.sup.4 in the combination of all four radicals R.sup.1
to R.sup.4 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.
[0346] The preferred embodiments of the hydrolysis of the
fluorinated m-nitrobenzotrichlorides XA to 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.
[0347] The hydrolysis of fluorinated m-nitrobenzotrichlorides XA to
fluorinated m-nitrobenzoyl chlorides IIA takes place at
temperatures less than 80.degree. C. (<80.degree. C.),
preferably between 29 and <80.degree. C., very preferably
between 49.degree. C. and <80.degree. C., with particular
preference between 59.degree. C. and <80.degree. C., if
appropriate in an inert organic solvent in the presence of an acid
and/or a catalyst.
[0348] Suitable solvents are aliphatic hydrocarbons such as
pentane, hexane, cyclohexane and mixtures of C.sub.5-C.sub.8
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 being given to aliphatic
hydrocarbons and halogenated hydrocarbons.
[0349] Mixtures of the stated solvents can also be used.
[0350] 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 <80.degree. C.,
preferably from 60 to <80.degree. C., more preferably from 60 to
75.degree. C. This version of the reaction regime is preferred.
[0351] 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.
[0352] 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.
[0353] The acids are used generally in an equimolar amount, but may
also be used catalytically.
[0354] Suitable catalysts are Lewis acids such as iron(III)
chloride, iron sulfate, cerium(III) chloride or copper(II)
chloride; iron(III) 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.
[0355] 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.
[0356] 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 carrying out extraction with aqueous
mineral acids such as hydrochloric acid or sulfuric acid.
[0357] Alternatively the reaction mixture obtained can also be
supplied in the form of its melt directly to the next reaction
stage, without further purification.
[0358] 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.
[0359] 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:
##STR00026##
[0360] 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:
##STR00027##
[0361] The variables R.sup.1, R.sup.2, R.sup.3 and R.sup.4 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.
[0362] The present invention accordingly further provides a process
for preparing sulfonamides I, more particularly fluorinated
sulfonamides IA, 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.
[0363] 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.
[0364] This reaction of the benzotrichlorides X with m-nitrobenzoic
acids VII takes place typically at temperatures of 70.degree. C. to
160.degree. C., preferably 70.degree. C. to 120.degree. C., with
particular preference 80.degree. C. to 110.degree. C., if
appropriate in an inert organic solvent in the presence of a
catalyst.
[0365] Suitable solvents are aliphatic hydrocarbons such as
pentane, hexane, cyclohexane and mixtures of C.sub.5-C.sub.8
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.
[0366] Mixtures of the stated solvents can be used as well.
[0367] 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.degree. C.,
preferably 80 to 110.degree. C. This version of the reaction regime
is preferred.
[0368] Suitable catalysts are Lewis acids such as iron(III)
chloride, iron sulfate, cerium(III) chloride or copper(II)
chloride, for example, particular preference being given to
iron(III) chloride.
[0369] 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.
[0370] The benzotrichlorides X and m-nitrobenzoic acids VII are
preferably reacted with one another in equimolar amounts.
[0371] 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 carrying out extraction with aqueous
mineral acids such as hydrochloric acid or sulfuric acid.
[0372] Alternatively the reaction mixture obtained can be supplied
in the form of its melt directly to the next reaction stage,
without further purification.
[0373] 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.
[0374] 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:
##STR00028##
[0375] In connection with the aniline derivatives VI the variables
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 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.
[0376] The reduction of the sulfonamides Ito aniline derivatives VI
is accomplished, for example, 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 <0 V and more
particularly less than or equal to -0.1 V, e.g. in the range from
-0.1 to -1.0 V (in acidic aqueous solution at 15.degree. 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 HCl in an ether or an alcohol or a
mixture thereof, for example, or organic carboxylic acids,
appropriately acetic acid, propionic acid or butyric acid.
[0377] 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. Tray. 80
(1961), 1075).
[0378] Depending on the nature of the metal and acid, the reaction
temperature is situated generally in the range from -20 to
+120.degree. C., preference being given, when using alkanoic acids
such as acetic acid, to using temperatures in the range from 50 to
100.degree. 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.
[0379] 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.degree. C., preferably 65 to 75.degree. 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.
[0380] 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.
