EP1957443A2

EP1957443A2 - Method for producing sulfonamides

Info

Publication number: EP1957443A2
Application number: EP06830101A
Authority: EP
Inventors: Thomas Schmidt; Joachim Gebhardt; Sandra LÖHR; Michael Keil; Jan Hendrik Wevers; Michael Rack; Guido Mayer; Axel Pleschke
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2005-12-01
Filing date: 2006-11-23
Publication date: 2008-08-20
Also published as: JP5555426B2; AU2006319263A1; US20120310010A1; KR20080072093A; AU2006319263B2; KR101430949B1; IL215280A0; KR101422433B1; EA200801432A1; US8263806B2; AR057211A1; US20100228054A1; CA2821517A1; IL215279A0; IL191503A; EA201100377A1; KR101422434B1; KR20130093695A; CA2821516A1; KR20130093696A

Abstract

The invention relates to methods for producing sulfonamides of formula I, wherein the variables have the designations cited in the description, by reacting m-nitro-benzoic acid chlorides of formula II with aminosulfons of formula III, under the influence of B equivalents of base IV. Said method is characterised in that, during step a) the aminosulfon of formula III is reacted with B1 equivalents of base IV, and during step b), the reaction mixture resulting from step a) is reacted with m-nitro-benzoic acid chlorides of formula II and B2 equivalents of base IV; B, B1 and B2 having the designations cited in the description.

Description

Process for the preparation of sulfonamides

description

The present invention relates to a process for the preparation of sulfonamides I.

where the variables have the following meanings:

R ¹ , R ² , R ³ and R ^{4 are} hydrogen, halogen, cyano, nitro, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -alkoxy or C ₁ -C ₆ -haloalkoxy;

R ⁵ and R ^{6 are} hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, C ₃ -C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkenyl, C ₁ -C ₆ -cycloalkyl Alkoxy, phenyl or benzyl.

In the prior art, for example in WO 01/83459, a process for the preparation of heterocyclylsubstituierten Phenylsulfamoylcarboxamiden by the reaction of benzoic acid derivatives with sulfamides, optionally in the presence of a coupling reagent is described.

Furthermore, it is known, for example, from WO 04/39768 that N-aroylsulfonamides can be prepared by reaction of corresponding benzoic acid derivatives with sulfonated diamides under the influence of bases by initially introducing sulfonic acid diamides and the base and then adding the benzoic acid derivative.

The present invention is therefore based on the object to provide a simple, economical and process-capable process for the preparation of sulfonamides I, in which on the one hand the by-product formation is significantly reduced, and at the same time high yields and high purity of desired product can be achieved.

It has surprisingly been found that this object is achieved by a process in which m-nitrobenzoyl chlorides II are reacted with aminosulfones IM under the influence of from 1.5 to 3 equivalents of base IV based on the aminosulfone IM, characterized in that in step a) the Amino sulfone IM is reacted with 0.1 - 1, 3 equivalents of base IV, and in step b), the reaction mixture resulting from step a) with m-nitro-benzoic acid chloride Il and the remaining part of the base IV is dissolved. Accordingly, the present invention relates to a process for the preparation of sulfonamides I.

where the variables have the following meanings:

R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, Ci -C ₆ -alkyl, -C ₆ - haloalkyl, Ci-C ₆ alkoxy or Ci-C ₆ haloalkoxy;

R ⁵ and R ⁶ is hydrogen, Ci-C ₆ alkyl-Al, C ₃ -C ₆ alkenyl, C ₃ -C ₆ kinyl -alkyl, C ₃ -C ₇ - cycloalkyl, C ₃ -C ₇ cycloalkenyl, d- Ce-alkoxy, phenyl or benzyl;

by reaction of m-nitro-Benzoesäurechloriden Il

where the variables R ¹ , R ² , R ³ and R ^{4 have} the abovementioned meanings;

with aminosulfones IM

H ₂ N-SO ₂ NR ⁵ R ⁶ II I,

where the variables R ⁵ and R ^{6 have} the abovementioned meanings; under the influence of B equivalents of base IV, characterized in that in step a) the aminosulfone IM is reacted with B1 equivalents of base IV, and in step b) the reaction mixture resulting from step a) with m-nitro-benzoic acid chloride Il and B2 equivalents Base IV is implemented;

wherein B is 1, 5 - 3 equivalents of base IV with respect to the aminosulfone IM;

B1 represents a subset of B and in the range of 0.1-1.3 equivalents

Base IV is relative to the aminosulfone IM; and B2 represents a subset of B and is the difference of B and B1.

Depending on the substitution pattern, the sulfonamides I prepared by the process according to the invention may contain and lie one or more centers of chirality then as enantiomer or diastereomeric mixtures. The invention thus provides a process for preparing both the pure enantiomers or diastereomers and mixtures thereof.

The organic moieties mentioned for the substituents R ¹ to R ⁶ and R ^a , R ^b and R ^c are collective terms for individual enumerations of the individual group members. All hydrocarbon chains, ie all alkyl, haloalkyl, alkoxy and haloalkoxy moieties can be straight-chain or branched. Unless otherwise indicated, halogenated substituents preferably carry one to five identical or different halogen atoms. The meaning halogen in each case represents fluorine, chlorine, bromine or iodine.

Furthermore, for example:

C 1 -C ₄ -alkyl: for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1, 1-dimethylethyl;

C 1 -C 6 -alkyl: C 1 -C ₄ -alkyl as mentioned 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;

_{Ci-C4-haloalkyl:} a Ci-C ₄ -alkyl radical as mentioned above which is partially or completely, chlorine, bromine / or iodine with fluorine and is substituted, methyl eg chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoro- , 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;

C 1 -C 6 -haloalkyl: C 1 -C ₄ -haloalkyl as mentioned above, and also, for example, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6 -lodhexyl and tridecafluorohexyl; C2-C6 alkenyl: eg 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;

C ₂ -C ₆ alkynyl: eg 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;

Ca-Cs-cycloalkyl: e.g. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;

C3-C7 cycloalkenyl: e.g. 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-cycloheptatolenyl, 2,4,6-cycloheptatrienyl; C 1 -C ₄ -alkoxy: eg methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy and 1, 1-dimethylethoxy;

C 1 -C 6 -alkoxy: C 1 -C ₄ -alkoxy as mentioned 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;

Ci-C4-haloalkoxy: a Ci-C4-Alkoxyτest as mentioned above, which is partially or completely substituted by fluorine, chlorine, bromine and / or iodine, al. 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;

Ci-Cδ-haloalkoxy: Ci-C4-haloalkoxy as mentioned above, as well as e.g. 5-fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy, undecamluoropentoxy, 6-fluorohexoxy, 6-chlorohexoxy, 6-bromohexoxy, 6-iodohexoxy and tridecafluorohexoxy;

In particularly preferred embodiments of the method according to the invention, the variables R ^1, R ^2, R ^3, R ^4, R ⁵ and R ⁶ as defined below, which considered alone or in combination with each other particular embodiments illustrating the method according to the invention:

Preference is given to the embodiment of the process according to the invention in which R ^{1 is} hydrogen, halogen or C ¹ -C 6 -alkyl; preferably hydrogen or halogen; very preferably hydrogen, fluorine or chlorine; particularly preferably hydrogen; means. Likewise preferred is the embodiment of the process according to the invention in which R ^{2 is} hydrogen, halogen, cyano, C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; preferably hydrogen or halogen; very preferably hydrogen, fluorine or chlorine; particularly preferably hydrogen or fluorine, very preferably hydrogen; also very preferably fluorine, means.

Also preferred is the embodiment of the process according to the invention, in which R ^{2 is} hydrogen or halogen; preferably halogen; very preferably fluorine or chlorine; particularly preferably fluorine, means.

Likewise preferred is the embodiment of the process according to the invention in which R ^{3 is} hydrogen, halogen or C ₁ -C ₆ -alkyl; preferably hydrogen or halogen; very preferably hydrogen, fluorine or chlorine; particularly preferably hydrogen.

Also preferred is the embodiment of the process according to the invention in which R ^{4 is} hydrogen, halogen, cyano, C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; preferably hydrogen, halogen or cyano; very preferably hydrogen, fluorine, chlorine or cyano; particularly preferably hydrogen, chlorine or cyano, very preferably hydrogen; also most preferably chlorine or cyano; very preferably chlorine; means.

Also preferred is the embodiment of the process according to the invention in which R ^{4 is} halogen or cyano; preferably halogen; very preferably fluorine or chlorine; most preferably chlorine; means.

Likewise preferred is the embodiment of the method according to the invention, in which R ^{4 is} hydrogen, halogen or cyano; preferably hydrogen or halogen; very preferably hydrogen, fluorine or chlorine; particularly preferably hydrogen or chlorine; means.

Equally preferred is the embodiment of the process according to the invention in which R ⁵ and R ^{6 are} independent of one another

Is hydrogen, Ci -C ₆ -alkyl or C ₂ -C ₆ alkenyl; preferably hydrogen or C 1 -C 6 -alkyl; very preferably C 1 -C 6 -alkyl; particularly preferably C 1 -C 4 -alkyl; means.

Also preferred is the embodiment of the inventive method in which R ^{5 is} hydrogen or Ci-C ₆ -alkyl; preferably hydrogen or C 1 -C 4 -alkyl; very preferably C 1 -C 4 -alkyl; particularly preferably methyl; means.

Also preferred is the embodiment of the method according to the invention, in which R ^{6 is} hydrogen or C ₁ -C ₆ -alkyl; preferably hydrogen or C 1 -C 4 -alkyl; very preferably C 1 -C 4 -alkyl; means.

In a very preferred embodiment of the process according to the invention, the variables R ¹ , R ² , R ³ , R ^{4 have} the abovementioned meanings, in particular the meanings mentioned as being preferred, where at least one of the radicals R ¹ to R ^{4 is} fluorine.

In a further very preferred embodiment of the process according to the invention, the variables R ¹ , R ² , R ³ and R ^{4 have the} following meanings: R ^{1 is} hydrogen;

R ^{2 is} hydrogen or halogen; preferably halogen; very preferably fluorine; R ^{3 is} hydrogen; and R ^{4 is} hydrogen, chlorine or cyano, preferably chlorine or cyano; very preferably chlorine. In a further very preferred embodiment of the process according to the invention, the variables R ¹ , R ² , R ³ and R ^{4 have the} following meanings: R ^{1 is} hydrogen; R ^{2 is} hydrogen or halogen; preferably halogen; very preferably fluorine; R ^{3 is} hydrogen; and R ^{4 is} hydrogen or halogen, preferably hydrogen or chlorine; very preferably chlorine, very preferably hydrogen.

In a further very preferred embodiment of the process according to the invention, the variables R ¹ , R ² , R ³ and R ^{4 have the} following meanings:

R ^{1 is} hydrogen;

R ^{2 is} fluorine;

R ^{3 is} hydrogen; and

R ^{4 is} halogen, preferably chlorine.

In a further, very preferred embodiment of the process according to the invention, the variables R ¹ , R ² , R ³ , R ⁴ and R ^{5 have the} following meanings: R ^{1 is} hydrogen; R ^{2 is} hydrogen or halogen; preferably halogen; very preferably fluorine; R ^{3 is} hydrogen; and

R ^{4 is} hydrogen or halogen, preferably hydrogen or chlorine; very preferably chlorine, very preferably hydrogen; R ⁵ and R ⁶ is hydrogen, Ci -C ₆ -alkyl or C ₂ -C ₆ alkenyl; preferably hydrogen or Ci-Cδ-alkyl; very preferably Ci-Cδ-alkyl; particularly preferably C 1 -C 4 -alkyl.

