DE102005057681A1 - Preparation of fluorinated m-nitro-benzoic acid chloride compound, useful to prepare sulfonamide compound, comprises reacting a fluorinated m-nitro-benzoic acid compound with a chlorinating agent in the presence of a phosphine derivative - Google Patents

Abstract

Preparation of fluorinated m-nitro-benzoic acid chloride compound (I) comprises reacting a fluorinated m-nitro-benzoic acid compound (II) with a chlorinating agent, in the presence of a catalytic amount of phosphine derivative (III). Preparation of fluorinated m-nitro-benzoic acid chloride compound of formula (I) comprises reacting a fluorinated m-nitro-benzoic acid compound of formula (II) with a chlorinating agent, in the presence of a catalytic amount of phosphine derivative (III) of formula (Ra-P(=X n)(Rb)-Rc). R 1>-R 4>H, halo, CN, NO 2, 1-6C alkyl, 1-6C haloalkyl, 1-6C alkoxy or 1-6C haloalkoxy (where at least one of the residue is F); Ra-Rc : 1-6C alkyl or phenyl (optionally substituted by 1-4C alkyl); X : O or two single bonded Cl atom; and n : 0 or 1. An independent claim is included for the preparation of a sulfonamide compound of formula (V) comprising reacting (I) with an aminosulfone compound of formula (NH 2-SO 2NR 5>R 6>) (VI). R 5>, R 6>H, 1-6C alkyl (preferred), 3-6C alkenyl, 3-6C alkynyl, 3-7C cycloalkyl, 3-7C cycloalkenyl, 1-6C alkoxy, phenyl or benzyl. [Image] [Image].

Description

wobei die Variablen die folgenden Bedeutungen haben:
R¹, R², R³ und R⁴ Wasserstoff, Halogen, Cyano, Nitro, C₁-C₆-Alkyl, C₁-C₆-Halogenalkyl, C₁-C₆-Alkoxy oder C₁-C₆-Halogenalkoxy;
wobei mindestens einer der Reste R¹ bis R⁴ Fluor bedeutet.The present invention relates to a process for the preparation of fluorinated m-nitro-benzoic acid chlorides 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 ;
where at least one of the radicals R ¹ to R ^{4 is} fluorine.

In the prior art (eg WO 89/02891, WO 04/106324, WO 04/035545 and US 6,251,829 ) describe processes for the preparation of fluorinated benzoic acid chlorides from fluorinated benzoic acids. However, in the processes described in the prior art, the problem of cleavage of the fluoride substituent occurs, especially when catalysts such as N, N-dimethylaminopyridine (DMAP) or nitrogen-containing 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 requires therefore more elaborate Apparatus of higher quality Materials. Furthermore leads the Cleavage of the fluoride to impurities or secondary components in value product.

Becomes however, if the process is carried out without a catalyst, the yields are significantly lower or higher Reaction temperatures required.

Of the The present invention is therefore based on the object of providing a simple, economical and processable process to provide for the preparation of fluorinated m-nitro-benzoic acid chlorides, by the one hand, the fluoride cleavage is significantly reduced, and at the same time high yields and high purity of desired product can be achieved.

It became more surprising Way found that this task by a method in which fluorinated m-nitrobenzoic acids II are reacted with chlorinating agents, characterized that the reaction in the presence of catalytic amounts of a phosphine derivative III and optionally in the presence of a Lewis acid, solved becomes.

wobei die Variablen die folgenden Bedeutungen haben:
R¹, R², R³ und R⁴ Wasserstoff, Halogen, Cyano, Nitro, C₁-C₆-Alkyl, C₁-C₆-Halogenalkyl, C₁-C₆-Alkoxy oder C₁-C₆-Halogenalkoxy;
wobei mindestens einer der Reste R¹ bis R⁴ Fluor bedeutet,
durch Umsetzung fluorierter m-Nitro-Benzoesäuren II

wobei die Variablen die folgenden Bedeutungen haben:
R¹, R², R³, R⁴ Wasserstoff, Halogen, Cyano, Nitro, C₁-C₆-Alkyl, C₁-C₆-Halogenalkyl, C₁-C₆-Alkoxy oder C₁-C₆-Halogenalkoxy;
wobei mindestens einer der Reste R¹ bis R⁴ Fluor bedeutet;
mit Chlorierungsmitteln,
dadurch gekennzeichnet, dass die Umsetzung in Gegenwart katalytischer Mengen eines Phosphinderivats III

wobei die Variablen die folgenden Bedeutungen haben:
R^a, R^b, R^c C₁-C₆-Alkyl oder Phenyl, welches gegebenenfalls durch C₁-C₄-Alkyl substituiert sein kann;
X Sauerstoff oder zwei einfach gebundene Chloratome;
n 0 oder 1
erfolgt.Accordingly, the present invention relates to a process for the preparation of fluorinated m-nitrobenzoyl chlorides 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 ;
where at least one of the radicals R ¹ to R ^{4 is} fluorine,
by reaction of fluorinated m-nitrobenzoic acids II

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 ;
wherein at least one of R ¹ to R ^{4 is} fluorine;
with chlorinating agents,
characterized in that the reaction in the presence of catalytic amounts of a phosphine derivative III

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.