[0381] 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.degree. C.,
advantageously 20 to 50.degree. 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
C.sub.1-C.sub.4 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.
[0382] 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.
[0383] 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.
[0384] 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.
[0385] The reaction takes place typically at temperatures of
0.degree. C. to 100.degree. C., preferably at 10.degree. C. to
50.degree. C., either solventlessly or in an inert solvent (cf.
e.g. Tepko et al., J. Org. Chem. 1980, 45, 4992).
[0386] Depending on the solubility of the substrate for
hydrogenation, suitable solvents are aliphatic hydrocarbons such as
pentane, hexane, cyclohexane and mixtures of C.sub.5-C.sub.8
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.
[0387] It is also possible to use mixtures of the stated solvents.
In addition it is also possible to operate without solvent.
[0388] 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.
[0389] 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, ZrO.sub.2,
TiO.sub.2, SiO.sub.2, carbonates and the like, preferably activated
carbon.
[0390] 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.
[0391] The transition metals can also be used in the form of
activated metals such as Raney nickel or in the form of
compounds.
[0392] 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/1C, pp. 520-526).
[0393] The catalysts are used generally in an amount of 0.005 to 10
mol % (calculated as metal), preferably 0.001 to 10 mol %, 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.
[0394] 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.
[0395] 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.
[0396] In the case of chlorinated sulfonamides I the hydrogenation
is carried out--depending on the sensitivity of the
substituent--preferably at 20 to 170.degree. C., with particular
preference at 20 to 140.degree. C., with great preference at 20 to
80.degree. C.
[0397] In the case of sulfonamides I having reactive halogen
substituents it is further advisable to carry out hydrogenation in
neutral solution, where appropriate with only 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.
[0398] 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).
[0399] The reduction of the sulfonamides Ito 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.degree. C.,
preferably between 60 to 80.degree. C. It is judicious to use 3 to
4 mol of sodium sulfide per mole of sulfonamide I.
[0400] The examples which follow serve to further illustrate the
invention:
1. Preparation of the Fluorinated m-Nitrobenzoyl Chlorides IIA The
Yields of Fluorinated m-Nitrobenzoyl Chloride IIA were, Unless
Stated Otherwise, Determined by Means of Quantitative HPLC:
Sample Preparation:
[0401] 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:
[0402] Column: symmetry C18 5 .mu.m 250.times.4.6 mm from
Waters.RTM.
[0403] Wavelength: 222 nm
[0404] Eluent: gradient of A (0.1% by volume of H.sub.3PO.sub.4 in
H.sub.2O) and B (0.1% by volume of H.sub.3PO.sub.4 in CH.sub.3CN);
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.
[0405] Flow rate: 1 ml/min
[0406] Pressure: approx. 150 bar
Calibration:
[0407] 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.
[0408] 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.
[0409] 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:
[0410] 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.
[0411] 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 <25 mg/l
of fluoride).
[0412] The error limit is +/-0.002 g/l.
[0413] The following units were used:
TABLE-US-00001 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)
##STR00029##
[0415] 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.degree. 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.degree. C. for a further 2 h.
[0416] 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.
[0417] 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 .sup.19F-NMR with internal
standard) of the title product were obtained as a solution in
chlorobenzene.