In a preferred embodiment of the process according to the invention, sulfonamides IA produced, the variables having the following meanings:

R ¹ , R ² , R ³ and R ^{4 are} hydrogen, halogen, cyano, nitro, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -

Haloalkyl, Ci-C ₆ alkoxy or Ci-C ₆ haloalkoxy; and wherein at least one of the radicals R ¹ to R ⁴ is fluoro, and R ⁵ and R ⁶ is hydrogen, Ci-C ₆ -alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ -alkyl kinyl, C ₃ - C ₇ -cycloalkyl, C ₃ -C ₇ -cycloalkenyl, C ₁ -C ₆ -alkoxy, phenyl or benzyl.

In a further preferred embodiment of the method according to the invention can on this

are prepared, wherein the variables R ² , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meanings mentioned above, in particular those previously mentioned as preferred meanings.

In a further preferred embodiment of the process according to the invention, sulfonamides Lb

are prepared, wherein the variables R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 have} the abovementioned meanings, in particular those previously mentioned as preferred meanings.

In a further preferred embodiment of the process according to the invention, sulfonamides Lc are prepared, wherein the variables R ¹ , R ² , R ⁴ , R ⁵ and R ^{6 have} the meanings given above, in particular those previously mentioned as preferred meanings.

In a further preferred embodiment of the method according to the invention sulfonamides l.d

are prepared, wherein the variables R ¹ , R ² , R ³ , R ⁵ and R ^{6 have} the meanings given above, in particular the meanings mentioned above as preferred.

In a further preferred embodiment of the process according to the invention, sulfonamides V.e

wherein the variables R ² , R ⁴ R ⁵ and R ^{6 have} the abovementioned meanings, in particular the meanings mentioned above as preferred, and wherein at least one of the radicals R ² and R ^{4 is} fluorine.

In the following, the preferred embodiments of the method according to the invention are described, these considered individually and in combination with each other represent special embodiments of the method according to the invention.

The m-nitro-Benzoesäurechloride II and with aminosulfones IM can be reacted in equimolar amounts with each other.

Advantageously, the molar amounts in which m-nitro-Benzoesäurechloride II, preferably fluorinated m-nitro-Benzoesäurechloride IIA and aminosulfones IM are reacted together, 1: 0.9 - 1, 8; preferably 1: 0.9-1.5; very preferably 1: 0.9 - 1, 2; particularly preferably 1: 0.95-1.2; most preferably 1: 0.95-1.1 for the ratio of II, preferably IIA, to IM.

The reaction of m-nitro-benzoic acid chlorides Il according to the invention with Aminosul- fönen IM to sulfonamides I is usually carried out at temperatures from -30 ° C to 120 ° C, preferably from -10 ⁰ C to 100 ° C, particularly preferably 0 ° C to 80 ° C, in an inert organic solvent under the influence of 1, 5 -3 equivalents of a base IV with respect to the aminosulfone IM and optionally in the presence of a catalyst.

Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, heptane, cyclohexane and mixtures of Cs-Cs-Al kanen, 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, anisole and tetrahydrofuran, esters such as ethyl acetate, propyl acetate, n-butyl acetate, methyl isobutyrate, isobutyl acetate; and dimethylsulfoxide, dimethylformamide and dimethylacetamide; particularly preferably aromatic hydrocarbons and halogenated hydrocarbons.

It is also possible to use mixtures of the abovementioned solvents or mixtures of the abovementioned solvents with water.

The reaction according to the invention of the m-nitrobenzoyl chlorides II with aminosulfones IM to form sulfonamides I takes place in the presence of a total of 1.5 equivalents of base IV with respect to the aminosulfone IM. These 1, 5 - 3 equivalents of base IV represent the total base amount "B", which is used in the process according to the invention represents.

In step a) of the process according to the invention, the aminosulfone IM is reacted with 0.1-1.3 equivalents of base with respect to the aminosulfone IM. These 0.1-1.3 equivalents of base IV are a subset of the aforesaid total base amount B and are also referred to as base amount "B1".

In step b) of the process according to the invention, the reaction mixture resulting from step a) is reacted with m-nitrobenzoyl chloride II and the remaining amount of the total base amount B less Bl. The remaining amount of the total base amount B is also called the base amount "B2".

Thus, the following relationship between B, B1 and B2 applies: B1 + B2 = B. As bases IV are generally 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 bicarbonate, alkali metal and alkaline earth metal alkoxides such as sodium, sodium, potassium, potassium tert-butoxide, KaIi- um-tert. Pentanolate and dimethoxy magnesium, as well as organic bases, for example tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine and 4-dimethylaminopyrid in as well as bicyclic amines such as 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN) into consideration. Particularly preferred are alkali metal and alkaline earth metal hydroxides and tertiary amines.

Particularly preferred are alkali metal and alkaline earth metal hydroxides, alkali metal hydroxides are extremely preferred.

There are used 1, 5 - 3 equivalents of base IV (total base amount B) based on the A- minosulfon IM. Very preferably B stands for 1, 8-2.5 equivalents based on the aminosulfone IM.

1, 8-2.5 equivalents based on the m-nitrobenzoyl chlorides M, particularly preferably on the fluorinated m-nitrobenzoyl chlorides IIA, are also very highly preferred.

where the variables have the following meanings: R ¹ , R ² , R ³ and R ^{4 are} hydrogen, halogen, cyano, nitro, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -alkoxy or C ₁ -C ₆ -haloalkoxy ; wherein at least one of R ¹ to R ^{4 is} fluorine; used.

In step a) of the process according to the invention, preference is given to initially introducing the aminosulfone IM in an inert solvent. Subsequently, B1 equivalents of base IV, ie, 0.1-1.3 equivalents, preferably 0.1-1 equivalents, more preferably 0.2-0.95 Equivalent base IV, added. Particularly advantageously, the base IV is added over a certain period of time. Very preferably, the B1 equivalents of the base IV are added continuously, very particularly preferably uniformly, continuously over a certain period of time. This period of addition of the B1 equivalents of Base IV in step a) can be from 1 minute to 20 hours. In general, this period is 1 min to 6 hours, preferably 1 min to 3 hours.

However, it is also possible, preferably according to the variants described above, to add the aminosulfone IM to the desired base amount B1, in particular to the base amount B1 mentioned as being preferred.

Preference is given in step b) of the process according to the invention to the m-nitrobenzoyl chloride II, preferably the fluorinated m-nitrobenzoyl chloride IIA, preferably diluted in an inert solvent, and the B2 equivalents of base IV to the reaction mixture resulting from step a) , preferably also diluted in an inert solvent.

Preferably, in step b), the addition of the m-nitrobenzoyl chloride II and the B2 equivalents of base IV simultaneously (= parallel addition), very preferably at the same time over a certain period, more preferably simultaneously continuously over a certain period of time, most preferably at the same time continuously over a certain period of time to the reaction mixture resulting from step a). This period of addition of the m-nitrobenzoyl chloride II and the B2 equivalents base IV in step b) can be from 1 minute to 20 hours. In general, this period is 1 min to 6 hours, preferably 1 min to 3 hours.

However, it is also possible, preferably according to the variants described above, to add the reaction mixture resulting from step a) and the base amount B2 simultaneously, preferably over a certain period of time, to m-nitrobenzoyl chloride II, preferably diluted in an inert solvent.

Furthermore, the m-nitro-benzoic acid chloride II, preferably the fluorinated m-nitro-benzoic acid chloride IIA, also in bulk, i.e., e.g. in the form of its melt, with the aminosulfone IM, wherein IM is preferably dissolved in an inert solvent, are reacted under the influence of a base, preferably as described above.

In a further variant of the process according to the invention, the reaction can also be carried out in an aqueous multiphase system. This variant is preferred. In another variant of the process according to the invention, the reaction can also be carried out in an aqueous multiphase system with and without phase transfer catalyst (PTC).

The reaction preferably takes place in an aqueous multiphase system in the presence of phase transfer catalysts.

The reaction preferably takes place in an aqueous multiphase system in the presence of phase transfer catalysts such as quaternary ammonium salts, phosphonium salts, polyglycols and crown ethers.

Suitable quaternary ammonium salts include

Tetra (C 1 -C 18) alkylammonium fluorides, chlorides, bromides, silidides, hydrogen sulfates, hydroxides, perchlorates, borates, diborates or tetrafluoroborates, such as tetramethylammonium fluoride tetrahydrate, tetramethylammonium chloride, Tetramethylammonium bromide, tetramethylammonium iodide, tetramethylammonium hydroxide, methyltri-butylammonium chloride (eg ALIQUAT® 175). Methyltrioctylammonium chloride, methyltricaprylylammonium chloride (eg ALIQUAT® 336, ALIQUAT® HTA1), tetraethylammonium chloride, tetraethylammonium chloride hydrate, tetraethylammonium bromide, tetraethylammonium hydroxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride Trihydrate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogensulfate, tetrabutylammonium hydroxide, tetrabutylammonium perchlorate, tetrabutylammonium tetrafluoroborate, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium hydroxide, tetrahexylammonium bromide, tetrahexylammonium iodide , Tetraoctylammonium bromide, cetyltrimethylammonium bromide, dodecyltrimethylammonium bromide, dodecyltrimethylammonium chloride, C 12 -C 14 -alkyltrimethylammonium borate, C 12 -C 14 -alkyltrimethylammonium diborate; N-phenyl (C 1 -C 18) trialkylammonium fluorides, chlorides or bromides such as phenyltrimethylammonium chloride; N-benzyl (C 1 -C 18) trialkylammonium fluorides, chlorides or bromides such as benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltributylammonium bromide; Pyridinium fluorides, chlorides or bromides such as 1-cetyl pyridinium chloride monohydrate, cetyl pyridinium bromide.

Suitable phosphonium salts are, for example, tetraphenylphosphonium chloride or bromide, benzyltriphenylphosphonium chloride, benzyltriphenylphosphonium bromide; Alkyl-phenyl-phosphonium chlorides, bromides, silides, acetates, such as methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, ethyltriphenylphosphonium acetate, butyltriphenylphosphonium chloride, butyltriphenylphosphonium bromide; Tetraalkyl (Ci-Cis) - phosphonium chloride or bromide such as tetrabutylphosphonium bromide. Suitable polyglycols and crown ethers are, for example, diethylene glycol dibutyl ether ("butyl diglyme"), 18-crown-6 and dibenzo-18-crown-6.

Preference is given to tetra (C 1 -C 18) -alkylammonium hydrosulfates and tetra (C 1 -C 6) -alkylammonium chlorides, very preferably tetra- (C 1 -C 6) -alkylammonium hydrogensulfates and tetra (C 1 -C 6) -alkylammonium Chlorides used.

Very particular preference is given to using tetra (Ci-Ci8) -alkylammonium chlorides, exceptionally preferably tetra (Ci-C6) -alkylammonium chlorides.

Likewise preferred are tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulfate, methyltributylammonium chloride, tetrapropylammonium chloride, tetrapropylammonium bromide, benzyltriphenylphosphonium chloride, benzyltriphenylphosphonium bromide or dibenzo-18-crown-6.

As a rule, 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 , prefers the fluorinated m-nitrobenzoyl chlorides IIA, a.

Very preferably 0.01 to 20 mol%, more preferably 0.05 to 5 mol%, particularly preferably 0.1 to 2 mol% of the phase transfer catalyst based on the m-nitrobenzoyl chlorides II, preferably the fluorinated m-nitrobenzoyl chlorides IIA used.

The multiphase system comprises an aqueous phase and at least one organic liquid phase. In addition, solid phases may occur during the course of implementation. The aqueous phase is preferably a solution of alkali 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. Particular preference is given to using alkali metal or alkaline earth metal hydroxides, especially sodium hydroxide or potassium hydroxide.

Aliphatic, cycloaliphatic or aromatic, optionally halogenated hydrocarbons, cyclic or open-chain ethers or mixtures thereof are preferably suitable for the organic phase, with respect to the aliphatic, cycloaliphatic or aromatic, optionally halogenated hydrocarbons, cyclic or open-chain ethers to the above Reference is made.