The according to the inventive method available fluorinated m-nitro-benzoic acid chlorides I can as starting materials for the preparation of sulfonamides V are used, which in turn valuable Intermediates for the synthesis of pharmacologically active compounds or pesticides are. Therefore, another object of the present invention the provision of a process for the preparation of sulfonamides V starting from fluorinated m-nitrobenzoic acid chlorides I.

The fluorinated m-nitrobenzoic acids I can depending on the substitution pattern, one or more chiral centers contain and are then as Enantiomeren- or Diastereomerengemische in front. The invention thus relates to a process for the preparation both the pure enantiomers or diastereomers and their Mixtures.

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 listings of the individual group members. All hydrocarbon chains, ie all alkyl, haloalkyl, alkoxy and haloalkoxy moieties can be straight-chain or be branched.

Provided unless otherwise stated, halogenated substituents preferably bear one to five identical or different halogen atoms. The meaning halogen stands each for Fluorine, chlorine, bromine or iodine.

• – C₁-C₄-Alkyl: z.B. Methyl, Ethyl, n-Propyl, 1-Methylethyl, n-Butyl, 1-Methylpropyl, 2-Methylpropyl und 1,1-Dimethylethyl;
• – C₁-C₆-Alkyl: C₁-C₄-Alkyl, wie voranstehend genannt, sowie z.B. 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-l-methylpropyl und 1-Ethyl-3-methylpropyl;
• – C₁-C₄-Halogenalkyl: einen C₁-C₄-Alkylrest wie vorstehend genannt, der partiell oder vollständig durch Fluor, Chlor, Brom und/oder Iod substituiert ist, also z.B. Chlormethyl, Dichlormethyl, Trichlormethyl, Fluormethyl, Difluormethyl, Trifluormethyl, Chlorfluormethyl, Dichlorfluormethyl, Chlordifluormethyl, 2-Fluorethyl, 2-Chlorethyl, 2-Bromethyl, 2-Iodethyl, 2,2-Difluorethyl, 2,2,2-Trifluorethyl, 2-Chlor-2-fluorethyl, 2-Chlor-2,2-difluorethyl, 2,2-Dichlor-2-fluorethyl, 2,2,2-Trichlorethyl, Pentafluorethyl, 2-Fluorpropyl, 3-Fluorpropyl, 2,2-Difluorpropyl, 2,3-Difluorpropyl, 2-Chlorpropyl, 3-Chlorpropyl, 2,3-Dichlorpropyl, 2-Brompropyl, 3-Brompropyl, 3,3,3-Trifluorpropyl, 3,3,3-Trichlorpropyl, 2,2,3,3,3-Pentafluorpropyl, Heptafluorpropyl, 1-(Fluormethyl)-2-fluorethyl, 1-(Chlormethyl)-2-chlorethyl, 1-(Brommethyl)-2-bromethyl, 4-Fluorbutyl, 4-Chlorbutyl, 4-Brombutyl und Nonafluorbutyl;
• – C₁-C₆-Halogenalkyl: C₁-C₄-Halogenalkyl wie voranstehend genannt, sowie z.B. 5-Fluorpentyl, 5-Chlorpentyl, 5-Brompentyl, 5-Iodpentyl, Undecafluorpentyl, 6-Fluorhexyl, 6-Chlorhexyl, 6-Bromhexyl, 6-Iodhexyl und Tridecafluorhexyl;
• – C₂-C₆-Alkenyl: z.B. 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-3pentenyl, 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 und 1-Ethyl-2-methyl-2-propenyl;
• – C₂-C₆-Alkinyl: z.B. Ethinyl, 1-Propinyl, 2-Propinyl, 1-Butinyl, 2-Butinyl, 3-Butinyl, 1-Methyl-2-propinyl, 1-Pentinyl, 2-Pentinyl, 3-Pentinyl, 4-Pentinyl, 1-Methyl-2-butinyl, 1-Methyl-3-butinyl, 2-Methyl-3-butinyl, 3-Methyl-1-butinyl, 1,1-Dimethyl-2-propinyl, 1-Ethyl-2-propinyl, 1-Hexinyl, 2-Hexinyl, 3-Hexinyl, 4-Hexinyl, 5-Hexinyl, 1-Methyl-2-pentinyl, 1-Methyl-3-pentinyl, 1-Methyl-4-pentinyl, 2-Methyl-3-pentinyl, 2-Methyl-4-pentinyl, 3-Methyl-1-pentinyl, 3-Methyl-4-pentinyl, 4-Methyl-1-pentinyl, 4-Methyl-2-pentinyl, 1,1-Dimethyl-2-butinyl, 1,1-Dimethyl-3-butinyl, 1,2-Dimethyl-3-butinyl, 2,2-Dimethyl-3-butinyl, 3,3-Dimethyl-1-butinyl, 1-Ethyl-2-butinyl, 1-Ethyl-3-butinyl, 2-Ethyl-3-butinyl und 1-Ethyl-1-methyl-2-propinyl;
• – C₃-C₈-Cycloalkyl: z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl und Cycloheptyl;
• – C₁-C₄-Alkoxy: sowie die Alkoxyteile von Di-(C₁-C₄-alkoxy)-C₁-C₄-alkyl und Hydroxy-C₁-C₄-akoxy-C₁-C₄-alkyl, z.B. Methoxy, Ethoxy, Propoxy, 1-Methylethoxy, Butoxy, 1-Methylpropoxy, 2-Methylpropoxy und 1,1-Dimethylethoxy;
• – C₁-C₆-Alkoxy: C₁-C₄-Alkoxy wie voranstehend genannt, sowie z.B. Pentoxy, 1-Methylbutoxy, 2-Methylbutoxy, 3-Methoxylbutoxy, 1,1-Dimethyl-propoxy, 1,2-Dimethylpropoxy, 2,2-Dimethylpropoxy, 1-Ethylpropoxy, Hexoxy, 1-Methylpentoxy, 2-Methylpentoxy, 3-Methylpentoxy, 4-Methylpentoxy, 1,1-Di-methylbutoxy, 1,2-Dimethylbutoxy, 1,3-Dimethylbutoxy, 2,2-Dimethylbutoxy, 2,3-Dimethylbutoxy, 3,3-Dimethylbutoxy, 1-Ethylbutoxy, 2-Ethylbutoxy, 1,1,2-Tri-methylpropoxy, 1,2,2-Tri-methylpropoxy, 1-Ethyl-1-methylpropoxy und 1-Ethyl-2-methylpropoxy;
• – C₁-C₄-Halogenalkoxy: einen C₁-C₄-Alkoxyrest wie voranstehend genannt, der partiell oder vollständig durch Fluor, Chlor, Brom und/oder Iod substituiert ist, also z.B. Fluormethoxy, Difluormethoxy, Trifluormethoxy, Chlordifluormethoxy, Bromdifluormethoxy, 2-Fluorethoxy, 2-Chlorethoxy, 2-Brommethoxy, 2-Iodethoxy, 2,2-Difluorethoxy, 2,2,2-Trifluorethoxy, 2-Chlor-2-fluorethoxy, 2-Chlor-2,2-difluorethoxy, 2,2-Dichlor-2-fluorethoxy, 2,2,2-Trichlorethoxy, Pentafluorethoxy, 2-Fluorpropoxy, 3-Fluorpropoxy, 2-Chlorpropoxy, 3-Chlorpropoxy, 2-Brompropoxy, 3-Brompropoxy, 2,2-Difluorpropoxy, 2,3-Difluorpropoxy, 2,3-Dichlorpropoxy, 3,3,3-Trifluorpropoxy, 3,3,3-Trichlorpropoxy, 2,2,3,3,3-Pentafluorpropoxy, Heptafluorpropoxy, 1-(Fluormethyl)-2-fluorethoxy, 1-(Chlormethyl)-2-choorethoxy, 1-(Brommethyl)-2-bromethoxy, 4-Fluorbutoxy, 4-Chlorbutoxy, 4-Brombutoxy und Nonafluorbutoxy;
• – C₁-C₆-Halogenalkoxy: C₁-C₄-Halogenalkoxy wie voranstehend genannt, sowie z.B. 5-Fluorpentoxy, 5-Chlorpentoxy, 5-Brompentoxy, 5-Iodpentoxy, Undecafluorpentoxy, 6-Fluorhexoxy, 6-Chlorhexoxy, 6-Bromhexoxy, 6-Iodhexoxy und Tridecafluorhexoxy;