[0418] 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)
##STR00030##
[0420] 22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic
acid
[0421] 16.8 g (0.14 mol) of thionyl chloride
[0422] 0.1 g (0.00036 mol) of triphenyl phosphine oxide
[0423] Yield*: 46.5 g (>99% of theory) of the title compound as
a solution in chlorobenzene
[0424] Fluoride value: 0.01 g/l
EXAMPLE 1.3
4-fluoro-5-nitrobenzoyl chloride (without catalyst)
[0425] 18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid
[0426] 16.8 g (0.14 mol) of thionyl chloride
[0427] Yield*: 47.3 g (86% of theory) of the title compound as a
solution in chlorobenzene
[0428] Fluoride value: 0.26 g/l
EXAMPLE 1.4
2-chloro-4-fluoro-5-nitrobenzoyl chloride (without catalyst)
[0429] 22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic
acid
[0430] 16.8 g (0.14 mol) of thionyl chloride
[0431] Yield: 47.0 g (95% of theory) of the title compound as a
solution in chlorobenzene
[0432] Fluoride value: 0.02 g/l
EXAMPLE 1.5
4-fluoro-5-nitrobenzoyl chloride (with DMAP)
[0433] 18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid
[0434] 16.8 g (0.14 mol) of thionyl chloride
[0435] 0.1 g (0.0008 mol) of 4-dimethylaminopyridine
[0436] Yield*: 40.8 g (96% of theory) of the title compound as a
solution in chlorobenzene
[0437] Fluoride value: 0.03 g/l
EXAMPLE 1.6
2-chloro-4-fluoro-5-nitrobenzoyl chloride (with DMAP)
[0438] 22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic
acid
[0439] 16.8 g (0.14 mol) of thionyl chloride
[0440] 0.1 g (0.0008 mol) of 4-dimethylaminopyridine
[0441] Yield: 46.8 g (97% of theory) of the title compound as a
solution in chlorobenzene
[0442] Fluoride value: 0.05 g/l
EXAMPLE 1.7
4-fluoro-5-nitrobenzoyl chloride (with DMF)
[0443] 18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid
[0444] 16.8 g (0.14 mol) of thionyl chloride
[0445] 0.1 g (0.0014 mol) of dimethylformamide
[0446] Yield*: 40.8 g (98% of theory) of the title compound as a
solution in chlorobenzene
[0447] Fluoride value: 0.02 g/l
EXAMPLE 1.8
4-fluoro-5-nitrobenzoyl chloride (with pyridine)
[0448] 18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid
[0449] 16.8 g (0.14 mol) of thionyl chloride
[0450] 0.1 g (0.0013 mol) of pyridine
[0451] Yield*: 40.8 g (96% of theory) of the title compound as a
solution in chlorobenzene
[0452] Fluoride value: 0.03 g/l * In these examples, the yield was
determined by means of .sup.19F-NMR with internal standard.
EXAMPLE 1.9
2-chloro-4-fluoro-5-nitrobenzoyl chloride (with pyridine)
[0453] 22.3 g (0.1 mol) 2-chloro-4-fluoro-5-nitrobenzoic acid
[0454] 16.8 g (0.14 mol) of thionyl chloride
[0455] 0.1 g (0.0013 mol) of pyridine
[0456] Yield: 46.8 g (98% of the title compound as a solution in
chlorobenzene
[0457] Fluoride value: 0.13 g/l
[0458] These experiments show that the process according to the
invention distinctly reduces the fluoride elimination:
[0459] 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
[0460] 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.degree. 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.
[0461] After the end of the metered addition the system was stirred
at 75.degree. 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.degree. C. After cooling to approximately
20.degree. 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 (<10 ppm).
EXAMPLE 1.11
[0462] 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.degree. 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.degree. 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
[0463] In the same way as example 1.11, 296 g (1 mol) of
2-chloro-4-fluoro-5-nitrobenzotrichloride, 0.95 g (5.7 mmol) of
iron chloride and 18.2 g (1 mol) of water were reacted at
80.degree. C. This gave 238 g of 2-chloro-4-fluoro-5-nitrobenzoyl
chloride with a purity of 97% (97% of theory).
EXAMPLE 1.13
[0464] In the same way as in example 1.11, 296 g (1 mol) of
2-chloro-4-fluoro-5-nitrobenzotrichloride, 0.5 g (3 mmol) of iron
chloride and 18.2 g (1 mol) of water were reacted at 120.degree. C.
After the end of the metered addition of the water, stirring was
continued for 30 minutes at 120-125.degree. C. The system was
subsequently cooled to 60.degree. 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
[0465] 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.degree. 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.degree. 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
[0466] 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.degree. 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.degree. C. for
2 h. The mixture was acidified by means of addition of conc.
hydrochloric acid, cooled to 0.degree. C. and stirred for 1 h.
[0467] The solid was filtered off and washed once with HCl
solution. 6.7 g (73% of theory) of the title compound were
obtained.
[0468] .sup.1H NMR (500 MHz, CDCl3) .delta.=9.30 ppm (br. s., NH),
8.45 (d, Ar--H), 7.45 (d, Ar--H), 3.5 [q, CH.sub.2CH.sub.3], 1.30
(t, CH.sub.2CH.sub.3).