If a water-miscible solvent is used for the organic phase, the reaction can also be carried out without a phase-transfer catalyst. In a preferred embodiment of the process according to the invention, the multiphase system consists of aqueous sodium 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 organic phase.

In a particularly preferred embodiment of the process according to the invention, the multiphase system consists of aqueous sodium or potassium hydroxide solution as the aqueous phase and of optionally halogenated aromatic hydrocarbons, such as e.g. Toluene, xylene or chlorobenzene, most preferably halogenated aromatic hydrocarbons, e.g. Chlorobenzene, or mixtures of these organic solvents as the organic phase.

When using a multiphase system, for example, the m-nitro-benzoic acid chloride II, preferably the fluorinated m-nitro-benzoic acid IIA, and the phase transfer catalyst without additional solvent or in one of the aforementioned organic solvents or solvent mixtures submit.

Thereafter, the aqueous solution of the amount of base B2 and the reaction mixture resulting from step a) is added either successively or simultaneously with mixing and then brings the reaction to completion in the temperature range mentioned.

When using a multiphase system in step a) of the process according to the invention, preference is given to initially introducing the aminosulfone IM in an inert solvent. Next, B1 equivalents of Base IV, i.e., 0.1-1.3 equivalents, preferably 0.1-1 equivalents, more preferably 0.2-0.7 equivalents of Base IV are added, advantageously added over a period of time.

Subsequently, when using a multiphase system in step b), it will be preferable first to add the phase transfer catalyst to the reaction mixture resulting from step a). Subsequently, the m-nitrobenzoyl chloride II, and the amount of B2 are added. It is particularly preferable to add the m-nito-benzoic acid chloride II and the base amount B2 in parallel, very preferably in parallel and over a certain period of time, to the reaction mixture resulting from step a).

However, it is also possible, when using a multiphase system in step b) of the process according to the invention, first to add the m-nitrobenzoyl chloride II and the base amount B2 to the reaction mixture resulting from step a), and then to add the phase transfer catalyst. The reaction can be carried out at atmospheric pressure, reduced pressure or under elevated pressure, optionally under inert gas, continuously or batchwise.

The end of the reaction can easily be determined by the skilled person by routine methods.

The work-up of the reaction mixture can be carried out by customary methods. In general, the solvent used by conventional methods, for example by distillation, remove. It is then possible to take up the crude product in a water-immiscible organic solvent, extract any impurities with optionally acidified water, dry and remove the solvent under reduced pressure. For further purification, the usual methods such as crystallization, precipitation (for example by adding a non-polar solvent such as pentane, cyclohexane, heptane or toluene, or mixtures of the solvents mentioned) or chromatography can be used.

When using a two-phase system will usually work up extractive.

The final product can also be obtained by precipitation (e.g., by adding a nonpolar solvent such as pentane, cyclohexane, heptane or toluene, or mixtures of the solvents mentioned).

In a preferred reaction variant of the process according to the invention, after completion of the reaction in a step c), the reaction mixture is diluted by adding water and / or aqueous mineral acids, the pH of the aqueous phase being adjusted to pH <7.

Particularly preferably, the pH of the aqueous phase is adjusted to pH = 2-6.5, particularly preferably to pH = 3-5.0.

Suitable aqueous mineral acids for this purpose are aqueous mineral acids known to the skilled person, such as e.g. Hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid.

Subsequently, the workup of the reaction mixture can be carried out according to the customary methods. In general, the phases are separated and the solvent used by conventional methods, for example by distillation, remove. For further purification, the usual methods such as crystallization (for example, by addition of a non-polar solvent such as pentane, cyclohexane, heptane or toluene, or mixtures of said solvents) apply. When using a two-phase system will usually work up extractive. In a further preferred variant of the reaction of 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 variant of the method according to the invention is particularly preferred in cases where no clear solution is evident from step c).

Preferably, the dilute reaction mixture obtained in step c) is heated to a temperature just below the boiling point and the phase separation is carried out at this temperature. Subsequently, the desired product can be prepared by conventional methods, e.g. Removing the solvent and optionally subsequent crystallization, be recovered.

Furthermore, the organic phase resulting from step d) can, if necessary, be subjected repeatedly to a step c) and, if appropriate, step d), wherein the repetition of steps c) and d) can be carried out as often as desired, preferably once.

The aminosulfones IM required for the preparation of the sulfonamides I are known in the literature (Houben-Weyl, Methods of Organic Chemistry Vol. E11, 1985, page 1019; Hamprecht et al., Angew. Chem. 93, 151, 1981) or can be prepared according to the cited literature.

The m-nitrobenzoyl chlorides II required for the preparation of the sulfonamides I are known from the literature and can be prepared, for example, by reacting m-nitrobenzoic acids VII

where the variables have the following meanings:

R ¹ , R ² , R ³ , R ^{4 are} hydrogen, halogen, cyano, nitro, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -alkoxy or C ₁ -C ₆ -haloalkoxy; be reacted with chlorinating agents VIII.

Accordingly, the present invention additionally relates to a process for the preparation of sulfonamides I, characterized in that the m-nitro-benzoic acid chlorides II required for this purpose are prepared from m-nitrobenzoic acids VII and chlorinating agents VIII.

In particularly preferred embodiments of the process according to the invention, the variables R ¹ , R ² , R ³ and R ^{4 of} the m-nitrobenzoyl chlorides II have the abovementioned Connection with sulfonamides I meanings, in particular those mentioned there as preferred meanings, which considered alone or in combination with each other represent special embodiments of the method according to the invention.

For the preferred embodiments of the reaction of m-nitrobenzoic acids VII with chlorinating agents VIII, the conditions mentioned 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, in particular those there as preferred mentioned embodiments.

In particular, the prior art (e.g., WO 89/02891, WO 04/106324, WO 04/035545, and US 6,251,829) describes processes for preparing fluorinated benzoic acid chlorides from fluorinated benzoic acids. However, in the processes described in the prior art, the problem of cleavage of the fluorine substituent occurs, especially when catalysts such as N, N-dimethylaminopyridine (DMAP) or nitrogenous bases, such as pyridine, picoline or lutidine are used.

The liberated fluoride in turn has a damaging effect on the apparatus technology ("fluoride corrosion") or therefore requires correspondingly more complex apparatus made of higher-value materials.

However, if the process is carried out without a catalyst, the yields are significantly lower or higher reaction temperatures are required.

The present invention is therefore further based on the object to provide a simple, economical and process-capable process for the preparation of fluorinated m-nitro-Benzoesäurechloriden IIA, by the one hand, the fluoride elimination is significantly reduced, and high yields and high purity of desired product can be achieved ,

It has surprisingly been found that this object is achieved by a process in which fluorinated m-nitrobenzoic acids VII are reacted with chlorinating agents VIII, characterized in that the reaction takes place in the presence of catalytic amounts of a phosphine derivative IX and optionally in the presence of a Lewis acid , is solved.

Accordingly, the present invention further relates to a process for the preparation of fluorinated m-nitro-benzoic acid chlorides IIA where the variables have the following meanings:

R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, Ci -C ₆ -alkyl, -C ₆ - haloalkyl, Ci-C ₆ alkoxy or Ci-C ₆ haloalkoxy; where at least one of the radicals R ¹ to R ^{4 is} fluorine,

by reacting fluorinated m-nitrobenzoic acids VIIA

where the variables have the following meanings:

R ¹ , R ² , R ³ , R ^{4 are} hydrogen, halogen, cyano, nitro, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -

Haloalkyl, -C ₆ alkoxy or -C ₆ haloalkoxy; wherein at least one of R ¹ to R ^{4 is} fluorine;

with chlorinating agents VIII,

characterized in that the reaction in the presence of catalytic amounts of a phosphine IX

X "

R- PR ^c IX,

where the variables have the following meanings:

R ^a , R ^b , R ^{c is C} ₁ -C ₆ -alkyl or phenyl which may optionally be substituted by C 1 -C ₄ -alkyl;

X oxygen or two singly bound chlorine atoms; n 0 or 1

he follows. Furthermore, the present invention relates to a process for the preparation of fluorinated sulfonamides IA (= sufonamides I, wherein at least one of the radicals R ¹ to R ^{4 is} fluorine), characterized in that the fluorinated m-nitrobenzoyl chlorides IIA required for this purpose according to the above Process be prepared from fluorinated m-nitrobenzoic acids VII.

The following are the preferred embodiments of the reaction of fluorinated m-nitro-benzoic acids VIIA with chlorinating agents VIII in the presence of catalytic amounts of a phosphine derivative IX called, which considered alone or in combination with each other represent special embodiments of the method according to the invention.

This process according to the invention for the preparation of 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:

VIIA IIA where the variables have the meanings given above in connection with the preparation of fluorinated m-nitrobenzoyl chlorides IIA.

This reaction is usually carried out at temperatures of 20 ° C to 160 ° C, preferably 2O ⁰ C to 12O ⁰ C, particularly preferably 70 ° C to 120 ° C, in an inert organic solvent.

The reaction pressure during the process according to the invention can be, for example, in the range from 500 mbar to 10 bar. Preferably, the reaction is carried out in the range of normal pressure, that is, in the range of 0.9 to 1.2 bar.

The reaction time required for the reaction is generally in the range of 1 h to 24 h, in particular in the range of 2 h to 8 h.

The process according to the invention can in principle be carried out in bulk. However, the process according to the invention is preferably carried out in an inert organic solvent. In principle, all solvents which are capable of dissolving the fluorinated m-nitrobenzoic acids VIIA, the chlorinating agent and the phosphine derivative IM at least partially and preferably completely under the reaction conditions are suitable.

Suitable solvents are, for example, aliphatic hydrocarbons such as pentane, hexane, cyclohexane and mixtures of Cs-Cs-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, particularly preferably aromatic see hydrocarbons or halogenated hydrocarbons.

It is also possible to use mixtures of the solvents mentioned.

As chlorinating agent VIII find common chlorinating agents such as oxalyl chloride,

Phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosphoryl chloride (POCb) Use. Furthermore, gaseous or liquid phosgene, corresponding dimers (trichloromethyl chloroformate, "diphosgene") or corresponding trimers (carbonic acid bis (trichloromethyl ester), "triphosgene") can also be used (see R. Beckert et al., Organikum, 22nd Edition 2004, p 496-499).

Preferred chlorinating agents VIII are oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride and phosphoryl chloride (POCb); very preferred is thionyl chloride.

The fluorinated m-nitro-benzoic 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.

As catalysts, phosphine derivatives IX

R- PR ^c IX,

R ^b where the variables have the following meanings:

R ^a , R ^b , R ^{c is} Ci-Cβ-alkyl or phenyl, which may optionally be substituted by CrC ₄ -AlkVl;

X oxygen or two singly bound chlorine atoms; n 0 or 1 used.

Triphenylphosphine, triphenylphosphine oxide (TPPO), triphenyldichlorophane, tri (C 1 -C 6 -alkyl) phosphine, tri (C 1 -C 6 -alkyl) phosphine oxide and tri (C 1 -C 6 -alkyl) dichlorophosphane are preferred; particularly preferably triphenylphosphine, triphenylphosphine oxide and tri (C 1 -C 6 -alkyl) phosphine oxide; most preferably triphenylphosphine oxide; Use.

The phopsphine derivative IX is generally used in amounts of from 0.01 to 5 mol%, preferably 0.1 to 1 mol%, particularly preferably 0.1 to 0.5 mol%, based on the amount of fluorinated m-nitrobenzoic acid used VII used.

In addition, the process according to the invention can additionally be carried out in the presence of Lewis acids. Lewis acids used are conventional Lewis acids (see, for example, Lewis Acids in Organic Synthesis, ed., Yamamoto, Vol. 1 and 2, Weinheim 2000).