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;
• C ₁ -C ₄ -haloalkyl: a C ₁ -C ₄ -alkyl radical as mentioned above which is partially or completely substituted by fluorine, chlorine, bromine and / or iodine, eg chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, Trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro 2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1- (fluoromethyl) -2-fluoroethyl, 1- (chloromethyl) -2-chloroethyl, 1- (bromomethyl) -2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl and nonafluorobutyl;
• 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-iodohexyl and tridecafluorohexyl;
• C ₂ -C ₆ 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;
• C ₃ -C ₈ -cycloalkyl: for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;
• - C ₁ -C ₄ -alkoxy: and the alkoxy moieties of di- (C ₁ -C ₄ -alkoxy) C ₁ -C ₄ -alkyl and hydroxy-C ₁ -C ₄ -acoxy-C ₁ -C ₄ -alkyl for example, 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;
• C ₁ -C ₄ -haloalkoxy: a C ₁ -C ₄ -alkoxy radical as mentioned above which is partially or completely substituted by fluorine, chlorine, bromine and / or iodine, eg 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;
• C ₁ -C ₆ -haloalkoxy: C ₁ -C ₄ -haloalkoxy as mentioned above, and also, for example, 5-fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy, undecafluoropentoxy, 6-fluorohexoxy, 6-chloro-hexoxy, 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 and R ⁴ have the following meanings, which considered alone or in combination with each other represent particular embodiments of the method according to the invention, and
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:
Preferred is the embodiment of the method 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 method 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,
most preferably hydrogen;
also exceptionally preferably fluorine,
means.