EXAMPLE 2.2
N-(4-fluoro-3-nitrobenzoyl)-N'-1-propyl-N'-methylsulfonamide
[0469] 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.degree. 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 conc. hydrochloric acid and
stirred for 1 h. The solid was filtered off, washed once with 1N
HCl solution and recrystallized from chlorobenzene. A final
filtration and drying 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.degree. C.
[0470] .sup.1H NMR (500 MHz, d-DMSO) .delta.=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(CH.sub.3).sub.2], 2.95 (s, CH.sub.3), 1.15 ppm [d,
CH(CH.sub.3).sub.2].
EXAMPLE 2.3
N-(4-fluoro-3-nitrobenzoyl)-N'-1-propyl-N'-methylsulfonamide
[0471] 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.degree. 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.degree. C. for 12 h. The mixture was diluted by means of
addition of 140 g of water and acidified with conc. hydrochloric
acid, cooled to 0.degree. C. and stirred for 1 h. The solid was
filtered off and washed once with HCl solution. 7.6 g (86% of
theory) of the title compound having an m.p. of 164-165.degree. C.
were obtained.
EXAMPLE 2.4
N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N'-1-propyl-N'-methylsulfonamide
[0472] 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.degree. 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
tetrahydrofuran was added dropwise. The reaction mixture was
subsequently stirred at 25.degree. C. for 2 h and acidified by
means of addition of conc. 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.degree. C. were obtained.
[0473] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=9.1 ppm (s, NH),
8.4 (d, Ar--H), 7.45 (d, Ar--H), 4.25 (sept., iPr--H), 2.95 (s,
Me), 1.25 (d, iPr--H).
EXAMPLE 2.5
N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N'-1-propyl-N'-methylsulfonamide
[0474] 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.degree. 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.degree. C. for 1 h and then acidified by means of
addition of conc. hydrochloric acid. Finally, the mixture was
cooled to 0.degree. C., and the precipitated solid was filtered off
and washed with 1N HCl solution. 72.5 g (82% of theory) of the
title compound were obtained.
[0475] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=9.1 ppm (s, NH),
8.4 (d, Ar--H), 7.45 (d, Ar--H), 4.25 (sept., iPr--H), 2.95 (s,
Me), 1.25 (d, iPr--H).
EXAMPLE 2.6
[0476] A solution of 41.1 g (0.27 mol) of
N-methyl-N-(1-methylethyl)sulfamoylamide and 0.75 g (12.0 mmol) of
tributylmethylammonium chloride in 633 g of chlorobenzene was
admixed at 20.degree. 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.degree. 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.degree. C. The
precipitate was isolated by filtration and dried at 70.degree. 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 .mu.m 250.times.4.6 mm
from Waters.RTM.; wavelength: 222 nm, 205 nm; eluent: gradient of A
(0.1% by volume H.sub.3PO.sub.4 in H.sub.2O) and B (0.1% by volume
H.sub.3PO.sub.4 in CH.sub.3CN); flow rate: 1 ml/min; pressure:
about 150 bar).
EXAMPLE 2.7
[0477] A solution of 43.1 g (0.277 mol) of
N-methyl-N-(1-methylethyl)sulfamoylamide 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.degree. 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.degree. 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.degree. 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.degree. C. The resulting organic phase was admixed with a
further 280 g of isohexane and then cooled to 0.degree. C.
Filtration, washing with water and drying under reduced pressure at
70.degree. 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
[0478] A solution of 43.1 g (0.277 mol) of
N-methyl-N-(1-methylethyl)sulfamoylamide 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.degree. 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.degree. 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.degree. 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.degree. C. The resulting organic phase was admixed with a
further 280 g of isohexane and then cooled to 0.degree. C.
Filtration, washing with water and drying under reduced pressure at
70.degree. C. gave 82.1 g (87% of theory, purity 97%) of
N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N'-isopropyl-N'-methylsulfamide.
In the solid, HPLC analysis found no contamination with
2-chloro-4-fluoro-3-nitrobenzoic acid.
EXAMPLE 2.9
[0479] A solution of 8.22 g (54.0 mmol) of
N-methyl-N-(1-methylethyl)sulfamoylamide 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.degree. 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.degree. 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.degree. C.