Particularly suitable Lewis acids are boron compounds such as boron halides (eg BF3, BCb, BF3 etherate), boric acid (H3BO3), boric anhydride, boric acid esters (eg boric acid tri-C 1 -C 4 -alkyl ester), borate (eg sodium borate / borax), boronic acids ( eg C 1 -C 6 -alkylboronic acids, arylboronic acids, in particular phenylboronic acid), boronic acid C 1 -C 4 -alkyl esters (for example C 1 -C 6 -alkylboronic acid C 1 -C 4 -alkyl esters, arylboronic acid C 1 -C 4 -alkyl esters), cyclic boric acid esters (for example Tris (C 1 -C 4 alkoxy) boroxine, in particular trimethoxyboroxine, and triethanolamine borate).

Particular preference is given to boric acid, boric tri-C 1 -C 4 -alkyl esters or cyclic boric acid esters.

The Lewis acid is generally used in amounts of from 0.01 to 5 mol%, preferably 0.1 to 1 mol%, based on the amount of m-nitrobenzoic acid II used.

The process can be carried out both continuously and discontinuously (batch or semibatch).

In the process according to the invention, the reactants and reagents can in principle be combined in any desired order, ie the reactants and the phosphine derivative IX and, if appropriate, the Lewis acid can be introduced into the reaction vessel separately or simultaneously and successively and reacted. Advantageously, the fluorinated m-nitro-benzoic acid VIIA and the phosphine derivative IX and optionally the Lewis acid in an inert solvent before, and are mixed with stirring, for example, the chlorinating VIII added. But you can also submit the chlorinating agent VIII together with the phosphine derivative IX and optionally the Lewis acid and then add the fluorinated m-nitro-benzoic acid VIIA, preferably dissolved in an inert solvent.

The reaction mixtures can be worked up in the usual way, e.g. by distilling off the solvent and removing the excess chlorinating reagent.

The final products are z.T. in the form of viscous oils, which are freed or purified under reduced pressure and at moderately elevated temperature of volatile fractions. If the intermediate and end products are obtained as solids, the purification can also be carried out by recrystallization or digestion.

Preferably, no further purification takes place after the end of the reaction.

The fluorinated m-nitrobenzoic acids VIIA required for the preparation of the fluorinated m-nitrobenzoyl chlorides IIA are known in the literature or can be prepared by nitration of the corresponding benzoic acids or by nitration of the corresponding benzoic acid methyl esters and subsequent saponification (eg R. Beckert et al ., Organikum, 22nd edition 2004, pp. 358-361).

The fluorinated m-nitrobenzoyl chlorides IIA obtainable by the process according to the invention can be used as starting materials for the preparation of sulfonamides IA, which in turn are valuable intermediates for the synthesis of pharmacologically active compounds or crop protection agents.

It is therefore another object of the present invention to provide a process for the preparation of sulfonamides IA starting from fluorinated m-nitrobenzoyl chlorides IA.

Depending on the substitution pattern, the fluorinated m-nitrobenzoyl chlorides IIA can contain one or more chiral centers and are then present as enantiomer or diastereomer mixtures. The invention thus provides a process for the preparation of both the pure enantiomers or diastereomers and mixtures thereof.

The organic moieties mentioned for the substituents R ¹ to R ⁶ and also R ^a , R ^b and R ^c represent generic terms for the abovementioned meanings Individual listings of the individual group members. All hydrocarbon chains, ie all alkyl, haloalkyl, alkoxy and haloalkoxy parts can be straight-chain or branched.

Unless otherwise indicated, halogenated substituents preferably carry one to five identical or different halogen atoms. The meaning halogen in each case represents fluorine, chlorine, bromine or iodine.

In connection with the fluorinated m-nitrobenzoyl chlorides IIA, the variables R ¹ , R ² , R ³ and R ⁴ have the abovementioned meanings, in particular the meanings mentioned above as preferred, where in the combination of all four radicals R ¹ to R ³ ^4, at least one of the radicals R ¹ to R ^{4 is} fluorine, and wherein these meanings mentioned above, taken alone or in combination with each other represent special embodiments of the method according to the invention.

Preference is given to the embodiment of the process according to the invention in which R ^{1 is} hydrogen, halogen or C ₁ -C ₆ -alkyl; preferably hydrogen or halogen; very preferably hydrogen, fluorine or chlorine; particularly preferably hydrogen; means.

Also preferred are the embodiment of the method according to the invention in which R ² is hydrogen, halogen, cyano, Ci-C ₆ alkyl or _Ci-C6 haloalkyl; preferably hydrogen or halogen; very preferably hydrogen, fluorine or chlorine; particularly preferably hydrogen or fluorine, very preferably hydrogen; also very preferably fluorine, means.

In addition, the embodiment of the method according to the invention is preferred in which R ^{2 is} hydrogen or halogen; preferably halogen; very preferably fluorine or chlorine; particularly preferably fluorine, means.

Likewise preferred is the embodiment of the process according to the invention in which R ^{3 is} hydrogen, halogen or C 1 -C 6 -alkyl; preferably hydrogen or halogen; very preferably hydrogen, fluorine or chlorine; particularly preferably hydrogen.

In addition, the embodiment of the inventive method is preferred in the

R ^{4 is} halogen or cyano; preferably halogen; very preferably fluorine or chlorine; most preferably chlorine; means.

In addition, the embodiment of the inventive method is preferred in the

R ^{4 is} hydrogen, halogen or cyano; preferably hydrogen or halogen; very preferably hydrogen, fluorine or chlorine; particularly preferably hydrogen or chlorine; means.

In a very preferred embodiment of the process according to the invention, the variables R ¹ , R ² , R ³ and R ^{4 have the} following meanings: R ^{1 is} hydrogen; R ^{2 is} hydrogen or halogen; preferably halogen; very preferably fluorine; R ^{3 is} hydrogen; and R ^{4 is} hydrogen, chlorine or cyano, preferably chlorine or cyano; very preferably chlorine. In a further very preferred embodiment of the process according to the invention, the variables R ¹ , R ² , R ³ and R ^{4 have the} following meanings: R ^{1 is} hydrogen; R ^{2 is} hydrogen or halogen; preferably halogen; very preferably fluorine; R ^{3 is} hydrogen; and R ^{4 is} hydrogen or halogen, preferably hydrogen or chlorine; very preferably chlorine, very preferably hydrogen.

In a further very preferred embodiment of the process according to the invention, the variables R ¹ , R ² , R ³ and R ^{4 have the} following meanings: R ^{1 is} hydrogen; R ^{2 is} fluorine;

R ^{3 is} hydrogen; and R ^{4 is} halogen, preferably chlorine.

In an extremely preferred embodiment of the process according to the invention, it is possible to use fluorinated m-nitrobenzoyl chlorides IIA.a (corresponds to formula IIA where R ¹ = fluorine)

wherein R ² , R ³ and R ^{4 have} the abovementioned, in particular the abovementioned preferred definitions.

In a further extremely preferred embodiment of the process according to the invention, it is possible to use fluorinated m-nitrobenzoyl chlorides IIA.b (corresponds to formula IIA where R ² = fluorine)

wherein R ¹ , R ³ and R ^{4 have} the abovementioned, in particular the abovementioned preferred definitions. In a further extremely preferred embodiment of the process according to the invention, it is possible to use fluorinated m-nitrobenzoyl chlorides IIA.c (corresponding to formula IIA where R ³ = fluorine)

wherein R ¹ , R ² and R ^{4 have} the abovementioned, in particular the abovementioned preferred definitions.

In a further extraordinarily preferred embodiment of the process according to the invention, fluorinated m-nitrobenzoyl chlorides IIA.d (corresponding to formula IIA with R ⁴ =

wherein R ¹ , R ² and R ^{3 have} the abovementioned, in particular the abovementioned preferred definitions.

In a further extremely preferred embodiment of the process according to the invention, it is possible to use fluorinated m-nitrobenzoyl chlorides IIA.e (corresponds to formula IA with R ¹ and R ³ = H)

where the variables R ² and R ^{4 have} the abovementioned meanings, in particular the meanings mentioned above as preferred, and wherein at least one of the radicals R ² and R ^{4 is} fluorine.

Furthermore, m-nitrobenzoyl chlorides II can also be prepared by hydrolysis of the corresponding benzotrichlorides X in the presence of a catalyst or in a weakly acidic medium. hydrolysis

X Il wherein the variables have the following meanings: R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, C -C alkyl ₆ -alkyl, -C ₆ - haloalkyl, Ci-C ₆ alkoxy or C -Cδ -haloalkoxy.

Accordingly, the present invention additionally relates to a process for preparing sulfonamides I, characterized in that the m-nitro-benzoic acid chlorides II required for this purpose are prepared by hydrolysis of benzotrichlorides X in the presence of a catalyst or in a weakly acidic medium.

In particularly preferred embodiments of the method according to the invention, the variables R ^1, R ^2, R ³ and R ⁴ of m-nitro-benzoic acid chlorides Il as defined above in connection with the sulfonamides I, in particular there as being preferred meanings mentioned, which for considered alone and in combination with each other represent special embodiments of the method according to the invention.

For the preferred embodiments of the hydrolysis of corresponding benzotrichlorides X, the following apply in connection with the hydrolysis of fluorinated m-Niztro-Benzotrichloriden XA conditions, in particular those mentioned there as preferred embodiments.

The prior art (e.g., O. Scherer et al., Liebigs Ann. Chem., 1964, 677, 83-95, WO 06/090210) describes processes for preparing aromatic acid chlorides from the corresponding benzoic acids. However, in the reaction conditions described in the prior art, the problem of cleavage of aromatic substituents on the aromatic occurs.

The liberated fluoride has the disadvantages described above in connection with the preparation of benzoic acid chlorides from the corresponding benzoic acids.

Accordingly, it is another object of the present invention to provide a process for the preparation of fluorinated m-nitrobenzoyl chlorides IIA by hydrolysis of corresponding fluorinated m-nitrobenzenetrichlorides XA, by the fluoride cleavage is significantly reduced, and at the same time high yields and purity of desired product can be achieved.

It has surprisingly been found that this object is achieved by a process in which fluorinated m-nitro-benzotrichlorides XA are hydrolyzed in the presence of a catalyst or in weakly acidic medium at temperatures below 80 ° C.

Accordingly, the present invention further relates to a process for the preparation of fluorinated m-nitrobenzoic acid c hhkloriden IIA

where the variables have the following meanings:

R ¹ , R ² , R ³ and R ^{4 are} hydrogen, halogen, cyano, nitro, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -alkoxy or C ₁ -C ₆ -haloalkoxy; where at least one of the radicals R ¹ to R ^{4 is} fluorine,

by hydrolysis of fluorinated m-nitro-benzotrichlorides XA

where the variables R ¹ , R ² , R ³ and R ^{4 have} the meanings given above

characterized in that the reaction in the presence of a catalyst or in weakly acidic medium and at temperatures below 80 ° C.

he follows.

Furthermore, the present invention relates to a process for preparing fluorinated sulfonamides IA, characterized in that the fluorinated m-nitro-benzoic acid chlorides IIA required for this purpose are prepared by the abovementioned process from fluorinated m-nitro-benzotrichlorides XA. The variables R ¹ , R ² , R ³ and R ⁴ have the meanings mentioned above in connection with the fluorinated m-nitrobenzoyl chlorides IIA, in particular the meanings mentioned above as preferred, where in the combination of all four radicals R ¹ to R ⁴ at least one of the radicals R ¹ to R ^{4 is} fluorine, and wherein these meanings mentioned above, taken alone or in combination with each other represent special embodiments of the method according to the invention.

In the following, the preferred embodiments of the hydrolysis of the fluorinated m-nitro-Bezotrichloride XA are described to fluorinated m-nitro-Benzoesäurechloriden IIA, which considered alone or in combination with each other represent special embodiments of the method according to the invention.