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

Likewise preferred is the embodiment of the method 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.
means.

Likewise preferred is the embodiment of the method 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,
most preferably hydrogen;
also most preferably chlorine or cyano;
very preferably chlorine;
means.

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,
also 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.

herstellen, wobei R², R³ und R⁴ die oben genannten, insbesondere die oben genannten bevorzugten Definitionen haben.In an extremely preferred embodiment of the process according to the invention, fluorinated m-nitrobenzoyl chlorides Ia (corresponds to formula I where R ¹ = fluorine)

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

herstellen, wobei R¹, R³ und R⁴ die oben genannten, insbesondere die oben genannten bevorzugten Definitionen haben.In a further extraordinarily preferred embodiment of the process according to the invention, it is possible to use fluorinated m-nitrobenzoyl chlorides Ib (corresponding to formula I where R ² = fluorine)

wherein R ¹ , R ³ and R ^{4 have} the abovementioned, in particular the abovementioned preferred definitions.

herstellen, wobei R¹, R² und R⁴ die oben genannten, insbesondere die oben genannten bevorzugten Definitionen haben.In a further extraordinarily preferred embodiment of the process according to the invention, it is possible to use fluorinated m-nitrobenzoic acid chlorides Ic (corresponding to formula I where R ³ = fluorine)

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

herstellen, wobei R¹, R² und R³ die oben genannten, insbesondere die oben genannten bevorzugten Definitionen haben.In a further extremely preferred embodiment of the process according to the invention, it is possible to use fluorinated m-nitro-benzoic acid chlorides Id (corresponding to formula I where R ⁴ = fluorine)

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

herstellen, wobei die Variablen R² und R⁴ die zuvor genannten Bedeutungen, insbesondere die zuvor als bevorzugt genannten Bedeutungen haben, und wobei mindestens einer der Reste R² und R⁴ Fluor bedeutet.In a further extremely preferred embodiment of the process according to the invention, it is possible to use fluorinated m-nitrobenzoyl chlorides Ie (corresponding to formula I where 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.

The process according to the invention comprises the reaction of fluorinated m-nitrobenzoic acids II with chlorinating agents in the presence of catalytic amounts of a phosphine derivative III:

These Implementation usually takes place at temperatures of 20 ° C up to 160 ° C, preferably 20 ° C up to 120 ° C, especially preferably 70 ° C up to 120 ° C, in an inert organic solvent.

Of the Reaction pressure during the method according to the invention may for example be in the range of 500 mbar to 10 bar. Preferably For example, the reaction is in the range of atmospheric pressure, that is, in the range of 0.9 to 1.2 bar.

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

The inventive method can basically carried out in substance become. Preferably leads the process according to the invention however, in an inert organic solvent.

Basically all solvents, which are the fluorinated m-nitrobenzoic acids II, the chlorinating agent and the phosphine derivative III at least partially and preferably Completely able to dissolve under the reaction conditions, suitable.

Suitable solvents include aliphatic hydrocarbons such as pentane, hexane, cyclohexane and mixtures of C ₅ -C ₈ alkanes, aromatic hydrocarbons such as toluene, o-, m- and p-xylene, halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene, ethers such as diethyl ether , Diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, particularly preferably aromatic hydrocarbons or halogenated hydrocarbons.

It can also mixtures of the solvents mentioned be used.

The chlorinating agents used are customary chlorinating agents, such as oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosphoryl chloride (POCl ₃ ). 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 Chorierungsmittel are oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride and phosphoryl chloride (POCl _3); very preferred is thionyl chloride.

The fluorinated m-nitrobenzoic acids II and the chlorinating agent are generally in equimolar Quantities reacted together. It may be advantageous to use the chlorinating agent in an excess on the m-nitrobenzoic acids II use. Preference is given to using the chlorinating agent and the fluorinated m-nitrobenzoic acids II in a relationship of 2: 1, more preferably 1.5: 1.

wobei die Variablen die folgenden Bedeutungen haben:
R^a, R^b, R^c C₁-C₆-Alkyl oder Phenyl, welches gegebenenfalls durch C₁-C₄-Alkyl substituiert sein kann;
X Sauerstoff oder zwei einfach gebundene Chloratome;
n 0 oder 1
eingesetzt.As catalysts, phosphine derivatives III

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
used.

Preferred are triphenylphosphine, triphenylphosphine oxide (TPPO), triphenyldichlorophosphane, tri (C ₁ -C ₆ -alkyl) phosphine, tri (C ₁ -C ₆ -alkyl) phosphine oxide and tri (C ₁ -C ₆ -alkyl) dichlorophosphine;
particularly preferably triphenylphosphine, triphenylphosphine oxide and tri (C ₁ -C ₆ -alkyl) phosphine oxide;
most preferably triphenylphosphine oxide;
Use.