EXAMPLE 2.10
[0480] 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.degree. 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.degree. 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.degree. C. and filtered. The
resulting solid was washed on the filter with dilute sulfuric acid
(pH 1) and finally dried at 70.degree. 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
[0481] 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.degree. C. After 12 h the solution was depressurized, the
reaction mixture was filtered and the solvent was removed by
distillation. This gave 80.1 g (98%) of the title compound in the
form of a beige solid (m.p.: 148-150.degree. C.).
[0482] In addition to the implementation described above, table 1
lists further experiments carried out in the same way as the above
process:
TABLE-US-00002 TABLE 1 p H.sub.2 T t Yield No. Catalyst system mol
% [bar] [.degree. C.] [h] Solvent [%] 1 10% Pd/C 0.91 5 26 12
methanol 98 2 10% Pd/C 0.23 5 26 9 methanol 98 3 3% Pt/C 0.49 5 26
9 methanol 95 4 5% Ir/C 0.49 5 26 9 methanol 74 5 5% Ru/C 0.49 5 26
9 methanol 78 6 5% Pt/C 0.52 5 26 9 methanol 95 7 1%Pt/0.1%Cu/C
0.51 5 26 9 methanol 99 8 10% Pd/C 0.94 5 26 9 toluene/methanol 96
1:1 9 5%Pd/0.1%Pt/ 0.24 5 26 9 methanol 55 0.1%Fe/C 10 1%Pt/2%V/C
0.24 5 26 9 toluene 98 11 1%Pt/0.2%Ni/C 0.23 5 26 9 toluene 79 12
10% Pd/C 0.29 5 26 9 chlorobenzene/ 97 methanol 1:1 13 10% Pd/C 0.6
5 26 12 n-butyl acetate 99 14 10% Pd/C 0.91 5 26 12 dichloromethane
92 15 5-10% Pd/C 0.26 5 26 9 chlorobenzene 87 16 10% Pd/C 0.26 5 26
12 ethyl acetate 77 17 1%Pt/0.1%Cu/C 0.25 5 26 9 chlorobenzene 98
18 1%Pt/2%V/C 0.25 5 26 9 chlorobenzene 96 19 10% Pd/C 0.30 5 26 12
tetrahydrofuran 87 20 10% Pd/C 0.26 5 26 12 ethyl acetate/ 97
methanol 1:1 21 1%Pt/2%V/C 0.50 5 26 9 methanol 94 22 10% Pd/C 0.11
5 26 9 methanol 64 23 1%Pt/0.1%Cu/C 0.24 5 26 9 toluene 89 24 10%
Pd/C 0.50 2 26 9 methanol 97 25 10% Pd/C 0.15 2 26 9 methanol 96 26
1%Pt/2%V/C 0.24 5 50 9 chlorobenzene 77 27 5% Pt/C 0.25 5 30 9
chlorobenzene/ 97 methanol 7:1 28 5% Pt/C 0.26 5 50 9 chlorobenzene
96 29 1%Pt/0.1%Cu/C 0.25 5 50 9 chlorobenzene 93 30 10% Pd/C 0.51 2
50 9 methanol 97 31 10% Pd/C 0.51 5 70 9 chlorobenzene 98
EXAMPLE 3.2
N--(N-(2-Chloro-4-fluoro-3-aminobenzoyl)-N'-isopropyl-N'-methylsulfamide
[0483] 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 mg
(0.055 mol %) of 3% Pt/C and hydrogenated with 5 bar of hydrogen
with stirring at 70.degree. 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.degree. C.).
EXAMPLE 3.3
N--(N-(2-Chloro-4-fluoro-3-aminobenzoyl)-N'-isopropyl-N'-methylsulfamide
[0484] 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.degree. 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.degree. C.).
EXAMPLE 3.4
N--(N-(2-Chloro-4-fluoro-3-aminobenzoyl)-N'-isopropyl-N'-methylsulfamide
[0485] 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.degree. 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.degree. C.).
EXAMPLE 3.5
N--(N-(2-Chloro-4-fluoro-3-aminobenzoyl)-N'-isopropyl-N'-methylsulfamide
[0486] 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.degree. 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.degree. C.).
* * * * *