The hydrolysis of fluorinated m-nitro-Bezotrichloriden XA to fluorinated m-nitro-Benzoesäurechloriden IIA is carried out at temperatures below 80 ° C (<80 ° C), preferably between 29 and <8O ⁰ C, very preferably between 49 ⁰ C and <8O ⁰ C, particularly preferably between 59 ⁰ C and <80 ° C, optionally in an inert organic solvent in the presence of an acid and / or a catalyst.

Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane and mixtures of Cs-Cs-Al alkanes, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether, dioxane and tetrahydrofuran, ketones such as tert-butyl methyl ketone , as well as dimethylformamide and dimethylacetamide, particularly preferred are aliphatic hydrocarbons and halogenated hydrocarbons.

It is also possible to use mixtures of the solvents mentioned.

The reaction of the fluorinated m-nitro-benzotrichlorides XA to give fluorinated m-nitro-benzotrichlorides IIA can also be carried out at temperatures <80 ° C., preferably from 60 to <80 ° C., more preferably from 60 to 75 ° C., solvent-free in the melt become. This variant of the reaction procedure is preferred.

Preference is given to 1 eq. Water based on the fluorinated m-nitro-benzotrichloride XA added to the reaction mixture. Advantageously, the water will be uniform over a period of time, e.g. within 1 to 12 hours, preferably within 2 to 6 hours.

As acids find inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid and trifluoroacetic acid, particularly preferably sulfuric acid, for example aqueous sulfuric acid or oleum, use. The acids are generally used in equimolar amounts, but they can also be used catalytically.

Suitable catalysts are Lewis acids, e.g. Ferric chloride, ferric sulfate, cerium (III) chloride or cupric chloride; especially preferred is ferric chloride. It is preferable to use 0.003-0.1 equivalent, more preferably 0.003-0.001, most preferably 0.003-0.006 equivalent of the catalyst with respect to the benzotrichloride X.

The reaction of the fluorinated m-nitro-benzotrichlorides XA to give fluorinated m-nitro-benzotrichlorides IIA can also be carried out only in the presence of a suitable catalyst without additional acid. This variant of the reaction procedure is preferred.

The reaction mixtures are prepared by conventional methods known to those skilled in the art, e.g. by removing the solvent, worked up. The catalyst can be prepared by extraction methods known to those skilled in the art, e.g. by dissolving the reaction mixture in a suitable solvent, e.g. in aromatic hydrocarbons such as toluene, o-, m- and p-xylene and chlorobenzene, preferably chlorobenzene, and subsequent extraction with aqueous mineral acids such as hydrochloric acid or sulfuric acid, remove.

But you can also perform the resulting reaction mixture in the form of its melt without further purification directly to the next reaction stage.

The fluorinated m-nitro-benzotrichlorides XA required for the preparation of the fluorinated m-nitro-benzoic acid chlorides IIA are known in the literature [e.g. WO 06/090210] or can be prepared according to the cited literature.

Furthermore, m-nitrobenzoyl chlorides II can also be prepared by reacting corresponding benzotrichlorides X with m-nitrobenzoic acids VII in the presence of a catalyst:

X VII In particular, fluorinated m-nitrobenzoyl chlorides IIA can also be prepared by the reaction of fluorinated m-nitro-benzotrichlorides XA with fluorinated m-nitrobenzoic acids VIIA in the presence of a catalyst:

XA VIIA IIA

The variables R ¹ , R ² , R ³ and R ⁴ have the meanings mentioned above in connection with the m-nitrobenzoyl chlorides II, and the fluorinated m-nitrobenzoyl chlorides IIA, in particular the meanings mentioned above as preferred, these being considered above meanings alone as well as in combination with each other represent special embodiments of the method according to the invention.

Accordingly, the present invention further relates to a process for the preparation of sulfonamides I, in particular fluorinated sulfonamides IA, thereby gekennzeich- net that the required m-nitro-Benzoesäurechloride II, in particular the fluorinated m-nitro-Benzoesäurechloride IIA according to the above method Benzotrichloriden X and m-nitrobenzoic acids VII, in particular from Benzotrichlori- the XA and fluorinated m-nitro-benzoic acids VIIA are produced.

In the following, the preferred embodiments of the reaction of the beZrichrichloride X, and m-nitro-benzoic acids VII to m-nitro-Benzoesäurechloriden Il are described, which considered alone or in combination with each other represent special embodiments of the method according to the invention.

This implementation of benzotrichlorides X m-nitro-benzoic acids VII is usually carried out at temperatures of 7O ⁰ C to 160 ° C, preferably 7O ⁰ C to 12O ⁰ C, more preferably 8O ⁰ C to 11 ⁰ ° C, optionally in an inert organic Solvent in the presence of a catalyst.

Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane and mixtures of Cs-Cβ-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. such as dimethylformamide and dimethylacetamide, particularly preferred are aliphatic hydrocarbons and halogenated hydrocarbons. It is also possible to use mixtures of the solvents mentioned.

The reaction of the benzotrichlorides X with m-nitro-benzoic acids VII to m-nitro-benzotrichlorides II can also be carried out at temperatures of 70 to 120 ° C., preferably 80 to 1 10 ° C solvent-free in the melt. This variant of the reaction procedure is preferred.

Suitable catalysts are Lewis acids, e.g. Ferric chloride, ferric sulfate, cerium (III) chloride or cupric chloride, particularly preferred is ferric chloride.

It is preferable to use 0.003-0.1 equivalent, more preferably 0.003-0.001, most preferably 0.003-0.006 equivalent of the catalyst with respect to the benzotrichloride X.

The benzotrichlorides X and the m-nitrobenzoic acids VII are preferably reacted with one another in equimolar amounts.

The sulfonamides I and IA obtainable by 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.

It is therefore a further object of the present invention to provide a process for the preparation of aniline derivatives VI by reduction of sulfonamides I, which have been prepared beforehand by the processes according to the invention described above: R ⁵ R ⁶

VI

In connection with the aniline derivatives VI, the variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meanings mentioned above in connection with the sulfonamides I, in particular the meanings mentioned above as preferred, where considered alone and in combination with each other represent special embodiments of the method according to the invention.

The reduction of sulfonamides I to aniline derivatives VI succeeds, for example, with nascent hydrogen. For this purpose, the nitro compound is reacted with an acid in the presence of a base metal. By nature, base metals are those that are dissolved by a Brönsted acid with evolution of hydrogen. Such metals generally have a normal potential <0 V and in particular less than or equal to -0.1 V, z. B. in the range of -0.1 to -1, 0 V (in acidic aqueous solution at 15 ⁰ C and 1 bar). Examples of suitable metals are Zn, Fe and Sn, in particular Fe. Suitable acids for this purpose are both inorganic mineral acids, for example hydrochloric acid or dilute sulfuric acid, or mixtures of inorganic acid and one of the aforementioned solvents, for example gaseous HCl in an ether or an alcohol or in a mixture thereof, or organic carboxylic acids, suitably acetic acid, propionic acid or butyric acid, into consideration.

The reaction conditions correspond essentially to the reaction conditions used for the reduction of aliphatic or aromatic nitro groups to aliphatic or aromatic amino groups with nascent hydrogen (see, for example, H. Koopman, Rec. Trav. 80 (1961), 1075).

Depending on the nature of the metal and acid, the reaction temperature is generally in the range of -20 to + 12O ⁰ C, wherein preferably using temperatures of from 50 to 100 ⁰ C when using alkanoic acids such as acetic acid. The reaction time can be a few minutes to several hours, z. B. about 20 minutes to 5 hours. Preferably, the sulfonamide I to be reduced is introduced in the reaction vessel and then, while mixing in, the respective metal, preferably in finely divided form, in particular as powder, is added to the reaction mixture. Preferably, the addition takes place over a period of 10 minutes to 2 hours. Of course, one can also submit the metal and the acid and add the sulfonamide I, optionally together with an inert solvent. Often you leave that Reaction mixture at the reaction temperature for a certain period, for. B. 10 minutes to 4 hours to react.

Preferably, the reduction of I to VI is carried out 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. Preferably, acetic acid is used. The amount of iron powder is preferably 2 to 5 moles, especially 2.5 to 4 moles, per mole of sulfonamide I. The amount of acid is not critical as a rule. It is expedient to use at least an equimolar amount of acid, based on the sulfonamide I, in order to reduce the starting compound as completely as possible. The reaction can be carried out continuously or batchwise. The reaction temperatures then lie in the range of 50 to 100 ⁰ C, preferably 65 to 75 ⁰ C. In one embodiment, for example, sets the iron powder in acetic acid before and then outputs the sulfonamide Mn barrel the reaction rate. Preferably, the addition takes place within 20 to 60 minutes while mixing the ingredients, for. B. with stirring. After completion of the addition is allowed to react for 0.5 to 2 hours, preferably for about 1 hour at the reaction temperature. However, one can also add the iron powder with stirring to the mixture of sulfonamide I in glacial acetic acid and complete the reaction as described above.

The work-up for obtaining the aniline derivative VI can be carried out according to the methods customary for this purpose. In general, you will first remove the solvent, for example by distillation. For further purification, customary processes such as crystallization, chromatography, for example on silica gel, stirring with a solvent, for example aromatic hydrocarbons such as benzene, toluene or xylene or aliphatic hydrocarbons such as petroleum ether, hexane, cyclohexane, pentane, carboxylic esters such as ethyl acetate, etc and apply mixtures thereof.

Other suitable reducing agents 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 borohydride. For this purpose, the sulfonamide I in an inert solvent with the complex metal hydride at 10 to 65 ⁰ C, preferably 20 to 50 ⁰ C in contact. The reaction time is preferably 2 to 10 hours, advantageously 3 to 6 hours. The reaction is preferably carried out in an organic solvent which is inert to the reducing agent. As a solvent come - depending on the chosen reducing agent - z. As alcohols, for example, Ci-C4 alcohols such as methanol, ethanol, n-propanol, isopropanol or n-butanol, and mixtures thereof with water or ethers such as diisopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dioxane or tetrahydrofuran a consideration. In general, 0.5 to 3, advantageously 0.75 to 2.5 mol of metal hydride, metal halohydride, borohydride or boranate per mole of sulfonamide I is used. The procedure follows the procedure described in Organikum, VEB German publishing house of the sciences, Berlin 1976, 15th edition, P. 612-616.

Another suitable reducing agent for the conversion of the sulfonamide I in the aniline VI is hydrogen in the presence of catalytic amounts of a transition metal catalyst, in particular with transition metals of the 8th subgroup. This reduction of the sulfonamides I to aniline derivatives VI with hydrogen is preferred.

In the following, the preferred embodiments of this reduction are described, these considered individually and in combination with each other represent special embodiments of the method according to the invention:

The reaction is usually carried out at temperatures of 0 ° C. to 100 ° C., preferably at 10 ° C. to 50 ° C. either solvent-free or in an inert solvent (cf., for example, Tepko et al., J. Org. Chem. 1980, 45, 4992).

Suitable solvents are, depending on the solubility of the substrate to be hydrogenated aliphatic hydrocarbons such as pentane, hexane, cyclohexane and mixtures of

Cδ-Cs-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 dimethylsulfoxide, dimethylformamide and dimethylacetamide,

Carboxylic acids such as acetic acid, or aqueous solutions of organic acids such as acetic acid and water, particularly preferably alcohols such as methanol, ethanol, n-propanol, isopropanol, n-

Butanol and tert-butanol; aromatic hydrocarbons such as toluene, o-, m- and p-xylene and also chlorobenzene.

It is also possible to use mixtures of the solvents mentioned. Furthermore, it is also possible to work solvent-free.

Preferred transition metal catalysts contain a transition metal from the group Ni, Pd, Pt, Ru, Rh and Ir. Particularly preferred are palladium, platinum, ruthenium and iridium. The transition metal catalysts can be used as such or in supported form. Preferably, supported catalysts are used. Examples of carriers are activated carbon, alumina, ZrO.sub.2, U.sub.2O, SiO.sub.2, carbonates and the like., Preferred is activated carbon.