The Phopsphine derivative II is usually added in amounts of from 0.01 to 5 mol%, preferably 0.1 to 1 mol%, particularly preferably 0.1 to 0.5 mol% used on the amount of m-nitro-benzoic acid II used.

Furthermore can the inventive method additionally be carried out in the presence of Lewis acids. As Lewis acids find usual Lewis acids Use (see, e.g., Lewis Acids in Organic Synthesis, ed. Vol. 1 and 2, Weinheim 2000).

As the Lewis acids, in particular boron compounds such as boron halides are suitable (for example, BF _3, BCl _3, BF ₃ etherate), boric acid (H ₃ BO _3), boric anhydride, boric acid esters (eg Borsäuretri-C ₁ -C ₄ -alkyl), 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 (eg tris (C ₁ -C ₄ alkoxy) boroxine, in particular trimethoxyboroxine, and triethanolamine borate).

Boric acid, tri-C ₁ -C ₄ alkyl esters or cyclic boric acid esters are particularly preferred.

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

The Process can be both continuous and discontinuous (batch or semibatch) become.

In the process according to the invention, the reactants and reagents can in principle be combined in any order, ie, the reactants and the phosphine derivative III and optionally the Lewis acid can be introduced separately, simultaneously or successively into the reaction vessel and be led to the reaction.

Advantageous one sets the fluorinated m-nitro-benzoic acid II and the phosphine derivative III and optionally the Lewis acid in an inert solvent before, and with mixing, e.g. Stir, the chlorinating agent to.

you but also the chlorinating agent together with the phosphine derivative III and optionally the Lewis acid and then the fluorinated m-nitrobenzoic acid II, preferably solved in an inert solvent, to admit.

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

The End products fall z.T. in the form of viscous oils, which under diminished Pressure and moderately elevated temperature of fleeting Shares are freed or cleaned. Unless the intermediate and Final products can be obtained as solids, cleaning can also by recrystallization or digestion.

Prefers no further purification takes place after the reaction has ended.

The for the Preparation of the fluorinated m-nitro-Benzoesäurechloride I required fluorinated m-nitro-benzoic acids II are known in the literature or can by nitration tion of the corresponding benzoic acids or by nitration of the corresponding methyl benzoate and subsequent saponification See, for example, R. Beckert et al., Organikum, 22nd ed., 2004, Pp. 358-361).

The according to the inventive method available fluorinated m-nitro-benzoic acid chlorides I can as starting materials for the preparation of sulfonamides V are used, which in turn valuable Intermediates for the synthesis of pharmacologically active compounds or pesticides are.

wobei die Variablen R⁵ und R⁶ unabhängig voneinander die obenen genannten Bedeutungen haben,
umgesetzt werden.For example, the obtained according to the inventive fluorinated m-nitro-Benzoesäurechloride I with aminosulfones IV H ₂ N-SO ₂ NR ⁵ R ⁶ IV, where the variables R ⁵ and R ⁶ independently of one another 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 alkoxy, phenyl or benzyl;
mean;
to sulfonamides V

where the variables R ⁵ and R ⁶ independently of one another have the meanings given above,
be implemented.

The variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the abovementioned meanings, in particular the meanings mentioned above as preferred.

In particularly preferred embodiments of the method according to the invention, the variables R ⁵ and R ⁶ as defined below, which if taken alone by themselves and in combination, and in combination with the previously mentioned meanings, in particular with the above the meanings mentioned as preferred of the radicals R ¹ , R ² , R ³ and R ^{4 represent} particular embodiments of the method according to the invention:
Preferred is the embodiment of the method according to the invention, in which
R ⁵ and R ^{6 are} hydrogen, C ₁ -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.

Likewise preferred is the embodiment of the method according to the invention, in which
R ^{5 is} hydrogen or C ₁ -C ₆ -alkyl;
preferably hydrogen or C ₁ -C ₄ -alkyl;
very preferably C ₁ -C ₄ -alkyl;
particularly preferably methyl;
means.

Likewise 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 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,
also very preferably hydrogen;
R ⁵ and R ^{6 are} hydrogen, C ₁ -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.

hergestellt werden, wobei die Variablen R², R³, R⁴, R⁵ und R⁶ die zuvor genannten Bedeutungen, insbesondere die zuvor als bevorzugt genannten Bedeutungen haben.In a preferred embodiment of the process according to the invention, sulfonamides Va

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.

hergestellt werden, wobei die Variablen R¹, R³, R⁴, R⁵ und R⁶ die zuvor genannten Bedeutungen, insbesondere die zuvor als bevorzugt genannten Bedeutungen haben.In a further preferred embodiment of the process according to the invention, sulfonamides Vb

be prepared, wherein the variables R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, in particular have the meanings mentioned above as preferred.

hergestellt werden, wobei die Variablen R¹, R², R⁴, R⁵ und R⁶ die zuvor genannten Bedeutungen, insbesondere die zuvor als bevorzugt genannten Bedeutungen haben.In a further preferred embodiment of the process according to the invention, sulfonamides Vc

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.

hergestellt werden, wobei die Variablen R¹, R², R³, R⁵ und R⁶ die zuvor genannten Bedeutungen, insbesondere die zuvor als bevorzugt genannten Bedeutungen haben.In a further preferred embodiment of the process according to the invention, sulfonamides Vd

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.

hergestellt werden, wobei die Variablen R², R⁴ R⁵ und R⁶ die zuvor genannten Bedeutungen, insbesondere die zuvor als bevorzugt genannten Bedeutungen haben, und wobei mindestens einer der Reste R² und R⁴ Fluor bedeutet.In a further preferred embodiment of the process according to the invention, sulfonamides Ve

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.

Geeignete Lösungsmittel sind aliphatische Kohlenwasserstoffe wie Pentan, Hexan, Heptan, Cyclohexan und Gemische von C₅-C₈-Alkanen, aromatische Kohlenwasserstoffe wie Toluol, o-, m- und p-Xylol, halogenierte Kohlenwasserstoffe wie Methylenchlorid, Chloroform, Dichlorethan und Chlorbenzol, Ether wie Diethylether, Diisopropylether, tert.-Butylmethylether, Dioxan, Anisol und Tetrahydrofuran, Ester wie Ethylacetat, Propylacetat, n-Butylacetat, Methylisobutyrat, Isobutylacetat; sowie Dimethylsulfoxid, Dimethylformamid und Dimethylacetamid; besonders bevorzugt aromatische Kohlenwasserstoffe und halogenierte Kohlenwasserstoffe.The reaction of the fluorinated m-nitro-benzoic acid chlorides I with aminosulfones IV to give sulfonamides V takes place on the basis of known processes (cf., WO 01/83459 and WO 04/039768), usually at temperatures from -30 ° C. to 120 ° C., preferably -10 ° C to 100 ° C, particularly preferably 0 ° C to 80 ° C, in an inert organic solvent in the presence of a base and optionally a catalyst:

Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, heptane, cyclohexane and Mixtures of C ₅ -C ₈ -alkanes, aromatic hydrocarbons such as toluene, o-, m- and p-xylene, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, 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 can also mixtures of said solvents, or mixtures of the solvents mentioned be used with water.

When Bases 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 bicarbonates such as sodium bicarbonate, alkali metal and alkaline earth metal alcoholates such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, Potassium tert-pentoxide and dimethoxy magnesium, also organic Bases, e.g. tertiary Amines such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, Lutidine and 4-dimethylaminopyridine as well as bicyclic amines such as e.g. 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) into consideration.

Especially Preference is given to alkali metal and alkaline earth metal hydroxides and tertiary Amines.

The Bases are generally equimolar, in excess or optionally used as solvent become.

Prefers the bases will be in excess, especially preferably 3-1.5 equivalents, most preferably 2.5-1.8 equivalents based on the fluorinated m-nitro-Benzoesäurechloride I used.

In usually, the fluorinated m-nitro-benzoic acid chloride I, preferably dilute in an inert solvent, to the aminosulfone IV, preferably also diluted in one inert solvents, given. But you can also submit the fluorinated m-nitro-benzoic acid chloride I and the Add aminosulfone IV.

Farther the fluorinated m-nitro-benzoic acid chloride I can also be in substance, i.e., e.g. in the form of its melt, with the aminosulfone IV, where IV is preferably dissolved in an inert solvent, be implemented.

The Educts are generally in equimolar Quantities reacted together. Preferably, the molar amounts, in which I and IV are reacted together 0.9 to 1.2, preferably 0.95 to 1.1 for The relationship from I to IV.

In another variant of the method according to the invention can be the Implementation also in an aqueous Perform multiphase system with and without phase transfer catalyst.

Preferably the reaction 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 tetraalkyl (C ₁ -C ₁₈ ) ammonium fluorides, chlorides, bromides, iodides, hydrogen sulfates, hydroxides, perchlorates, borates, diborates or tetrafluoroborates such as tetramethylammonium fluoride tetrahydrate, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetramethylammonium hydroxide, methyltributylammonium 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, cetyl trimethyl ammonium bromide, dodecyl trimethyl ammonium bromide, dodecyl trimethyl ammonium chloride, C ₁₂ -C ₁₄ alkyl trimethyl ammonium borate, C ₁₂ -C ₁₄ alkyl trimethyl ammonium diborate;
N-phenyltrialkyl (C ₁ -C ₁₈ ) -ammonium fluorides, chlorides or bromides such as phenyltrimethylammonium chloride;
N-benzyltrialkyl (C ₁ -C ₁₈ ) -ammonium 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, iodides, acetates such as methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, ethyltriphenylphosphonium acetate, butyltriphenyl phosphonium chloride, butyltriphenylphosphonium bromide;
Tetraalkyl (C ₁ -C ₁₈ ) phosphonium chloride or bromide such as tetrabutylphosphonium bromide.

suitable Polyglycols and crown ethers are e.g. Diethylene Glycol Dibutyl Ethers ("butyl diglyme"), 18-crown-6 and Dibenzo-18-crown-6.