It is also possible to use transition metal catalysts which have different subgroup elements, eg. As copper, iron, nickel or vanadium, doped in different proportions.

The transition metals can also be used in the form of activated metals such as Raney nickel or in the form of compounds.

Furthermore, the transition metals can also be used in the form of compounds. Suitable transition metal compounds are, for. B. palladium oxide and platinum oxide. Also suitable are noble metal sulfides such as platinum sulfide (see Houben-Weyl, Methods of Organic Chemistry, Bd. IV / 1 C, pp 520-526).

The catalysts are generally used 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%, particularly preferably 0.005 to 0.5 mol %, in each case based on the sulfonamide I to be reduced.

The reduction can be carried out at normal hydrogen pressure or under elevated hydrogen pressure, for example at a hydrogen pressure of 0.01 to 50 bar, preferably 0.1 to 40 bar, more preferably 1 to 20 bar, particularly preferably 1 to 16 bar.

Optionally, the nitro compounds of the formula II before the hydrogenation by stirring with activated carbon or recrystallization from an organic solvent by adding a second solvent, for. As acetone / water, purified.

In the case of chlorine-containing sulfonamides I, the hydrogenation is preferably carried out at 20 to 170 ^° C., more preferably at 20 to 140 ^° C., very preferably at 20 to 80 ^° C., depending on the sensitivity of the substituent.

In the case of sulfonamides I with reactive halogen substituents, it is also advisable to hydrogenate in neutral solution, possibly with only slightly elevated pressure, with small amounts of nickel, palladium, platinum, ruthenium, rhodium or even iridium catalysts. Also suitable are noble metal sulfides such as platinum sulfide.

The workup of the reaction mixture is carried out after separation of the catalyst by known methods. As a rule, the solvent is first removed, for example by distillation. For further purification, customary processes such as extraction, crystallization, chromatography (for example on silica gel) or stirring with a solvent (for example aromatic hydrocarbons such as benzene, toluene or xylene or aliphatic hydrocarbons such as petroleum ether, hexane, cyclohexane, pentane, carboxylic esters such as ethyl acetate, etc and mixtures thereof).

The reduction of sulfonamides I to aniline derivatives VI can also be carried out with sodium sulfide, advantageously in aqueous ammoniacal solution, in the presence of ammonium chloride. The reaction temperature is generally between 40 and 90 ^° C., preferably between 60 and 80 ^° C. It is expedient to use from 3 to 4 mol of sodium sulfide per mole of sulfonamide I.

The following examples serve to further explain the invention:

1. Preparation of the fluorinated m-nitrobenzoic acid chlorides IIA

The yields of fluorinated m-nitro-benzoic acid chloride IIA were determined by quantitative HPLC, unless otherwise stated:

Sample preparation:

First, the fluorinated m-nitrobenzoic acid chlorides IIA formed as the product were converted into the corresponding methyl esters. For this purpose, the samples to be determined of fluorinated m-nitrobenzoic acid chlorides IIA were weighed into a 100 ml volumetric flask and made up to 100 ml with methanol. The mixture was stirred for 10 more minutes at room temperature.

Chromatographic conditions:

Column: Symmetry C18 5μm 250 x 4.6mm from Waters®

Wavelength: 222 nm

Mobile phase: gradient of A (0.1% by volume H ₃ PO ₄ in H ₂ O) and B (0.1% by volume H ₃ PO ₄ in

CH ₃ CN); 10 min 70% B, then B in 15 min from 70% to 100% increasing, then in 2 min back to 35%, then 7 min 35% B.

Flow: 1 ml / min

Pressure: approx. 150 bar

Calibration: Calibration was carried out with an external standard (= equivalent nitrobenzoic acid methyl ester). A total of 5 samples of the pure sub- weighing in the following concentrations (accuracy +/- 0.1 mg): about 0.1 g / l, about 0.2 g / l, about 0.3 g / l, about 0.4 g / l, about 0.5 g / l.

With the help of a suitable PC program, a calibration grade was created. For the substances listed above this was a linear function. Standard deviation,

Correlation coefficient and straight-line equation were calculated.

For each of the components, their concentration can be determined based on the respective external standard.

The fluoride values were determined by the following measuring method:

1 - 2 ml of the sample were extracted with 50 ml of demineralized water (VE = vollentsaltzt). After separating the aqueous phase, depending on the expected concentration, an aliquot part thereof was used for measurement. The measurement was carried out in a buffer solution (TISAB) at pH 5.26 by means of an ion-selective electrode (measurement concentration> 1 mg / l fluoride, detection limit <25 mg / l fluoride). The error limit is +/- 0.002 g / l.

The following devices were used: ion-sensitive fluoride electrode e.g. Fa. Metrohm 6.0502.150 reference electrode e.g. Metrohm 6.0733.100 ion meter e.g. Fa. Radiometer PHM 250

Example 1.1: 4-Fluoro-5-nitro-benzoic acid chloride (with TPPO)

18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid and 0.1 g (0.00036 mol) of triphenylphosphine oxide (TPPO) were introduced into chlorobenzene and the suspension was heated to 95 ° C. with stirring , Then 16.8 g (0.14 mol) of thionyl chloride were added within 10 minutes. The reaction mixture was stirred for 2 h at 105-1 10 ° C.

Then, the reaction mixture was allowed to cool to room temperature and determined the fluoride content of the solution, which was 0.01 g / l.

Subsequently, the solvent and excess thionyl chloride were removed by distillation.

After addition of chlorobenzene 40.8 g (98% of theory was obtained, determined by means of ¹⁹ F-

Internal standard NMR) of the title product as a solution in chlorobenzene.

Analogously to Example 1.1, the following Examples 1.2 to 1.9 were carried out: Example 1.2: 2-Chloro-4-fluoro-5-nitro-benzoic acid chloride (with TPPO)

22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitro-benzoic acid

16.8 g (0.14 mol) of thionyl chloride

0.1 g (0.00036 mol) of triphenylphosphine oxide

Yield ^* : 46.5 g (> 99% of theory) of the title compound as a solution in chlorobenzene

Fluoride value: 0.01 g / l

Example 1.3: 4-Fluoro-5-nitro-benzoic acid chloride (without catalyst)

18.5 g (0.1 mol) of 4-fluoro-5-nitro-benzoic acid

16.8 g (0.14 mol) of thionyl chloride

Yield ^* : 47.3 g (86% of theory) of the title compound as a solution in chlorobenzene Fluoride value: 0.26 g / l

Example 1.4: 2-Chloro-4-fluoro-5-nitro-benzoic acid chloride (without catalyst) 22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid 16.8 g (0, 14 moles) of thionyl chloride. Yield: 47.0 g (95% of theory) of the title compound as a solution in chlorobenzene. Fluoride value: 0.02 g / l

Example 1.5: 4-Fluoro-5-nitro-benzoic acid chloride (with DMAP) 18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid 16.8 g (0.14 mol) of thionyl chloride

0.1 g (0.0008 mol) of 4-dimethylaminopyridine

Yield ^* : 40.8 g (96% of theory) of the title compound as a solution in chlorobenzene

Fluoride value: 0.03 g / l

Example 1.6: 2-Chloro-4-fluoro-5-nitro-benzoic acid chloride (with DMAP)

22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitro-benzoic acid

16.8 g (0.14 mol) of thionyl chloride

0.1 g (0.0008 mol) of 4-dimethylaminopyridine

Yield: 46.8 g (97% of theory) of the title compound as a solution in chlorobenzene Fluoride value: 0.05 g / l

Example 1.7: 4-Fluoro-5-nitro-benzoic acid chloride (with DMF) 18.5 g (0.1 mol) of 4-fluoro-5-nitrobenzoic acid 16.8 g (0.14 mol) of thionyl chloride 0.1 g (0.0014 mol) of dimethylformamide Yield ^* : 40.8 g (98% of theory) of the title compound as a solution in chlorobenzene fluoride value: 0.02 g / l

Example 1.8: 4-Fluoro-5-nitro-benzoic acid chloride (with pyridine) 18.5 g (0.1 mol) of 4-fluoro-5-nitro-benzoic acid

16.8 g (0.14 mol) of thionyl chloride

0.1 g (0.0013 mol) of pyridine

Fluoride value: 0.03 g / l

Example 1.9: 2-Chloro-4-fluoro-5-nitro-benzoic acid chloride (with pyridine)

22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitro-benzoic acid

16.8 g (0.14 mol) of thionyl chloride

0.1 g (0.0013 mol) pyridine Yield: 46.8 g (98% of the title compound as a solution in chlorobenzene

Fluoride value: 0.13 g / l

^* In these examples, the yield was determined by ¹⁹ F NMR with internal standard.

These experiments show that the process according to the invention significantly reduces fluoride splitting:

If the process according to known reaction conditions without catalyst or with catalysts such as DMAP, DMF or pyridine carried out, there is a fluoride elimination, which leads to a fluoride concentration of 0.02 to 0.26 g / l, whereas the fluoride concentration, if the reaction takes place under the conditions according to the invention, is only 0.01 g / l.

Example 1.10

A mixture of 475 g (1.6 mol) of 2-chloro-4-fluoro-5-nitrobenzotrichloride and 1.5 g (9.1 mmol) of iron chloride were initially charged and melted by heating to 75.degree. Within 2 h, 29.2 g (1.6 mol) of water were metered below the surface. During dosing, hydrogen chloride was produced, which was removed via a suitable exhaust system. During the reaction, the internal temperature rose slightly. After the end of the metering was stirred at 75 ° C for 3 h. By passing in nitrogen, residues of hydrogen chloride were expelled. The warm melt was transferred with stirring into a kettle containing 367 g of chlorobenzene, which was heated to 10 ° C. After cooling to about 20 ° C., this organic phase was extracted once with 300 g of 32% aqueous hydrochloric acid. After phase separation, 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 content of the free fluoride organic phase was less than 0.01 g / 1000 g (<10 ppm).

Example 1.1 1 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 initially charged and melted by heating to 70 ° C. Within 2 h, 18.1 g (1 mol) of water were metered below the surface. During dosing, hydrogen chloride was produced, which was removed via a suitable exhaust system. During the reaction, the internal temperature rose slightly. Towards the end of the dosage, a precipitate formed, which had dissolved again at the end of the stirring time. After the end of the metering was stirred at 75 ° C for 3 h. By introducing nitrogen, residues of hydrogen chloride were expelled. 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

296 g (1 mol) of 2-chloro-4-fluoro-5-nitrobenzo trichloride, 0.95 g (5.7 mmol) of iron chloride, and 18.2 g (1 mol ) Water reacted. This gave 238 g of 2-chloro-4-fluoro-5-nitrobenzoyl chloride with a purity of 97% (97% of theory).

Example 1.13

Analogously to Example 1.1 1, 296 g (1 mol) of 2-chloro-4-fluoro-5-nitrobenzo trichloride, 0.5 g (3 mmol) of iron chloride and 18.2 g (1 mol) of water were reacted at 120.degree , After the end of the metered addition of the water, stirring was continued for 30 minutes at 120-125 ° C.

AnschlussOend was cooled to 60 ° C. By introducing nitrogen, residues of hydrogen chloride were expelled. The warm melt was cooled and solidified. This gives 236 g of 2-chloro-4-fluoro-5-nitrobenzoyl chloride having a purity of 95% (95% of theory). The content of free fluoride was 0.110 g / 1000 g (1 10 ppm).