Prefers are tetrabutylammonium fluoride, tetrabutylammonium hydrogensulfate, methyltributylammonium Chloride, tetrapropylammonium chloride, tetrapropylammonium bromide, Benzyltriphenylphosphonium chloride, benzyltriphenylphosphonium bromide or dibenzo-18-crown-6.

In usually one sets the phase transfer catalyst 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 fluorinated m-nitro-Benzoesäurechloride I am one.

The Multiphase system includes an aqueous Phase and at least one organic liquid phase. In addition, in the Course of implementation, even solid phases occur.

The aqueous Phase is preferably a solution of alkali or alkaline earth metal hydroxides or carbonates in water. In terms of suitable alkali or alkaline earth metal hydroxides or carbonates referred to the above. Particularly preferably used Alkali or alkaline earth hydroxides, especially sodium hydroxide or potassium hydroxide.

Preferably come for the organic phase aliphatic, cycloaliphatic or aromatic, optionally halogenated hydrocarbons, cyclic or open-chain Ethers or mixtures thereof, wherein with respect to the aliphatic, cycloaliphatic or aromatic, optionally halogenated hydrocarbons, cyclic or open-chain ethers to the aforementioned is taken.

In a preferred embodiment the method according to the invention the multiphase system consists of aqueous sodium or potassium hydroxide solution as aqueous Phase and from toluene, chlorobenzene, dioxane, dichloroethane, dichloromethane, Tetrahydrofuran or methyltetrahydrofuran or from mixtures of these organic solvent as an organic phase.

at Using a multiphase system one can, for example, the fluorinated m-nitro-benzoic acid I and the phase transfer catalyst without additional solvent or in one of aforementioned organic solvents or solvent mixtures submit. Then you give the watery solution the base and aminosulfone IV either sequentially or simultaneously while mixing and then brings in the specified temperature range the implementation comes to an end.

The Reaction may be at atmospheric pressure, reduced pressure or under elevated pressure, optionally under inert gas, continuously or discontinuously carried out become.

The work-up of the reaction mixture can be carried out by customary methods. In general, the solvent used by conventional procedural ren, 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 (eg by adding a nonpolar solvent such as pentane, cyclohexane, heptane or To luol, or mixtures of said solvents) or chromatography.

at Using a two-phase system one is usually extractive worked up.

you The final product can also be precipitated (e.g., by adding a non-polar solvent such as pentane, cyclohexane, Heptane or toluene, or mixtures of said solvents) win.

The for the Preparation of sulfonamides V required Aminosulfone IV are known in the literature (Houben-Weyl, Methods of Organic Chemistry Vol. E11, 1985, p. 1019; Hamprecht et al., Angew. Chem. 93, 151, 1981) or can according to the cited Literature be made.

The The following examples serve to further explain the invention:

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

The yields of fluorinated m-nitro-benzoic acid I were, unless otherwise described, by means of quantitative HPLC determines:

Sample preparation:

At first you convicted the fluorinated m-nitro-Benzoesäurechloride formed as a product in the corresponding Methylester. For this purpose, the samples to be determined of the fluorinated m-nitro-benzoic acid chlorides Weighed into a 100 ml volumetric flask and this with methanol 100 ml filled up. It was left for 10 min stir at room temperature.

Chromatographic conditions:

• Column: Symmetry C18 5 μm 250 × 4.6 mm 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.
• River: 1 ml / min
• Pressure: approx. 150 bar

Calibration:

The Calibration was carried out with an external standard (= corresponding nitrobenzoic acid methyl ester). to Creation of the standard were a total of 5 samples of pure substances weighed 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 Using a suitable PC program, a calibration grade was created. For the listed above substances this was a linear function. Standard deviation, correlation coefficient and straight line equation were calculated.

For each of the Components can thus their concentration relative to the respective external standard can be determined.

The fluoride values were by the following measuring method certainly:

1-2 ml of Sample was extracted with 50 ml deionized water (VE = fully deionized). After separating the aqueous Phase became dependent of the expected concentration an aliquot part of the same Measurement used.

The Measurement was carried out in a buffer solution (TISAB) at pH 5.26 by means of 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 eg Fa.Metrohm 6.0502.150 reference electrode eg Fa.Metrohm 6.0733.100 ion meter eg 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) Triphenylphosphine oxide (TPPO) were initially charged in chlorobenzene and the suspension with stirring to 95 ° C heated. Subsequently 16.8 g (0.14 mol) of thionyl chloride were added within 10 minutes. The reaction mixture was stirred for 2 h at 105-110 ° C.

Then they left the Cool the reaction mixture to room temperature and determine the fluoride content the solution, which was 0.01 g / l.

Then removed the solvent as well as excess thionyl chloride by distillation.

After addition of chlorobenzene, 40.8 g (98% of theory, determined via ¹⁹ F-NMR with internal standard) of the title product as a solution in chlorobenzene.

22,3 g (0,1 mol) 2-Chlor-4-fluor-5-nitro-benzoesäure
16,8 g (0,14 mol) Thionylchlorid
0,1 g (0,00036 mol) Triphenylphosphinoxid
Ausbeute*: 46,5 g (>99% der Theorie) der Titelverbindung als Lösung in Chlorbenzol
Fluorid-Wert: 0,01 g/lThe following Examples 1.2 to 1.9 were carried out analogously to Example 1.1: Example 1.2: 2-Chloro-4-fluoro-5-nitrobenzoic 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-nitrobenzoic 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 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-nitro-benzoic acid
• 16.8 g (0.14 mol) 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-nitro-benzoic 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 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-nitro-benzoic 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 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
• Yield *: 40.8 g (96% of theory) of the title compound as solution in chlorobenzene
• 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) of 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 fluoride elimination is significantly reduced by the process according to the invention:
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.

2. Production the sulfonamides V

Example 2.1: N- (2-chloro-4-fluoro-3-nitro-benzoyl) -N ', N'-diethylsulfonamide

A Mixture of 8.22 g (27.0 mmol) of N, N-diethyl-sulfamoyl-amide, 5.40 g (53.0 mmol) triethylamine and 170 ° mg lutidine was dissolved in 40 g 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 added. The reaction mixture was then added 70 ° C 2 h touched. The Mixture was added 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 (Ar-H d,), 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) of dimethylaminopyridine (DMAP), 11.0 g (0.107 mmol) of triethylamine were dissolved in 30 ml of toluene at 70 ° 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 removed filtered, 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 (CH ₃ ) ₂ ].

Example 2.3: N- (4-Fluoro-3-nitro-benzoyl) -N'-i-propyl-N'-methylsulfonamide

A solution from 4.10 g (27.0 mmol) of N-methyl-N- (1-methylethyl) -sulfamoylamide in 50 g of dioxane were at 25 ° C with 4.30 g (50% in water) of NaOH. During this addition, a solution from 5.32 g (25.0 mmol) of 4-fluoro-3-nitrobenzoic acid chloride and 20 g of dioxane dropped thereto. The reaction mixture was then added 25 ° C 12 h stirred. The mixture was mixed by adding conc. Hydrochloric acid acidified, cooled on 0 ° C and Stirred for 1 h. The solid was filtered off and washed once with HCl solution. One received 7.6 g (86% of theory) of the title compound with a mp of 164-165 ° C.

Example 2.4: N- (2-Chloro-4-fluoro-3-vitro-benzoyl) -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 NaOH at 25 ° C with 41.0 g (50% in water) added. 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 tetrahydrofuran was added dropwise thereto. The reaction mixture was then stirred at 25 ° C for 2 h and by adding 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., / Pr-H), 2.95 (s, Me), 1.25 (d, / Pr-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 acidified at 20 ° C with 41.0 g (50% in water) of NaOH added. 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 1N 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., / Pr-H), 2.95 (s, Me), 1.25 (d, / Pr-H).

Claims (9)

Process for the preparation of fluorinated m-nitro-benzoic acid chlorides I

wherein 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 reacting fluorinated m-nitrobenzoic acids II

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, characterized in that the reaction in the presence of catalytic Menen a phosphine III

where the variables have the following meanings: R ^a , R ^b , R ^{c is} C ₁ -C ₆ -alkyl or phenyl which may be optionally substituted by C ₁ -C ₄ -alkyl; X oxygen or two singly bound chlorine atoms; n is 0 or 1. Process according to claim 1, 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. Process according to claims 1 or 2, characterized in that the chlorinating agents are selected from the group of oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride and phosphoryl chloride (POCl ₃ ). Process according to claims 1 to 3, characterized in that the ratio of chlorinating agent to fluorinated m-nitrobenzoic acids II is 1.5 to 1. Process according to Claims 1 to 4, characterized in that the phosphine derivatives III are selected from the group consisting of triphenylphosphine, triphenylphosphine oxide and tri- (C ₁ -C ₆ -alkyl) phosphine oxide. Process according to claims 1 to 5 characterized in that the reaction is carried out additionally in the presence of a Lewis acid. A method according to claim 6 characterized in that the Lewis acid is selected from the group boric acid, Borsäuretri-C ₁ -C ₄ -alkyl or cyclic boric acid ester. Process for the preparation of sulfonamides V

wherein 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, 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 alkoxy, phenyl or benzyl; characterized in that fluorinated m-nitro-Benzoesäurechloride I

wherein 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, prepared by reacting fluorinated m-nitrobenzoic acids II

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 in the presence of catalytic amounts of a phosphine derivative III

where the variables have the following meanings: R ^a , R ^b , R ^{c is} C ₁ -C ₆ -alkyl or phenyl which may be optionally substituted by C ₁ -C ₄ -alkyl; X oxygen or two singly bound chlorine atoms; n is 0 or 1; with aminosulfones IV H ₂ N-SO ₂ NR ⁵ R ⁶ IV, where the variables have the following meanings: 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 alkoxy, phenyl or benzyl; be implemented. Process according to claim 8, 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.