Example 1.14

A mixture of 148 g (0.5 mol) of 2-chloro-4-fluoro-5-nitrobenzotrichloride and 0.5 g (3 mmol) of iron chloride were initially charged and melted by heating to 85 ° C. Within 1 h were added 1 1 1 g (1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid as a solid. During dosing, hydrogen chloride was produced, which was removed via a suitable exhaust system. During the dosage, a precipitate was formed. The temperature was raised to 120 ° C and it was stirred for 2 h. The precipitation dissolved again. By introducing nitrogen, residues of hydrogen chloride were expelled. The warm melt was cooled and solidified. There was obtained 2-chloro-4-fluoro-5-nitrobenzoyl chloride with a purity of 95% (94% of theory). 2. Preparation of sulfonamides I

Example 2.1: N- (2-Chloro-4-fluoro-3-nitrobenzoyl) -N ', N'-diethylsulfonamide A mixture of 8.22 g (27.0 mmol) of N, N-diethyl-sulfamoyl-amide, 5.40 g ( 53.0 mmol) of triethylamine and 170 ° mg of lutidine was added in 40 g of chlorobenzene at 70 ° C with 12.4 g (25.0 mol) of 2-chloro-4-fluoro-3-nitrobenzoic acid chloride in 12 g of chlorobenzene.

The reaction mixture was then stirred at 70 ⁰ C for 2 h. The mixture was mixed by adding conc. Hydrochloric acid acidified, cooled to 0 ° C and stirred for 1 h. The solid was filtered off and washed once with HCl solution. This gave 6.7 g (73% of theory) of the title compound.

¹ H-NMR (500 MHz, CDCl 3) δ = 9.30 ppm (br.s, NH), 8.45 (d, Ar-H), 7.45 (d, Ar-H), 3.5 [q, CH ₂ CH ₃ ] , 1.30 (t, CH ₂ CH ₃ ).

Example 2.2: N- (4-Fluoro-3-nitro-benzoyl) -N'-i-propyl-N'-methylsulfonamide

8.22 g (54.0 mol) of N-methyl-N- (1-methylethyl) -sulfamoylamide, 36.0 mg (0.30 mmol)

Dimethylaminopyridine (DMAP), 11.0 g (0.107 mmol) of triethylamine were dissolved in 30 ml_

Toluene at 70 ⁰ C with 10.2 g (49.1 mmol) of 4-fluoro-3-nitrobenzoic acid chloride in 30 ml of toluene. The suspension was then stirred at RT for 2 h. The mixture was mixed by adding 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 in vacuo gave 14.3 g (87% of theory) of the title compound as yellowish crystals of mp 164-165 ° C. ¹ H-NMR (500 MHz, d-DMSO) δ = 12.3 ppm (b.s., NH), 8.85 (d, Ar-H), 8.40-8.45 (m, Ar-H), 7.75 (t, Ar -H), 4.25 [sept, CH (CH ₃ ) ₂ ], 2.95 (s, CH ₃ ), 1.15 ppm [d, CH (CHa) ₂ ].

Example 2.3: N- (4-Fluoro-3-nitro-benzoyl) -N'-i-propyl-N'-methylsulfonamide A solution of 4.10 g (27.0 mmol) of N-methyl-N- (1-methylethyl) -sulfamoylamide in 50 g of dioxane were added at 25 ° C with 4.30 g (50% in water) NaOH. During this addition, a solution of 5.32 g (25.0 mmol) of 4-fluoro-3-nitrobenzoic acid chloride and 20 g of dioxane was added dropwise thereto. The reaction mixture was then stirred at 25 ° C for 12 h. The mixture was diluted by adding 140 g of water and treated with conc. Hydrochloric acid acidified, cooled to 0 ° C and stirred for 1 h. The solid was filtered off and washed once with HCl solution. This gave 7.6 g (86% of theory) of the title compound with a mp of 164-165 ⁰ C. Example 2.4: N- (2-Chloro-4-fluoro-3-nitrobenzoyl) -N'-i-propyl-N'-methylsulfonamide A solution of 41.1 g (0.27 mol) of N-methyl-N- (1 methylethyl) -sulfamoylamide and 2.41 g (3.00 mmol) of tetrabutylammonium chloride in 500 g of tetrahydrofuran was mixed at 25 ° C with 41.0 g (50% in water) NaOH. During this addition, a solution of 59.7 g (0.25 mol) of 2-chloro-4-fluoro-3-nitrobenzoic acid chloride and 65 g

Tetra hydrofu ran dripped. The reaction mixture was then stirred at 25 ⁰ C for 2 h and by the addition of conc. Hydrochloric acid acidified. This was followed by extraction with dichloromethane. The combined organic phases were dried over magnesium sulfate and the solvent removed in vacuo. This gave 67 g (76% of theory) of the title product with a mp of 125-127 ° C.

¹ H-NMR (400 MHz, CDCl ₃ ) δ = 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-nitro-benzoyl) -N'-i-propyl-N'-methylsulfonamide A solution of 41.1 g (0.27 mol) of N-methyl-N- (1) methylethyl) -sulfamoylamide and 0.75 g (1.25 mmol) of tributylmethylammonium chloride in 630 g of chlorobenzene was added at 20 ° C with 41.0 g (50% in water) NaOH. During this addition, a solution of 59.7 g (0.25 mol) of 2-chloro-4-fluoro-3-nitrobenzoic acid chloride and 65 g of chlorobenzene was added dropwise. The biphasic reaction mixture was then stirred at 20 ° C for 1 h and then by addition of conc. Hydrochloric acid acidified. Finally, the mixture was cooled to 0 ° C, the precipitated solid was filtered off and washed with 1 N HCl solution. This gave 72.5 g (82% of Thoerie) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ = 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:

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 added over 60 min at 20 ° C with 41.0 g (50% in water) NaOH. The addition of a solution of 59.7 g (0.25 mol) of 2-chloro-4-fluoro-3-nitrobenzoic acid chloride and 62 g of chlorobenzene was carried out within 15 minutes after addition of the base within 45 min. The reaction mixture was then stirred at 20 ° C for 1 h and diluted by adding 430 g of water. The aqueous phase was acidified with conc. Hydrochloric acid acidified to pH 1 and treated with 320 g of cyclohexane. The resulting mixture was cooled to 0 ° C. The precipitate was filtered and dried in vacuo at 70 ° C. This gave 80.1 g (88% of theory) of N- (2-chloro-4-fluoro-3-nitrobenzoyl) -N'-i-propyl-N'-methylsulfamide in a purity of 96%. The solid contained 2.2% of 2-chloro-4-fluoro-3-nitrobenzoic acid (determined by quantitative HPLC: Column: Symmetry C18 5 μm 250 × 4.6 mm from Waters®, wavelength: 222 nm, 205 nm; Gradient of A (0.1 vol% H ₃ PO ₄ in H ₂ O) and B (0.1 vol% H ₃ PO ₄ in CH ₃ CN); Flow: 1 ml / min; Pressure: approx. 150 bar).

Example 2.7: 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 reacted over a period of 60 minutes at 20.degree. 50% in water) NaOH. After 15 minutes of addition of the base, a parallel addition of 64.0 g (0.26 mol) of 2-chloro-4-fluoro-3-nitrobenzoic acid chloride in 67 g of chlorobenzene began. This addition took place within 45 min. The reaction mixture was then stirred at 20 ° C for 1 h and diluted by adding 424 g of water and 138 g of isohexane. The aqueous phase was acidified with conc. Hydrochloric acid acidified to pH 5.5 and then separated at 68 ° C. The organic phase was extracted a second time with the addition of 430 g of water and 60 g of isohexane, and the phases were separated at 68.degree. The resulting organic phase was treated with a further 280 g of isohexane and then cooled to 0 ° C. After filtration, washing with water and drying in vacuo at 70 ° C were 82.4 g (87% of theory, purity 96.5%) of N- (2-chloro-4-fluoro-3-nitro-benzoyl) -N ' -i-propyl-N'-methylsulfamids obtained.

Example 2.8:

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 added over the course of 60 min at 20 ° C with 43.7 g (50 % in water) NaOH. After 15 minutes of addition of the base, a parallel addition of 65.0 g (0.26 mol) of 2-chloro-4-fluoro-3-nitrobenzoic acid chloride in 70 g of chlorobenzene began. This addition took place within 45 min. The reaction mixture was then stirred at 20 ° C for 1 h and diluted by adding 424 g of water and 138 g of isohexane. The aqueous phase was acidified with conc. Hydrochloric acid acidified to pH 4.5 and then separated at 68 ° C. The organic phase was extracted a second time with the addition of 430 g of water and 60 g of isohexane, and the phases were separated hot at 68.degree. The resulting organic phase was treated with a further 280 g of isohexane and then cooled to 0 ° C. After filtration, washing with water and drying in vacuo at 70 ° C were 82.1 g (87% of theory, purity 97%) of N- (2-chloro-4-fluoro-3-nitro-benzoyl) -N'-i -propyl-N'-methylsulfamide obtained. No contamination by 2-chloro-4-fluoro-3-nitrobenzoic acid was found in the solid by HPLC analysis.

Example 2.9:

A solution of 8.22 g (54.0 mmol) of N-methyl-N- (1-methylethyl) -sulfamoyl-amide in 25 g of water and 6.48 g (162.4 mmol) of NaOH was treated with 1.74 g (5.40 mmol) of tetrabutylammonium bromide (TBAB). and 10 g of chlorobenzene. Subsequently, at

25 ° C added dropwise a solution of 10.49 g (48.6 mmol) of 4-fluoro-3-nitrobenzoic acid chloride and 25 g of chlorobenzene in 40 min. The biphasic reaction mixture was closing at 25 ° C for 3 h. After phase separation, the organic phase was dried over magnesium sulfate and the solvent removed in vacuo. This gave 4.56 g (46.2%) of N- (4-fluoro-3-nitrobenzoyl) -N'-i-propyl-N'-methylsulfamide having a mp of 164-165 ° C.

Example 2.10:

A solution of 10.5 g (69.0 mmol) of N-methyl-N- (1-methylethyl) sulfamoyl amide 190.0 mg (0.80 mmol) of tributylmethylammonium chloride in 160 g of chlorobenzene, and 0.86 g of water was treated with 10.9 g (137.0 mmol, 50%) NaOH. Subsequently, a solution of 15.8 g (66.0 mmol) of 2-chloro-4-fluoro-3-nitrobenzoic acid chloride and 16 g of chlorobenzene was added dropwise at 20 ° C in 65 min. The biphasic reaction mixture was then stirred at 20 ° C overnight. The reaction mixture was diluted with 106 g of water and acidified to pH 1 with sulfuric acid (98%). After phase separation, the organic phase was cooled to 0 ° C and filtered. The resulting solid was washed on the filter with dilute sulfuric acid (pH 1) and finally dried in vacuo at 70 ° C. This gave 9.3 g (37.3% of theory) of N- (2-chloro-4-fluoro-3-nitrobenzoyl) -N'-i-propyl-N'-methylsulfamide. In addition, an organic phase was formed, containing 6.08 g (24.4% of theory) of N- (2-chloro-4-fluoro-3-nitrobenzoyl) -N'-i-propyl-N'-methylsulfamide and 3.29 g (22.5% of theory) 2-chloro-4-fluoro-3-nitrobenzoic acid (determination by quantitative HPLC analog Ex 2.3)

3. Preparation of aniline derivatives VI

Example 3.1: N- (N- (4-Fluoro-3-amino-benzoyl) -N'-isopropyl-N'-methylsulfamide 89.0 g (0.28 mol) N- (4-fluoro-3-nitro-benzoyl) 5.9 g (10 mol%) of Pd / C were added to N'-isopropyl-N'-methylsulfamide in methanol and hydrogenated with 2-5 bar of hydrogen with stirring at 25-30 ° C. After 12 h the solution became The reaction mixture was filtered and the solvent was removed by distillation, giving 80.1 g (98%) of the

Title compound as a beige solid (mp: 148-150 ° C).

In Table 1, in addition to the above described implementation, further experiments are performed, which were carried out analogously to the above method:

Table 1

Example 3.2: N- (N- (2-Chloro-4-fluoro-3-amino-benzoyl) -N'-iso-propyl-N'-methylsulfamide 8.00 g (23.0 mmol) N- (2-chloro-4- fluoro-3-nitro-benzoyl) -N'-iso-propyl-N'-methylsulfamide were added in 33 g of toluene and 8 g of methanol with 190 mg (0.055mol%) 3% Pt / C and with stirring at 70 ° C. hydrogenated with 5 bar of hydrogen, after 12 h the solution became relaxed, the reaction mixture is filtered and the solvent removed by distillation. 4.7 g (64%) of the title compound were obtained as a solid (mp: 147-149X).

Example 3.3: N- (N- (2-Chloro-4-fluoro-3-amino-benzoyl) -N'-iso-propyl-N'-methylsulfamide 8.00 g (0.023 mol) N- (2-chloro-4- fluoro-3-nitrobenzoyl) -N'-isopropyl-N'-methylsulfamide and 70 mg (6 mol%) ammonium chloride were dissolved in 33 g toluene and 8 g methanol with 0.19 g (0.15 mol%) 10% Pd / C After stirring for 10 h, the solution was decompressed, the reaction mixture was filtered and the solvent was removed by distillation to give 6.4 g (89%) of the title compound as a solid (mp: 147-149 ° C)

Example 3.4: N- (N- (2-Chloro-4-fluoro-3-amino-benzoyl) -N'-iso-propyl-N'-methylsulfamide 182.4 g (0.500 mol) N- (2-chloro-4- fluoro-3-nitro-benzoyl) -N'-iso-propyl-N'-methylsulfamide were added in 391 g of methanol with 1.33 g (0.005 mol%) 1% Pt-2% V / C and stirring at 60 ° C. Hydrogenated with 5 bar hydrogen After 6 h, the solution was decompressed, the reaction mixture filtered and the solvent removed by distillation to give 157.1 g (97%) of the title compound as a solid (mp.: 147-149 ° C).

Example 3.5: N- (N- (2-Chloro-4-fluoro-3-amino-benzoyl) -N'-iso-propyl-N'-methylsulfamide 8.00 g (0.023 mol) N- (2-chloro-4- fluoro-3-nitro-benzoyl) -N'-isopropyl-N'-methylsulfamide were dissolved in 75 g toluene and 8 g methanol with 0.24 g (0.05 mol%) 2.4% Pt / 2.4% Pd / C Hydrogenated with 5 bar of hydrogen with stirring at 70 ° C. After 1 1 h, the solution was decompressed, the reaction mixture filtered and the solvent removed by distillation to give 6.48 g (90%) of the title compound as a solid (mp: 147-). 149 ° C)

Claims

claims:

1. Method for

where the variables have the following meanings:

R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, Ci -C ₆ -alkyl, -C ₆ - haloalkyl, Ci-C ₆ alkoxy or Ci-C ₆ haloalkoxy; R ⁵ and R ⁶ is hydrogen, Ci-C ₆ -alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ -alkyl kinyl, C ₃ -C ₇ -

Cycloalkyl, C ₃ -C 7 -cycloalkenyl, C ₁ -C ₆ -alkoxy, phenyl or benzyl;

by reaction of m-nitro-Benzoesäurechloriden Il

with aminosulfones IM

H ₂ N-SO ₂ NR ⁵ R ⁶ II I,

where the variables R ⁵ and R ^{6 have} the abovementioned meanings;

under the influence of B equivalents of base IV, characterized in that in step a) the aminosulfone IM is reacted with B1 equivalents of base IV, and in step b) the reaction mixture resulting from step a) with m-nitro-benzoic acid chloride Il and B2 equivalents Base IV is implemented;

B1 represents a subset of B and in the range of 0.1-1.3 equivalents

2. A process for the preparation of sulfonamides I according to claim 1, characterized in that B stands for 1, 8 - 2.5 equivalents of base IV with respect to the aminosulfone IM.

3. A process for preparing sulfonamides I according to claim 1 or 2, characterized in that in step a) the aminosulfone is initially charged in an inert solvent and then B1 equivalents of base IV are added.

4. A process for the preparation of sulfonamides I according to any one of claims 1 to

3, characterized in that B1 is 0.1 to 1 equivalent of base IV with respect to the aminosulfone IM.

5. A process for the preparation of sulfonamides I according to any one of claims 1 to

4, characterized in that in step b) the m-nitro-benzoic acid II and the B2 equivalents of base IV are added simultaneously to the reaction mixture resulting from step a).

6. A process for the preparation of sulfonamides I according to any one of claims 1 to 5, characterized in that the reaction is carried out in an aqueous multiphase system.

7. A process for the preparation of sulfonamides I according to any one of claims 1 to 6, characterized in that the m-nitro-Benzoechloride Il by

- Reaction of m-nitrobenzoic acids VII

where the variables have the following meanings:

R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, Ci -C ₆ -alkyl, -C ₆ - haloalkyl, Ci-C ₆ alkoxy or Ci-C ₆ haloalkoxy; with chlorinating agents VIII; or by

- Hydrolysis of corresponding benzotrichlorides X

where the variables have the following meanings: R ¹ , R ² , R ³ and R ^{4 are} hydrogen, halogen, cyano, nitro, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -

Haloalkyl, Ci-C ₆ alkoxy or Ci-C ₆ haloalkoxy; in the presence of a catalyst or in weakly acidic medium; or by

Reaction of corresponding benzotrichlorides X with m-nitrobenzoic acids VII in

Presence of a catalyst

getting produced.

8. A process for preparing sulfonamides I according to any one of claims 1 to 6, characterized in that the m-nitro-Benzoesäurechloride Il by reaction of m-nitro-benzoic acids VII

Haloalkyl, -C ₆ alkoxy or -C ₆ haloalkoxy; with chlorinating agents VIII;

getting produced.

9. A process for preparing sulfonamides I according to any one of claims 1 to 6, characterized in that the m-nitro-Benzoesäurechloride Il by hydrolysis of corresponding benzotrichlorides X

where the variables have the following meanings:

R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, -C ₆ alkyl, -C ₆ - haloalkyl, -C ₆ alkoxy or -C ₆ haloalkoxy; in the presence of a catalyst or in weakly acidic medium;

getting produced.

10. A process for the preparation of sulfonamides I according to any one of claims 1 to 6, characterized in that the m-nitro-Benzoesäurechloride Il by reacting corresponding Benzotrichloride X

where the variables have the following meanings: R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, C -C alkyl ₆ -alkyl, -C ₆ - haloalkyl, Ci-C ₆ alkoxy or Ci-C ₆ -haloalkoxy;

with m-nitrobenzoic acids VII

where the variables have the following meanings: R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, Ci-C ₆ -alkyl, -C ₆ - haloalkyl, -C ₆ alkoxy or -C ₆ haloalkoxy;

be prepared in the presence of a catalyst.

1 1. Process for the preparation of fluorinated m-nitrobenzoyl chlorides IIA

where the variables have the following meanings: R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, Ci-C ₆ -alkyl, -C ₆ - haloalkyl, -C ₆ alkoxy or -C ₆ haloalkoxy; where at least one of the radicals R ¹ to R ^{4 is} fluorine,

by reacting fluorinated m-nitrobenzoic acids VIIA

wherein the variables have the following meanings: R ¹ , R ² , R ³ , R ^{4 is} hydrogen, halogen, cyano, nitro, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -alkoxy or C ₁ -C ₆ -haloalkoxy ; wherein at least one of R ¹ to R ^{4 is} fluorine;

with chlorinating agents VIII,

R- PR ^c IX,

R ^b where the variables have the following meanings:

R ^a , R ^b , R ^{c is C} 1 -C 6 -alkyl or phenyl which is optionally substituted by ^C 1 -C 4 -alkyl

Alkyl may be substituted;

X oxygen or two singly bound chlorine atoms; n 0 or 1

he follows.

12. The method according to claim 11, characterized in that R ^{1 is} hydrogen; R ^{2 is} hydrogen or halogen; R ^{3 is} hydrogen; and

R ^{4 is} hydrogen or halogen; wherein at least one of R ² and R ^{4 is} fluorine; mean.

13. The method according to claims 1 1 or 12, characterized in that the chorating agent VIII is selected from the group oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride and phosphoryl chloride (POCl ₃ ).

14. The method according to any one of claims 1 1 to 13, characterized in that the ratio of chlorinating agent VIII to fluorinated m-nitro-benzoic VIIA 1, 5 to 1.

15. The method according to any one of claims 1 1 to 14, characterized in that the phosphine derivatives IX are selected from the group consisting of triphenylphosphine, triphenylphosphine oxide and tri- (Ci-C6-alkyl) phosphine oxide.

16. The method according to any one of claims 11 to 15, characterized in that the reaction is carried out additionally in the presence of a Lewis acid.

17. The method according to any one of claims 1 1 to 16, characterized in that the Lewis acid is selected from the group boric acid, boric acid tri-C 1 -C 4 -alkyl ester or cyclic boric acid esters. 5

18. Process for the preparation of sulfonamides I

where the variables have the following meanings: R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, Ci-C ₆ alkyl, -C _6-0 haloalkyl, dC ₆ alkoxy or dC ₆ haloalkoxy; wherein at least one of the radicals R ¹ to R ⁴ is fluoro, R ⁵ and R ⁶ is hydrogen, Ci-C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ kinyl Al,

C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkenyl, C ₆ alkoxy, phenyl or benzyl; 5 characterized in that fluorinated m-nitro-Benzoesäurechloride IIA, which were prepared according to any one of claims 1 1 - 17,

aminosulfones with IM _Q H ₂ N-SO ₂ NR ⁵ R ⁶ III in which the variables have the following meanings: R ⁵ and R ⁶ is hydrogen, Ci-C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ -Al kinyl, C ₃ -C ₇ - cycloalkyl, C ₃ -C ₇ cycloalkenyl, C ₆ alkoxy, phenyl or benzyl; 5 are implemented.

19. The method according to claim 18, characterized in that R ^{1 is} hydrogen; R ^{2 is} hydrogen or halogen; R ^{3 is} hydrogen; R ^{4 is} hydrogen or halogen; wherein at least one of R ² and R ^{4 is} fluorine; and

R ⁵ and R ^{6 are} C ¹ -C ⁶ -alkyl.

20. Process for the preparation of fluorinated m-nitro-benzoic acid chlorides IIA

where the variables have the following meanings: R ^1, R ^2, R ³ and R ⁴ is hydrogen, halogen, cyano, nitro, C -C alkyl ₆ -alkyl, -C ₆ - haloalkyl, Ci-C ₆ alkoxy or Ci-C ₆ -haloalkoxy; where at least one of the radicals R ¹ to R ^{4 is} fluorine,

by hydrolysis of fluorinated m-nitro-benzotrichlorides XA

characterized in that the reaction takes place in the presence of a catalyst or in weakly acidic medium and at temperatures below 80 ° C.

21. A process for the preparation of fluorinated m-nitro-Benzoesäurechloriden IIA according to claim 20, characterized in that the hydrolysis is carried out solvent-free in the melt.

22. Process for the preparation of aniline derivatives VI

where the variables have the following meanings: R ¹ , R ² , R ³ and R ^{4 are} hydrogen, halogen, cyano, nitro, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -alkoxy or C ₁ -C ₆ -haloalkoxy ;

R ⁵ and R ⁶ is hydrogen, Ci-C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ kinyl -alkyl, C ₃ -C ₇ - cycloalkyl, C ₃ -C 7 cycloalkenyl, C Cδ- Alkoxy, phenyl or benzyl

by reduction of sulfonamides I, characterized in that the sulfonamides I were prepared according to one of claims 1 to 10.

23. A process for the preparation of aniline derivatives VI according to claim 22, characterized in that the reduction is carried out with hydrogen in the presence of catalytic amounts of a transition metal catalyst.